Telix Pharmaceuticals Aktie

Good morning, everyone, and welcome to our R&D Day. For those of you I haven't met, my name is Annie Kasparian, and I lead Investor Relations and Corporate Communications across U.S. and Europe. It's a pleasure to welcome you today. Our presentation today includes forward-looking statements that are subject to substantial risks. Actual results may differ materially. You are cautioned not to rely on the forward-looking statements, which are made only as of today's date and are recommend -- and we recommend you refer to these statements along with these risk factors across our ASX and SEC filings.

Today, you will hear from Telix management, Dr. Christian Behrenbruch, Managing Director and Group CEO; Mr. Kevin Richardson, CEO for Precision Medicine Business; Mr. Richard Valeix, CEO for Therapeutics Business; Dr. David Cade, Group Chief Medical Officer; and Dr. Michael Wheatcroft, Vice President for Discovery Sciences.

I also wanted to point out or acknowledge that we have our recently appointed Chairman of the Board, Mr. David Gill, joining us in the audience today. In addition to hearing from our management, you will also hear from prominent key opinion leaders, including Dr. Alicia Morgans, Associate Professor of Medicine at Harvard Medical School and Director of Adult Survivorship Program at Dana-Farber. Dr. Varun Sundaram, a surgical urologist and advanced prostate cancer specialist at Urology Austin; Dr. Sumanta Pal, also known as Dr. Monty, Professor and Research Co-Director of Kidney Cancer Program, City of Hope, and Dr. Arthur Braat, Associate Professor at University Medical Center Utrecht.

Our agenda today will begin with a strategic overview by Dr. Behrenbruch, followed by an update of our R&D capabilities and pipeline. We will then move into prostate cancer portfolio, where we will hear from both management and our clinical experts. Dr. Morgans will provide an update on the 591 program, while Dr. Sundaram will discuss the BiPASS study.

We will take questions specific to 591 program immediately following Dr. Morgans' presentation since she will join us virtually. All other questions will be reserved for the dedicated Q&A sessions. Our renal cancer portfolio -- on renal cancer's portfolio, you'll hear -- you'll get an opportunity to hear from Dr. Monty. And on brain cancer portfolio, you'll get an opportunity to hear from Dr. Braat. Dr. Behrenbruch will share some closing remarks, after which lunch will be served. We encourage you to stay around for lunch. Today's event is being webcast live and available for replay.

So with that, I'd like to introduce you to Dr. Behrenbruch.

I really appreciate you coming here today to join us for this R&D Day. We are trying to get into the habit of doing this on an annual basis. I think it's a great opportunity to get you up to speed on what's going on in the company. Very grateful to our KOLs who are here today, managed to find -- carve time out of their really valuable clinical time to be here. So extremely grateful for that. Thank you.

I was going to say next slide, and then I realized I had to drive it myself. So first of all, this slide is Telix in a nutshell in terms of our corporate strategy. As we've built the business over the last 10 years, these different pillars of the business have come into real focus. Today, we will talk about the Precision Medicine business. It's an incredibly important part of what we do. It's the way that we finance our R&D and the structure growth, but there's going to be a strong emphasis today on the presentations around our therapeutics pipeline, which given the historical investor focus on the revenue-generating part of the business has perhaps received less attention. So part of our goal today is to get you up to speed with what the latest activities are across some of the really exciting data that these programs are generating and to sort of help you to understand the disease focus areas that are important to the company.

One of the things that's also evolved over the last, I guess, 2 or 3 years is really a purchase price premium on early-stage assets in the radiopharma space. When I started the company over a decade ago, I didn't really have the appetite to do really early-stage stuff. It felt like there were enough assets and opportunities out there without having to sort of go into the lab, but we now feel that there are opportunities and reasons for looking at novel targets, looking at novel targeting methods. And so we'll touch a little bit on that today. And we've -- obviously, in the last couple of years, we've made some transactions that are around building that in-house capability.

I'm grateful to be joined today by Richard Valeix and Kevin Richardson, who really represent the commercial drivers of the business. Kevin, in particular, leads our Precision Medicine portfolio. But we see the commercial organization that we've built as a asset to our organization, just as definitively as our infrastructure or our pipeline. Nuclear medicine products are not typical pharma products, all right? And the way that we sell them, deliver them, educate, it's really about delivering a clinical workflow, all the way from a dose being delivered to the loading dock of a hospital through how do you calibrate a scanner, do dosimetry, manage a patient, radiation safety, and even waste recovery.

So this is a really unusual business. And that's why the emphasis on supply chain and manufacturing is so important. You can't reliably deliver a dose, whether it's a diagnostic or a therapeutic product every single day and manage the whole delivery process of getting that into clinical practice, you actually don't have a business. And it's astonishing how few people in radiopharma really understand that. Today, we have 3 approved products. Really excited, and I realize there's a little time coming, but really excited to have gotten Pixclara approved last week. This is an important product for neuro-oncology patients in the United States. We do intend to expand the availability of this product globally.

Pixclara builds on the very vibrant franchise that we built in prostate cancer imaging. We were second to market, but we really believe that we are delivering as the market leader in this space. You're going to see some fantastic discussion today around what we're doing with BiPASS, which is a step change in prostate cancer. And our 2-track or 2-product strategy has proven to be very successful in terms of managing the reimbursement dynamics in the United States. And this is really how the growth of the business has evolved over the last couple of years. As you can see, we've really built a vibrant business, but the growth drivers for our Precision Medicine business will continue.

And I think a particular note, aside from getting the resubmissions and commercialization launch of Pixclara and Zircaix going, the step change in our business that you're going to see come out of BiPASS and the operational and margin benefit of running our own nuclear pharmacy network is something that's really starting to take shape for us. You would have seen in our half year results, RLS went from being the fifth largest distribution partner that we had at the time that we acquired them to the second largest. And when we put product volume through our own nuclear pharmacy network, we not only have greater control over customer delivery, but it has a beneficial margin impact as well.

And so you're going to see as the company matures and evolves that we're going to be a lot more selective about how we manage our distribution strategies in key markets. This is the company today. We are commercially active in 22 countries. We do supply product beyond that, but as a regulatory approved product, it's 22 countries today. We are expanding in 2027 into China. We have an NDA that's in review right now. We have agreed with the Japanese regulators on an accelerated approval pathway in Japan for Illuccix, and we are commercially active in terms of preparation for commercialization in Korea as well. So really, if you look at the supply chain infrastructure, clinical capabilities that we've built inside the company, it really is about servicing all of this.

Now today, I'm not going to talk very much about the ITM transaction, of course, in the breaks and whatnot, I'm happy to take your questions. But just to note that this transaction really expands this footprint. ITM is commercially active in 65 countries. And we see the opportunity to push our product pipeline and slipstream that isotope availability and reach a whole lot more patients as well as deliver to the next level of standard in the key commercially critical markets that we already serve. And so our tagline is creating a global radiopharma powerhouse, and I couldn't be more excited about what the combination of the 2 companies will deliver, of course, subject to closing conditions.

We are a company that has grown through execution on our development pipeline, building a commercial team, but we also have been a company that has grown inorganically through strategic investment and partnerships. These are some of the key ones. I can tell you that all of the transactions that we have undertaken as a company have really led to the growth in our revenue and global reach. I'm particularly, as I said, excited about the ITM transaction, but you'll obviously be aware that we have a partnership with Regeneron, which we'll get a little bit of airplay today in the R&D Day as well as some of the enabling technologies that we've invested in like ARTMS and IsoTherapeutics Group.

These are acquisitions that are actually enabling these next generation of assets that you're going to hear about today to come into fruition. So when I think about the future, we believe that we are creating a radiopharma company that has really no peer. I think that there's a growing appreciation in the investor community that radiopharmaceuticals are melting ice cubes. The supply chain and distribution is incredibly complicated and that customer delivery excellence matters, and you only achieve that if you have that vertical integration. Supply chains are, there's no magic radiopharmaceutical or radioisotope store in the sky. So if you're committed to delivering a pipeline, you have to have that infrastructure coming in behind it.

And I'm not going to go into all the details, but between isotope supply chain, pipeline augmentation and really the talent that comes through in this merger, I think that there's a really bright future for what the combined organization looks like. And so just to kind of wrap it all up and bring it back to my opening strategy slide. As we think about what does a business that has global supply chain reach, the best therapeutics pipeline in the industry, a cash-generative business now on the Precision Medicine and the manufacturing piece. I think if you think about what the combined businesses look like, essentially, it's a book ending of a therapeutics pipeline with Precision Medicine and manufacturing.

Their isotope business is very profitable. It's cash generative. It's highly differentiated. There isn't another radiopharma company that has scaled to deliver terabecquerel level of production output. And then when you see those 2 commercial businesses supporting the pipeline, you can see that the combined company has a very bright future indeed. So yes, exciting future and a lot to talk about and to understand over the next few months as we close that transaction out. That's it for me today. I just want to again reiterate, thank you for coming. And now I get to hand over to a very special guy in the Telix organization.

Mike actually was employee #1 of the company. So he's been here from the very beginning, we've all aged appropriately, commensurately. But I'm really appreciative for Mike to come out today and give you a little bit of an overview on what's happening on the early stage and innovation side of the business. So Mike, over to you.

So I'm never quite sure when Chris says a special guy. I think it's a positive thing, right? So you'll see the VP Discovery Scientist, some of them have been running the R&D efforts in Telix for a number of years. And I hope to give you a little overview of a bit of insights into how we think about drug development and drug discovery. What goes into the design of a radiopharmaceutical and hopefully, not too much of a science lesson, but more of a guideline to what we think about. And just kind of slightly differentiated in the industry we see.

So I'm going to spare the slide where you've got a targeting agent and a radioisotope attached to a chelator and those things. But this audience knows that we have a targeting agent, which is the cancer-specific part and the radioisotope, which is the payload. But I think one thing that really doesn't get enough airtime, if you like, is around target selection. The actual cancer target you deliver to is probably the principal feature of the actual drug in terms of the therapeutic window of that particular drug as defined by that target, both in efficacy in terms of making sure you deliver enough radiation to that cancer cell but also making sure it's selective enough that actually you're not hitting kind of off-target tissues and creating a safety issue.

And all the good things we like in targets, so we want to have a high expression. We want to be very specific. You want to have a high prevalence in the disease you're going after. But one key thing as well we really look for in a target is the ability to internalize, the flip inside and drag the radiation inside the cell. That's how we get really great efficacy by retaining that radiation inside the cancer cell. So Telix has got in its late-phase -- late-phase portfolio, we have a number of really well-validated targets with PSMA, CA9, LAT1, and FAP. I'd add to that list as well. We're also starting to explore those novel targets in our early-stage research as well.

So there are many different targeting agents you can use for delivering radiation. And I think the key thing we believe is that each one has different properties. And they have a different set of properties, and it's somewhat of a trade-off of things like pharmacokinetics, how quickly does your delivery vehicle get into the tumor? How quickly does it penetrate? How quickly does it clear from the blood and also how well does it internalize. And I think this kind of approach, we value all these different approaches. It is a trade-off of these sort of parameters.

So -- and that's why Telix has this kind of unusual targeting agent agnostic approach. We think that antibodies and small molecules all have their place, and it's about how you use them and for what purpose that really matters. So for example, sort of small molecules and peptides on the left-hand side of the screen, very small. They actually penetrate tumors really rapidly, and that's great, but they also wash out really quickly as well, and may not be as specific as, for instance, antibodies, which have a great specificity to cancer. And they may be, because they use slow kinetics, they can, they do take some time to get into and saturate that tumor with radiation.

But once they're in that sort of sustained circulation alongside this ability to internalize and get into the cancer cell means that the cancer cells exposed to radiation for a long period of time. So we get kind of length of time, length of exposure to irradiate that tumor is really a beneficial thing.

So in Telix, we're starting to also look at -- we're always looking to optimize, and we're now looking at sort of what we think might be a sweet spot in the middle somewhere in this diagram with engineered antibody fragments called minibodies. So essentially, these are sort of cutdown versions of full IgGs. They're slightly smaller and they clear quickly, et cetera. So we're starting to look at these as a new delivery format in the research and early clinical studies. So we have 2 minibody programs in early development, 1 targeting AV beta-6 integrin and another targeting DLL3, both in different forms of lung cancer. And again, this smaller format, we think, is really exciting because it can -- not only has it kind of clear quickly, but it actually is shown in clinical studies that were just done -- just down the road in Memorial Sloan Kettering Cancer Center.

We've already validated this early-stage minibody with -- this has already been clinically validated in studies where you've shown really quite a faster -- much faster uptake into tumors in this red line here on the tumor compared to IgGs. So when you think about the targeting agent, you then think about which payload are you going to choose. And obviously, like diagnostic versus therapeutic is a key 1, the mission profile. And really, the secret sauce here is matching your radioisotope with the properties of your targeting agent. So often, you would choose your pharmacokinetics of your [indiscernible] drug to match that of the decay properties of the radioisotope.

And this freedom to choose different targeting agents means we could -- we have much more freedom to choose a complete array of radioisotopes. And I think, again, matching the targeting agent with the disease with the isotope, that agnostic approach to not just sticking with 1 thing being best, but actually thinking what's best for the situation you're using it in. And it really underpins that strength of that approach. And so while clinical studies have really shown the benefits of alphas in potency -- in terms of potency, it does also have a very short path length. It doesn't penetrate very deep into tissue.

So we think the optimal use of those alpha emitters will be around that early disease or small volume disease, micrometastatic disease. And that can -- we hope will have a real great benefit in those sort of diseases. But we still see value in beta emitters in those bulkier diseases or diseases where you may have heterogeneity, so patches of cancer and healthy tissue. So the ability to crossfire radiation across those bulky tumors is actually a real benefit. So the answer really here is that no one isotope is going to be best. It's really about what's the best application for the actual disease.

And so when you come -- when you designed your molecule and you may have the best radioisotope, best radiopharmaceutical therapy in the world, but it's no use unless you can make it and deliver it. So it's no secret, as Chris showed before, that we've been developing the Telix Manufacturing Solutions network, a TMS network, which is a global network of sites, both serving radioisotope production as well as -- so acquisitions such as ARTMS help us do that. That's a technology that adds to any cyclotron to produce radioisotopes that are consistent and reproducible and reliable.

So no matter where you are in the world, you're getting reproducibility of that radioisotope raw material, which is something that often gets overlooked if you're using multiple different providers. We also have our own in-house production of certain isotopes such as lead-212, a generator initiative, so that we can fully support the full range of radioisotopes. Within TMS, we also have dose production and radiopharmacy, dose production and delivery. And obviously, our RLS network across the U.S. is an extensive network to actually make our products and deliver them to sites reproducibly and reliably. That's reliability and reproducibility of delivery is really important for both clinical and commercial success.

And I'm very pleased to also announce that we've added a new facility in Melbourne, Australia, where we run a lot of our clinical studies, where we actually have a clinical manufacturing and imaging site. So actually now [ staying ] into some the clinical utility, clinical dosing. And so just to wrap up, one thing we wanted to talk about is that Telix's core strategy is about theranostics. It's about the interplay of the diagnostics and the therapeutics.

And so while imaging is powerful on its own, it really has a synergy with the therapeutics, both in terms of showing clinical proof of concept, the ability to look at dosimetry to estimate dosing for the therapeutic, also looking at are you dosing the right patient population. But as this slide shows, showing disease response to a therapeutic is supremely valuable. They work in synergy together as a theranostic. And so while we have a lot of emphasis on our commercial pipeline being diagnostics, it's really what we're very pleased to be able to show is the progress we're making in our therapeutic pipeline.

And with that, I'll hand over to Richard Valeix, our CEO of Therapeutics business.

Hi, everyone. It's my pleasure to be on stage with you today. And my role today will be to present to you an overview of the therapeutics late-stage portfolio that we are currently developing. So probably you're familiar with this slide, but what I wanted to bring to you today is that the Telix has probably the largest and the deepest portfolio under development currently in the radiopharma world.

So we can say that, as mentioned by Mike, we are a diagnostic company because you will see that in front of each therapeutic compound, you can find a diagnostic one or a Precision Medicine one as well I used to call that because it helps to diagnose some disease, but it helps also to select the patients as patient selections, eligibility for therapy and also monitoring the efficacy of our therapeutic compounds. So that's really a good synergy that you can see there and it's illustrated with the pairing of therapeutic and diagnostic compound.

If we look at the disease areas that we are working on, you can see that we have a huge tropism and a huge focus on the urology oncology. And namely, we have the prostate cancer treatment that we are developing heavily, but we have also some compounds in the kidney disease area. So we will come back on these compounds in the -- during the presentations today.

But really what I wanted to highlight there, it's the urology is really one of our core disease area and focus. We are also working in neuro-oncology, where, as you know, recently, we obtained the marketing authorization for Pixclara, our Precision Medicine compounds. And we are developing 2 assets in the treatment of neuro-oncology disease. The first one is in recurrent glioblastoma. And as you know, it's a really debilitating disease where no recent approved drugs have demonstrated a huge value for the patients. And third, we have the pan-tumor [indiscernible] pan-indication compounds and targets.

I would just focus on the 400 that it's, in fact, a FAP compound that we acquired a year ago. FAP is currently under the sunlight, as you saw in the press recently, but I really wanted to focus the fact that we have here 2 compounds that we name the FAPs with a diagnostic compound and also a therapeutic compound. These 2 compounds have probably the most data published on the field. So if you are interested with, we can provide you the latest publication on these 2 compounds, which derisk the development of that because we have already proof of evidence with expanded access programs in various centers.

The attention I wanted to bring to you, it's not illustrated there or perhaps, yes, we have 3 Phase III trials ongoing, 2 in urology with ProstACT GLOBAL in prostate, with Luteon trial in kidney and with IPAX BrIGHT in recurrent glioblastoma. That's amazing to have 3 Phase III trial running in parallel with this portfolio. What I wanted also to highlight is something that Mike said that with the recent acquisition of ITM and all the vertical integration that we have done recently, we have a platform that authorized us to deal with antibody peptide and also more recently with minibodies and nanobodies. So that's for the targets.

And with ITM, we have also now secured the access for all the isotopes that we are dealing with in this portfolio. So you can see that it confers us probably a unique capability that even some competitors and big competitors that don't have yet. I wanted also to highlight some partners that we are dealing with. So you're aware about the Regeneron deal that we made earlier this year. It's very interesting to develop antibodies with Regeneron, which is probably one of the most well-known company developing ADC drugs, and they have a pipeline of antibodies that it's difficult to imagine.

So we are currently dealing with 4 initial programs under development in a co-development, co-promotion deal that we have signed earlier this year. And currently, we are extremely proud of that. Very quickly, ITM, you understood that the deal has different dimensions. But if I look mainly on the therapeutic compounds, we acquired ITM-11, which is a Phase III data which has demonstrated efficacy in neuroendocrine tumor, which is the first indication for radiopharmaceutical drug. So that's very exciting to be capable to launch these new assets in neuroendocrine tumor. It will authorize us to start to work in therapy with these new compounds for the treatment of the neuroendocrine tumor. So that's very exciting, and I can tell you that the team internally are extremely attached to that.

Now I will hand over to David Cade, our Chief Medical Officer, to introduce the topics related to our therapeutic compound in prostate.

So it's now my great pleasure to introduce the first of our 4 key opinion leader presenters, Dr. Alicia Morgans, who's dialing in virtually. And Annie tells me that we might be just a couple of minutes early. So tell me if you'd like me to flip the order, Annie. But Dr. Morgans is an Associate Professor of Medicine at the Harvard Medical School. She's a Genitourinary Medical Oncologist and the Director of the Adult Survivorship Program at the Dana-Farber Cancer Institute. And as a clinician and investigator, Dr. Morgans has very extensive expertise in trials in prostate cancer as well as patient-reported outcome measures, which we sometimes forget as a field.

This is an emerging area that's critically important to the way we design our Phase III trials these days, the way patients flow through a trial and what's important in terms of other measures that we don't think of. So as well as that, Dr. Morgans is very focused on incorporating patient preferences and the beliefs into clinical decision-making outside of the trial context when she's seeing patients in the clinic at the Dana-Farber. So have we got Dr. Morgans online? Yes, go on. Okay.

All right. So let's change the order slightly. Dr. Morgans is going to cover our TLX591 program, and I will cover our TLX597 program. But before we go into discussing our small molecule candidate, TLX597, I think it's really important to understand and appreciate why we have both a small molecule and an antibody in our pipeline. And it's critically important to understand -- to do that, it's critically important to understand the main prostate cancer disease states. And of course, it's a spectrum, but I think it's reasonable that we can categorize early and late prostate cancer and the implications for how we best manage our patients. And let me just go forward to -- perfect. So while the pictograms here are highly simplified, they do illustrate the baseline characteristics of the 2 main populations of patients that we see in clinic.

And on the left-hand side, we have patients with early metastatic disease. That's typically, not always, but typically of smaller volume, typically responsive to androgen pathway suppression with ADT and ARPI drugs. These patients are usually newly diagnosed, so they're otherwise fit apart from early prostate cancer. And so really, the objectives of treatment are to maximize quality of life to delay progression into the androgen pathway modulation resistant state and to prolong overall survival as far beyond 5 years or 6 years as we can. So they're really the objectives in this early population.

On the right-hand side, we have patients with later metastatic disease. Their tumor burden is now increased. They've got bulkier disease. The disease has now become resistant to androgen pathway suppression. And so our objectives of treatment evolve in this group of patients really to now optimizing the combinations of therapy that are remaining for us to use and controlling bulky disease and ultimately really prolonging the remaining usually 2 or 3 years of life that these patients have with acceptable quality of life.

And so this slide summarizes our portfolio approach to metastatic prostate cancer, utilizing 2 distinct mechanisms of action that are really adapted to each of those 2 categories of disease state within the continuum of care. And as the first-in-class radio antibody drug conjugate, TLX591 is administered in 2 doses, 2 weeks apart, which really enables it to be layered on top of a backbone of conventional ARPI or taxane chemotherapy that a patient with metastatic APMR disease would typically receive. And so far, we've confirmed the safety of this approach from Part 1 of our ProstACT GLOBAL study as well as having confirmed the encouraging early efficacy of 8.8 months of radiographic progression-free survival in the earlier ProstACT SELECT study. TLX597, which is our next-generation small molecule, on the other hand, is really designed to enable dose intensification and adaptive dosing. And these are 2 very important points that I'll go into in a bit more detail in a moment.

So dose intensification and dose adaptation is really suitable for patients with earlier metastatic androgen pathway modulation sensitive or naive disease. These are the new terms for metastatic hormone-sensitive and metastatic castrate-resistant prostate cancer. We use the new terms now. And really, the aim with dose intensification and dose adaptation is to delay progression into the APMR state, while at the same time, maximizing quality of life. Now delving into TLX597 in a little bit more detail, you'll see here on the right-hand side, what's a very highly favorable biodistribution and pharmacokinetics of the small molecule. And what you can see is that there's very, very low uptake in the salivary glands. That's the top smaller football there and also very low uptake in the kidneys, which is the lower football. And low uptake at 5 hours in the salivary glands and kidneys, but very prolonged residence time in both the soft tissue and the bony compartments of the tumor volume.

Now this pattern is quite remarkable. It's really not what we've come to expect from the earlier small molecule radioligand therapies. And this is unsurprisingly reflected in the resulting dosimetry with TLX597 imparting about half the dose to the kidneys and about 1/3 of the dose to the salivary glands while delivering about twice the dose to the tumor target compared to the current first-generation small molecule RLT. So these are very attractive properties of this small molecule. Now some very interesting work go forward. Some very interesting work of the past, I'd say, 2 or 3 years has highlighted 2 very important factors that may enable us to improve on what we've already achieved with the small molecule RLTs to date.

Now firstly, PSMA receptor density, the density of PSMA expression is an important factor in treatment response with lutetium PSMA therapy. And then secondly, Johan de Bono's group at the Royal Marsden in the U.K. has shown that this PSMA receptor density can be manipulated. We can markedly upregulate that density in response to ionizing radiation, like that from lutetium. And you can see this, I think, very clearly on the right-hand side, I think the pictures are crystal clear. This is a patient who has received 2 doses of TLX597 on day 1 and day 3. And you can see that in the post-treatment imaging after the day 3 fraction, there's much higher total tumor volume on SPECT imaging. And this is due to the upregulation of the PSMA target. So the first dose has caused upregulation of the target. And when we dose again with the second dose on day 3, there's much more target to hit.

So this is a very attractive property that we aim to exploit with dose intensification. And this is the overall concept of dose intensification using both a higher injected activity of lutetium. So 8.5 gigabecquerels is substantially more than we would typically give. And it's given in what I would describe as a compressed schedule on days 1 and day 3 and day 15 instead of the usual schedule of every 6 weeks.

And this is to exploit that upregulated PSMA expression and the incomplete tumor DNA repair in the first early period after the first dose. And so to evaluate the potential of dose intensified TLX597, we undertook the optimal PSMA Phase II randomized trial in men with metastatic APMR disease. And this has been led by Professor Louise Emmett in Sydney. And this is a multicenter study that enrolled a vision like population of patients who had received prior ARPI and chemotherapy. And we completed enrollment in this study back in June and anticipated the initial top line readout around the time of ASCO GU in early 2027, and that data is very eagerly anticipated.

So let's now look at a couple of case studies, which really illustrate why the OPTIMAL-PSMA data will be so interesting. So this is a 71-year-old patient with very diffuse skeletal metastases who previously was treated with ARPI and 2 separate lines of taxane chemotherapy. And there's 2 important points that you can see here. So firstly, the question is, can a dose intensified regimen be undertaken safely. So with TLX591 and a highly favorable dosimetry profile, it appears that the answer to that question about can it be done safely is yes. Specifically, we can see that this patient's kidney function remains normal and his bone marrow function remains normal. So they are 2 very sensitive indicators of the tolerability of an intensified regimen.

And then secondly, does a dose intensified regimen seem to deliver clinical benefit. Well, here, we can see a 97% PSA response at week 10 and serial SPECT imaging performed after each of those first 4 doses demonstrates very clear disease shrinkage. So in this patient, this is a very nice example of the apparent viability of dose intensification. This is a second case with even more pronounced skeletal metastases as well as infiltration of the bone marrow. And in this patient, that's -- the bone marrow has been infiltrated to the extent that these patients become both anemic and thrombocytopenic, low platelets. And he was anemic and thrombocytopenic at baseline. So this is a very delicate and fragile patient to treat.

But encouragingly, he tolerated the dose intensified regimen very well. And not only did he tolerate it through the reduction of the disease burden infiltrating his marrow, his anemia and his thrombocytopenia improved in the absence of blood transfusion. So his overall health state improved from a dose intensified regimen. And then from an efficacy perspective, this patient had a 99% PSA response out to week 20. So a very durable reduction in his PSA expression. So again, I think this patient is a really nice example of the viability of that dose-intensified approach.

So in summary, we believe the unique profile of TLX597 fundamentally enables 3 important development pathways. So the first of those is dose intensification, which is being evaluated in OPTIMAL-PSMA, as I've described. Secondly, the use in earlier metastatic hormone-sensitive prostate cancer, where safety and quality of life are critically important given the patient's relatively longer life expectancy. And then thirdly, I think it's quite evident that this favorable small molecule could be an ideal candidate or an ideal delivery vector for alpha isotopes. And so to close out, this is OPTIMA-e, e for early. And this is a Phase II study with TLX597 in earlier metastatic APMS disease that commenced enrollment back in July and which we anticipate will generate some very important clinical data about the earlier use of this small molecule in the coming 12 months.

Now Annie, would you like to switch to Dr. Morgans? Keep going. Okay. Good. So let's go beyond lutetium, and we'll have a quick tour of our assets further in the disease journey. So let's move really briefly to our targeted alpha therapies for prostate cancer. And I think the clinical experience we've gained as a field with the first-generation small molecules has probably taught us 2 basic principles. And the first of those is that alpha isotopes like actinium-225 and lead-212 must be kept away from the salivary glands as xerostomia dry mouth is the main dose-limiting toxicity, which really markedly impacts and degrades the patient's quality of life.

So we've got to avoid the salivary glands. And then secondly, alpha isotopes must be kept away from the kidneys as renal injury is a significant safety concern. And so while they're early stage, we're evaluating a reengineered radioantibody drug conjugate approach with TLX592, which like TLX591 is a highly specific antibody to the tumor expressed PSMA, as my colleague, Dr. Wheatcroft pointed out very nicely. It keeps away from PSMA expressed on endogenous tissues like the salivary gland. As well as TLX597, due to its biodistribution profile, which I've gone into a bit of detail, it really makes it an ideal candidate, we believe, probably the most attractive small molecule for targeted alpha therapy development because it keeps away from the salivary glands and the kidneys. So I think this slide summarizes our approach very nicely. I wanted to provide some brief insights on our TLX5 -- on our TLX090 asset, which beyond alpha aligns to our approach of really serving the patient across their disease journey.

So TLX090 is a -- it's a novel candidate that we're developing for actually quite late-stage patients where the palliation of metastatic bone pain, which is a very common hallmark of late-stage disease needs to be addressed. So TLX090 employs Samarium-153 DOTMP, which is a bone-seeking small molecule that uses that novel chelator that we're developing as an alternative to the mainstays, which are opioids and targeted external beam radiation therapy for very specific foci of bone pain. And each of these opioids and EBRT do remain suboptimal for different reasons. And so on the right side, we can see here from an earlier Phase I study at both dosing levels of TLX090, there are significant reductions in the pain scores achieved quite early at 6 weeks, but these are durable reductions in pain out to 4 months following treatment. And these are patients with a relatively brief prognosis in terms of survival. So this is a meaningful improvement in pain scores and improvement in quality of life.

So to conclude, while I won't spend too much time here, this, I think, really nicely summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are really tailored to both the disease state itself, early and late disease as well as the condition of the patient. And the way I would summarize it is that TLX591, which Dr. Morgans, I think, will talk about in a moment, yes, good. It utilizes an antibody targeting vector to deliver the therapeutic payload, which really enables ultra-specific and prolonged tumor retention with very limited radiation to the healthy organs. And then furthermore, that short 2-dose regimen is intended to be combined with the other standards of care that the patient would otherwise be receiving in the metastatic APMR setting. And this is really the intent of ProstACT GLOBAL is a Phase III trial that's ongoing in 7 countries. Whereas there's a very significant opportunity in early metastatic APMS disease for TLX597 due to its potentially best-in-class dosimetry profile that really makes it uniquely suitable for earlier use as well as the dose intensification to achieve those further efficacy gains that we're looking for.

So with that, can I invite Dr. Morgans to go. Okay. Thanks, Annie. Dr. Morgans, can you hear us?

Yes, I can.

Good. Good. I have introduced you. And I've just done 597. We've changed the order for you. So I'll hand the floor over to you, Dr. Morgans.

Thank you so much, David, and wonderful presentation. I really appreciate being here with everybody. And apologies that I'm virtually here because I am also in clinic today, as you may see from my coat and background. I'm an Associate Professor of Medicine at Harvard Medical School and the Director of the Survivorship Program for Dana-Farber Cancer Institute, where I'm also a GU Medical oncologist. I take care of patients with prostate cancer.

And let's go on to the next slide, please. And I think I'm very grateful that everyone is here to think and learn a little bit about prostate cancer and the way that Telix is trying to address it. I'm not sure that the slide is advanced, but hopefully, we can see the slide that shows the prostate cancer disease overview, which is the next slide. Thank you. And apologies if there's a delay on my end.

Prostate cancer is the most common cancer in men, and it's the second leading cause of cancer death in the United States. This is actually something that's true in many countries around the world where we see the incidence of prostate cancer actually increasing in many, many countries. Importantly, 1 in 8 men will be diagnosed with prostate cancer during their lifetime and 1 in 44 die from it, but actually many become long-term survivors after a diagnosis with prostate cancer, many actually living with metastatic disease and metastatic disease remains associated with certainly poor outcomes than cured disease. The 5-year survival rate is 30% versus 90% for earlier disease that's curable. And despite all of our therapeutic advances, prostate cancer remains a substantial unmet need. As we can see on that incidence chart for the United States on the right-hand side, there's actually been an increase in diagnosis of prostate cancer, particularly in the advanced and metastatic settings over the last number of years. And so this is something we are actively trying to combat.

If we go to the next slide, we can see the prostate cancer patient journey through various phases of advanced disease. And just to orient everyone, I think we've heard from David about the newer nomenclature that we are now using to be, I think, more sensitive to avoiding the use of certain things like the word castration. But let's talk about this broader landscape because the standard of care in prostate cancer absolutely has been evolving in the last number of years and importantly, incorporating radiopharmaceuticals into that landscape and into having quite an important role within this algorithm. For patients with metastatic disease, they typically would start in what we used to call the hormone-sensitive setting or metastatic hormone-sensitive prostate cancer that we're now calling mAPMN/S, androgen pathway modulation naive or sensitive. And this is where we are commonly using androgen receptor pathway inhibitors or ARPIs, as the backbone of our treatment in combination with ADT and docetaxel sometimes added in there as well for patients with high volume and very aggressive metastatic disease.

In July of 2026, lutetium-177 PSMA-617 also received approval in the United States in this earlier setting. But I think it's important for everyone to recognize that although we do have that approval, and I think in clinic, we're certainly grateful to have options. There's definitely been some caution around that and whether we should really jump on board and absolutely integrate that immediately into our algorithms because there's not yet a demonstrated overall survival benefit, and there is moderate acute toxicity. And importantly, just to level set for today's discussion, we don't know the late and long-term toxicity that might be associated with this regimen as we use it in this early disease state. So -- just moving along to the next settings, as patients do have progression of disease and that occurs in the setting of usually medical castration or pharmacologic castration, they move into first, second and then third line plus metastatic APMR or androgen pathway modulation resistant settings.

In the first and second-line treatment settings, we do have options, including AR pathway inhibitor or ARPI switch, taxane chemotherapy, lutetium-177 PSMA-617 that we can use before or after taxane chemotherapy and PARP inhibitors for certain patients who have HRR alterations. And by third line and further than that, our options tend to narrow down to things like cabazitaxel chemotherapy or perhaps lutetium-177 PSMA-617 in a post-taxane setting if patients have not already received it. But I think also importantly, just calling attention to the bottom of the slide is that throughout all of this, particularly in the earlier settings, renal toxicity and quality of life considerations are something that are increasingly important to us in clinical decision-making and important as we move radioligand therapy into these early disease settings. And this is really critical because we think about these earlier-stage patients as typically being healthier, being more active and certainly having a longer life expectancy.

And things like renal toxicity or salivary gland toxicity are things that we need to address with our newer generation of radiopharmaceutical agents as we're hoping to incorporate them into the earlier settings, but we really need to balance that with cautious optimism that really considers those adverse events and the potential there. It looks like the slide that we're seeing now is the slide that's looking at advancing past first-generation PSMA RLTs. This slide is really thinking about our toxicities here. And lutetium-177 PSMA-617 has transformed outcomes for patients with metastatic prostate cancer. And the clinical trial data from things like VISION, PSMAfore and PSMAddition, the registration trials have been practice changing, as we've mentioned. But as we're moving into these earlier settings, patients are thinking about being really conservative or at least thoughtful about those toxicities that I mentioned, xerostomia and renal impairment.

And if we look at this slide, this is the U.S. package insert, the adverse event data across those clinical trials is presented and xerostomia occurred in somewhere between 39% to 61% of patients in the studies -- and most cases were categorized as low grade, but they can still have an impact, a severe impact in some cases, on patient quality of life. I think -- as we think about xerostomia, I think many of us who grade these toxicities don't necessarily realize that grade 2 xerostomia means that patients are already altering what they eat. Even though the number seems low, there is a real impact on patients, and they are relying on things like mouth lubricants and saliva substitutes, and they're often having to alter their diet to be more focused on pureed food or soft food, moist foods in order to be able to safely swallow and get enough nutrition. But Grade 3, again, the number seems low or at least in the middle of the range when we think of all the CTCAE adverse event grades here.

But Grade 3 is quite serious, and this is the highest grade for xerostomia. This means some patients are unable to adequately nourish themselves and they do need tube feeding or IV nutrition. So we have to -- even if the numbers look relatively low in terms of the grade, we have to be aware that they can affect patients. On the renal side, we are definitely thinking about and concerned about long-term nephrotoxicity, especially, as I said, as those agents move into earlier lines of therapy when patients are going to be on treatment and exposed to the cumulative risk of renal toxicity for much longer, and they do need good kidneys because they're going to need further therapies for their disease over time. If we go on to the next slide, this is really going to be an opportunity to focus on TLX591, which I think is an exciting novel therapy for patients with prostate cancer. We can go on to the next slide.

This is a radio antibody-drug conjugate, and it's meant to really address some of these key unmet needs. Just to lay those out as a recap here, TLX591 is a differentiated PSMA-targeted radiopharmaceutical that's using a monoclonal antibody to target prostate cancer that's expressed PSMA on its surface, and it targets that with high specificity, enabling a really precise delivery to the cancer tissue of the radioactive payload. And it addresses a number of these clinical needs that have been unmet, especially having a nice 2-dose 15-day cycle that helps us in clinic by facilitating a more feasible integration with our standard of care AR pathway inhibitors or our chemotherapeutic agents as we often need to deliver those as well. It has a very low radiation dose that's imparted to the salivary glands into the kidneys. And these are, as I just mentioned, the 2 main organs that can be injured when we're using small molecule agents to target PSMA, and it's really a transient and mainly self-limiting hematologic profile, which is also something we're thinking about in clinic, especially as we think about bone marrow suppression being something that could limit later lines of therapy for our patients.

There's also a specific internalization and prolonged retention of the agent within the prostate cancer cell, which is going to be visible clearly on post-treatment imaging, which helps us in clinic make sure that we're really getting the drug to where it needs to go. And there's also the potential for real-world advantages from lower administration activity and lower radiation doses to normal tissues, especially to the kidneys. And as we can see on the slide, we can see this mechanism of action where drug is binding to PSMA and then it undergoes receptor-mediated endocytosis. Coming into the prostate cancer cell where it is then taken into the endosome. It undergoes lysosomal metabolism and ultimately is broken down and excreted primarily through the liver.

If we go on to the next slide, we can see the schema for the ProstACT GLOBAL, the Phase III study of TLX591. Part 1 has been completed. The FDA is aligned to advance to Part 2 in the U.S., which is also important. So this is the overall design. ProstACT GLOBAL is a Phase III study, as I mentioned. And you can -- as you can see, the Part 2 is the randomized treatment expansion that's going to enroll 490 patients. And this is currently enrolling patients in 7 countries. They include Australia, New Zealand, Canada, Singapore, South Korea, the U.K. and Turkey. And the study also has regulatory approvals for Part 2 in China and Part 1 in Japan. On the left-hand side of the slide, you can see Part 1, which was performed for safety and dosimetry, and this part has been completed. This was a prerequisite of the FDA that was required before commencing Part 2 in the United States. And just to show, we can see that Part 2, which is a randomized treatment expansion, it's a 2:1 randomization to TLX591 plus abiraterone, enzalutamide or docetaxel versus abiraterone, enzalutamide or docetaxel. And as I said, 490 patients currently enrolling. And patients can get into this study if they have metastatic APMR, and they've had exposure and progression of disease to one prior AR pathway inhibitor or ARPI.

Let's go to the next slide. Here, we can see the primary objective of Part 1's outcome here. The primary objective of Part 1 ProstACT GLOBAL was to assess the safety of TLX591 when it was given concomitantly with standard of care abiraterone or enzalutamide or followed by standard of care docetaxel chemotherapy. And overall, the 3 cohorts showed an acceptable safety profile. There were no new safety signals when compared to prior studies, including the most recent ProstACT SELECT study. The most common treatment-emergent adverse events were things that we might expect or would expect fatigue, nausea and dry mouth. And almost all of the non-hematologic adverse events were grade 1 or 2, which, as I mentioned before, is really on the mild side with the exception of 1 Grade 3 dizziness event. Hematologic adverse events comprised Grade 3 and 4 thrombocytopenia, which is a low platelet count number. This occurred in 14% and 31% of patients, respectively, Grade 3 and Grade 4 as well as grade 3 and grade 4 neutropenia, which is a lowering of the neutrophil count, a type of white blood cell, which occurred in 22% and 25% of patients, respectively.

And these hematologic events were actually in line with the profile expected for 1 of these radioantibody drug conjugates and are transient, manageable, and we're going to go into that in a little bit more detail on the next slide. So let's go to the next slide. This slide shows the platelet kinetics across all 3 cohorts. You can see the blue is the patients receiving abiraterone. Orange red is enzalutamide and green is those patients who had docetaxel. What we could see is that the platelet level nadir is around 43 days after dose 1, and there's recovery to Grade 1 adverse event or better roughly 15 days later. So again, short-lived and quite predictable. And the recovery patterns were consistent across -- generally consistent across the cohorts. I think this is important, too, because docetaxel, obviously being a cytotoxic, it's reassuring to see that we still see that nice recovery.

As I mentioned in the prior slide, the hematologic events are the main adverse events of interest for this class of therapy. And in terms of thrombocytopenia or that low platelet count, we can see that they were consistent, the nadir occurring 43 days after 6 weeks after that first dose of TLX591. No patients experienced any febrile neutropenia, which is a relatively common adverse event that can occur when patients get treatments like chemotherapy that cause low neutrophil counts and no patients experienced any spontaneous bleeding, which is something that can occur when patients have low platelet counts. So in summary, these hematologic adverse events are quite well characterized. They're well understood from prior clinical studies with the agent. They were self-limited and they resolved spontaneously without intervention in the majority of patients for Part 1.

If we can go into the next slide, what we can see that the safety was the primary objective of Part 1 of ProstACT GLOBAL. The main secondary endpoint was to look at the PK, the biodistribution and the radiation dosimetry of TLX591 when it was given concurrently with standard of care. And overall, these 3 cohorts receiving different agents, abiraterone in green, docetaxel in pink here and enzalutamide in sort of a teal color, we can see 3 cohorts demonstrated a predictable PK profile. And if you think about where you want the radioactivity to be, you do want that to either be circulating in the blood pool so that it's available to bind to and be taken up by the tumors in the tumors themselves or in the liver where the drug is going to be cleared from the body as we saw and talked about earlier. So for these 2 graphs, the importance is that the graph on the left shows the blood radioactivity concentration and that's sustained but declining over time.

And in the right-hand graph, we can see that it's basically the reciprocal of that, demonstrating that the tumor radioactivity or the lesion activity is increasing early and then sustained over time because the antibody has been internalized and it has a prolonged retention within the tumor. So the exposure and washout kinetics were quite consistent across the 3 cohorts, indicating no evidence of TLX591 interacting with any of the ARPI agents that it was co-administered with, which is very important.

If we go on to the next slide, this is, I think, really importantly demonstrating normal organ dosimetry. So this is making sure that our normal tissues are not being exposed to large levels of radiation that will exceed a threshold of harm. So these are the organs where -- that we certainly want to keep the radiation away from. And we can see quite clearly that Part 1 confirmed that the radiation exposure, which you can see in the dark blue to these normal organs is quite low and well below the safety limits that have been determined for external beam radiation therapy and the radioligand therapy literature.

And those are outlined in the gray and the orange colored hashed marked bars that we can see on the same -- overlaid on the same graph here. So a particular note, you can see that with TLX591, there's very low radiation dose in part to the kidneys and the salivary glands. We've talked about these being 2 normal tissues that the small molecule radioligand therapies tend to hit actually quite hard. And this reduces the risk of developing kidney impairment and dry mouth when you have that low exposure to those organs as we can see here. And each of these that we already talked about can really affect the patient's quality of life during treatment and certainly their lives over years to come. So on the right-hand side of the chart, you can see the liver, which is relatively radiotolerant in terms of organ tolerance. And this is the primary clearance organ. And so it has clearly received the highest dose. And from there, the activity is going to be cleared from the body via the right and left colon rectum and via stool ultimately.

If we can go on to the next slide. I am happy to share 3 cases of patients who have enrolled in the study so far just to illustrate the biodistribution and tumor retention characteristics and also, I think, to illustrate some cases where we might consider use in the future. What we can see here is the case of an 83-year-old gentleman who has known metastatic APMR disease with metastatic disease in the chest. He was actually diagnosed with prostate cancer in 2012 and had a prostate removal or radical prostatectomy at that time. He was treated with enzalutamide therapy starting in November of 2023 in combination with ADT, and he unfortunately had progression of disease in June 2025. And he had a baseline gallium PSMA PET that identified metastatic disease in the thoracic vertebral bodies and ribs, as we can see here illustrated in that baseline or post-treatment SPECT is showing some of this.

So TLX591 treatment was started on August 5, 2025. He had a second dose on August 19, 2025 and he experienced a transient Grade 4 thrombocytopenia or low platelet count and did recover. He received his first docetaxel chemotherapy about 10 weeks later on October 28, and he completed 6 cycles. His current patient status is bilateral peripheral neuropathy. This is something nerve damage or irritation that can happen with docetaxel chemotherapy, but he has had no progression of disease reported during his last patient visit, and that was the time of data cutoff, 341 days after his treatment.

If we can go on to the next slide. This is a patient -- the second patient, and he has also known metastatic APMR, previously exposed to ADT enzalutamide, and he received abiraterone in combination with TLX591. So you can see the sustained tumor-associated imaging signals over 15 days after the first administration, really demonstrating, I think, so clearly to me as a clinician, at least at that 15-day mark, we can see those areas of uptake in addition, of course, to the liver. This is something that I think just shows the way the drug hangs in those tumor cells and hopefully is able to provide a long and prolonged radiation to them.

So this patient was diagnosed with prostate cancer in 2019. He was treated with ADT and received his first ARPI enzalutamide in the first-line metastatic APMR setting, and he progressed on that treatment and the treating physician or investigator in this case determined that he should get abiraterone standard of care in combination with TLX591. He had a baseline gallium PSMA PET that identified metastatic disease in the chest, abdomen and pelvic lymph nodes. And he was treated as we can see, and he ultimately had stable disease for 339 days, but did have progression of disease on March 13, 2026. That is very actually impressive and quite reassuring for him, not something we would expect with second-line ARPI treatment, abiraterone being something that we used after enzalutamide and has minimal expected value there.

So if we go into the next slide, this is a patient case, a final patient. He's a 62-year-old gentleman with known metastatic APMR previously treated with triplet therapy in the metastatic APMN/S setting with ADT, darolutamide and docetaxel, diagnosed with metastatic disease in 2017, high-grade disease, Gleason 9 started docetaxel in October 2017 through February 2018. Darolutamide started in February 2022 and a progression of disease in May of '25. His baseline PSMA-PET on gallium-PSMA-11 was demonstrated to show uptake and the investigator initiated concurrent standard of care enzalutamide on June 30, 2025, 14 days before TLX591, had the first dose on July 9 and the second dose of TLX591 on July 23.

And as you can see, starting on the left in the darker green, early vascular hepatic distribution, then to the right in lighter green, persistent uptake in the metastatic sites out to 15 days, representing that signature of TLX591 rather than a small molecule ligand, which we would not expect to see there. So the patient was on study an extended follow-up as a data cutoff imaging out to day 337 with no treatment discontinuation recorded and no progression of disease through day 337 and the time -- that was the time of data cutoff. So the message here is really that TLX591 plus enzalutamide was well tolerated after previous docetaxel therapy and achieved a durable response in a post-darolutamide setting, again, post ARPI, that second ARPI is expected to have minimal benefit.

So that concludes my presentation. I appreciate your time, and I'll wrap up here, David, and hand back to you.

So since Dr. Morgans is joining us virtually, this is Annie. We can take a couple of questions. If you do have any questions, please raise your hand, and these would be specific to Dr. Morgans. There will be a broader Q&A session a little bit later after the conclusion of all the presentations. Please raise your hand if you any questions.

Of course, Laura. Hi Laura, nice to see you here in New York.

I was wondering if you could talk a little about your experience with using lutetium PSMA-617 and in particular, your view on some of the real-world evidence that was presented at ASCO on whether or not or rather how much the renal toxicity is a problem? And what considerations do you think we're really trying to solve for in this population that's post at least 1 ARPI?

Sure. So I have used quite a lot of lutetium PSMA-617. This is something I've used in clinical trials as well as in standard of care in various settings. And I think that from a treatment opportunity standpoint, patients are very keen to get radioligand therapy or these targeted radioactive drugs. But I would say we are still defining the potential renal toxicity. I think that there are -- there's likely an underrepresentation of the renal toxicity that is likely occurring. It's not something that is as big of a concern when you're only using these drugs in the very late lines of therapy because patients don't have an extended time to live and to need additional therapies over time.

But especially as we move things into earlier settings, I would say that despite the real-world evidence that may be coming out, I think we have an incomplete characterization. Often this renal toxicity is thought to be somewhat delayed and maybe incompletely captured. So I think we as a field are continuing to try to work to put some of that forward. And then can you just repeat the last part of your question was really around, I think, ARPI?

Sorry, the last part of the question was what do you think the main toxicity considerations we're trying to solve for in that population?

Okay. Thank you. Yes. So I think that these are the main toxicities that we're trying to solve for. As we just discussed, the xerostomia as well as the renal toxicity. I had -- just as an example, I had a patient who was on PSMAfore. This was the -- apologies, he was on PSMAddition. This is a metastatic APMN/S or formerly metastatic hormone-sensitive prostate cancer setting. He has had excellent disease control has been followed and follow-up actually at this point, probably 4 years, and the challenge that he has faced, he's an older Italian gentleman, love gardening, getting fresh tomatoes, he and his wife make a beautiful fragrance sauce. They've even brought them into us. He's not able to taste sauce in the same way after having his treatment. So it is -- and this is something that he notices and brings up and talks to me about in clinic, and it's been upsetting to him. It is not to the point that he is unable to eat and needs a feeding tube. That's really not the issue for him. But his life has been altered in ways that we think are meaningful to him and hopefully are contributing to his disease control, but it's something that I think he would have liked to avoid if this was going to be possible.

Kidney toxicity, also something, as I said, difficult to pin down. But if you don't have highly functioning kidneys, you're not able to necessarily treat your other medical problems or potentially get other therapies for prostate cancer, which can limit you over time and absolutely affect the longevity and certainly the quality of your life. So I think any time we can reduce toxicity and ensure that the trade-off that patients are making in terms of having activity against the cancer and maintenance of themselves and their opportunity and ability to take care of the rest of them, it's going to be a win for patients and something that's going to be helpful in terms of therapeutic development.

If there are no -- okay, it looks like we have -- we have 1 more.

Just wanted to hear about your perspective, like what kind of patient baseline characteristics would make a patient not very ideal or ideal for TLX597?

Sure. So I think the biggest barrier to getting treatment is, if I were to say a patient who could not get treatment is a patient who has preexisting bone marrow suppression. This might be a patient with myelodysplastic syndrome or who has low platelet counts for some reason or some suppression of blood counts. This is relatively rare. These are going to be the same patients who are not going to be able to take things like chemotherapy or other radiopharmaceuticals, things that cause low blood counts. And again, it's relatively rare, but that would be the main patient population, I would think. Luckily, these agents are well tolerated and things that even patients who have functional limitations and mobility troubles or other medical problems are generally able to take and this agent -- so TLX591 importantly, plays well with other medicines that we use commonly, these AR pathway inhibitors and can precede chemotherapy. So it really opens the door for most patients to be able to get this kind of a treatment, do it safely and well.

Thank you so much, Dr. Morgans. I think with that, I'll transition to David Cade, who will introduce us to Dr. Sundaram. Thank you.

Thank you.

Thanks, Annie. Yes. And just on behalf of the 40-odd folks, I think, in the room, I'd just like to acknowledge and thank Dr. Morgans for dialing in. She actually has a very busy clinic this morning at the Dana-Farber. She had a patient prior and a patient after. So obviously, the next patient will be very fortunate to be being cared for by a clinician of that capability.

So now we're going to switch from, I think, a very comprehensive review of prostate therapeutics to prostate precision medicine. And this is a very important session. We've obviously got a majority of men in the room. And while I'm very fortunate with my colleagues to be the developers of this next approach, many of us, unfortunately, are likely to be customers of the next approach.

So it's my real pleasure to introduce our next key opinion leader presenter, Dr. Varun Sundaram, who moved to Central Texas as a surgical urologist after originally practicing as a urologist in Gresham, Oregon, I think, is your original hometown. He completed his undergraduate studies and his medical degree at Washington University in St. Louis and subsequently went on to finish his general surgery internship and urology residency at UT Southwestern in Texas, where my Texan colleague is also educated. Dr. Sundaram is now a very busy urologist at Urology Austin, the largest private urology practice in Texas. And the last thing I would say is it's always entertaining to invite a surgeon to the stage, so for obvious reasons. So Varun, welcome up.

All right. Thanks for the intro. So I brought a little prop, and we'll get to that in a second. But thank you guys for having me today. My focus is primarily on the BiPASS trial, the use of PET scans to help minimize the biopsies and the risks of biopsies. So currently, as a urologist, when we're evaluating patients with prostate cancer with elevated PSA, we rely heavily on a biopsy. This is typically done with a probe transrectally. The biopsy can be either transperineal or through the rectum itself. And it will sometimes require 15, even 24 samples to obtain all the tissue that we need. It really depends on where the lesions are seen on the MRI. And even if a lesion is seen, we typically sample the rest of the prostate because there's a chance that there's clinically significant cancer elsewhere. So a lot of our technique and our prior thoughts were kind of a blind shotgun approach. Let's hit this with a bunch of needles. Hopefully, 1 of them will land and we'll detect something.

And there are risks to that, infection, urinary retention, bleeding, people can develop clots in their bladder afterwards and then they can't urinate. Hematospermia is a relatively benign thing, but it is very, very shocking to the patient and their partner. And people recover in the next couple of days. If they end up getting admitted for sepsis, it can be even longer. So here's just a quick video of this -- what you see here is the ultrasound probe. This would go in a patient's rectum. So I'm about to show you the needle as well, but the entire time we're doing this biopsy, which is somewhere between 10 and 20 minutes, depending on how you do it, there is this probe in the rectum, which is probably the worst thing for the patients. That's the biopsy gun that we use, and Kevin was nice enough to get one delivered here. This is not a small needle. The patients will hear this 15 to 25 times as we're biopsying them. and it's hard not to jump every time you hear this click.

Once they've had it and they come back for another one, they're sort of primed for it, but that can actually make things worse and they're expecting this click and worrying about the pain. So if we can avoid these things, we should avoid them. And that's where the BiPASS study, I think, has shown a lot of light. Typically, when we get an elevated PSA, we'll order an MRI of the prostate, and that's a multiparametric MRI, 3T MRI. That's a very complicated study, and we'll get to that in a bit, too. And then if that shows a lesion or if the PSA is too big -- too -- sorry, too high for the size of the prostate, so the PSA density is elevated, we'll do a random biopsy as well. And so this is 800,000 biopsies every year, some sources, say, 1 million. And a lot of them are negative. We do this biopsy because the PSA is elevated, the PSA density elevated or the MRI showed something. And a lot of them could have been avoided because they're negative, patient had a spurious elevation.

They don't have a true lesion or tumor. And there's a large percentage of patients who refuse a biopsy. And there have been a lot of tools that have been developed in a post-PSA setting saying, "Hey, you got an elevated PSA. Let's do some tumor marker. Let's do a biomarker. Let's see if we need to go on to a biopsy". unfortunately, those weren't developed in a post-PSA post-MRI model. So the second you get an MRI, a lot of those are fairly useless clinically. And so using Telix BiPASS, that would be a post-MRI model, and that would allow us a certain level of diagnostic accuracy we don't have right now, and we can avoid these things. We talked a little bit about the risk of biopsy. But again, hematuria, rectal bleeding, sepsis is the biggest risk. And there's about a 3% risk of sepsis with a transrectal biopsy, about a 1% or less with the transperineal biopsy. The other issue is false negatives. You can do a biopsy, see no cancer and then subsequently a year or 2 later, you detect the patient with cancer. It's probably not because they didn't have it at that time, but that you missed it because you're doing a -- partially blind approach.

So the primary 1 and 2 studies helped to develop a sensitivity and a specificity and a scoring system for the PSMA. And what you see here is that the sensitivity of a PET scan plus the MRI is much more than the MRI alone. The idea is that this will allow us to reduce a lot of these unnecessary biopsies, right? So ideally, about 50% of them are unnecessary. If we can reduce those, patients benefit significantly from that. But before each study or before each biopsy, a PET scan can help us say, okay, this lesion is a little bit more aggressive, this lesion is a little bit less aggressive. Primary established the proof of concept and primary 2 showed that it can safely reduce biopsies while still maintaining a clinically significant detection of prostate cancer. And so then comes the BiPASS trial. This was a Phase III trial, which I got to give a little shout out for Urology Austin.

We were the leading enrollers in this study. And it took a look at patients who had an MRI of the prostate, had an elevated PSA and we're going to go on to biopsy already. And the patients then got a PSMA scan before their biopsy and then the biopsy was then random or guided towards PSA or MRI targets. And there's a 6-month follow-up. So we're still in the process of that follow-up. But the primary objective was to detect clinically significant cancer and to help identify which patients we can avoid a biopsy in. And we talked about that. I think, again, the most important thing is this will likely be utilized between MRI and biopsy for almost all patients. So even if not everyone is spared a biopsy, everyone can have the diagnostic benefit of getting a PSMA scan. And the target population for that is somewhere between 800,000 and 1 million patients every year.

So the idea is after the publication of the study is that patients with either symptoms or elevated PSA, they get a PSMA scan. They get a multiparametric MRI and then we stratify their risk. If they have a PI-RADS 5 lesion or a very high risk on PSMA, we go straight to biopsy. If it's a little bit less than PI-RADS 5, 1 or 4, but the PET is still positive, you still go to a biopsy because of the really high specificity. And then finally, if you have PI-RADS 1 or 2 or even a PI-RADS 3, but the PET is negative, you can really talk about avoiding biopsy in those patients, which there is a significant population in the U.S. that wants to hear you say anything but you need a biopsy or you need another biopsy. You'd be surprised at how many urologists are out there in the community, mostly in sort of rural settings where they don't have access to an MRI, they don't have access to a PET scan. So you'll get patients from there who've had 3, 4, maybe even 5 biopsies, and we still can't find out why they have an elevated PSA.

Those patients love it when you say, "Hey, we don't need to do this". And so we can reduce the amount of biopsies. We can eliminate the need for biopsy, and we really affect patient care by reducing anxiety and worry over a procedure that can be invasive and can cause significant harm. Ending up with sepsis in the hospital is a huge issue, and it drives up health care costs to the tune of millions every year. The other benefit of the gallium PSMA scan is it is less likely to show an indeterminate bone lesion than F-18. And this is really important because when we do these scans, pre-biopsy, pre-radiation, if we detect a bone lesion, that drastically changes our treatment course where we now go from talking to somebody about caring their cancer to talking to someone about keeping them alive as long as possible. And so even if we don't suspect or have a high likelihood of belief in a bone lesion, finding this creates a lot of anxiety and stress for the patient, creates a lot of unnecessary workload.

And frankly, it will delay treatment by quite a bit in the time it takes to get another MRI of the area, get a CT scan specifically at the spine or the chest. So having a tracer that is more sensitive and specific to bony lesions and so is less likely to give us false positives is huge. And here's an example of an anterior rib lesion. You see on the CT scan on the FDG, you see a little light upper activity. But on the gallium scan, there's nothing there. And this -- the reason for the false positives can be numerous things. They can be small benign bone lesions. They can be prior trauma, fractures. There are numerous causes in somebody's 70 years of life, why they can have a little bit of imaging findings at a bone. And so having a tracer like gallium is extremely important for minimizing the concern. So currently, we use a multiparametric MRI. And what you see are 3 different phases. You see the T2-weighted imaging, the DWI and the ADC.

And these are very complex. They don't look very similar. One of them looks like a radar scan from the 50s. And the quality of the MRI is not the most important thing. It's the quality of the radiologist or the urologist reading those MRIs. And I'll be honest, most urologists don't know how to read these. We rely heavily on our radiologists. And the vast majority of literature for MRIs and prostate cancer was developed using a single site and a single radiologist. So a person who read thousands upon thousands of scans. That is not the truth in everyday practice. These are not the people we have access to, to read MRIs. They read -- they have to read less than 5% of all the MRIs done in the U.S. So that means 95% of the MRIs done in the U.S., you can't use the pivotal studies and the excellent diagnostic accuracy of MRIs based on papers because that was 1 person reading every single study for all of those papers. And so I'm lucky I have a guy that is very good, and I have patients drive just to see him for their MRI, but not everybody has that. And I only have one of those in the town of Austin, Texas. So I think that says a lot.

Well, thank you for that highly effective and visceral presentation. We appreciate it. So we've just heard a lot of great science up here today. And now I want to talk a little bit about translating that science into really highly effective patient experiences for the technologies that we're bringing to market. So this is the way we see on the diagnostic side. This is the way we currently see the PSMA-PET market. You can see the biopsy. So right now, everything that we look at is from the biopsy behind that. So if you look at our current indications, it's initial staging, it's biochemical recurrence and then radioligand selection -- treatment selection. So you can see that we've also targeted and have ambition to go after response to treatment on APM resistance as we think about what that looks like in non-metastatic disease and then, of course, progression for that and then monitoring progression. So we are ambitiously chasing a lot of indications further down the line. But all of them are after the biopsy.

So what I'd like to kind of think about is that there's really nothing more frustrating than an idea whose time has not come yet, right? So you've got this idea, you're trying to bring it to market, but really the confidence in the scan was not there. So we've been working through how to do this with primary 1, primary 2 and now BiPASS. But really, what we had to do is get some experience with it, and we've done that. So now that we've done that, imagine, if you will, a world where we have the confidence in PSMA PET scan, and then you can see nothing is really more powerful than an idea whose time has come. So when you think about that shift, so if you look at what happens before the biopsy, this 800,000 scans that he was speaking of and the 200,000 men that say no to biopsy each year. So really, if you just look at it before and you look at it after BiPASS, imagine, if you will, this world where every patient that needs a biopsy that is indicated for a biopsy gets a BiPASS first.

And so what you see is this capturing of over 800,000 scans or 800,000 patients that are indicated for biopsy get a scan first. Now we believe there's another 200,000, if you look at that little gray area above that, that actually say no to the biopsy. And from his demonstration, you can see why you might say no to that. And so we think that just that market is approaching $1 billion. Just getting the people who said no to biopsy is about $1 billion. But when you look at the 800,000 scans that we can capture because of the increased sensitivity and specificity, then imagine, if you will, a world where BiPASS gets approved by the FDA. As we've said, we've aligned with the FDA on a new NDA for BiPASS, and we intend to address that indication. And so what happens after? So the question that we pose to our Strategic Advisory Boards is what happens if we get a BiPASS indication for the pre-biopsy setting? Well, then you get an initial staging even with BiPASS.

So you have this baseline and initial staging immediately pre-biopsy. So that will most likely decrease. And then because of the imaging that you're getting and your surgical selection that you see now with the BiPASS image that you saw a few minutes ago, you'll see that even biochemical recurrence may decrease as well. And then as you look at response to non-metastatic, we start thinking about how to really assess that response using the primary scores. And we really think about what that may do in terms of why wait? Why wait for your PSA to increase? And we go after that indication as well. And so you can see the redistribution, if you will, of what we see in PSMA scans today with what may be tomorrow if BiPASS is approved. So some really exciting things that will happen for men, for men around the world and a big part of what we're trying to do as we look at what we can do for men in this area.

So we -- you got to hear from a urologist about his experience and the way he views it. And one of the things that as we talked to the Austin Urology group in this trial is that when they get a biopsy and it's negative, you can't necessarily tell a patient they don't have prostate cancer. You just tell them that we didn't find any prostate cancer. And so that patient, while he was indicated once, they will still track his PSA every 6 months, and they'll bring him back in again on a watch and wait to get another biopsy. So that could be another BiPASS. But as we start thinking about the patient side of this, then we surveyed over 1,000 patients that got a biopsy, and it comes out just like you would think when poised the question, would you rather have a PSMA scan first and possibly avoid a biopsy, then, of course, 95% of the men said overwhelmingly that they would rather do that.

Now it kind of makes you wonder about the other 5%. But I think that as we are really kind of understanding and educating this, we have not started any education at all on the patient side of this. So this is just a patient advocacy group that we worked through and did the study with and just positioned this or propose this idea to them, and you can see that it's overwhelming. And so much so that as we know now that when patients get educated about other alternative methods, especially for something that they're trying to avoid in general, then they are more than willing to either discuss it with their doctor or ask to discuss it with their doctor. And you can read some of the comments as well about the experience they've had.

Now what does that do for -- what does that really do for our TAM, we call it, or our opportunity? We see that overall, we're approaching a $20 billion opportunity in the -- and this is U.S. only. So we have the initial 670,000 scans that we're working with in the current state. We believe there's another 800,000 in BiPASS, another 200,000 that we can activate that are saying no. And then when you net that out, we see that the TAM in that first 3 indications really just about doubles or a little bit more. And then as we progress in our indication expansion strategy, then you'll see we've got another $250,000 or $0.25 million that we're going to chase down. Now because of what we're doing in the theranostic area, and you've got to hear some great presentations on our therapies, we look at that TAM in general. Remember, our idea is to really derisk the targets by having the initial tracer in the diagnostic area and really understanding that the theranostic strategy does a couple of things for us. It derisked the tracer. But also over the past 3 to 4 years, we've built relationships as we prepare for therapy, we built relationships with regulators, with customers, with payers, not just here in the U.S. but globally.

And that's a really important part of the theranostics strategy as we have that both commercial, regulatory and payer experience. So as you combine those 2 TAMs and you look at metastatic APM, both naive and sensitive, and about 16,000 patients, we believe, when you look at first line and second line and resistant, then we think it's about 22,000. And then, of course, in second line plus, we see it over 12,000 patients. So when you look at the entire portfolio on a theranostics perspective, then you can see that we're approaching $20 million -- $20 billion. And we think that the portfolio and pipeline that the team put together for you enables us to achieve that. So thank you very much.

Thank you, Kevin. We're going to open it up for Q&A. So if I can please ask all the speakers to go to the stage. And if you have any questions, please raise your hand. Let's just give a minute for them to get situated. All right. Please go ahead, Andy.

This is Andy Hsieh, William Blair. Kevin, you mentioned about the NDA submission based on the BiPASS study. I'm curious if you can elaborate a little bit just about kind of how you can achieve that. Obviously, we're in this game every 3 years, you got to have something new, but it would be helpful for the investment community to know how -- what's the detailed strategy there?

Yes. I would say that we've aligned with the FDA that we want to pursue a new NDA. And of course, in pursuing a new NDA, that would allow us to get an NDC and HCPCS code and then ultimately work for a transitional pass-through code. So while it's not necessarily part of our life cycle management overall broadly for the portfolio, it is. But we believe this as a more of a disruptive technology in the way that we're going to redistribute and move pre-biopsy versus post biopsy. So it ultimately fits into that. But having that as a -- the FDA agreed that it was a big enough change in the product and the indication that they believe we could pursue an NDA. So that's what we're doing.

Any other questions?

So there's new PET/MRI systems from GE in 2022 got FDA approved. Siemens Healthineers got approved in January 2026. So is the rollout of these new better, more sensitive PET MRIs going to help the diagnostic pathway?

Well, I think I would manage that from where the market is today and where it may go. Now if you think about how that combination between a PET MR and BiPASS and how those could work together, I think we see a lot of synergy in that. And we believe that the sensitivity and specificity of BiPASS will achieve our endpoints. And then so we see that as a good thing for the direction we want to go. And just based on their rollout and how we manage that, we would be happy to help support and drive that.

Can you speak to the cost impact in the physician office in regards to current biopsies and practice versus a PET approach?

Sure. The health economics, we believe, is somewhat neutral in terms of how we approach that from either a PET/CT PSMA versus a biopsy. Now each and every one of the clinics, of course, have a different RBU system on the facilities -- on the technical side for what the physician does. But as you know, including Dr. Sundaram's practice is there's many of the private practice urologists that are -- that have scanners now, and that's an emerging -- that's really part of the emerging part of what we're doing. So we believe it's at worst, a net neutral. And because of what we think that is going to happen downstream and the overall complication rates is going to be net positive for BiPASS. And if you wanted to comment on?

I can say for the urologists, those who own their own PET scanners, it's net positive. The revenue from a PET scan is far outweighs that of a biopsy. But the other thing you have to think of is we're all at capacity right now. I don't think I can add another 10% of biopsies on to my schedule or any of my partners. And so if anything, we need avenues and ways of evaluating things that don't directly tie up our clinic, our time and our biopsy machine. So I think -- I would say that I think it can only be net positive. And in those settings where they don't have their own PET scanner, again, they're also at capacity. We're not making more urologists in a timely fashion.

Any other questions? All right. If there are no other questions, I'll hand it over to David Cade to go to the next session.

Okay. Thank you. Let's keep going. Okay. So I think we've had a very comprehensive tour through both our therapeutic and prostate cancer pipeline. So let's switch now to kidney cancer. So prostate and kidney are obviously the main parts of our urology franchise. Our next speaker, I'm delighted to say is Dr. Monty Pal, a globally -- Dr. Pal is a very much globally recognized leader in the research and management of kidney cancer. He's the Co-Director of the Kidney Cancer Program at City of Hope. So thank you for coming all this way. And he serves as the Clinical Trials Medical Director at its Comprehensive Cancer Center, which is a very busy Comprehensive Cancer Center. Over the course of his career, he's led and contributed to many, I would say, practice-changing clinical studies that have advanced the standard of care in kidney cancer, publishing more than, I think it's 500 papers over your career and really leading a significant portfolio of clinical trials.

So please join me in welcoming Dr. Pal up. Thank you.

Perfect. Perfect. Well, really delighted to be here, and thank you for the very, very kind introduction. Really excited to share with you some of the latest developments in the space. But before we jump into that, just a quick disease overview. So with respect to kidney cancer, it's really a disease that's been rising in prominence. The estimates suggest by about 3% per annum for several decades now. It represents the 14 most common diagnosed cancer worldwide. And if you look at the age standard incidence and mortality, it tends to be highest in North America as well as in Europe. This is a male predominant disease with about a 3:1 to 2:1 ratio. And when we think about kidney cancer in that vernacular, about 90% of cases are going to be renal cell carcinoma. And within that, about 85% are going to represent clear cell renal cell carcinoma. So that's by far the most common histology and it makes up the lion's share of what I tend to see in the clinics.

Now I will point out, and we highlighted a bit of the disease burden that incidence rates are rising, as I mentioned, 3% per annum for several decades. A lot of that hinges on better imaging techniques. A lot of that also hinges on the fact that we have exposure to more carcinogens in the natural environment. And what's really quite strange is that despite the increase in the available imaging that we have to diagnose the disease, unfortunately, still about 30% of patients are diagnosed with metastatic disease in the get-go. And despite the many advancements that we'll highlight momentarily, 5-year survival remains rather dismal for this disease. And there's about 180,000 death that occur worldwide. As we shift to the treatment challenges, I think the one thing that I'd really emphasize is that at this point in time, kidney cancer therapy is really maybe a 1 or 2-trick pony.

When we think about the different therapeutic modalities that we have, we have checkpoint inhibitors. We have VEGF-targeted therapies and typically, those are tyrosine kinase inhibitors. And although there are a certain subset of patients, I'd estimate around 10% that can have durable complete responses to these therapies, the vast majority of these individuals inevitably progress, primary and acquired resistance occurs across the vast majority of these therapies. And truthfully, when we get beyond frontline management of this disease, we have very little in the third line and fourth line to offer patients. And in fact, many would argue that second-line therapies as they stand currently can actually be very redundant. And I'll make that point in some of my subsequent slides. There's certainly a need for better tolerated therapies. It's estimated that about 4,700 patients per year in the U.S. are going to need third-line options.

And at this point in time, the management strategy tends to be use of another targeted therapy. So I'll put the patient in front of you who's received a regimen like nivo/ipi upfront, maybe cabozantinib in the second setting. What we have are just more targeted therapies to offer after that, lenvatinib, tivozanib, et cetera, and we'll discuss this in subsequent slides. And intellectually and frankly, logistically at the clinic is not very satisfying to rechallenge the patient with a very similar class of options. I will say that adverse effects tend to really sort of plague the third and fourth-line settings. Patients have already been exposed to treatments and have significant incurred toxicities like diarrhea, fatigue, et cetera. And this only gets magnified as you get into later line of therapy. So it would be ideal to have therapies that can provide durable disease control with manageable toxicity. I'm really with the mindset that we're only going to get there if we really introduce novel mechanisms of action in this later setting.

So what targets can we exploit that we haven't to date? Ironically, it's actually one of the entities that we use to diagnose renal cell carcinoma and that's CA9 or carbonic anhydrase 9. So this is a transmembrane glycoprotein. If we think of its physiologic function, it works in oxygen sensing. It's a pH regulator as well. And as we'll highlight in the next slide, it's really induced by Von Hippel-Lindau tumor gene in many cases, but also by hypoxia as well. And we see this in about 95% of cases of clear cell renal cell carcinoma. Our pathologists routinely use this. They use PAX8 and a handful of other strains to really classify clear cell renal cell carcinoma. And when we think about the mechanism here, I'll start with the mutations that really sort of underlie clear cell RCC. And as I mentioned in the previous slide, that's this VHL alteration. When we think about VHL and its native function, it's ubiquitin ligase, it tends to sort of target certain elements for destruction.

When VHL is altered, and this happens in a somatic fashion in about 55% to 60% of patients in germline setting as well and a small fraction of patients, what we see is that there tends to be accumulation of 1 of the products that really sort of drives kidney cancer growth, and that's hypoxia-inducible factor HIF. Now HIF is actually -- CA9, as I've mentioned before, is a transcriptional target of HIF. And when we have this accumulation of HIF in the context of VHL alterations, you tend to see increased transcription of CA9. And again, we've described the function of CA9. One important element to really bear in mind is that CA9 expression is really seen minimally on normal tissues. And that's, I think, one of the key elements that lends itself to being a therapeutic target. So let's talk a little bit about the different targeting approaches to CA9.

An agent that's maybe well known to some of the audience is girentuximab. This is an IgG1 kappa light chain chimeric monoclonal antibody. And it actually is very highly specific for CA9. It leads to internalization. And one of the elements that I'll point out is that girentuximab has been very heavily studied. Many may remember a presentation from ASCO several years ago, the ARISER study in which there was an extensive look at girentuximab in patients with renal cell carcinoma. So there is extensive safety data around this. We know that this entity is hepatically cleared.

Moving on to the developments based on girentuximab. We have the 89 zirconium payload, which is useful in the context of imaging. This is a positron emitter with a half-life of 3.3 days. And again, this is suitable for PET imaging. What I'm going to be focusing on though is listed on the right, and that's the 177 lutetium payload. And this is a medium energy beta emitter, half-life of 6.7 days, and this is really suitable for antibody-based therapy.

So I'm going to get into the development plan that we have for this in just a moment here. But before I do that, let me just sort of articulate the standard pathway for management of advanced renal cell carcinoma. So after the time of diagnosis and surgery, we have more than a modest fraction of patients who develop disease recurrence usually with metastatic sites, including lung, bone, liver, lymph node, et cetera. And there's a small fraction of patients, I'd estimate about 5% to 10% who really fit in the top of that first-line graphic. Those are patients with oligometastatic disease who have maybe limited sites of spread. In those situations, we can target patients with site-directed radiation or site-directed surgery. That's not the lion's share of what I tend to see in clinic.

About 20% of frontline patients have what's deemed to be favorable risk disease. These are based on prognostic factors, including time from diagnosis to treatment, serum hemoglobin levels, calcium levels, et cetera, et cetera. But those patients are generally approached with a combination of VEGF TKI in association with checkpoint inhibitor. About 70% to 80% of patients are going to have what's turned intermediate poor risk disease. And these are patients with certainly a briefer prognosis and poor outcomes even in the context of therapy. Most of these patients are approached with either the combination of TKI with IO or with a dual IO/IO regimen such as nivolumab and ipilimumab. There's a very rare subset of patients in this day and age who would get TKI monotherapy. Those are patients with absolute contraindications to checkpoint inhibitors, and that's a fleeting population.

As we move to the second-line setting, this is really where the challenge arises. There's so much redundancy in what we do. Even for the patient who's been frontline treated with a TKI and I-O-based regimen, you're oftentimes just going to rechallenge with another TKI-based strategy. I'm happy to chat about some of the more recent developments in the landscape. But if you think to really what has been introduced perhaps over the course of the past year or 2, we have therapies that target a hypoxia-inducible factor or HIF like belzutifan. We most recently have under consideration for approval a combination of lenvatinib with belzutifan. I find that these options are maybe a little bit less palatable because, again, many of these therapies fall along the same signaling axis as VEGF and therapies that we use in the frontline setting. So again, patients are already facing substantial toxicities that they've incurred in the frontline setting from those therapies. In the third-line setting, the problem gets magnified where, again, there's a lot of redundancy. We're again rechallenging with VEGF inhibitors, mTOR inhibitors, largely a pool of drugs that can maybe be envisioned as all cytostatic.

So I wanted to outline some of the rationale that belies the Luteon studies that I'll be highlighting in just a moment. And this hinges on, again, the use of 177 lutetium bound girentuximab. And what I'll point out here is that there is data from previous studies. These were investigator-initiated trials in a Phase I study that included 23 patients in a Phase II study that included 14 patients, there's a couple of really important lessons learned. The first is that patients who received the maximum number of cycles were actually those who had received lower doses of therapy. So you can see that it was those individuals who received less than 3,145 megabecquerels of treatment that were really able to sustain a greater extent of dosing. There were none, in fact, if you'd received in excess of 4,000 megabecquerels.

More treatment, frankly, correlates with better outcomes. So if you looked at patients who received 3 cycles of therapy, median overall survival was 49.3 months. That falls down to 22.2 months amongst those that received 2 cycles. You're down to 18.7 months if you just received 1 cycle of therapy. So there really seems to be some diminution of benefit if you're not receiving 3 cycles of treatment in the course of these early studies. There also seem to be, and this is perhaps expected, an increase in hematologic toxicity with higher doses. We didn't really see any grade 3/4 leukocyte or platelet toxicities in patients that received a dose of 1,887 megabecquerels, and we'll talk about that dose in just a moment. This dose is well tolerated and allowed for multiple cycles of therapy.

Now beyond these observations from initial studies, there's also a bit of pharmacologic rationale that belies our approach and the studies I'll highlight in just a moment. And that's the fact that if you look at TLX250 tumor residence time, there seems to be little or no relevant therapeutic activity that's maintained after about 3 weeks or so. So with that in mind, if we fractionate therapy, we feel that we may potentially really maximize efficacy and reduce those intervals at which the patient is really receiving no therapeutic benefit. If you're spacing out at 3-month intervals, 4-month intervals, et cetera, you have a long period of time in which tumors aren't exposed to sufficient dose of therapy. Using the strategy that we've suggested here, each fraction stays low enough to avoid dose-limiting toxicities as well.

And moving forward, there's 2 strategies that we'd like to assess. The first uses, again, that dose of 1,887 megabecquerels every 2 months for a total of 3 cycles, and this is really based on activity seen in previous studies. And we're taking the further step of assessing 1,258 megabecquerels every month for a total of 6 cycles. So how is this incorporated in our forthcoming study? So there's 2 studies I'd like to highlight here, but very similar in premise, LUTEON and LUTEON ATLAS, and I'm the principal investigator for LUTEON ATLAS. Some similarities. This involves the same patient population, patients with advanced or metastatic renal cell carcinoma. These patients should have had disease progression on or after 2 to 3 prior lines of therapy. So again, this is an area of unmet need as I think I painted a picture of my previous slides. And these patients have to be CD9 positive by 89 zirconium TLX250 PET.

Now lending itself to some of the differences between these designs in the U.S., there is a safety lead-in that's mandated. So there's 3 patients in each of the 2 dosing cohorts. These patients can be sort of melded into the dose optimization schema that you see that's running both in the LUTEON study in Australia and the LUTEON ATLAS study in the U.S. and EU. So you can see the 2 schedules that we're evaluating. I've already highlighted that dosing strategy on the previous slide, but you can see this comparison of monthly dosing as well as look at every 2-month dosing. Now again, one of the differences is that in the design of LUTEON in Australia, we have the flexibility to actually migrate directly into a Phase III design. And I think that's quite unique. You can see here that the randomization proposed is either to our drug versus investigator's choice of therapy. Sample size is still to be determined. I think it's a very pragmatic design in this setting.

And with that, I will pass it on to, I believe, Dr. Cade. Thank you.

Look, that's -- I'd like to thank Dr. Pal. You're a very modest collaborator, Dr. Pal. I mean you've been fundamental in the original and finessing of the design of the LUTEON family of studies. And I think that's ultimately going to generate some extraordinary data that we believe will move the field. So what I'd like to do is I think Dr. Sundaram and my colleague, Kevin Richardson, articulated how we believe BiPASS is fundamentally going to change the diagnostic practices for prostate cancer. And one of the very fortunate parts of my role as a physician in industry is to be able to work with collaborators like Dr. Sundaram and Dr. Pal, and Dr. Morgans to design trials that ultimately generate data that will change practice. And I think we feel very strongly that Zircaix and the data from the completed ZIRCON Phase III trial will fundamentally change how we manage kidney cancer. So let's move on to Zircaix for which we'll be refiling our biologics license application very shortly.

Now the clinical use of -- for Zircaix, I think, is very clear. But let's just recap what that clinical use case is. Now given the increasing number of what we call incidental renal masses, and there's a slightly more memorable term for those in clinic, we sometimes refer to them as incidentalomas. These are incidental masses identified in the kidney through really the proliferation of conventional imaging with CT or MRI or even ultrasound that's widely used to examine other abdominal pathologies that might be from completely unrelated conditions. And so when a clinician, whether they're a urologist or a surgeon who takes care of abdominal pathologies or whether they're a radiologist, when they're confronted with a newly identified renal mass, it's clear that this needs to be characterized very accurately without doubt is either a clear cell renal cell carcinoma, ccRCC, which is the most common and aggressive form of kidney cancer, or non-ccRCC, either a more indolent malignancy or a benign lesion.

And now while conventional imaging can provide detailed information about structure and vascularity, these modalities still lack the ability to distinguish between benign and malignant lesions in the kidney. And so consequently, similar to what we've just seen, I think, very clearly in prostate cancer, for kidney cancer, today's standard remains renal biopsy, which has very significant drawbacks. Primarily, it's highly invasive. It's a very large-bore needle through the loin or through the back. And that carries significant complications such as pain and bleeding through pranging an arterial vessel that might require surgery or an interventional radiologist to stop that bleeding. And of course, cancer seeding. So if it is a cancer that will put the needle into, when we withdraw the needle, we can actually seed malignant cells along the tract of the needle when we pull it out. So this slide really nicely summarizes the results of our ZIRCON Phase III trial, which I think demonstrated 2 key takeaways.

Now the first of those is that ZIRCON fundamentally validated carbonic anhydrase 9 or CA9 as a new target for therapeutic radiopharma development for renal cell carcinoma. And this really forms the rationale for Telix's decision to take shareholder capital and invest that into the LUTEON studies, which Dr. Pal has described so nicely. Secondly, I think what -- for me, what ZIRCON has clearly demonstrated is the accuracy of Zircaix to noninvasively delineate clear cell renal cell carcinoma from non-ccRCC lesions. And it's this latter use as a noninvasive tool using a new modality of PET, CA9 PET to characterize ccRCC from indeterminate renal masses. And we're really excited about bringing this to clinicians and their patients following eventual FDA approval.

Now let's look at a couple of case studies. I think the case studies are very illustrative of why Zircaix is so eagerly anticipated for the clinic. And this is a patient for whom a small renal mass was initially detected on conventional imaging. And so again, what we call an incidentaloma. But to work that up to really investigate that further, this patient had more formalized contrast CT and MRI, which elucidated bilateral masses, no evidence of extended or metastatic disease. So the initial plan was to do partial nephrectomy, so nephron-sparing partial nephrectomy of the larger lesions on the right kidney and a procedure that is radiofrequency ablation to the smaller lesion on the left kidney. But fortunately for this patient he went on to have a Zircaix PET scan which turned out to be negative and following his negative Zircaix PET scan the decision was then made to change from surgery and radiofrequency ablation to active surveillance much to the relief of this patient.

So for this patient, partial nephrectomy, which is a very significant operation and radiofrequency ablation were safely avoided. So the use case in this setting I think, is crystal clear. Now this is a second case, which is almost diametrically the opposite to that first patient. So this is a 78-year-old patient. So they're getting elderly, and we have to be very careful about what surgical procedures we want to do in an older patient. So this patient had already been diagnosed with advanced kidney cancer based on histopathology obtained from a biopsy. So his diagnosis is known. And what this demonstrates is that Zircaix is able to detect the extent of metastatic disease. So this guy had advanced renal cell carcinoma identified in several organ systems. Obviously, the primary in the kidney remains there. He's not a surgical candidate, but it's also in his spine and in his lungs and the scan can also distinguish tumor thrombus because renal cell carcinoma has a propensity to invade the renal vein that supplies -- that drains the blood from the kidney. It's a property of renal cell carcinoma that enables it to gain access up the renal vein to the heart and can cause significant cardiovascular problems with advanced disease. So what this Zircaix's information was able to confirm was that this patient definitely is not a surgical candidate. He has multisite metastatic disease and clearly is going to require systemic therapy, as Dr. Pal has described.

So I'll pause there, and I'll hand back to you, Kevin.

Thanks, David. So I'm just going to take a few minutes to kind of pull this together in what we see as the opportunity. You will have seen from Chris' opening slide, really the next 3 to 4 years and how that evolves to our overall growth strategy. So to put that into a couple of simple terms, our growth strategy over the next couple of years, as you can see from the second product is to expand our products into multiple disease states, expand those products with new indications, as you've seen for BiPASS, and I'll mention another one here for Zircaix. And then as you saw from his presentation, we're in 22 countries.

So we're going to expand the geographies in which we sell those products, giving us a multiproduct, multinational revenue stream to kind of diversify what we're doing. And then that really evolves over the next 3 or 4 years into our overall theranostic strategy, which simply put gives us the diagnostic platform gives us a platform of target understanding and derisk that revenue diversification to derisk that and then ultimately building these relationships that we need to be an effective therapeutic company with payers and regulators, right, as well as our customer base because they are very similar and synergistic.

And so to describe that, and specifically, as it relates now to our second product that we're talking about with TLX250 PX or Zircaix as a brand name, you'll have to remember that many of these patients come in really by accident. So usually, you go in for a scan for something else. And the doctor says, "Yes, you've got a broken rib or no, you don't have what you came in here for, but we found something in your kidney, and you need to go see a urologist. It's most likely benign, but we need to make sure."

So he sends you to a urologist or into radiology scanning to make sure for the appropriate type test. Now what that does for us is that we already have now back to that synergistic that we're talking about, we already have these relationships with urologists, especially as we start thinking about refer her to imaging. But now urologists are much more involved in the -- in both the order to get the referral as well as the prescription to refer to a radiologist.

Now it will ultimately be read by a board-certified radiologists. Preferably, as you heard Dr. Sundaram described preferably a nuclear med physician, right, that really has the expertise in reading that. But then once we get that diagnosis, to David's point that the Zircon change of management is really what the most important part of this is, as we think through now we're going to be alongside of people we've already been working with in this growth strategy of a surgical urologist, a med-onc, a radiation oncologists and/or an interventional radiologist along with for the ablative treatments that are possible.

So what does that do for the opportunity? We described -- we described the prostate opportunity as approaching $20 billion and 130 or quite a few patients. As we think about what that looks like for renal cell carcinoma, again, expand the product, our first indication, diagnosing indeterminant renal masses. We believe that's over $0.5 billion or 100,000 patients as we think about expanding the indication back to our growth strategy, that is metastatic disease in clear cell. And then as you saw from the therapeutic study, we believe there's 5,000 patients in that third line, third line plus in clear cell renal cell carcinoma.

And then in that second line plus, as we continue to look at how effective this product is and move it upstream a bit into second line, we believe that's twice as many patients in that second line and approaching 11,000 patients or $2.5 billion. So describing our renal portfolio theranostic portfolio. We see that approaching about $5 billion -- $4 billion to $5 billion in opportunity. So again, how -- you can see now how that fits into our overall strategy of growing the platform both from a diagnostic standpoint over the next couple of years with the imminent launch of Zircaix and then as we roll that into theranostics. So anyway, thank you for your time.

All right. We'll open it up to Q&A again. If I can please have the speakers up and then please raise your hand if you have a question. Anyone, any questions?

So as I understand it, CA9 is a general marker for hypoxia, which is like almost definitively what a cancer is. So is there a path forward for all advanced cancers for CA9, either a diagnostic agent or a therapeutic agent or both?

Do you want to comment on the...

Sure, sure. Yes. So indeed, I mean, I think there's a specific reason to think that CA9 may be overabundant in renal cell carcinoma based on VHL alterations in the disease. That lends itself to increased transcription of CA9 ultimately through the pathways that I cited. There certainly is abundant expression of CA9 in a handful of other diseases. We see it across a spectrum of some gynecologic cancers, for instance. So I certainly see outlets for CA9-directed therapies in other settings to beyond renal cell carcinoma.

Yes. I'd just add to that, that it often gets put to us that why don't you do a basket trial, basket trial being a term for not the species of cancer that might be included in a trial, but including patients that express the target and that target might be expressed across numerous different species of cancer.

For example, it might be kidney cancer that's included in the basket and ovarian cancer, for example, that's included in the basket. And while on the surface, that's an attractive approach. FDA does make it a little bit more complex than that. And so our philosophy is, as Dr. Paul has described, is to obtain a first beachhead with kidney cancer, both because there is a major unmet need in kidney cancer.

Patients do progress through the available therapies often quite quickly and kidney cancer has a very high prevalence and specificity of expression of that target. So that's where we plan to go first, and I think that's a very responsible way to go about it.

Dr. Paul, in terms of efficacy of some of the TKIs that you see in the second and third line, could you speak to where you see the hurdle for Circa in terms of efficacy, what you'd like to see to be excited about the product? And then, David, maybe in terms of CA9, what the next sort of interesting indications could be beyond renal cell?

So maybe I can comment on your first question there. The benchmarks for third-line therapy are not particularly impressive. So if you look, for instae, the data for belzutifan, which is perhaps most abundantly used in that setting, median progression-free survival is 5.6 months. Median PFS was also 5.6 months for its comparator in that study, everolimus. And the hazard ratio between the 2 just happened to be 0.75 favoring belzutifan. So I would say that, that benchmark is one that's easily surpassed by a lot of novel therapies.

If you think to other potential strategies in the third-line setting, tivozanib comes to mind. And there, the TIVO-3 study, which actually looked at tivozanib in the third, fourth line setting produced an almost identical benchmark with a PFS of around 5.5 months. So I actually think that the strategy here provides a potential comparator that is easily surpassed

So Jeff, yes, I think you asked about where else could it go. So I think if renal cell carcinoma in the first instance was able to be -- to have its overall survival prospects improved upon, that would lead us to investigate other species of cancer that express the target. So we'd look at things like bladder cancer, -- we'd look at female genitourinary cancers. We'd probably start there.

Say, for example, specifically, ovarian cancer is characteristically diagnosed late and often in younger women, and we certainly need better options for such malignancies. So I think that's where we'd probably go looking.

Maybe a question for Dr. Paul, if you don't mind. I guess in the adjuvant setting, from a clinical trial perspective, I hear a lot of investigators talk about patient selection, maybe patients who don't really need pembro or belzutifan are getting it, vice versa. And I'm just curious about your view on having a diagnostic agent, CA9, for example, as a potential selection biomarker down the road. Is that something that could be very interesting? And maybe from Telix perspective, could Zurchix be something positioned there? Or you might need something that is kind of in ITM's pipeline with a small molecule gallium-68?

Yes. So just to paint a really brief picture of the landscape for adjuvant treatment of renal cell carcinoma was pretty barren until about 5 or 6 years ago. There was an approval for adjuvant sunitinib. Frankly speaking, that's very rarely utilized. Pembrolizumab entered the marketplace several years back and now is supported through the KEYNOTE-564 study with positive not just disease-free survival data, but also overall survival data. And I think that there is a pension for most patients who are candidates to actually receive pembrolizumab, where I think a lot of the debate lies in the more recently presented LITESPARK-022 clinical trial, which looked at pembrolizumab plus belzutifan versus pembrolizumab alone as an adjuvant strategy.

And there, we saw a significant improvement in disease-free survival, no benefit in OS. Paradoxically, it was actually the patients who were at lower risk would seem to benefit to a greater extent from belzutifan. And it really begs for an appropriate biomarker. If you're going to give a drug with toxicities like hypoxia and anemia, which belzutifan carries in the adjuvant setting, it would be ideal to have a biomarker for benefit.

And to your point, I actually think that given the relationship of CA9 to HIF and VHL and so forth, I think that there's a lot of rationale in exploring perhaps Zurcaix as a potential biomarker for benefit there. I mean that's speculation, but I think that it's definitely a worth study. It's a great point.

All right. Any other questions? All right. If not, then we'll move on to the brain cancer portfolio. So I'll ask David to introduce our next speaker, Dr. Braat.

Okay. We -- thank you, Annie, and thank you, Dr. Paul, for the Q&A session. I'm absolutely delighted to invite our next key opinion leader speaker who's come all the way from Europe. And I think it just really is a reflection of the collaboration in the field, particularly in glioblastoma, which is -- it's a devastating diagnosis. We've got so much more work to do. I think you'd concur Dr. Bratt, it's been a drug development, not a graveyard, but certainly a drug development desert over the last 20 years.

The last major advance really was stoo regimen back in the mid-2000s. So Dr. Bratt is a nuclear medicine physician, a Dutch nuclear medicine physician at the University Medical Center in Utrecht in the Netherlands, specializing in a whole range of different radionuclide treatments. He completed his PhD thesis, which is in a different area, an earlier area that was very close to my heart, hepatic radioembolization in neuroendocrine neoplasm back in 2019, I think.

And in 2023, Dr. Braat was appointed as Associate Professor of Translational Nuclear Oncology at the University Medical Center in Utrecht. He also serves as an advisory board on the European Neuroendocrine Tumors Group, NEPS. So liver, neuroendocrine tumors and also a leading researcher in brain cancer as well. And I think, obviously, you can tell from my accent, I'm Australian, come from Sydney. But if I was a Western European, I would come to your center for treatment of my glioblastoma without a doubt. So Dr. Braat, over to you.

Thanks, David, for the kind introduction. So thanks for the opportunity to speak about glioblastoma because as David already mentioned, it's a big clinical unmet need. I came in to touch with glioblastoma patients when I finished my PhD. And yes, speaking from the heart, these are people from my age young people in the middle of society, having small kids, but are confronted with brain cancer.

So as mentioned by David, I think this is striking. We see the brain cancer incidences rising over the past 20 to 30 years. And as mentioned, the only real breakthrough we had was in the '90s, beginning of the 2000s is stoop regimen. And stoo regimen is nothing more than having external beam radiation therapy combined with classic tilozotomide and afterwards, get tilozotomide maintenance therapy.

And if your patient is lucky before they go into Stupp regimen, they get a surgical resection. But of course, if the tumor is in a very unfortunate location, patients don't get a resection because they'll get some neurological problems. But this is the advances we have. So as you look at these curves, you can see there's still a very big plateau in survival benefit over the past 20 years. So we really have to make some changes there.

So overall, survival is poor. Patients have a mean overall survival of about 2 years. So -- and after 2 years, more than 90% of patients has already progressed. So after initial therapy within the first half year, most of our patients already show progressive disease.

So this is just a feature of how aggressive glioblastomas really are. And as pointed out, we don't have really any other therapies. There's lomustine. It was back from the '80s. It showed a progression-free survival benefit of 1.5 months, but we really don't have anything better. And that's the reason why the NCCN guidelines, but also EANO guidelines actually state that in case your patient has a recurrence, you should go for clinical trial participation because that may be a better alternative than getting just standard lomustine for therapy.

Another thing is imaging. Imaging with MRI, it's our gold standard, but having changes within the brain is very difficult, especially after radiation therapy, where you can see these post-treatment changes, pseudoprogression, radiation necrosis, and it's very difficult to distinct radiation necrosis versus tumor progression.

So with FET-PET, it's starting to generate a lot of evidence nowadays. It's [Technical Difficulty] the MR. So going straight for FET and large amino acid transporter, the 2 subtypes, but that one is the most interesting at the moment. It's highly expressing gliomas, and it's also expressed in your normal blood-brain barrier. And the blood-brain barrier is actually our biggest challenge besides having a glioblastoma, which has very infiltrative growth, so you don't see it as well on imaging. The blood-brain barrier also blocks drugs from passing into the tumor.

TLX101 with 4 weeks, 10 months after 3 cycles, you can see the fact that accumulation is decreasing. The tumor itself on MR is still the same. So on MR, stable disease. But with molecular imaging, you can see the accumulation is decreasing. Unfortunately, we are pausing his treatment at the moment because he's getting more epileptic seizures. So in isolation, that's, of course, quite tricky. But at this time, he's still doing quite well. He has no neurological complaints. So for now, this only gives us a signal that maybe this is also something for oligodendroglioma patients and not for GBM patients alone.

So advancing from recurrent setting to first-line setting because also in first-line setting, as mentioned, 90% gets a recurrence within the first 2 years after initial therapy. There's the IPAX-2 study. It completed combining Stupp, so external beam radiation therapy with temozolomide with TLX101. So from my own experience, it was well tolerated, nothing in particular happened. So the safety readout and the official efficacy readout will follow because it's been completed now. So eagerly awaiting those results.

In line with the rest of the presentations we had earlier this morning, of course, also for phenylalanine, we're going from beta emission towards alpha emission. As mentioned, beta emission with iodine-131 is a bit tricky because we have these high-energy gammas, which patients need to be in isolation in. That's not a particular setting as a patient you would like to be in if it's your last treatment option, you want to be at home with your family. So going for alpha makes clear sense from an emotional societal perspective.

So together with Telix, we're doing this first-in-man astatine-211/phenylalanine study in [indiscernible] in which astatine-211, which is an alpha emitter, it's less known than actinium-225, but it's more promising in my perspective. It has a shorter half-life, just 7 hours. So it has a very high dose rate. And the other nice thing is of a few things, the only alpha emitter you can decently image. So this is a phantom scan of a SPECT -- on the SPECT scanner, and you can see lesions as large as 1 cc. So if you have dedicated SPECT time and reconstruction methods, you can actually image this alpha emitter. That's something we cannot do with actinium-225 and with lead, it's also a bit tricky.

So in this Phase I study, we're going to do a classical dose escalation study in which we're going to administer this intraarterially because in my belief, we should treat localized disease locally. And by giving it intraarterial, we'll get a very high drug concentration in the tumor and hopefully get better responses. So this is also supported by KWF, the Dutch Cancer Society. And together with Telix, we're going to initiate the study in 2027.

Looking a little bit further, I think another unmet clinical need in neuro-oncology is leptomeningeal disease. It's metastatic disease, so primarily breast cancer, lung cancer and melanoma. Once patients are diagnosed with leptomeningeal disease, their survival is approximately somewhere between the 3 and the 5 months. Of course, their blood-brain barrier is leaking. But what we know is if patients get systemic therapy and their metastases tend to respond initially, but then the BBB recovers. And once the BBB is recovered, their systemic therapy doesn't work anymore and their leptomeningeal disease takes over. So also for these patients, we have a big problem because depending on the location of the leptomeningeal disease, patients can get neurological problems.

So just as an example, I think that one is also very interesting here. This is one of my pediatric patients with a PXA. You can see there's a very small enhancing intracranial lesion. But next to it, you can see a little bit extension of FET signal outwards. And on another level, you can also see FET uptake outwards into the old resection cavity. And it also showed some foci in the spinal cord, which we did not acknowledge on MRI. And a couple of months later, of course, on MRI, we did start to see contrast enhancement on those locations, and it was confirmed to be leptomeningeal disease.

So I guess also for molecular imaging with FET-PET, that's an interesting thing to figure out for leptomeningeal disease, but also in the future for therapy. And with that, thanks for the attention. And I'll give it to, I guess, Kevin, right?

Thank you very much. As you can see now as we're rolling through the different indications, both from a therapy standpoint and then a diagnostic standpoint on Pixclara, I think you'll continue to see what I talked about in the last session is this platform growth strategy that we're building out. So it's really nice to see this in succession where we started with prostate.

And Chris showed a slide some of the excellent results we've been able to achieve over the last 4 years, building this base of business that is generating the revenue we need to continue to build the future part of the business, which is part of the diagnostic/therapeutic theranostic strategy that we have derisking revenue.

So we start really adding to this platform we're talking about over the next couple of years, where we have launched Illuccix, Gozellix, and then we expand into neuro-oncology next, and we have an imminent launch in urology with Zircaix. So you can start to see that expand the product part of the growth strategy work. We've talked about bypass for prostate. We talked about ZIRCON for metastatic disease in kidney. And now we're talking about our fourth product or third product in the portfolio, Pixclara, where we have just received a PDUFA and approval. So really excited. The first dose announcement is imminent as well as we kind of plan through that process of getting the manufacturing set up, and it is, and we're going to the first dose just this month. So really exciting news we'll have to announce soon.

But as he spoke of, we also have an MAA in Europe that we've applied for and submitted. So we will take Pixclara or Pixlumi under its brand outside of the U.S. as a part of the overall expand the geography strategy as well. Now this product has been called FET-PET for many years and used in Europe. So it's in -- it's already in guidelines around the world. So when you're launching a product, specifically in the U.S., you want good clinical data, you want it in the guidelines, you want the approval and you want reimbursement, right? So you kind of see all that lining up for us here in the U.S.

Now the second piece of that and part of the overall growth strategy is to -- and we have submitted an IND here in the U.S. for brain mets, and we'll talk through the opportunity there. But it was also granted orphan drug designation because of the high unmet need that we were just speaking of, really being able to understand immediately whether it's pseudoprogression and/or it is true progression and being able to change quickly the treatment that you want to offer the patient. This is the first drug approved, and it's really a first-in-class imaging agent approved for glioma.

So as you may know, we did an expanded access program of over 100 patients. So we have good experience with this. We've been educating the market on the disease state and the unmet need. And one of the most interesting things, I think, that of the data besides the good clinical data as we think about the commercial data for this is that out of over 100 patients, we didn't have patient cancel. Which I thought was a really interesting statistic because this is a pretty sick patient. And -- but over 100 patients, the caregiver or the patient was so inclined to get this because they wanted to know exactly what happened after the last treatment and quickly get another treatment if they needed that somehow the caregiver or the patient got themselves to get the scan and did not cancel at any time. So a really important statistic.

Now we've done a little bit of research just to kind of prep the market and over 70% of our physicians say they're ready to refer because this goes -- this is a refer down to the nuclear med physician who's going to read it. We have reader training set up to make sure that we get the best results. If there's one thing I've learned in this business over the past 4 years is that you want to make sure your first dose is as good as the 1,000th dose in a hospital. So we do that through our modular approach. I've talked about that in our commercial team. We have MSLs and clinical theranostic specialists that are technical specialists in the nuclear medicine lab. And it's really important to make sure that, that first dose is just like the 1,000th dose.

And so 80% of these physicians are going to rely on the NCCN guidelines here in the U.S., of which, of course, we're a part of. And the great thing is this isn't an outside of the hospital refer or order. It's going to be in-house in most of these places. As you know, this really isn't an outpatient scan in terms of IDTF or a self-standing facility. There's about 150 centers in the U.S. that are really active in this, 100 of them or so are really busy as we think about this as a more specialized. Now that doesn't really curtail the opportunity that we see. We still see this as a large opportunity for 2 reasons. Number 1 is we think it's a significant part of the market that we have both a theranostic point of view. So we want to be able to really expand that as well as the therapy side of the opportunity that's out there.

So that's what this looks like. So if you remember, we had a $20 billion opportunity or approaching that in prostate, approaching a $5 billion in urology, kidney or renal cell and then now a $3.5 billion opportunity. So now you can really start to see the growth strategy stack up, if you will, as we're thinking about products going to 3, 3 products going to 4 or 5, multiple indications and of course, over 22 countries that we already have a footprint in that we can take this. So we have filed the IND for brain mets, and we see that as about a $500 million opportunity that we plan to progress as well as we commercialize what we think is the right thing to do, even though it's a smaller opportunity for us because of this high unmet need and the desire to get to a better therapy, we're going to bring Pixclara to market and build that footprint or that platform for us to launch from.

And then as we think about the therapeutic side and the theranostic platform in that second line, we see about 8,000 patients and then about 25% to 50% more than that in the first line and wild-type. So really an exciting platform for patients as we bring this to market and really part of our mission as a company as we think about radiation oncology as our core platform. And so when you add those 3 together, we're approaching about a $30 billion opportunity over the next 3 to 5 years, of which that first platform, if you just added up the diagnostic opportunities, you would see that along with bypass, somewhere approaching $4 billion to $5 billion of opportunity realizable. And really, if you look at our past experience and history, we've grown 16 quarters in a row in an area where we were second to market. Now imagine, if you will, a world where we're first to market in Pixclara, and we're first to market in Zircaix or in clear cell renal cell carcinoma. So I think that ends my presentation as we change out of the first 3 products and move into TLX400.

Look, I can -- just listening to you, Kevin, one thing I can say unequivocally is it's very gratifying to be part of a clinical and a medical and an R&D and a regulatory team that does all of the work as a team to get Pixclara finally through the FDA and to be able to now hand it to what is clearly the best commercial team in the business. And I know that you and your team will get not just a drug, but a clinical workflow to patients and the clinicians who look after those patients, and that will be to the benefit of those patients and hopefully, their longevity through the improved imaging. So Kevin, it's always a pleasure to know that's going to land in the right hands.

So we are now on the home stretch, and you can tell that we're on the home stretch because we're getting into the earlier-stage assets. So Richard, you and I are going to close it out before we hand back to Chris. We're going to cover the early-stage assets. Now I'm going to start with the first of those, which is TLX400. So let's turn briefly to our pan-cancer asset, TLX400, which while being earlier stage, as Richard, you articulated right at the opening, this is a Phase I asset.

Our TLX400 FAP asset, FAP being fibroblast activation protein has been engineered to improve upon the existing multiple. There's many of these existing FAP candidates. None of them we believe are particularly encouraging. But the TLX400 one, we really like. And we like it because it's able to exhibit very prolonged tumor retention.

That's critically important to achieving a high dose, minimized off-target organ uptake and enhanced systemic clearance. So it goes where we want, it doesn't go where we don't want, and it clears out the excess very efficiently.

So we believe FAP is an important target for both molecularly imaging patients diagnostically, but also, I think, more importantly, for therapy due to the FAP targets prevalence on over -- it's about 90% of epithelial cancers that it's expressed on. And it's primarily expressed in the stroma or the scaffolding of a solid cancer, the fibrous tissue that holds the cancer together. But in some of those cancers, it's also expressed on the tumor cell membrane itself. But it's relatively absent, perhaps relatively absent in most normal adult tissues.

Now you can see here on the right that TLX400 FAP has to date achieved some very encouraging disease control and progression-free and overall survival rates in early studies across thyroid and breast and some soft tissue sarcoma cancers in patients where we're using it in these studies that have really exhausted all of their conventional therapy options. So really, this is a last gas shot in patients that are refractory to conventional therapy, and they're clearly deriving significant disease control benefit.

And I think besides the encouraging, these are early signals of potential efficacy, really the key takeaway is the favorable biodistribution of TLX400, which has been designed to overcome the limitations of the first generation or alternative FAP-targeted radiotherapies. So again, very low normal organ uptake, which enables higher administered radio activities and longer tumor residence times. So this is a candidate that we believe holds a lot of promise.

Now again, I love the case studies because they really articulate the potential of an asset. So this is a -- let's look at a couple of case studies now. This is a case study from our FAP program, which really illustrates why FAP as a pan-cancer target. And I think the question earlier was about CA9 as a pan-cancer target. FAP is also a pan-cancer target and why it's such a high interest one.

So this is a patient, a female patient in her mid-50s with advanced breast cancer, which you can see in -- on the left-hand side, in the baseline FDG, the conventional PET, but also the FAP-based imaging has a very disseminated involvement in her auxiliary or armpit, thoracic and abdominal lymph nodes. So very broad lymph node involvement as well as her liver and some skeletal involvement as well. So this is a very advanced disease. This patient who had received multiple prior lines of both systemic hormone and chemotherapy went on to receive a total of, I think it was 5 cycles of lutetium TLX400 and was able to achieve and enjoy a very significant and durable reduction in her disease burden as well as her very significant improvement in her clinical symptoms as well. So this is a very late-stage patient who has had a positive impact with quality of life but also disease burden reduction.

Now this is a recent study in 19 patients with a type of thyroid cancer known as medullary thyroid cancer. And I think this really demonstrates the potential versatility of FAP as a target for therapeutic radiopharmaceutical development across a broad range of cancers. So in this study, 19 patients with progressive medullary thyroid carcinoma were treated with either -- it was lutetium or actinium-225 labeled 400, TLX400, receiving in this series, a median of 5 cycles. And so of the 19 patients enrolled, 17 patients were evaluable and radiological response was assessed in 15 of these patients, resulting in a disease control rate, so stable -- and sorry, a partial and complete response of 80%, PFS of 26 months and overall survival of 42 months. So very prolonged disease control durations, extending survival. Now only 2 of these patients experienced Grade 3 adverse events. The other hematological and biochemical adverse events were all mild. They're all Grade 1 or Grade 2.

So I think the key takeaway here is that the early TLX400 FAP data encourages -- it demonstrates really encouraging disease control rates with acceptable safety, which has been a challenge to date and preliminary, and I emphasize because it's early, preliminary evidence of increased survival duration in patients with really advanced medullary thyroid carcinoma. So I promise we're on the home stretch. So Richard, I'd like to invite you up to close it out.

Thank you, David. Perhaps one comment on the 400 that you can imagine that FAP is targeting the microenvironment. So we probably will have to develop this compound in combination with other classical treatments. That's really where the potential of this drug is because there's a few cancer where we have the expression of the FAP directly on the tumor cells, but the vast majority of the cancer are with the microenvironment that we need to destabilize in order to authorize the classical treatment to treat the tumor cells. So I'm very passionate about this one.

Let's move to the last 2 compounds that we have in our portfolio at early stage, the TLX66 and TLX300. So our 66 compound, it's an antibody that we are developing and we want to use to develop in the bone marrow conditioning for authorizing the hematologists to do the transplantation that they are doing on a regular basis. So this compound is extremely interesting because we can also extrapolate potentially use in all the disease which needs a bone marrow transplantation. And we recently obtained some very interesting long-term data that I will present in a minute. So you will see that we had some initial IITs in Europe, and these IITs have been followed with some striking data that I can share with you here.

So we have 90 patients across multiple malignancies, mainly hematological malignancies, as you can see there. And what is really interesting is the safety profile of these patients after treatment because you can look on the right part of the slide that the patients with AML or multiple myeloma represents a probability of survival, which is quite striking because we have here a long-term follow-up of more than 200 months. So that's really amazing because usually the issue with that is when you have a bone marrow conditioning preparation, the patients have no immunity anymore and then you treat the patients with the classical treatment, but the safety is really a concern for these patients. So we expect a lot from this compound. It's still early stage. So we have to continue the development, the manufacturing of the antibody. But that's something that we expect to develop, especially for the hematology malignancies.

We also have the second compound, the TLX300, which is this one targeting the PDGFR alpha receptor. This antibody is well known because it's a license that we have and the partnership with Eli Lilly. So that's something we are currently also developing currently with -- sorry, zirconium radioisotope that we are attaching to this antibody in order to define the dosimetry and pharmacodynamic and pharmacokinetic profile of the compound. Currently, we are running this clinical trial named ZOLAR as you can see here.

So we evaluate the safety and the specific characteristics of this antibody in order to see where we can use usually, we are used to say that these receptors, the PDGFR alpha are very well known to be expressed in the soft tissue sarcoma.

So that's something which we are interested because if you make the correlation with the FET, you understand that we can here create a kind of portfolio around the soft tissue sarcoma disease, which are extremely heterogeneous that with 2 compounds targeting 2 different targets that, that could be some game changer for the future. So that's also something that we are developing in parallel of the rest of the portfolio on the early-stage steps, I would say. I think we touched at the end of the presentation.

Yes. This is our very last opportunity to ask questions, and I promise there's lunch after this. So if you have any questions, please raise your hand. And if I can please have the speakers up there.

Just a couple of questions on the TLX101 therapeutics for brain cancer. Just maybe a question for Dr. Braat. So if you look at the sort of the competitive landscape for treatment for brain cancer, what are you looking for in terms of overall survival bar for the IPAX BrIGHT study as clinically meaningful to you in your opinion? And then if the study becomes successful, ultimately, where do you see it fits into the current treatment landscape for brain cancer?

So we know from data from lomustine that their progression-free survival benefit is 1.5 months, which is very poor for any treatment we have within the oncology field. So my hope is that we at least reach 3 months, which is already for this very aggressive tumor, a big win because this means patients get time to settle their administration before they pass away. So having a progression-free survival benefit of 3 months is already a major impact in this field.

And what about overall survival? That's the primary endpoint?

Yes. So overall survival will probably be also around a year. With lomustine, we know it's somewhere around 7 months. So getting a year is, again, a big, big benefit.

And where do you see it fit into the current landscape for treatment?

So I think if we establish efficacy in IPAX BrIGHT, it will definitely get a place in first recurrence. I already noticed my neuro-oncologist referring patients to me before even discussing lomustine nowadays. They don't like lomustine. So if we confirm efficacy in IPAX BrIGHT, this will definitely have a place in first recurrence.

Yes, depending on IPAX-2, the question will be whether or not it also goes towards first line. I think if it's safe there, then we need an additional study to look at additional survival benefit. But if we can show efficacy there as well, then that will have major impact in the field.

Compared to other drugs that are currently being discovered, yes, there are not a lot of very promising targets at the moment. I've known there's been a big fuss about peptide vaccines from Germany.

I saw a couple of those patients myself as well. I'm not that interested in the vaccines. I think the field is going the opposite direction because they're more looking towards having high-intensity focused ultrasound, a method to open the blood-brain barrier to get other drugs in. So I think the neuro-oncology field is nowadays going more towards having sonication devices to get drug penetration. And all those technical developments, the HIFU is also still in Phase I. So that will take a long time.

Maybe just one last question for Kevin here for Pixclara commercial launch. So thanks for outlining all these -- the successful launch. Curious in terms of where do you see as the biggest barrier for adoption? Do you think this is physician awareness, reimbursement issues, PET capacity or any other issues around changing MRI-based workflow?

I don't really see any of those as a barrier. I would just say that as any time you incorporate a new test or a new scan into workflows, it just takes time to make sure they understand the ordering process to timing of the scan, which is appropriate for the patient and the timing of that patient in their really treatment workflow or algorithm. So I don't really see any of those as a barrier. Again, when I talked about what it takes for good adoption, good clinical data, we have it, reimbursement, we plan on processing through that. So upfront, we'll see a little bit of a scale up around waiting for using a NOC code upfront, which, as you know, we saw with PSMA, when there is no alternative, they'll use a NOC code, which helps them with reimbursement. And then if we're successful with PET, then you'll see that kind of pick up again once we do that because it's just easier in their workflow.

And then just understanding how it fits in and when it fits into what they're doing. And we're using that as a part of that. Now part of that education process is what the medical team that works with us, the MSLs and the CTS we talk about with their reader training. So all that is part of that education process to be able to help them integrate that into their workflow. And the data is pretty well known from FET-PET overseas, as you know. So it's in the guidelines. So a lot of those things that would consider to be barriers are already knocked down. So it really is just the adoption process and then availability as we scale up nationally over the next 2 to 3 months.

Any other questions? This is your very last chance.

I guess we're -- we got some data really kind of comparing iodine-131 and astatine-211 in the thyroid cancer space. So that's pretty comparable. I'm just wondering, one, can you extrapolate that to your neuro-oncology strategy there as you go from beta to alpha?

Me first. So yes, of course, we have the Alpha-T1 study from the Japanese colleagues nowadays that's been published on thyroid cancer. The only difficulty about that study is that patients already had a lot of iodine therapies in metastatic setting before they went on for astatine. So they were considered iodine refractory before getting astatine, which, in my opinion, doesn't really make sense because you're using the same transporter.

But even though they were considered iodine refractory, they had very nice results. And what I understood from the PI from that study is even in patients with bulky disease, they saw quite nice tumor reduction.

So as I showed in my slide, the case with the oligodendroglioma, which are often very big tumors, I feel switching from iodine to astatine, even for bulky tumors makes sense in this particular patient population. And yes, the other benefit is just getting it as a complete outpatient clinic therapy will be a major benefit because now they're in isolation for a week. So I think also from a societal and emotional perspective for the patient, it will be better.

All right. Any other questions? Okay. We have one more.

Maybe just a question on the payload selection. Iodine-131, you were just talking about the high-energy gammas there when there's lutetium available as a beta emitter with a lot of history in astatine, maybe a less robust supply chain when you have lead-212 and actinium. So maybe can you just comment on the selection of the isotope payloads here?

Yes. If I'm not mistaken, I think that we also selected iodine and astatine because there's also a question of penetration of the BBB. So we tested and we had some issues with lutetium. So mainly, I would say that it's because we can cross the blood-brain barrier when we attach mainly iodine. And you're right, astatine is currently not yet fully available for clinical practices, but there's massive investments that we saw from different companies in order to develop that. We have experience in Europe and also recently in U.S. from big companies. So that's where the demand will drive the manufacturing capabilities, if I would say like that.

Also -- and radiometal does not cross the blood-brain barrier just by innate charge. The other thing is that don't discount -- don't discount iodine-131. It's a fantastic radionuclide. It has the potential to have a really robust supply chain. It's very cost effective. And unlike the historical experience with the thyroid, we ultimately don't believe this has to be a long hospitalization period. It's a relatively small amount of the injected dose gets into the tumor and the rest clears out very fast.

There's no peripheral irradiation in the patient. And so when we get the dosimetry protocol right, you're going to be able to release patients from hospital pretty quickly. So that's just an evolution that people need to get comfortable with compared to the historical use of iodine-131.

All right. If there are no other questions, I'll ask Chris to make a few final remarks before we close the day.

So I realize that was a marathon session. And -- but hopefully, it was interesting and useful. It's good to see that everyone in the room has outstanding bladder control. So congratulations. It's also very gratifying for me to watch my team in action. So thank you. We've got a really talented group of people at Telix and very grateful again for all the KOLs that contributed to the session.

Hopefully, you can see -- some of you were at the R&D Day last year. You can see the huge progress that we've made as a company, a lot of new data, a lot of new clinical activity moving ahead, and that really reflects the whole cross-functional progress the company. So very, very pleased with the progress that's been made.

We do have a well-funded R&D program. We continue to feel that investment in R&D is important. And as you can start to see these products dropping out that have huge clinical utility, I think that R&D investment becomes increasingly justified. Just as a kind of a final wrap-up. So we really have evolved enormously as a company in the last few years in terms of our commercial trajectory, a multiproduct, multi-jurisdictional commercial business, the fact that we have now this very late-stage therapeutics pipeline, which we believe is having real clinical impact and has a sort of a tangibly proximal commercial potential as well.

And then as we start to think about the next phase of Telix's life, which is that pivot more from a precision medicine funded business to that manufacturing supply chain integration with the ITM acquisition, of course, subject to closing that and that combined therapeutic pipeline, I really feel that we're building a radiopharma company that has no peer in this space.

And so we look forward to keeping you informed of our progress in the coming months. A lot of catalysts between now and the end of the year or between now and the end of Q1 of next year. So watch this space, and thank you for your support and interest in the company. And lunch is going to be shortly available next door. So please do join us. It's an informal Q&A opportunity as well. Thanks a lot.

Good morning and good evening, everybody, and thank you so much for joining us today to discuss the announcement we made a short time ago regarding the merger of Telix and ITM. If we could just move to the next slide, please. Before we get into the official proceedings, I just have a few short disclaimers to read to you. This presentation contains forward-looking statements regarding our proposed transaction with the shareholders of ITM and expectations for ITM-11. These statements are subject to substantial risks, including, but not limited to, the outcome of the FDA's review following NDA resubmission, clinical trial results, regulatory approvals required in multiple jurisdictions and our ability to realize projected synergies.

Actual results may differ materially. You are cautioned not to rely on these forward-looking statements, which are made only as of today's date. Please refer to the risk factors across our ASX and SEC filings and the legal section noted in this announcement and the ASX and the full disclaimer of your materials. With that, let us move into the official proceedings. So I'm very pleased to be welcome today by Dr. Christian Behrenbruch, the Managing Director and CEO of Telix Pharmaceuticals, along with Dr. Andrew Cavey, CEO of ITM; and Darren Smith, Group Chief Financial Officer of Telix. We will run through some formal remarks and then move to questions as time allows. So with that, I'd like to hand over to Chris.

Good morning, everyone, and thanks for joining us today. Thanks, Kyahn, for the introductory comments. Today's news is a transformative step for Telix and for ITM. This transaction brings together 2 best-in-class companies that have really shaped the radiopharmaceutical industry over the past 2 decades, each with deep expertise, differentiated capabilities and a shared commitment to innovation for the benefit of patients. Telix and ITM have a long history of partnership and collaboration spanning almost a decade. Through that relationship, we developed a deep appreciation for ITM's capabilities, its technology platform and its excellent people. And so we entered this agreement with confidence of the strategic and cultural alignment between our firms.

As many of you know, this industry is undergoing a rapid evolution and a period of consolidation. It's always been our view that long-term leadership in radiopharmaceuticals will require control across the whole value chain from radioisotope supply and product development through manufacturing and logistics to ensure that we can meet the needs of patients worldwide. This is why this combination is strategically important. This merger brings together complementary strengths across supply chain, manufacturing, development, commercial reach and adds therapeutic pipeline depth, and we'll go into that in a little bit more detail in a minute.

Just as importantly, it combines 2 highly experienced teams with specialist capabilities that are very difficult to replicate. So in summary, and with reference to this graphic, ITM brings a commercially scaled and validated isotope business, particularly lutetium-177, and important capabilities in next-generation radioisotopes that are important to the pipeline, particularly with actinium and terbium. It also immediately adds revenue and cash generation to the group. This is a very commercially successful business and will be additive to Telix's financial position.

Secondly, we'll have the industry's most advanced therapeutic pipelines, including 4 therapeutic assets in Phase 3 trials. The addition of ITM-11 accelerates Telix's entry into the commercial therapeutic space and into a well-validated therapy market in neuroendocrine tumors, and we're really excited about that. Finally, this also builds on Telix's market-leading precision medicine platform and specialist commercial organization, which we believe are strategic assets in their own right.

As you'll see in a minute, ITM expands our global footprint and creates additional opportunities for life cycle management across our portfolio. And as we've demonstrated with our multiproduct PSMA imaging portfolio, this has been quite a successful hallmark of our sustained commercial growth. So in short, I believe that this transaction is accretive to shareholders with the strategic and financial benefits creating a pathway for significant value creation. Moving on to the next slide, please.

So overlaying the strategic rationale with the transaction terms, we believe this is a compelling and financially disciplined opportunity for Telix shareholders. At a high level, ITM adds a profitable and growing isotope manufacturing business, strengthening the group EBITDA and giving Telix greater control over a critical part of the therapeutic supply chain.

ITM-11 brings potentially an accelerated entry point into commercial therapeutics with a differentiated and novel late-stage candidate in neuroendocrine tumors that we believe is highly differentiated and well positioned to compete. ITM is expected to deliver a positive EBITDA contribution in 2027, supported by revenue growth and cost synergies between the businesses. So in terms of the structure, Telix will acquire 100% of the shares of ITM for $1.65 billion upfront on a debt-free, cash-free basis.

So that means a total of $1.25 billion upfront, that's less approximately the $400 million in debt and transaction costs will be the amount paid to the sellers. $302 million of net debt will be assumed by Telix at closing. A meaningful portion of the total consideration is also performance linked with $700 million of deferred milestones tied to ITM-11 regulatory approvals and a 2030 net sales target. The upfront consideration will be settled in Telix shares and released as ADRs after the escrow periods. The use of ADRs is expected to support greater liquidity and visibility on Nasdaq over time.

The deferred consideration will be paid in either cash or shares at our election and closing remains subject to shareholder approval and is expected to conclude before the end of 2026. I'm pleased to say that Andrew and the ITM leadership team will play an important role in the combined business, subject to Telix shareholder approval. Dr. Andrew Cavey and Dr. Barbara Weber, who are both members of the ITM Supervisory Board, will be appointed to the Telix Board, and I couldn't be happier about these additions to the Telix Board.

These additions reflect the strength of partnership and trust between the 2 parties. Both bring a great degree of scientific and commercial acumen with years of industry experience in our field, and I'm very much looking forward to working more closely with both of them. With that in context, I'm now going to hand over to Andrew to speak a little more about ITM's business, its manufacturing platform and the growth opportunity ahead. Over to you, Andrew.

Thank you, Chris, and I'm delighted to be with all of you here today to share more about this exciting announcement. Just to introduce myself, I'm Andrew Cavey. I'm the CEO of ITM. I joined just over 2 years ago, having spent much of my career in radiopharma, including some time at BMS, where I helped the company establish its entry into radiopharma and then at Novartis, where I co-led the company's RLT platform.

Let me turn to ITM. ITM was founded over 2 decades ago. And like Telix, it's been 1 of the foundational catalysts of the field. We have 2 pillars of value at ITM.

You can see these on both halves of the page, a leading radioisotope production and manufacturing business, that's on the left, and a radiopharmaceutical drug development capability on the right of the page, both under 1 roof. And having this dual competency is rare. Most of our peers specialize in 1 or the other and being able to bring this to Telix will offer us significant strength. But let me talk about the radioisotopes first on the left side. Our company has been built on the innovation and scale that we brought to non-carrier-added lutetium-177, which is now really the established therapeutic radioisotope in oncology, and it underpins more than 100 clinical trials today.

It's really the workhorse of the workhorse radioisotope of the industry. And we have a broad manufacturing business here with multiple customer relationships across pharma companies, including Telix, hospitals and scientific research institutes. Through doing this, we've really seen firsthand how demand for therapeutic radioisotopes has continued to grow, both for approved products and also clinical development programs. And we're not stopping there. We're also moving into actinium. But already today, we supply 1 of 2 approved products in this class, Pluvicto. And we think that commercial validation has come because of our consistent approach to quality and reliability as a partner.

To introduce the right side of the page, our second pillar of value, the radiopharmaceutical pipeline. Much like Telix, our central position in the industry for so long has allowed us to identify promising assets early. As we grew our isotope leadership and the deep relationships we had with customers who are researchers and research institutes gave us firsthand access to new innovation, and it allowed us to expand our own pipeline of radiopharma medicines. And today, that pipeline spans multiple cancer indications, late and early-stage assets, our lead late-stage assets, ITM-11, which I'll speak to more about in a moment. And we also have early-stage assets, including, for example, ITM-31 in glioblastoma.

And this pipeline also spans a range of radioisotopes across lutetium, actinium and terbium-161. Next page. Importantly, this is an existing growth platform. ITM delivered approximately 40% of revenue CAGR between 2021 and 2025. And if you look at where this goes next, to understand the outlook, it helps to look at the current status of clinical trials as these are lead indicators of future potentially approved products. And we really see the field here reaching an inflection point. In that middle bar chart on the page, you can see lutetium. Lutetium already supports 2 commercial therapies, and there are a further 41 assets in development behind these, speaking very much to the depth of the field and its future potential.

And if you look on the right-hand bar chart, that's on actinium. The next wave of radioisotope growth is also taking shape. Actinium is now the second most used radioisotope in clinical trials. There are 34 assets in development. And we see this as strong evidence that the industry is moving well beyond a single isotope. So overall, for us, the commercial opportunity is substantial. We see radioisotope markets forecasted to grow by roughly 30% annually through 2035 with risk-adjusted markets of over $2.1 billion for lutetium and around $1.4 billion for actinium-225 in that time period. Back over to you, Chris.

Thanks, Andrew. So just on the next slide here. I mean, just to wrap up sort of all of the pieces together, most of you will be familiar with Telix's growth strategy. We've talked about a lot over the last couple of years, which is really to build a global radiopharmaceutical platform with the capabilities that are necessary to develop, manufacture and commercialize products at scale. Combination with ITM fits that strategy very deliberately. It strengthens the areas where we believe that will matter most over time, which is securing radioisotope supply, differentiated manufacturing capacity and additive depth to the therapeutic pipeline.

ITM also adds proven commercial scale isotope production and expands our near-term therapeutic opportunity through ITM-11 and the broader pipeline and really brings a team with deep operating experience in a highly specialized part of the industry. So taken together, this reinforces the competitive moat around our combined platform and gives us a greater strategic control over all aspects of that radiopharmaceutical verticality as the field continues to grow. So I think now I'd like to ask Andrew to go back in and give us a little bit of a deeper dive into the ITM manufacturing platform and why that capability is so important.

Thanks, Chris. Yes, I know many of you will already be familiar with the field of radiopharma, but if you'll indulge me, I'll maybe just say a word about what radioisotopes are. These are the individual atoms that form the cancer-killing payload of the radiopharmaceutical medicine. And what makes them tricky is that they decay rather quickly. So in the case of lutetium-177, for example, within 10 days, you have to irradiate the raw material, manufacture this under GMP, deliver it across the world and inject it into a patient in that very short period of time. That's the proverbial delivering the melting ice cube around the world.

But at ITM, we have been doing this for a long time now. And we've built unique capabilities at each step of the value chain. And so let me take you through that. This little wheel here, if you start at 12:00 at the top of the page, that's the value chain for non-carrier-added lutetium-177. So what does it take to make it? Well, first, at the top right, you need to start with a raw material. In this case, enriched ytterbium-176, and we have substantial stockpiles of enriched ytterbium-176 underpinned by exclusive supply agreements. Next on the wheel at sort of 3:00, you need to take that ytterbium and you need a source of neutrons to irradiate it.

And we have, like other companies, an extensive research reactor network. But uniquely, we also have an exclusivity with the largest power plant in the world, giving us a much more reliable and regular access to neutrons. Then as you move to the bottom of this wheel, next in the chain, you need to purify the hot material you've got. We have the 2 largest GMP manufacturing plants in the world, both outside of Munich in Germany. And then from there on the left side of the wheel, you need to sell and distribute this around the world. And we do this daily to 400-plus customer sites around the world. Next page, please.

This page just shows an overview of the radioisotopes we play in today. Now I've talked a lot already about lutetium at the top of the page. As I said, it's the workhorse therapeutic radioisotope for the radiopharma industry. But maybe I'll just make 1 additional point on lutetium before I move on. ITM supplies lutetium for Pluvicto. Pluvicto is 1 of only 2 approved products in the class, an important medicine. And we see this as direct validation of our manufacturing position from the market itself.

I also mentioned that Telix is already a customer, and we really view the merger as a strong -- it gives us a strong ability to help ensure supply security for the supply of our merged pipeline as well. Just maybe touching on the other 2 isotopes. You see actinium here in the middle of the page and terbium below that on the ITM side. We are very much focusing on actinium-225, kind of the next wave of growth from our radioisotopes. To do this, we have formed a joint venture called Actineer with the Canadian Nuclear Laboratories, where we bring the best strengths, we think, of both organizations.

The path we've taken to produce actinium-225 involves starting with radium-226 as a raw material. It's a very difficult radioisotope to use with a 1,600-year half-life. And that's why we combined with CNL because they bring deep expertise and significant stocks of this precursor material, and they also have long-standing experience of managing the waste. And in turn, in this joint venture, we bring our expertise in GMP manufacturing and supply and distribution. We're also now exploring terbium-161. You can see that third bucket on this page. This is a promising isotope.

It's a beta emitter just like lutetium, but it also emits what are called Auger and conversion electrons, which in many ways, behave with short pathway length and high energy, akin to how alpha emitters behave. And these have shown strong data in preclinical data and early clinical data, which give us excitement to invest. But additionally, the supply chain for terbium-161 is highly synergistic with the supply chain of lutetium-177. It's essentially the same, although you start from a different raw material. And we view this strength of radioisotopes that we bring across these 3 isotopes as also very synergistic with what Telix has also been building over recent years. Maybe, Chris, do you want to talk about that?

I think this slide shows the complementarity. I'd say, in a nutshell, ITM is the master of reactor-based -- for the most part, reactor-based radionuclide production. We have a very strong cyclotron-based capability through the ITM acquisition. And as you can see, we've got a very complementary set of capabilities. But I think for Telix, this materially derisks, as Andrew said, the lutetium supply chain for our own therapeutic pipeline and strengthens our ability to plan, develop and ultimately commercialize these products, which are in late-stage development. And then we look forward to bringing the ITM team in with real experience in scaling radioisotope production for therapeutic use.

And I'd like to reiterate what Andrew has just said, that operating experience is difficult to build. It's highly competitively differentiated. And it gives the combined company a stronger foundation to move products all the way from early development to commercial supply. So I'd say together, the combined entity will have the broadest and most capable portfolio of both diagnostic and therapeutic radioisotopes and can cover both the workhorses that are being used today and the things that are in the combined pipeline as well as the next generation of isotopes that may ultimately shape the future of the field.

So I think this is a very exciting picture. And maybe just to continue this, if we can move on to the next slide. I think Andrew very eloquently noted their enormous customer reach and the fact that they deliver mission-critical isotopes to hundreds of customers around the world every day. In fact, I consider ITM's logistics team to be really unparalleled in the industry. And so what you can see from this map is that together, Telix and ITM bring a highly complementary global footprint, lots of opportunities to align our commercial teams. And that just covers everything from isotope production, radiopharmacy distribution and delivery and of course, spanning both diagnostic and therapeutic products.

Now in the U.S., our last mile delivery network already covers approximately 85% of the market. Internationally, the combined network spans more than 65 countries and including in key growth markets across Europe and Asia, including China and Japan, which are important focus areas for Telix at this point in time as well. And we think this reach really matters. In radiopharmaceutical supply opens markets where reliable isotope supply exists, then the commercial market follows because customers, that's hospitals and physicians, will have the confidence that product can be manufactured and delivered consistently.

And that's -- I think that's the precursor for commercial success. So for us, we see this as not just infrastructure and supply chain for the products we have today, but it's also infrastructure that can support new market entry, broader adoption and long-term category growth for the combined business. And I just want to note, we remain very committed to working with our partners, customers, hospitals and physicians. We have -- both companies have a lot of third-party relationships that are extremely important. And we've really built both companies on partnership and collaboration.

And so the combined organization will be there to support third-party development to continue to supply isotopes to all corners of the industry, but it is also about shoring up the pipelines that we have together. And I'm sure that we will continue to be an organization that helps to foster innovation across the industry for the benefit of patients in a collaborative way. Okay. Well, I'd like to just change gears a little bit and shift into the therapeutic opportunity of the ITM transaction. So just stepping back from ITM-11 specifically on the next slide, please. This slide shows selected elements of the broader portfolio optionality that comes with ITM, and we can see why this is more than a single product transaction.

Now clearly, ITM is the lead value driver given that it's a very late-stage program. It's completed Phase 3 development in its initial indication and already has potential expansion opportunities in areas such as more aggressive neuroendocrine tumors, lung NETs and pediatric indications. And so this gives us a lot of growth trajectory around this lead asset. And Andrew is going to talk a little bit more about the lead asset in a minute. ITM also brings some early-stage programs that are highly complementary to Telix's existing portfolio and areas of focus, particularly in neuro and uro-oncology, which, as you know, are key focus areas for Telix from a disease area perspective.

So when we go about optimizing the pipeline, we'll be thinking about how we prioritize the programs with the strongest strategic and commercial fit. That's those that provide life cycle management opportunities and also how we use the combined capabilities of Telix and ITM to build durable positions in these disease areas that we think are the winning areas to focus on. This is important strategically, but it's also important financially. It allows us to remain disciplined about R&D investment and capital allocation while pursuing the most compelling growth opportunities. And so maybe at this point, I'll hand back over to Andrew to go into a little bit more detail about ITM-11, which I think is a really exciting asset and a big part of this transaction. Andrew, over to you.

Yes. ITM-11. So ITM-11 is indicated in GEP-NETs, gastroenteropancreatic neuroendocrine tumors. And these are tumors where there remains a substantial unmet medical need. GEP-NETs are frequently diagnosed late, and the true population is in all likelihood underestimated. We are also seeing incidence of this disease increasing over recent years. And the market is attractive and what is already a commercially validated category and a market we estimate to be around $1.7 billion in the U.S. alone. So what is ITM-11? ITM-11 is a differentiated next-generation therapy combining an SSTR targeting molecule with our high-purity non-carrier-added lutetium-177.

We have already started to build a compelling clinical data package here. I'll start talking about COMPETE, which is our first Phase 3 study. COMPETE produced positive Phase 3 results last year -- early last year, demonstrating progression-free survival, and I'll show you those charts in a moment, but importantly, also in a harder-to-treat pancreatic neuroendocrine population. And we designed the study at the time when we designed it, we knew we needed a competitive edge. And so the study design was rather unique. It was a monotherapy of ITM-11 versus an active targeted therapy comparator in everolimus with a favorable dosing schedule every 12 weeks.

And also, it is a medicine that benefits from a longer shelf life. I'll come back to that in a moment, but that's very important in a field where you only have a limited time to get your medicine to your customer and to your patient. There's also meaningful room for expansion. We have other Phase 3 studies that are ongoing, and I'll also come to those in a moment. Next page, please. This was the first head-to-head study against an active comparator with ITM-11 as a monotherapy. Here on the chart, you can see the Kaplan-Meier curve showing the primary endpoint of progression-free survival. The dark blue line is ITM-11 with the red line, the comparator of everolimus.

And the primary endpoint was met convincingly. There was an impressive median progression-free survival reached at about 24 months with ITM-11 compared to about 14 months after everolimus, so a 10-month delta of PFS, and that represented about 33% reduction of risk of progression or death. And this is very much a meaningful -- a clinically meaningful outcome for patients and physicians alike. But importantly, this efficacy was also accompanied by a favorable safety profile. Grade 3 or 4 treatment-related adverse events occurred in 18% of patients receiving ITM-11 compared with 40% for everolimus.

I also touched on a moment ago, the longer shelf life. And this gives significant advantages when it comes to customers and nuclear pharmacies. In fact, this is an area where we view the merger with Telix. We think this will contribute, thanks to Telix's deep operational understanding of how radiopharmacies dispense products in the U.S. And so we see the totality of this data as positioning us to have the best-in-class product in the neuroendocrine tumor space. Next page, please. Data that you just saw was published in the Lancet a few months ago, and that provided us with important external validation.

We had also submitted the study to the FDA about a year ago. And on August 7, we received a complete response letter for ITM-11 from the FDA. I want to be clear about what that letter does and doesn't reflect. Importantly, the FDA did not identify any concerns regarding the clinical or nonclinical data package nor on the safety profile of ITM-11. The entirety of the CRL was contained around CMC and inspection items related to a third-party facility in the U.S., which received a Form 483. We are already working with that third party to address the items that were cited with a clear goal to resolve them as quickly as possible.

And we've also already announced our intention to resubmit. We will request an FDA Type A meeting before the end of the year to make sure that we fully address the FDA's feedback and we align on the remediation pathway. So overall, we think we have a full understanding of the CRL and our remediation is on track, and we're in process of working with the agency to align on our path forward.

Yes. And Andrew, if I could just chime in from Telix's perspective. I mean, we've obviously had direct experience in managing CRLs. So we understand the process and the practical steps required to work through it. Importantly, as Andrew said, the issues identified are CMC and inspection related. They are not clinical or safety issues. So we have full faith in the clinical data, and the FDA has not requested additional clinical data. I think it's also just worth noting that we know this third-party facility very well and the broader regulatory context. Radiopharmaceutical products are technically complex.

And in many ways, the regulatory framework is still evolving alongside the science, particularly when it comes to manufacturing and handling and delivery. So through our own experience, including Pixclara, we've demonstrated that a CRL is not the end of the road where the underlying product profile is very strong, and this is certainly the case here. From a transaction perspective, we have also reflected this appropriately in the deal structure. So a meaningful portion of the consideration, up to $700 million, is deferred and linked to regulatory approval milestones with specified achievement dates and net sales targets.

So I think that the parties have really apportioned risk appropriately in this transaction. And of course, I will note that it is a closing condition of the transaction that the ITM-11 NDA has resubmitted. So this is not expected to be a protracted and drawn-out process. So I think -- yes, I think that's sort of all I've really got to add on this topic. Maybe, Andrew, do you want to go on and talk about some of the upside of this program?

Yes. Let me talk a bit about our ongoing clinical development plan. Next page, please. Because we have several expansion programs for ITM-11, which represent significant opportunities. And importantly here, the investments for these opportunities are already behind us. So the first on the left of the page is the COMPOSE Phase 3 study. This addresses a more aggressive form of the disease evaluating ITM-11 in Grade 2 and Grade 3 SSTR-positive GEP-NETs where effective treatment options are frankly rather limited. The recruitment for this study is complete. We've enrolled our target population of, I think, 250 patients, and we're evaluating this in first and second line, again, importantly, against an active comparator with PFS as our primary endpoint.

On the right of the page, you see a third Phase 3 trial called the LEVEL study, evaluating ITM-11 in lung and thymic neuroendocrine tumors. And to give you a sense, lung NETs represent about 20% to 30% of all neuroendocrine tumors, but with really limited treatment options today. And for this study, the LEVEL study, we've recruited already approximately 90% of our target 170 patients, meaning the study is approaching full enrollment right now. With that, I'll hand back over to Chris and Darren for the next section.

Yes. Thanks, Andrew. It's really an exciting indication expansion and looking forward to seeing that extra data come out. Look, at this point in time, I think I'll hand over to Darren to go through the numbers in a little bit more detail. Darren, do you want to pick up?

Yes. Thanks, Chris, and hello, everyone. I want to spend a bit of time on the financials. As Andrew has outlined, ITM's radioisotope manufacturing business has delivered impressive revenue growth, primarily through the supply of lutetium. Importantly, this is a business operating in a high-growth market underpinned by long-term contracts with multiple customers. As discussed today, ITM is well placed to maintain its leading position as demand for therapeutic radioisotopes continues to grow, driven by commercial adoption and increasing clinical trial activity. For Telix, this adds a resilient and growing revenue stream and diversification.

On a pro forma basis, taking into account our current guidance, reported income and ITM's current run rate for the first half of 2026, the combined business would be on track to deliver revenue and income in excess of $1.3 billion this year. On the right-hand side of this slide, you can see that the combined business today would have 3 primary sources of revenue. Firstly, from our precision medicine product sales, including Illuccix, Gozellix and shortly Pixclara. Secondly, external revenue from Telix Manufacturing Solutions, predominantly third-party sales through RLS, our radiopharmacy network; and thirdly, revenue from ITM's isotope manufacturing business.

Together, TMS and ITM would represent just under 40% of the revenue on a pro forma basis for the first half of 2026. ITM is expected to contribute positively to the group's EBITDA from 2027 onwards, which I'll cover in the next slides. Next slide, please. Build on that, I wanted to spend a moment on the financial profile of ITM and why we believe it is an attractive fit for Telix. Firstly, ITM adds to our revenue. In the first half of 2026, ITM generated revenues of $156 million and an attractive gross margin of approximately 40%.

It is a very different margin profile to the external revenues currently generated by Telix Manufacturing Solutions, and it adds a high-quality revenue stream to the group. We see 2 key growth drivers. Firstly, the continued expansion of the isotope manufacturing business, which today is anchored in lutetium. However, there is the additional near-term growth potential for actinium, an isotope that is increasingly relevant across the industry in clinical development. And secondly, the potential approval of ITM-11, which would create an additional source of high-margin therapeutic revenue. This is directly aligned with Telix's stated growth strategy.

Moving to the second column. Note that ITM enhances our EBITDA, and we expect this transaction to be EBITDA positive from 2027. ITM's manufacturing division is expected to generate EBITDA of $106 million in 2026 on an annualized basis. We see 3 factors supporting a pathway to positive EBITDA contribution from ITM. The first one, continued revenue growth from the manufacturing business; secondly, cost synergies and operating efficiencies, including disciplined management of the group's operating expenses. ITM has initiated a cost-saving program following the receipt of the CRL, which is expected to bring the operating costs down to the FY '25 levels.

We see further synergies as a combined organization, which I will come to on the next slide. Historically, we have maintained operating expenses as a consistent percentage of revenue, and we do not see this changing with the addition of ITM. And thirdly, pipeline optimization across the combined R&D portfolio in keeping with our disciplined approach to capital allocation. The combined Telix and ITM pipeline is extensive, and that is an asset. In terms of prioritization, our immediate focus will be on the ITM-11 program. Clinical development is largely finished with 2 Phase 3 studies completed and the third indication expansion trial nearing its target enrollment.

We will selectively advance ITM's early-stage programs with a focus on those that complement our existing clinical areas of neuro and uro-oncology and where we see attractive life cycle management opportunities. This is very consistent with Telix's disciplined approach to building sustainable commercial franchises in our focused markets. Looking at the third column, we note that the combined group will have a strong cash balance with sufficient flexibility and balance sheet capacity to manage the capital needs of the enlarged business. This transaction does not change our approach to financial management. We will continue to invest in the pipeline, and we will do so in the same discipline around capital allocation and cost control, prioritizing the assets we believe can deliver the most attractive near- and medium-term returns.

ITM's existing debt of $302 million will be rolled over and deducted from the upfront consideration. So it is built into the valuation and deal structure. Turning to the next slide, please. In addition to the cost savings noted previously, we also believe we can generate cost synergies of $50 million over the first 2 years from efficiencies within the combined organization. This is in addition to the cost savings program already underway at ITM to achieve a positive EBITDA in 2027.

From a synergies perspective, we see value across several areas. This includes operating efficiencies from bringing together complementary infrastructure, manufacturing expertise and corporate functions. Second, there is a portfolio efficiencies as we prioritize investments across the combined R&D pipeline and focus capital on assets with the clearest clinical, commercial and financial return profile. I do want to reinforce that the value of this transaction is not driven by cost savings alone. Radiopharmaceuticals is a high-growth and emerging industry.

Therefore, the transactions we undertake has to be judged by its ability to accelerate our strategy, deepen our capabilities and create attractive growth opportunities over time. We have spoken today about the growth potential of ITM's manufacturing business. It is clearly important financially, but it is also strategically valuable. ITM strengthens our access to lutetium, which will be used for ITM-11, our 2 prostate cancer therapy programs and our kidney cancer therapy program. All of these are late-stage assets, and it is vital that we build this capability now to support the therapeutic programs as they move towards commercialization.

The transaction also deepens our pool of specialist talent in manufacturing, radiochemistry and scientific and clinical development, which are also key to our long-term success. Taken together, these factors support the financial and strategic rationale for the transaction. We expect ITM to broaden Telix's revenue base and to contribute positively to EBITDA in 2027. Over time, the opportunity is to translate that additional returns on invested capital through a successful commercial launch of ITM-11 and is supported by disciplined integration, focused R&D prioritization and continued cost control. Back to you, Chris.

Thanks very much, Darren. So just to close out, and this is our last slide before we go to Q&A. I want to bring this all back to why we believe this proposed transaction is important for Telix shareholders. Today, we've outlined why Telix and ITM fit together strategically. Telix brings a global precision medicine platform, development and commercial capabilities and a late-stage therapeutic pipeline. ITM brings scaled isotope manufacturing, specialist supply chain expertise, deep radiochemistry capability and a complementary therapeutic portfolio.

Subject to completion, those capabilities will create a stronger, more integrated radiopharmaceutical platform with the potential to support products from development through to patient delivery, so the full end-to-end solution. As Darren has just outlined, we believe the proposed transaction is financially disciplined with a structure that reflects the key value drivers and appropriately links a meaningful portion of consideration up to $700 million to future performance and regulatory milestones within specified achievement time frames. Of course, completion remains subject to Telix shareholder approval and other customary closing conditions.

Subject to completion, our combined focus will be clear, supporting ITM's manufacturing momentum, progressing the regulatory submission and launch pathway for ITM-11, and I can tell you that our commercial team is primed and ready to take on this challenge. And of course, prioritizing the combined pipeline around the areas of strongest strategic and commercial fit and bringing the 2 organizations together carefully and deliberately and with cost optimization in mind.

In short, we believe that this has the potential to add significant value to shareholders, patients, our partners and employees, and we are really excited about this opportunity ahead. So now with that said, I'm happy to open up the floor to questions.

[Operator Instructions] Your first question comes from Andy Hsieh with William Blair.

I have a question in terms of the value proposition of ITM-11. Just given the dynamic of having an incumbent and also potential generic coming online, I'm just curious about that product in the NET space. And also from a manufacturing perspective, Andrew, I'm curious if you can comment on the actinium production route from Actineer. Just kind of lay it out for us why the p,2n pathway is, in your view, the best approach just given several methods out there. So that's all I have.

Andrew, shall we divide and conquer on this one. Maybe I'll just give a little bit of a view from -- on ITM-11 from Telix's side. And then maybe, Andrew, you can fill in the gaps if I've missed them and then take on the actinium question. Look, fundamentally, we obviously see the increased competition in the NET space. We fully understand the commercial strategy of the incumbent. But this is also a highly differentiated product.

It is not a me-too product. It has a differentiated clinical profile. We believe that, that's supported in the data. We also see a clinical and label profile for this asset that's highly differentiated that we think lends itself to some unique commercial strategies. And then perhaps, Andrew, you can elaborate a little more on some of the logistics and supply chain advantages that this asset has.

Thank you. Yes, I certainly agree that I look at this -- I look at the strength of ITM-11, both on the basis of its clinical differentiation and its nonclinical differentiation. And so Chris talked about the former. I think on the nonclinical side, the fact that we have a longer shelf life than the incumbents opens up a lot of possibilities for us because it gives us more time to leverage the radiopharmacy network and to prepare more customer-friendly and patient-friendly doses that we can deliver directly to the nuclear medicine department.

We've also built a sort of an end-to-end customer experience pathway that allows us or that will allow us, subject to FDA approval, to touch on all the friction points that we're seeing in the market commercially today. And by the way, it's nice to reconnect, Andy. Nice to hear your voice.

Do you want to maybe pick up on the actinium?

Yes, we spent a lot of time choosing this radium-proton route with our Actineer joint venture. So as -- well, I don't know if our audience know, there are many ways to manufacture actinium-225. You can start with different starting materials. There has been a legacy route using thorium-229 generators. That is available today from historic supplies, but it's expensive and there's limited global thorium-229, which restricts supply. So that legacy route is available today, but dying and it's not fit for commercial scale. You have then other routes, 2 routes, including the radium-proton route, the p,2n route that we've adopted with Actineer and a radium-gamma route.

We see significant advantages with the p,2n route for a few reasons. First, the availability of starting materials. With our partnership with CNL, we have strong supply of radium-226. The p,2n route is also, we believe, the most scalable route, thanks in part also to the size of the targets that are used. It gives high-quality product with negligible traces. I mean often with actinium-225 production, you look at a byproduct actinium-227, and we see very, very, very negligible traces of that using the p,2n route. And importantly, it's a proven technology.

So unlike the radium-gamma route, which is theoretically able to supply, but not proven at scale, we believe that the p,2n route will allow a significant scale-up within 1 to 2 years. And it's sort of the combination of all of those reasons that we think the p,2n route will be the winning route and one also that will allow a significant cost advantage compared to the [ alternatives ].

That was your science lesson for the evening, Andy. I hope that was sufficient.

Your next question comes from Chris Cooper with JPMorgan.

Can I just firstly just get an idea of the current customer concentration. So the $273 million of revenue last year, how much of that was from Novartis or Pluvicto? And the reverse question, I guess, do you have a sense of what percentage of Pluvicto supply of lutetium comes from ITM?

Yes. We don't really disclose that information at this point in time, and we'll not be doing customer breakdown. Obviously, Novartis is a significant customer with a long-term and very robust supply contract. But the growth in the lutetium business for ITM has been fueled by a combination of Novartis, other large and medium-sized pharma companies and also direct-to-hospital supply of lutetium globally.

Chris, maybe I can add a point here, which is that we're very -- Novartis today with 2 approved products is the dominant source of demand. So it is a good thing that we're supplying them with robust contracts, as Chris put it. But importantly, you need to look beyond that and what -- where will future demand come from? No doubt also from Novartis. But we also have contracts across the radiopharmaceutical industry with many -- most of the biotech and pharmaceutical players. And that allows us -- and we have these clinical supply contracts that also lead into commercial supply. So we see this as a very strong base for future revenue growth as the science advances and clinical trial footprint advances.

And there's no change of control provisions at all in any of the existing long-term supply contracts you have?

Well, there are any contracts for which there is some sort of commercial variation are considered in the transaction parameters. But I think it's a well-managed aspect of the business. And obviously, we would have looked at very carefully in the transaction structure.

And one just quickly, if you don't mind, on ITM-11. So I see in the slides and you commented on this, Chris, the closing condition of the deal is an agreed path forward between Telix and ITM on the resubmission. How much flexibility is there? Does this need to be resubmitted? Or could there be some other sort of version that allows you to get comfortable that the deal can close? I'm just trying to assess the risk of delays to the closure just given that we've seen some of these CMC CRLs can be a little bit tricky.

Look, I think the ITM process is -- the CRL remediation is really well in hand. I mean they moved fast on it, and I'm very happy with the alacrity with which the issue has been managed. As I mentioned during the presentation, we have a high degree of familiarity with the manufacturing partner that received the 483. So we're also comfortable in our diligence that this is a rapidly resolvable situation.

We obviously aren't going to delay closing unnecessarily. We want to complete the merger. We want to progress the businesses. We want to achieve those synergies. So providing that we can see a Type A meeting having a good clear pathway with no additional wrinkles added into the process, I think we'd be comfortable closing on that basis.

Your next question comes from David Bailey with Morgan Stanley.

Chris, just maybe just in terms of the economics of the therapeutics pipeline for Telix post this transaction, can you just maybe talk a little bit about how you're thinking about the candidates coming through on the Telix side and how the economics may change post this transaction? And my second question would be is, on Slide 7, some very strong growth coming through for lutetium and actinium as well for both those radioisotopes. But in terms of the ITM capacity at the moment, what's the ability to grow from here? Is there further CapEx required to meet some of that demand? Can you talk a little bit about the growth CapEx profile for ITM as you look forward to that growth?

Sure, sure. Well, I'll get Andrew to comment on the growth capacity. That's a pretty straightforward one. But in terms of -- I mean, you can see what we've been building over the last few years on the distribution side, we want to streamline distribution costs and essentially give ourselves and select partners a market advantage in terms of the cost structure of our products. And clearly, that applies as well to the lutetium supply chain. When you look at the cost structure of a radioligand therapy, lutetium is a very significant part of that cost structure. And so being able to internalize the supply chain, the margin impact is really beneficial.

So we see this as being financially accretive in the next few years as the demand for lutetium skyrockets. We see that the margin contribution is beneficial as we go into our own product commercialization activity, including ITM-11. And then as far as meeting the demand going forward, part of the sort of the driver for this transaction is ITM has a second very substantial scale-up facility that is just in the process of being commissioned. It's a very significant investment, and I can only describe this facility as state-of-the-art. And that is going to not only provide redundancy to the primary manufacturing facility, but also is a very significant scale-up capacity step change. And I don't know, Andrew, do you want to chime in and add anything about the NOVA facility?

Yes. Maybe I'll just sort of give an overall answer that we've made very significant CapEx investments over recent years that have allowed us now to have very significant capacity for our lutetium production. Most of the lutetium that we produce today comes out of the first plant. And the -- as we open now the second manufacturing plant, it's already open and it's doing a lot of activity around warehousing and QC and lab space and reagent preparation and so on.

But as it starts to activate lutetium production, we will have significant capacity to accommodate future growth in the industry for lutetium. On the actinium side, one of the advantages for us of the p,2n route and of the stepwise scale-up that we're doing is we've already put in CapEx, but future CapEx will be scalable together with rise in demand. So we don't need to put in massive CapEx before the demand comes. We can build these things together, which we also think helps give us a strong financial profile in future years.

That is all the time we have questions for. I'll now hand back for any closing remarks.

All right. Well, thank you very much, everybody. I realize we sprung this one on you, but needless to say, we're extremely excited about the transaction and really the future impact of this merger is extremely exciting, both for Telix and ITM and for the industry overall. And we look forward to engaging individually with shareholders and investors over the coming weeks. Andrew and I will be working shoulder to shoulder during this period of completion and of course, the post-merger process when we get there. And so looking forward to keeping you informed as this evolves. Thanks for your time.

Okay. Good morning, everyone. We might get started. My name is David Bailey. I'm part of the health care team at Morgan Stanley based in Australia, joined today by Chris Behrenbruch and Kevin Richardson, CEO and CEO of Precision Medicine, respectively. Thank you very much both for joining us today. Great to have you here.

Chris, I might just start with you. The Pixclara FDA approval over the weekend is the first approved candidate for imaging glioma. My question is, with a company that's navigating the regulatory pathway for a new class of therapies, what are your takeaways and learnings? And what have been some of the challenges, I suppose, that you sort of observed and how that inform your future pipeline?

Well, good morning. And first of all, thanks very much for having Kevin and I. I think GBM is a tough space. And there hasn't been a lot of innovation, a lot of progress made. It's difficult to run clinical trials in that space, and we took a pretty innovative approach to that particular NDA submission.

As with all of our pipeline for every target that we go after, we develop both an imaging agent and a therapeutic. That's the strength of radiopharma. It's a unique -- it's the only class of drugs where you get to see where your drug goes in the body, whether it's being used for informing treatment decisions or whether it's actually therapeutically treating a patient.

We developed the Pixclara platform, and it really is a platform. It's got a huge breadth of indication potential. Obviously, we've started off with a fairly narrow label for the first approval, although the guideline use for Pixclara is a lot wider than our label. And we have currently other clinical activity running to expand the label over time in the fullness of time, and maybe Kevin can talk more about that later on.

But we developed that program because it is the -- it images the target that we are treating therapeutically. It's in the Phase -- TLX101 program is in Phase III right now. We've got some really exciting clinical data around that program. And so the imaging and the therapy is really very complementary and one de-risks the other.

So I think the strategy that we have as a company, it's been well informed. This is our third drug approval. It's been well informed by the prostate program, which, again, we take a very similar approach. And the field has really evolved to expect that patient selection and treatment response assessment is done with imaging. And that is not expected to be any different in glioma. In fact, it's more critical.

Understood. Okay. So a broader question here is that Telix has been in the radiopharma space for more than a decade, and you successfully navigated an increasingly dynamic landscape, including recent industry consolidation. You've also now got 3 imaging agents in the market. So my question is, what do you believe it takes to stay competitive in this market today? And how do you see this field evolving in coming years?

Yes. So I think, first of all, there is a growing bifurcation in the market approach between centrally manufactured products that rely more on cyclotron-based approaches or larger scale centralized manufacturing and then more of the nuclear pharmacy-centric business. And we're going to see a lot of the consolidation, kind of, fragment along those lines. I actually think the truth is to win in the space, you need to be able to do both, and that's the approach we've taken.

We see nuclear pharmacies as being the last mile delivery for therapeutics and diagnostics in equal measure. Just to illustrate that, many of our nuclear pharmacies are licensed in multiple states in the United States. Many of our nuclear pharmacies have broad therapeutic isotope licenses and have the infrastructure to, for example, dispense lutetium drugs.

And so we see the pharmacy working in tandem with a more efficient manufacturing infrastructure and to really -- to go that last mile. And where the theranostic space is going, it's moving away from this idea that we're going to do fixed dose administrations. I think radiopharma is the only field of oncology where we do a prescribed fixed dosing for a patient irrespective of their biology or their body weight or -- so to be able to go in and actually start to optimize treatment. You're going to need to have something that does dose calibration and dispensing into a prefilled syringe and you can't do that without a nuclear pharmacy.

So you really need to have both. You need to have the central manufacturing capabilities, which we have, and you need to have the last mile of delivery, which we also do both internally and with certain very important and select partners.

So the distribution piece is really critical. And I think historically, companies kind of thought, well, we can be a radiopharma company and we can do pipeline and we can create cool products, but they don't really think about how they're going to operationalize those products. So you need to have pipeline, right? You need to have supply chain manufacturing and infrastructure, and you need to have really control over your isotope supply chain, which we've made a number of critical investments in.

And then the nod to Kevin when he talks later on about some of the activities in precision medicine, you need to have a sales force because selling radiopharmaceuticals is not the same as selling conventional pharmaceutical products. You're not shipping a blister pack or a vial, you're actually delivering a clinical workflow that goes from the time that, that radioactive product is delivered to a customer site through how do you do injection, how do you do safety, ambulatory radiation exposure, scanning, dosimetry and even we do waste recovery, right?

So it's a full cycle of service that sits on the back. And if you don't have that, then you're ultimately not really going to deliver radiopharma. And so we've taken a very holistic approach. We think that on a strategic basis that there are many pieces of that value chain that we want to vertically integrate, and that's been reflected in our investment activities over the last few years.

An extension there is just maybe the RLS acquisition, how that sort of fits in with your strategy. Can you maybe talk a little bit about that and how it sort of fits in with some of the points you've mentioned.

Yes, that's right. I mean when we launched the company, we were entirely dependent on third-party distribution. But we're seeing some distribution moving up the value chain into pharmaceuticals. We're seeing some pharmaceutical companies being acquisitive about distribution, right, like we are and others.

And so ultimately, there's a scarcity value in the nuclear pharmacy networks and distribution. I think over the weekend, we heard about GE's acquisition of Sofie, which is yet another example of a company annexing distribution capacity. So I think that this is kind of the trend. We were ahead of the curve. We think that the assets that we acquired and the capabilities that we acquired are the best in the industry and give us an advantage in terms of how we take control of our product distribution in the future.

Yes. If I could just add a little bit to that. As we think about that base of delivering the product, it -- how you compete in the future is really what you're developing now. And so when you look at both the therapeutic pipeline and the diagnostic pipeline and the theranostic pairs that we're putting together, market leadership is about not only being able to develop those products, have the ideas and the discipline to go into those different therapies and into those disease states, being able to deliver it is a key component of that.

And then the third strategic pillar is building out a specialized commercial team that really represents the product and builds a preference for Telix products out in the marketplace each and every day. And our specialized team, we've talked about several times, but it's more modular. It's not just a salesperson. It's a field market access. It's a clinical specialist, it's a medical science liaison. So it's really about what does it take for that customer to be successful to bring it into their clinical workflow and make it a part of their patient service line that they offer. And it helps them then compete in the marketplace as well.

And strategically, the imaging with the therapeutic, do you see that as differentiated relative to your peers? Like do you think this is a strategy that Telix is looking to implement? Do you think that sets you apart from other players in this space?

Well, I think it does. I mean we can acknowledge the challenges of it, right? So the challenges of it that it's extra capital deployed that has maybe the products have a different return on investment, but they also have a different development risk associated with them. We've been very fortunate. We've built a business. This year, we do about $1 billion in sales, and it finances hundreds of millions of dollars of R&D, right?

So it hasn't been a detour for the company at all. It's paved the way -- as Kevin said, paved the way for building relationships with key oncology and radiology and nuclear medicine stakeholders. There isn't a better advertisement for a new therapeutic than the scan that shows the target expression from your toes to your nose kind of thing.

So we see huge strategic value, financial value and regulatory derisk. And I would even go so far as saying that we've seen the explosion of lots of small radiopharma companies. They treat radioactivity as just another payload. And those companies will find to their peril when they go and talk to regulators that they don't really have a game plan for patient selection.

And the regulatory view in the space is that if you're going to subject the patient to the exposure conditions of radiation, you have to make sure that, that patient is really eligible for that therapy. And these therapies are not for the faint-hearted. I mean when you see a scan of a patient that successfully responded to PSMA therapy or CAIX therapy or FAP therapy, that patient has undergone a dramatic biological response. These are highly potent therapeutics, and it's great.

The patient outcomes are amazing. They're actually only amazing, though, if you select the right patient. And that's why the imaging is so vitally important. So my -- our view is that a radiopharmaceutical therapeutic is not viable, particularly in advanced disease without a more sophisticated patient selection approach.

I'll come to derisking and label expansion in a second, maybe to Kevin. But to Kevin, to you, some very strong financials in the first half, driven by the PSMA franchise. Can you maybe talk a little bit about how you're thinking about the growth opportunities for precision medicine including Pixclara and Zircaix?

Sure. When we think about precision medicine, we do look at it longitudinal like that. We believe and can talk more about BiPASS in a little bit. But when we think of PSMA, we still see that franchise growing. But we also see that precision medicine and that diagnostic customer that we talk to, the nuclear med physician as kind of the key point of that nuclear scan.

And so we think Pixclara is that next stepping stone and then Zircaix as well. So when you really think about those 3 products, we're talking to really the exact same customer that's reading that scan. Two of those fit really well into the urology franchise. And then one of them is in the neurology franchise. And we have a specialized team, like I talked about that modular approach to really build out that neurology relationship and that referral right back into the nuclear med physician that's actually reading that scan.

So when we think about precision medicine, we think about it broadly now. And again, what we think a market leader does is expands the opportunity for their customers to treat their patients better and do that in multiple different disease states that they treat and work with each and every day.

So it's a big part of the way we see PSMA continuing to grow, building and developing a new market in neuro-oncology and then adding to it with Zircaix and doing something very similar to what we're doing now in PSMA and Zircaix by taking a disease state that has really no good way to diagnose it and the watch and wait, the scan anxiety that develops when you're told with -- if you have a lesion in your kidney, we're going to watch it with a scan every 6 months. That's got a lot of anxiety built to it.

And really what you want to know is simple, is that cancer or is that not? And we believe that Zircaix is going to help us kind of build out that. And we're seeing the confidence in PSMA scans and in nuclear med scans is growing each and every day, which is why we believe that the PSMA scans still have room to grow because more and more urologists every day believe and have confidence in that scan and what it's going to tell them.

Yes. And in terms of Zircaix, very strong data, ZIRCON-X, so some really good data there as well. It's within guidelines. So now it's just a matter of getting the bits and pieces sorted until we maybe see that approved later, sometime in 2026, '27?

Well, yes, we're very close to resubmitting. As you know, we had a late amendment to our CRL, which we had to respond to, which delayed our submission from around the middle of the year until around about -- and as I've repeatedly said, any time now, we still expect to resubmit that this year. The package is in good shape. So just a question of dotting the i's and crossing the t's.

And in terms of thinking about label expansion, I suppose there's two points here. One, you can internally fund your own R&D program. You've got the initial approval for Pixclara, but then you've got the ability to extend the label into metastases. So can you maybe talk a little bit about how that could expand the market even further above the initial label? And then I'll jump into BiPASS for something similar.

Sure. Well, maybe I'll do the maths, and Kevin as well. Well -- so there's a lot of misconceptions about Pixclara. It's -- when you have an orphan drug strategy, it's really different than a large indication strategy like for PSMA. So we also wanted to focus on the data that's most impactful to decision-making in GBM, right? And that's really -- there's a huge clinical conundrum when you have a patient that reoccurs.

You don't know whether the disease is actual progression, pseudo-progression, treatment-related effects. And that's where the clinical evidence for FET-PET is very strong. So if you want to build a beachhead with your stakeholder, you want to build one that's mission-critical. And that is the most mission-critical application for amino acid imaging.

And the package that we submitted to the agency and the corresponding label that we have now is quite broad, really covers the patient journey for GBM. Now the label -- the practice guidelines are much wider, and we want to, in the fullness of time through clinical activity, fill out the space to align the label with the practice guidelines. And a patient gets scanned many times in the journey of their GBM progression. It's not a single time point activity.

So when you're very dogmatic about the market opportunity for Pixclara, it looks at first blush like it's a small opportunity. But in fact, it's longitudinally a very significant opportunity in that progressive GBM -- progressive recurrent GBM space because you're constantly monitoring those patients.

And outside of the United States, where FET is more commonplace, still not super commonplace, but more commonplace, it's used just very regularly in that treatment management process. We then see a step change potential in the number of scans when you add the metastatic indication, so mets from non-CNS primaries, where really the goal is to better manage patient palliation, typically with external beam radiation.

So that's where we sort of see the next event horizon for Pixclara. We have our Phase III trial up and running now. That's recruiting. It's expected to recruit quite well. It's an unmet medical need. There's a lot of enthusiasm for the trial. We wanted to hold off on filing it until we had clarity with the FDA because we didn't want to confound the conversation. But when we are confident that we are on the right track, we filed it and that protocol is up and running.

And as I said, that's going to be, again, a really meaningful increase in the procedure volume for Pixclara and the patient impact. It also, I think, speaks really well to our partnership with Varian being able to increasingly guide treatment decisions around external beam radiation in certain application areas is very powerful, and we are very supportive of that.

Maybe just in terms of that orphan status versus the broader market, is there anything you sort of think about there from a sales perspective, a revenue opportunity perspective, anything -- compare and contrast versus the PSMA business?

Well, we haven't gone out really with a lot of -- we haven't gone out with a lot of sort of visibility yet on pricing. That will come in the coming months. But clearly, it's a more specialist product. It's a much lower volume product than, say, prostate. I mean it's still a great volume. It's still a decent number of scans. But -- so our pricing will reflect more of the niche nature of the market.

It's also -- we have to accommodate a wider variety of patients. So the label supports patients from 1 month and above. And so that's really -- again, as we deliver the product to the customer, there's a little bit of customization that's required there, and that will be reflected in the pricing structure.

Kevin, I might move on to BiPASS. You recently shared your view on how transformative this could potentially be. Can you talk about the landscape and the limitations today in diagnosing prostate cancer and what you're trying to accomplish in this regard?

Yes, really exciting kind of transformation, we think, in the space. Every 40-, 50-year-old man starts to start hearing friends, neighbors and family members that are going through this process with an increasing PSA, which is still a difficult test to kind of trace.

So then the pathway right now is increasing PSA too high over 4 or 5, you get an MRI scan. Your MRI scan has an index called PI-RADS, and they'll rate you like 1 through 5. And based on that, we have an indication right now that if you're a high-risk male or suspicious for metastatic disease, you can get a PSMA PET scan. That's where we kind of sit right now.

And so what happens now in the trial, it goes PSMA, MRI, PET and then biopsy. So if you do need a biopsy, there's about 800,000 biopsies a year right now in the U.S. There's really 1 million men that need it. So about 200,000 men just say no. And then later on, they get picked up in the high-risk male category if they progress. But what we think can happen is and the way the trial is set up is that if a patient has a negative PET, then they won't need to go on to the biopsy, which is super painful. It's a snap type core needle biopsy, 12 to 20x to really make that diagnosis. So it's not nothing. It's not a quick test. It's not a skin biopsy. It's pretty invasive.

And so those men that are negative on PSMA PET won't have to get that. They'll still go under -- if they're still in the same indications, they'll still go under the physician protocol of another scan every year or every 2 years based on their presentation. But what you'll hear from doctors when they do a biopsy and it comes back negative is the hard part. One of our -- really one of our leading physicians that did the recruitment would say, I can't tell you that you don't have prostate cancer because you have a negative biopsy, I can only tell you that we don't -- we didn't find it.

So that means you're going to come back in, watch your PSMA and maybe get another biopsy in a year or 2 anyway and still go under that biopsy needle. So we think that by looking at what the number of negative biopsies that we think we can rule out in PSMA will both do 2 things. It will transform one small step for mankind is not getting the biopsy, right? And then we think it will be transformational for the TAM that is involved with that because we think there's 800,000 to 1 million scans.

When you talk to our strategic advisory boards and some of our leading recruiters in that, they believe that done correctly and placed correctly in that algorithm of a patient presentation, that initial staging, you'll catch all that with the BiPASS biopsy. So that indication will decrease. And then because they're treating patients better because they've got a better view of the prostate cancer, they believe that biochemical recurrence will come down a bit.

And -- but the overall market then kind of shifts to the left, we call it before the biopsy, so it's pre-biopsy and then doubles basically from the entire market that we see what it is today at 600,000-plus scans to 1 million-plus scans on the other side, of which we believe that once a doctor starts with a gallium scan like Gozellix, then they'll want to follow that patient with a gallium scan so they can really look at apples-to-apples instead of apples to orange.

So we believe it's a big change in the thought process. And that's why I mentioned that urologists are so important because they're starting to understand the value and the power of a PSMA PET scan. That's why they're excited about the 250 product that we have, but they're also seeing now the value of how sensitive and specific it can be.

And we just sit down with the Strategic Advisory Board the other day and the selling process that they have to go through sometimes to get a man to do a biopsy is quite difficult at times because they're trying to do what's best for the patient and the patient has heard how difficult these can be and is not wanting to. So the idea is to be able to do this scan upfront, quickly rule out those that don't need it. And we call it none and done. And then as you find something positive, then you would simply target your biopsies in a more precise way where the prostate cancer is and yield better results.

And so that's the idea of BiPASS and what we're trying to demonstrate. So we'll see that data. That data, as you know, we finalized the enrolling in that trial last month. And now we've got a 6-month window that we've got to do follow-up, and then we'll start the FDA process again.

Yes. And just to add to that, I think it's instructive to think of the current indications that we have, which essentially bookend prostatectomy. That was the training wheels that we needed in the industry to get confident -- to get physician confident. Now because we've demonstrated the sensitivity and specificity, and it's exquisitely sensitive and specific and particularly gallium because it has a much lower incidence of indeterminate bone lesions, which is a hallmark of fluorinated products, we actually cannot only capture that upfront space, but we can keep it.

And so what we think is that, that's going to -- as Kevin is going to push the scan volume to the left and really reduce the need to bring patients in particularly for high risk. And because we're going to have better patient compliance, as Kevin pointed out, a lot of that 200,000 men that prefer not to, a lot of those are the people that get into the process too late and then end up contributing to the BCR pool on the back end. We're also going to see, hopefully, because that would be a great outcome for patients to see less recurrence because we're staging and diagnosing better on the front end. So I think it's a really big shift.

The specific numbers, I think that you provided, 670 is currently up to 1.32. So I'd be a bit more specific than a bit over 600,000 over 1 million. So quite significant. I suppose the extension here is there's some pretty good data out there already. So in a sense, somewhat derisked from a clinical data perspective. But maybe just briefly just in terms of what's out there in terms of other clinical data. And then from a payer perspective, you mentioned less biopsies being done from a reimbursement perspective, doesn't make sense from a public health perspective, right?

Yes. Well, it's -- I mean, the pharmacoeconomics health -- we did all the health economic studies. It's clear that it saves the health care system money by managing that biopsy process better. So from a reimbursement perspective, it's a clear business case. And then I think from -- and what was the other part of your question? Sorry, lag...

Data, already...

Well, yes, we always get to build on the shoulders of giants, right? So there's the PRIMARY and PRIMARY2 studies. We actually took the PRIMARY study data, which was published some time ago and the PRIMARY2 protocol when it was first announced. We actually took that collaboratively to the agency to see whether or not we could use PRIMARY2 as a registration-enabling study. And because it was a hypothesis validation study, it wasn't really statistically structured for a registration study. So the FDA declined, but BiPASS was born, which should really be thought of as PRIMARY3.

I mean the same investigators contributed to the study, designed the study. Obviously, we went through 4 or 5 turns with the agency to -- because this is a big health outcome if the study is successful, and there's a lot of sensitivity around changing practice of medicine. And so it took a few turns to get there. And I think that we have a high degree of confidence in the study because of the hundreds of patients that have been studied in well-powered and well-designed studies before it. So, we have a high degree of confidence.

Maybe just coming back to an earlier question I had. I mean, just given this iterative engagement with the FDA, do you think you're getting better and better at doing this? If you learned through previous applications and things like that, now you're sort of just finding that you're fine-tuning that process a little bit.

I don't think anyone ever gets good at dealing with the FDA.

Fair enough. We might move on to therapeutics, if we can. You've got several late-stage programs, Chris. Given your presence in prostate cancer, can you talk about the therapeutics portfolio and how the pipeline candidates are positioned within the prostate cancer treatment landscape?

Sure. So we have a Phase III trial that's recruiting now. It's actually recruiting nicely ex-U.S. This is for our 591 our antibody-directed therapy. This is in first- and second-line castrate-resistant disease. It's a very nice trial design because it incorporates a very flexible standard of care.

One of the things that I think is underappreciated by the market around this asset is the fact that it's a very short treatment duration. And the reason why clinicians love it so much is it's very easy to layer into the treatment journey, right? It's not 40 weeks of therapy like the current standard of care. It's 2 shots, 14 days apart, that's it. And it gives really -- it's been shown in prior studies and in sort of the widespread use of the asset that it gives really prolonged slow decline in PSA over a very long period of time. It's disease stabilizing. And we've presented preliminary PFS data that shows that it's competitive, but the dosing schedule and the amount of injected radiation is just a lot lower. And that's really important.

It's important that when a patient goes to get injected, they don't have radioactive pee, they don't have radioactive vomit. It's a very benign administration process. There's no salivary glands or no material salivary gland uptake. The quality of life issues are very high.

But the principal advantage is that it's a short deviation to nuclear medicine and then the patient goes back to their referral physician, right? And so in some countries as well, the standard of care is an inpatient process because of the relatively high levels of activity. So for example, in Japan, we already have a drug class ruling as an outpatient procedure because our imparted dose is so low. That has a big impact on reimbursement and economics. So some countries, we will win just based on that.

So -- anyway, very exciting Phase III trial. We have a futility analysis or an interim analysis that's based on futility that we expect to read out sometime around the end of this year or early next year. It's event-driven. So -- which we don't know exactly when it's going to be. But the trial is recruiting well ex-U.S., and we did have a good meeting with the FDA to look at the -- we had a run-in study that was -- we agreed with the agency as part of the Phase III activity. They were happy with the data.

We have a green light subject to an IND amendment, which is just in the process of kind of going through an IND amendment to then include U.S. patients in the study. But we don't see any barriers to doing that. And clearly, we've got a lot of investigators that are excited about bringing that asset on.

So that program, because it's an antibody, it's a macromolecule. It's designed really for targeting bulky disease. That's a very good asset in the castrate-resistant space. When you start looking at hormone-resistant, hormone-sensitive cancers is a very different biology. It's a very different disease burden. And so for the last few years, we've been researching a small molecule approach actually originally intended for use with actinium. The goal really to compare biologic versus small molecule delivery approaches for actinium. So we're not sold one way or another.

But the general goal is you want to have low hematologic toxicity. You want to have no real kidney dose. You want to watch the salivaries and the lacrimal glands because they tend to be damaged pretty badly by actinium. And that's -- if you're moving into an early patient population, and that's a man that's going to live for a very long time and they -- you blow out their salivary glands, life is a much less pleasant journey from that point onwards.

So that's how 597 came to be. And we see, given that the data in the hormone sensitive space, it's a bit controversial, let's say, it's not a slam dunk. We do see an opportunity for better assets to play a role there. And so we have to obviously demonstrate the clinical utility, but we feel like we've got a really winning asset there in terms of much higher imparted tumor dose, 1/5 of the kidney uptake, a similar sort of reduction in salivary gland uptake.

And so that means that the dose and dosimetry profile in what are relatively healthy patients compared to where we've been traditionally doing RLT. I think it's -- the 597 program is very exciting. So we've completed 120-patient randomized trial to look at dose intensification strategies there as well. So we're really taking advantage of the better dosimetry of this asset to much more aggressively treat the patient. It turns out that on the first dose of PSMA radioligand therapy in a castrate -- hormone-sensitive patient, PSMA levels rise.

So you can follow and slipstream that first dose a couple of days later with a far more aggressive treatment schedule. And we're really doing with 597, what we've been doing with 591, which is building that dose intensification, very short treatment schedule, day 1, day 5 -- I'd say day 1, day 3, day 15, and that's the substantive therapy for the patient. And I think that's a big new way of thinking in the field. And the data that we're generating is really exciting. So you'll see over the next 6 months, more as that data matures, you'll see more outcome. And if the asset lands the way that we think it will, we'll probably move it into a Phase III study next year.

And just to be clear, strategically, various parts of the patient disease progression. So it's not like one replacing the other...

No...

You're looking at 597, a hormone-sensitive, 591 is a castrate-resistant, just to be clear?

Correct. Yes. Yes. I mean we -- the OPTIMAL study was in castrate-resistant disease so that we have an apples-to-apples comparison when we go and talk to regulators to have that comparable safety profile. But we now have the OPTIMAL-e study running, which is the hormone-sensitive. And that trial is recruiting really fast and hopefully will be done in the next couple of months.

I got time for one more very quick one, if I can. earlier this year, you announced the collaboration with Regeneron to develop next-generation candidates. Can you walk us through the strategic rationale behind the partnership and what each company brings to the collaboration?

Yes. Look, we don't talk hugely about it. But fundamentally, we're one of the few companies that is really targeting agent agnostic. We develop small molecules. We developed peptides. We developed antibodies. We've always taken the view that the pharmacophore should be chosen on the basis of the scientific problem you're trying to solve, and I think that's really reflected in the pipeline.

But we do really like biologics, and it's an underexplored area in nuclear medicine, mainly because the historic academic leadership in nuclear medicine didn't have the resources to do -- to make antibodies and engineer proteins and stuff like that. So it's an underdeveloped opportunity. But with biologics, you get incredible selectivity. You can control the pharmacology of your assets.

And I just think that it's -- if we're really thinking about what does next-generation products look like where you want to match your pharmacology to your half-life of your isotopes, we've got things like actinium. We've got things like lead-212. We've got astatine, very high potential, let alone the things that we've been developing historically like based on lutetium.

But I think if you can really align particularly the alphas with the biology and the targeting agent, well, you're going to get much better next-generation medicines. So what we bring to the table in the partnership, we know how to do a first approximation, develop radiopharmaceuticals. We have the commercial infrastructure to manufacture, distribute and sell them. Regeneron, of course, is a commercially formidable organization, but I think their real strength is in the science of biologics. They're just a machine, cranking out superb proteins, protein engineering, bispecifics, just stuff that could be really a game changer in radiopharma. So I think they're very complementary forces, and it's an exciting collaboration from that perspective.

Okay. We are on time. So I'll finish there. Thank you both very much. Great to see you, and I hope to chat again soon.

Yes. Thanks for your time.

Good morning, and good evening, everybody. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communications at Telix, and it's my pleasure to welcome you today to our H1 2026 Interim Results Presentation and Call. You'll have seen our documents lodged on the ASX earlier this morning. Next slide, please.

Today, on our call, we'll be joined by Dr. Christian Behrenbruch, Managing Director and Group CEO; Darren Smith, our Group Chief Financial Officer; Kevin Richardson, CEO of the Telix Precision Medicine business; and Dr. David Cade, Chief Medical Officer. Following prepared remarks, we will open up the call to Q&A, starting with calls on the conference line. If we don't get your questions during the call, we will respond to you after the call is finished.

Just to move to the next slide, please. Brief note, please note that today's presentation includes forward-looking statements, including within the meaning of the U.S. Private Securities Litigation Reform Act of 1995 that relate to, among other things, anticipated future events, financial performance, plans, strategies and business developments. These forward-looking statements are based on current information, assumptions and expectations of future events that are subject to change and involve risks and uncertainties that may cause the actual results to differ materially from those contained in forward-looking statements.

These and other risks are described in our filings with the ASX and SEC, including our half year and annual reports. You are cautioned not to rely on these forward-looking statements, which are made only as of today's date, and the company disclaims any obligation to update such statements. Please refer to the disclaimer slide included in the presentation accompanying this webcast for further information.

With that, I'd now like to hand over to Chris.

Thank you very much, Ky. Good morning, and good evening, everyone. Before I go into our strategic priorities for this year, let me take a moment to remind everyone about our competitive advantages and what it takes to lead this field. We are a pure-play radiopharmaceutical firm, and our strength is based on five core pillars of activity.

Firstly, our therapeutic pipeline is highly differentiated and built around significant unmet medical need. We're advancing innovative therapies in areas that have seen little to no innovation for decades, with either first-in-class or best-in-class candidates. Our portfolio is diversified with multiple shots on goal, further derisking commercial success.

We've also built in-house R&D capabilities that enable us to develop and optimize both targeting agents and their radioactive radioisotope payload tailored to the specific biology of each disease. As we've said many times before, we are agnostic to the targeting agent in radioisotope. We let science guide these decisions. We are not wed to a narrative around a specific platform or approach.

Earlier this year, we announced a collaboration with Regeneron that combines our expertise in radiopharma with Regeneron's leadership in biologics and antibody engineering. This highly complementary partnership positions us to accelerate the development of next-generation candidates and really puts us in a good place to lead in the therapeutic space in the future.

Our Precision Medicine business is our third core pillar that's generating close to $1 billion in revenue and enables us to reinvest the significant capital into the business to continue this growth trajectory. The Precision Medicine business has enabled us to establish a presence across global markets where we continue to strengthen and guide our clinical activity.

We've built a specialist commercial organization, a team that represents some of the strongest talent in the industry and is our fourth core pillar in differentiating us from competition. We've invested and continue to invest in our manufacturing and supply chain capabilities. The RLS transaction last year has significantly strengthened our control over the entire value chain from production and quality assurance to the final dose delivery. It's brought us closer to the customer, enabled us to meet growing demand and positioned us well to deliver therapeutic solutions down the road.

Earlier this year, we shared three areas of focus, and I wanted to show the progress we're making against them. On the commercial front, we delivered approximately $390 million in precision medicine sales, up 27% year-on-year. This is driven by the successful launch of Gozellix and continued growth of Illuccix. We are now tracking towards the upper end of our guidance, very close to $1 billion in revenue.

On the regulatory front, we've completed the submissions for Pixclara and Pixlumi in both the U.S. and Europe, with a PDUFA date now assigned in the U.S. of the 11th of September. In terms of Zircaix, we received a corrected complete response letter from the FDA and the resubmission process is tracking against agreed time lines with the agency. We're putting the final touches on the package and ensuring that the resubmission fully addresses all outstanding items before filing, particularly third-party manufacturing deficiencies. And this, of course, remains one of our top priorities for the year.

On the Therapeutics front, we've advanced three Phase III candidates with full alignment with the FDA on Part 2 for TLX591, our prostate cancer therapeutic and started dosing patients for the other programs. And David will go into this in more detail later in the presentation. The BiPASS biopsy Phase III study is close to completing the targeted enrollment. The study has the potential to significantly increase the market and change the treatment paradigm in prostate cancer, and Kevin will share more on this game-changing program later in the presentation.

Next slide, please. This slide illustrates our growth since 2024. As you can see, we've continued to develop the business, doubling the revenue since the first half of 2024 and delivered approximately 22% year-on-year growth, really eclipsing the growth of peer firms and recent financial results. We've demonstrated market leadership with two approved and reimbursed products, strong market penetration and continued commercial execution. This really shows that our strategy works. The strategic transactions and R&D investments we've made are starting to pay off.

The acquisition of RLS has also, as I've mentioned, further diversified our revenue streams and allowed us to maintain a stable third-party revenue stream since the acquisition of last year. We are committed to building out full product suite capability of RLS as an independent pharmacy network, including third-party product solutions that benefit from one of the most capable distribution networks in North America.

Next slide, please. As our global footprint has grown, so has our manufacturing and distribution network. This is particularly important in the field of radiopharma, where the half-lives and shelf lives of products require just-in-time manufacturing and a highly specialized supply chain to avoid disruptions or delays to patients.

Last year, we expanded manufacturing and distribution capabilities in the U.S. and Japan, and these are investments that are critical to establish the foundation for a scalable infrastructure in the future. This year, we also opened up our new translational research site in Melbourne. This site offers an integrated platform housing R&D and patient care under one roof, and is designed to accelerate the development and delivery of theranostics through rapid derisking and proof-of-concept development. And this is really a capability that's unlike any other found elsewhere.

We continue to make CapEx investments at various sites, including Seneffe, Yokohama and RLS, where we're building out the manufacturing capabilities for therapeutics delivery, very important clearly to our next phase of growth. This includes increasing clean room capacity, installing cyclotrons, and making sure that the RLS network is equipped and licensed to do things like dispense lutetium therapeutics drugs.

With that, I'll hand over to our CFO, Darren Smith, who will provide an update on the financials. Over to you, Darren.

Thank you, Chris, and hello, everyone. Moving to the financials for the first half of this year. We reported revenue of $477 million, up 22% compared to the first half of '25. This was achieved through robust commercial execution that delivered strong demand on our precision medicine products. Kevin will speak to this later in the presentation.

EBITDA improved 146% year-on-year to $52 million, and net profit after tax was up to $38 million, reflecting strong business performance and continued control of operating expenditure. Our R&D investments represented 26% of our revenue, focused on accelerating near-term growth opportunities and developing our late-stage assets.

Gross margin for our Precision Medicine business was 65%, an improvement of 1% year-on-year. We also successfully increased our cash balance to $252 million through the refinance of our convertible bonds, a successful transaction with better terms. We are well placed with the financial capacity to accelerate growth.

Next slide, please, and turning to our income statement. As previously mentioned, we delivered double-digit growth both on the top line and the bottom line of our group P&L. Gross margin for the consolidated group improved 2% to 55%. This was supported by our strong growth on the top line, and we continued our healthy investment into our product development pipeline with a focus on near-term commercial opportunities in Phase III clinical studies for a number of our therapeutic candidates. At the same time, we have maintained a disciplined approach to managing our operating expenditure, reducing it by 1% as a percentage of sales.

Next slide, please. Moving to our Sankey diagram. This clearly illustrates how we generate our funds and how they flow through the business. On the left side of the chart, it shows that in the first half of 2026, Telix generated revenue and income of $523 million from our Precision Medicine business, TMS and Regeneron collaboration. The middle sections of the chart show that after covering cost of sales, OpEx and finance costs, Telix reported a commercial profit of $153 million, a 29% return on revenue and income generated, demonstrating the strength of the business.

I want to reiterate that we have a highly profitable business with strong cash-generating capabilities. But as we have said many times, rather than maximizing near-term earnings, we are reinvesting capital into growth opportunities that will drive long-term shareholder value. We continue investing our earnings into the business for the remainder of this year and the next year.

From this financial position and as illustrated on the right side of the Sankey graph, we have made a decision on how much we invest into our R&D development and how much we bank a profit. Again, I cannot overstate the importance of the investment we are making today and the significant value that will drive in the long term.

Next slide, please. Our Precision Medicine business continues to deliver double-digit growth, up 27% year-on-year from our differentiated products. Both Illuccix and Gozellix continue to drive strong demand across all market segments. Kevin will comment on this later. Gross margins of 65% improved 1% year-on-year, driven by a disciplined pricing and manufacturing and distribution efficiencies. R&D investment increased year-on-year, driven by Pixclara, Zircaix and BiPASS investments that will drive meaningful commercial uptake near term.

As Chris mentioned, we are significantly expanding our market across our portfolio, including prostate cancer imaging with BiPASS, brain metastases imaging from Pixclara, and renal mass imaging with Zircaix. Overall, that is in excess of 1 million scans that our customers will meaningfully benefit from. EBITDA grew 26% year-on-year to $132 million. While we expect healthy EBITDA growth to remain, we remain committed to reinvesting the capital into the business in our pipeline, as I've mentioned earlier.

Now moving to TMS. TMS generated third-party revenues of $89 million, up 10% year-on-year by RLS. Since the acquisition of RLS, we have maintained a stable base of third-party revenue, further diversifying our revenue streams. We have also successfully been driving manufacturing and supply chain efficiencies for RLS by selling a higher proportion of our own assets through them.

Internal revenues of $57 million improved 70% year-on-year, representing Illuccix and Gozellix distributors for RLS. This means RLS is now our second largest distributor of our products. We also continue to invest in our manufacturing sites at Seneffe, Yokohama and selected RLS sites to ensure the global readiness to deliver our precision medicine and therapeutic candidates.

Next slide, please. Our full year revenue guidance of between $950 million and $970 million is maintained for 2026. We do, however, expect that to land at the upper end of the range, and we expect continued growth in excess of 20% year-on-year of our Precision Medicine business. Please note, our full-time guidance does not reflect unapproved products, providing the potential for upside.

We updated our R&D guidance to a range of $230 million to $270 million, primarily reflecting new investment across the development program discussed today as well as our collaboration with Regeneron. Given the strength of our commercial business, we believe that we are well positioned to support and accelerate near-term growth.

I'll now hand you over to Kevin Richardson, our Precision Medicine CEO.

Thank you, Darren. First slide, please. As we've talked about before, we've continued to grow our PSMA business through a very pragmatic strategy focused on clinical differentiation and customer economics. We launched our two-product strategy to address the different needs of our two major customer segments, and that's proven to be the right approach.

As a result, we've now delivered growth every quarter with our strongest growth rates coming in the two quarters following the launch of Gozellix. That performance has enabled us to increase both unit share and revenue share for the 16th consecutive quarter.

In the second quarter, we delivered $202 million in revenue, up 9% quarter-over-quarter, following $186 million in the first quarter, which was up 16% quarter-over-quarter. Those results reflect not only our continued market demand, but also strong execution by our commercial, operational and customer-facing teams.

The launch of Gozellix has been very successful. Demand was strong from day 1, and the adoption we've seen reinforces that our two-product strategy is delivering exactly what we've intended. More importantly, it positions us well to continue innovating in the PSMA market with programs such as BiPASS and AlFluor as we expand our ability to meet the evolving needs of physicians and patients.

At the end of the day, demand for our products comes down to a few things that we work on every day. We meet customers where they are. We provide a high level of service and reliability. We clinically differentiate our products. We make them easy to order. We deliver on time every time. We maintain a consistent pricing strategy, and we invest heavily in education around both the science and the reimbursement of PSMA imaging. That combination continues to matter.

Our PSMA imaging agents have demonstrated fewer indeterminate bone lesions and higher inter-reader agreement compared with F-18-based agents, giving physicians greater confidence in clinical decision-making. When you combine that with the clinical performance and operational reliability and strong customer support, it continues to drive adoption across the market.

Next slide, please. Moving on to global expansion. We continue to execute well internationally with our PSMA portfolio now launched or initiated across 24 countries. At the same time, we are making progress in two of the most important pharmaceutical markets in the world, China and Japan.

In China, we submitted our NDA earlier this year and are awaiting review by the NMPA. In Japan, we've completed enrollment in our registration-enabling study, one of the fastest recruiting studies of its kind with more than 100 patients enrolled. We are now preparing our NDA submission while also awaiting feedback on conditional approval, which could support an accelerated path to market.

These are important milestones because China and Japan represent two of the largest pharmaceutical markets globally and significant opportunities for Telix over the long term. More broadly, our international expansion strategy is about much more than near-term diagnostic revenue.

Every market that we enter allows us to build relationships with regulators, payers, physicians and health systems while establishing the commercial and operational infrastructure we need for future therapeutic launches. In many ways, the Precision Medicine business is creating the foundation that will support the broader Telix portfolio for years to come.

Next slide, please. Moving on to Pixclara and Zircaix, our two most important near-term launches, starting with Pixclara. We've made significant progress over the last several months. As you've heard, we've been assigned September 11 PDUFA date in the United States and have also submitted Pixlumi in Europe. In addition, Pixclara has now been included in both NCCN and international clinical guidelines, further validating the importance of this imaging agent and the need it addresses.

With the regulatory submissions behind us, our commercial, medical affairs, market access and supply teams are launch ready and positioned to move quickly upon approval. What's particularly encouraging is the feedback we're receiving from the market. Our research continues to indicate strong physician interest and a high level of awareness of the unmet need. We're also continuing to expand the opportunity for Pixclara.

Earlier this year, we announced an IND submission in brain metastasis, an indication with a substantially larger addressable patient population than our initial target indication and one that further demonstrates the platform potential of this asset.

Now turning to Zircaix. As a potentially first-in-class radio labeled biologic to reach the market, it underscores both the significance of this imaging agent and the substantial unmet need in clear cell renal cell carcinoma. Importantly, our confidence in the opportunity remains unchanged.

Zircaix has received Breakthrough Therapy designation and Fast Track designation. It's supported by a strong ZIRCON clinical data package and is increasingly recognized within major international clinical guidelines. As a result, Zircaix remains one of our highest strategic priorities for 2026, and we remain fully committed to bringing this product to patients.

So when you step back, both Pixclara and Zircaix are first-in-class imaging agents addressing areas of significant unmet clinical need and further strengthening Telix leadership in precision medicine imaging. Zircaix is particularly important as the first radiobiologic imaging agent to help establish a regulatory pathway for this emerging class of products, creating opportunities not only for Telix, but the future of molecular imaging more broadly.

Next slide. Moving on to the current state of the PSMA market. Today, the PSMA imaging market is over 600,000 annual scans and is estimated to be approaching 2/3 penetrated. The majority of scan volume is concentrated in biochemical recurrence with initial staging representing the second largest indication. We also have approval for patient selection for patients receiving radioligand therapy, although this remains a relatively small contributor to the overall scan volumes.

And we've discussed previously, there are opportunities to continue expanding utilization through guideline updates increased physician adoption and additional clinical evidence and treatment response or monitoring indications. However, those opportunities are largely incremental and not expected to fundamentally change the size of the market.

So while we continue to see growth and market expansion, the current PSMA market remains primarily driven by biochemical recurrence and staging, which together account for the majority of scans performed today.

Next slide, please. Moving on to BiPASS. BiPASS has the potential to fundamentally change where PSMA imaging is used in the prostate cancer journey. Today, most PSMA imaging is performed at initial staging following biochemical recurrence.

BiPASS could move PSMA imaging to diagnosis, bringing it to the very beginning of prostate cancer diagnosis, which has the largest patient population. And if successful, we believe BiPASS could approximately double the existing PSMA imaging market by creating a new pre-biopsy market segment for Telix PSMA.

As we've discussed before, approximately 800,000 prostate biopsies are performed annually in the U.S., with roughly 75% proving negative. BiPASS has the potential to reduce unnecessary biopsies while improving confidence in patients who ultimately proceed to biopsy.

In addition, up to 200,000 patients delay or decline core needle biopsy each year because of its invasive nature. We believe patients are increasingly seeking less invasive approaches to prostate cancer diagnosis when supported by strong clinical evidence. But importantly, our confidence in BiPASS is supported by PRIMARY and PRIMARY2 studies, which demonstrated that PSMA PET, combined with MRI, improved prostate cancer detection and showed the potential to reduce unnecessary biopsies.

Strategically, bypass is important because it has the potential to anchor Telix PSMA at the beginning of the patient's prostate cancer diagnosis. If a physician adopts BiPASS, we believe they will increasingly prefer to use the same PSMA imaging agent throughout the patient's cancer journey, from diagnosis through staging, reoccurrence and ongoing monitoring.

Consistency of imaging and interpretation becomes increasingly important as the patients move through the continuum of cancer care. That's what makes this opportunity so compelling. BiPASS doesn't simply expand the market, it has the potential to redefine and redistribute it.

Through scientific innovation and clinical evidence, Telix has the opportunity to create and lead a new category of PSMA imaging in the pre-biopsy setting, possibly displacing the existing indications over time. Advancing science that reduces unnecessary procedures, reduces risk and increase in patient outcomes is true market leadership.

And with that, I'll hand it over to our Chief Medical Officer, Dr. David Cade.

Thanks, Kevin, for a great opportunity. Next slide, please. Well, this is our pipeline slide. And as you can see, our two primary areas of focus are within urologic and neurologic oncology. Within urologic oncology, we have our two late-stage programs in prostate and kidney cancer, but also follow-on alpha therapy candidates in earlier stages of development.

Looking at neuro-oncology, which is our other key area of focus, this is a field in which new drug innovation has really largely been stagnant over the past couple of decades. Here, against that background, we have a Phase III candidate, TLX101, that's shown promising data to date as well as an alpha therapy candidate utilizing astatine also in early development.

Within our other tumors domain, we're exploring different targets, including our TLX400 candidate targeting fibroblast activation protein or FAP, that's expressed within the tumor microenvironment across a very broad range of tumors. And therefore, this asset has pan-cancer potential.

I'd like to also briefly mention the imaging agents and how we think about these. So for every therapeutic candidate, we develop an imaging agent. And in many cases, these are true theranostic pairs. With imaging agents developed at the forefront, we generate significant clinical data before making additional investment decisions in the corresponding therapeutic program.

So by the time we advance a therapeutic candidate, we've already developed a strong understanding of its biodistribution and its selectivity for the intended target, which significantly addresses the level of risk in the therapeutic development pathway.

Let's go to the next slide, please. On this slide, I wanted to highlight a few programs that we're focused on and where we've made significant progress through the first half of this year. Starting with ProstACT Global, this is our Phase III candidate for metastatic castrate-resistant prostate cancer. We recently announced that the FDA had completed its review of the safety data from Part 1 of the study and that we've also fully aligned with the FDA on the protocol design for Part 2 of the study. So essentially, our next step is to amend the IND that we have and align the regulatory submissions for the U.S. with the European Medicines Agency.

Outside of the United States, we're also pleased with the progress we're seeing in Part 2 of ProstACT Global. We're currently enrolling patients in seven countries, and we look forward to providing an update on the preplanned interim analysis of radiographic progression-free survival, which is the primary endpoint, when that becomes available, remembering that this is a milestone that's event-driven. In other words, needing 81 disease progression events to trigger this first analysis.

Now before I move away from prostate cancer, I'd also like to highlight TLX597, our next-generation small molecule candidate that's shown some promising early data. We presented some of that data earlier this year, demonstrating a very low radiation dose to the salivary glands and the kidneys, while at the same time, delivering a high dose to the tumor. So this favorable dosimetry profile, high to tumors and low to normal tissues makes it an ideal candidate in the early metastatic hormone-sensitive prostate cancer setting.

There are currently two Phase II studies ongoing where enrollment is completed in OPTIMAL-PSMA in metastatic castrate-resistant prostate cancer. And we've now also started dosing patients in OPTIMAL-e in metastatic hormone-sensitive prostate cancer.

We're also advancing TLX090 in a Phase I study for the palliation of bone pain from skeletal metastases that occurs in patients with very advanced disease. TLX090, I think, fits very well within our urology domain, given most patients with metastatic prostate cancer will ultimately develop bony metastases.

Now moving on to IPAX BrIGHT. This is our Phase III study in glioblastoma. This study is evaluating TLX101 in combination with the chemotherapy agent, lomustine, and it continues to progress well. We're currently dosing patients in the first cohort, which commenced at the highest planned dose levels. Now if the combination demonstrates an acceptable tolerability profile, we'll advance into the expansion cohort to further characterize the safety of this combination of TLX101 plus chemotherapy.

Now moving on to LUTEON. This is our monotherapy study for renal cell carcinoma using a CA9, or carbonic anhydrase 9, targeting antibody. LUTEON is being run under a Phase III protocol in Australia, and it forms part of our global development program for TLX250, which also includes the Phase II LUTEON ATLAS study in the United States and Europe. We've advanced this study through its site activation and it has begun dosing patients.

And lastly, I wanted to highlight the collaboration we entered into earlier this year with Regeneron. Now this partnership builds on our well-established expertise across radiopharmaceutical development, and it reflects our shared commitment to advance the next generation of candidates with a focus on alpha therapies. We believe that we're uniquely positioned to drive innovation in this emerging field that's alpha therapies and to have the opportunity to play a leading role in the future of precision oncology.

Let's move to the next slide, please. Now this is a slide you may have seen before, but I believe it's valuable to describe how we are thinking about the therapeutic cascade across the continuum of prostate cancer care. TLX591, as I mentioned, uses a radio antibody drug conjugate to deliver the therapeutic payload. It has a long tumor retention with limited radiation exposure to healthy organs as well as a convenient two-dose regimen that really facilitates its combination together with a backbone of standard of care.

This candidate is well suited for the first-line and second-line metastatic castrate-resistant prostate cancer setting, which is a more advanced disease state that may benefit from a therapy with a more convenient dosing regimen that better enables it to be layered on top of the ongoing use of a standard of care backbone of therapy.

Now moving to TLX597, our small molecule candidate. This is a highly targeted next-generation small molecule radioligand therapy, which has demonstrated the highly favorable dosimetry profile I talked about earlier, which really makes it uniquely positioned for use in earlier metastatic hormone-sensitive prostate cancer where efficacy while maintaining quality of life in that early stage of disease is of other paramount importance. We believe the preliminary data are compelling, and we look forward to providing an update on the various trials once the data are sufficiently mature.

As patients' disease will almost always progress, we're studying the use of an actinium-based alpha therapy, TLX592, in the later line setting as we view that alpha therapies are sequential to beta therapies at this point in their development, so after beta therapies.

Now finally, our portfolio approach also captures our bone pain palliation candidate, TLX090. As I mentioned earlier, when cancer metastasized to the bone skeleton, in most cases, it results in pain and a significant degradation in quality of life. We see pain palliation as an equally critical component in late cancer care.

And with that, I'll hand back to you, Chris, for some final remarks.

Thanks very much, David. So to conclude, we entered the year with a strong lineup of catalysts. And at the halfway point, the list has expanded quite a bit. This is a significant and impactful year for the company for sure. We continue to successfully navigate the regulatory processes and advance our programs with two near-term launches. And as I said earlier, Zircaix is a top priority to us and will be refiled very soon.

We have three pivotal therapeutic trials that have generated readouts and continue to advance towards important upcoming clinical and regulatory milestones, and you can expect plenty of clinical touch points in the coming months. We have a strong pipeline of new assets advancing behind. These are assets that have generated some very compelling data, as David has outlined.

Our international expansion is progressing well and remains a critical component of our strategy to establish the needed infrastructure for future therapeutic launches. And overall, I believe that we're in a strong position with positive momentum across the business and multiple important catalysts ahead in the second half of the year.

I also wanted to note that we'll be hosting an R&D Day in New York on September 22, where we'll provide an overview of our pipeline assets and go into a bit more detail around the data. In addition to having our management there, you'll get an opportunity to hear perspectives from leading key opinion leaders in the space. So we're really excited to showcase all the progress we've made over the last 12 months.

And I'd very much like to acknowledge the efforts of my executive team who internalized some of the setbacks we've had last year and really rewired the way in which we approach our development and clinical activities.

Before we move to Q&A, I'd like to take a moment to thank my colleagues and all of our employees. Their dedication, hard work and commitment every day are what enables us to advance our mission of delivering life-changing treatments to patients.

And so with that, I'll hand it over to the operator for Q&A.

[Operator Instructions] Your first question comes from Chris Cooper from JPMorgan.

I guess market share has been an important factor for you this year with the PSMA imaging portfolio. We now know that TruVu has the reimbursement code coming into effect on the 1st of October. Just your latest thinking on how you expect that market share development to progress through the balance of the year, please, given that.

Well, we don't really see -- we don't really expect a huge amount of impact unlike Gozellix and Illuccix, which are really a -- these are two very different products that are delivered simultaneously to the market.

Based on the information that's been put out into the public domain, TruVu has really been positioned more as a manufacturing improvement. And as a consequence, it will be a product that will have to get rolled out across all segments of the market rather than be a market segmentation strategy that we've undertaken with our two-product strategy.

So we haven't modified our guidance. Our guidance bakes in what we think is going to be the realistic outcome for the year and, and really nothing has changed from our perspective. I don't know, Kevin, if you want to add anything?

I would just add that we see it as a similar product and our approach to the market has been very pragmatic, and we manage that across kind of all segments, and we believe that the two-product strategy was the right one and has proven to be very successful for us. And so we'll continue that.

And second one, please, just on the Zircaix, I guess. I mean, good to see the extension was granted, although probably a bit disappointing it was necessary. You say you're making good progress. And I think you just said there, Chris, the resubmission is going to happen very soon. I presume that means now the next couple of months, but we've also been assuming that for a while. How much of that is within your own control at this stage?

All of it.

Okay. And so it's correct to assume the resubmission should occur in the next month or two?

That would be a reasonable assumption.

Your next question comes from Laura Sutcliffe from Citi.

I have one on the BiPASS trial, please. I think target recruitment was increased for a second time earlier this year, which we understand is because there was a need to increase the statistical powering of the trial. Is that right? And if so, could you tell us a bit more about what motivated the need for the increased powering?

I think there's been a lot of chatter about statistical powering, and it's not something that we've spoken really openly about. When we started the trial, there are a number of design assumptions, and it's -- as the trial has matured, so too has our approach been to recruitment. Actually, the most interesting dynamic of the study was that we had a huge amount of uptake. We rapidly onboarded a lot of sites.

And in fact, the trial essentially recruited in 5 months, which I think is about the fastest study. And so because of the backlog of patients that we had in the study, we actually elected to fulfill the backlog. So it's not as simplistic as a statistical plan or a statistical analysis. It's more about the dynamic of the study itself. I don't know, Dave, if you want to add anything to that.

Just really, all I would add, Laura, is that it was a very close and, I think, collaborative dialogue with the FDA. The FDA understands the background of the PRIMARY and the PRIMARY2 studies that came from Australia, and they were large multicenter investigator-initiated trials, generating data not ultimately fit for an FDA filing.

So the FDA really understands that background, and BiPASS is an industry-sponsored study that builds on those studies with agreed endpoints, an agreed statistical analysis plan intended to support a regulatory filing, as Kevin has so nicely articulated.

Hopefully, that answers your question, Laura.

And then just to come back to Zircaix. I heard the comment you made in response to Chris' question just now about resubmitting in the next 1 to 2 months. Does the extension that you have from FDA come with any specific time frames or deadlines? And does it -- is its existence a consequence in any way of the corrective CRL that you received, which seems to say that the regulator failed to consider some CMC data that you submitted a year or so ago? Or are they unconnected?

They're unconnected. There wasn't any additional actions that came out of the delayed CRL. That was an administrative matter on the FDA side. So from our perspective, nothing really changed. And just to be clear, there's been a lot of chatter about deadlines and dates or something, but we're not quite sure where this really comes from. There's nothing that's restricted us for being flexible on the date of resubmission.

Your next question comes from Andy Hsieh from William Blair.

Congratulations on continued solid commercial execution. Two macro questions, if you don't mind. One, maybe against the backdrop of your comment on being modality agnostic and the Regeneron collaboration, it's a pretty animated, I would say, discussion at the ASCO radiopharma session about antibody modality, looking on a negative perspective. So I'm curious, Chris, if you can kind of opine on that or rebut against that.

Secondarily, Lantheus is, I guess, in the process of being merged with Curium. And I'm curious, just against that backdrop, do you see a difference in terms of your strategy or kind of continue everything as planned?

I think for the first question, data always speaks for itself. And I think that the rebuttal -- I mean, since you were there at the ASCO session, you know that the rebuttal from the floor was actually pretty vibrant as well. So I think nuclear medicine has a history of being developed on budget-conscious academic environments where there's no ability to even consider experimenting with a biologic. And so there's a lot of prejudice there that isn't driven by data. It's really driven by capability. And I think that exists to the present day.

At the end of the day, what we care about is what's the pharmacology of the drug, how does it interact with the target, how does it deliver a payload. And we obviously wouldn't be investing money into programs when we have an agnostic approach if we didn't feel that there was a merit to doing so.

So I would encourage anyone that's interested in debating that further, come to our R&D Day, and that would be the place certainly where we can go and do a deep dive on that perhaps rather than an investor half year results call.

I think regarding the second question, it will be disappointing not to have a competitor reminding us of their 2% growth compared to our 22% growth on their earnings calls. But I'm not sure that, that's something that we'll miss as a comparison in contrast. It sort of mystifies us a bit why you would bother acquiring a company with such a flat growth outlook.

But apparently, maybe it's a European mentality or something, I don't know. But nonetheless, we kind of see it as business as usual for us, and it will be interesting to see what happens in the future in the space.

Your next question comes from David Low from UBS.

Congrats on the quarter. I just want -- a couple of questions actually on BiPASS study. It seems like enrollment is going very fast. I mean could you just provide some early feedback from physicians enthusiasm on the study so far? And what successful outcomes will look like for that study?

I think, Dave, that's your wheelhouse. Do you want to pick that one up?

Yes. Look, we were pleasantly surprised. This study, multicenter international trial, but essentially, international means United States and Australia, multiple sites across both of those countries. The first site was a site in Melbourne started to kick the study off. That's where we got the ethics committee approval first before we got the IND and the IRB approvals to open the sites starting in Texas and then expanding in the U.S. from there.

But what pleasantly surprised us was the site in Melbourne almost had the study done and dusted by itself. They enrolled a very significant proportion of patients, and we didn't tell them to slow down.

But what that showed was that there's a very -- there's clearly a very significant physician desire to add the benefits of gallium PSMA PET imaging on top of MRI imaging because they believe, from their experience on study, that it furnishes the clinician with more useful information about whether to biopsy or not, if to biopsy, what type of biopsy to do, a template biopsy or an image-directed biopsy. And so the treatment planning can be done with a lot more certainty for the patient.

So that early experience and that rapid enrollment rate classically will tell you something about the investigators' feelings towards the clinical performance of the asset under study. And that then propagated when we were able to open the study at the sites in the U.S. And as Chris said, it enrolled within about 5 months for the total sample size of sort of 350-odd patients.

I would just add that our lead investigator for the U.S. is going to be at the R&D Day as well to talk through that. So it would be a good time to hear his opinion about your question.

I think that -- hopefully, that answers your question.

Your next question comes from David Stanton from Jefferies.

Just one from me. Can you give us sort of an update in terms of potential time lines for Pixlumi in terms of the marketing authorization application has been accepted? When might we hear a decision on that, please?

Look, we haven't really given updated time lines because there's some early review of the package that can lead to clock stops and stuff like that, that we haven't sort of crystallized. So I think that's more of a watch and wait at this point in time.

If you follow the review time line to the letter from submission, it's around an 18-month process. It can go a little bit faster, a little bit slower depending on clock stops and review times. But that's sort of the standardized approach.

I don't think there's anything in our submission that's particularly controversial, and we're not expecting any major issues. I think when we submitted the Pixlumi package, we had the benefit of having had it reviewed by a major regulator already. And so when we submitted it was with a high degree of confidence in the package that we were putting forward. So we'll certainly be keeping you updated on time lines. Do you have another question, David?

No, that's it.

Your next question comes from Melissa Benson from Barrenjoey.

I just had two. The first one is just to clarify on David's comments around ProstACT Global and the progress there. So you had a successful June FDA meeting we heard back there around Part 2. Have you now filed, I guess, the formality of the IND amendment paperwork? So we're kind of on track for U.S. sites this half?

And then similarly, you mentioned European progress. Last year, you talked about a clinical trial application over there, the European regulator to review that for the same thing for European sites. So just any update on whether you've submitted kind of a CTA for them to review.

Yes, I can answer that very quickly. We had a -- the review of the Part 1 data from ProstACT Global was sort of treated as an end of Part 1 meeting rather than a pre-Phase III meeting. So we have one more engagement coming up with the FDA in a couple of weeks' time, and then we'll be filing the IND on the back of that.

That's just a standard process as we go into Part 2 just to finalize the full scope of the IND amendment that we plan to submit to the agency, and it's just courtesy to have that pre-submission meeting. So we consider that to be sort of fairly much part and parcel from a regulator engagement perspective.

Regarding the European submission, our priority really has been to get U.S. patients into the study this year. And once we're over the hump with that on the U.S. side, then we'll turn to a broader focus. I do know we have Eurosphere jurisdictions already in the study, U.K., Turkey, but we'll add some other European countries that are keen to be involved in the study once the FDA submission is in. Do you have another question?

I did have one other, and this was actually on revenue guidance. So you've kind of maintained the $950 million to $970 million, but noted that you're at the -- on track for the top end. I guess the question just being like there was a lot of strength in the second quarter, particularly in the PSMA PET franchise. And if we infer that into the second half, it kind of -- it suggests that you should already be -- you're definitely on track, albeit above, and I think consensus is now sitting above.

So is that conservatism on your end to kind of not upgrade and move the guidance range? Or are you kind of factoring in anything in the second half or that we should be kind of aware of dynamically around seasonality or even like the Lantheus TruVu launch?

We've given guidance, and we're maintaining our guidance.

Your next question comes from Dennis Hulme from Taylor Collison.

I also got a question about BiPASS. If we assume if the trial results are positive -- two questions. Can you talk about the label claim that you expect to ask for BiPASS? And secondly, if it is approved, how do you see it being used? We saw in the PRIMARY2 trial that there's definitely a strong benefit in patients who have a PI-RADS score of 3 or less. Do you think that's use is likely to be targeted in that patient population at least initially? Or do you see a scope could be used more broadly, including in patients who have higher PI-RADS scores?

I'll let Dave comment on the clinical utility. We don't typically give label guidance until we've negotiated a label with the regulator. But obviously, the spirit of the study is to help guide decision-making around biopsy utilization. And so that will be the sort of context of the label. And I think there's a lot of misunderstanding. The goal of the study is really to make sure that the right patient gets a biopsy.

It's not about eliminating tissues. It's not about taking away the value of pathology in cancer diagnosis, but it's really about making sure that, that very large proportion of patients that do have a biopsy, the ones that aren't going to benefit from it, the ones that come back with unequivocal or negative findings, that those are the ones that are not being subjected to a fairly unpleasant and expensive procedure. And Dave, do you want to add anything in terms of the PI-RADS question?

Yes, I will. Yes. Thanks, Dennis. Good question. So in the -- like I talked earlier about the agreement that we came to with the U.S. FDA in terms of the design of the study and the patients who would be enrolled. So we agreed with the FDA that it would enroll PI-RADS 1, 2, 3 and 4, but not 5. PI-RADS is the 1 through 5 scoring system that a radiologist uses to score the MRI scan. So the PI-RADS 1 is not commonly seen in a 65-year-old man. PI-RADS 1 is typically a younger adult male, 20s, that has an absolutely normal prostate. And PI-RADS 5 is prostate cancer.

Now what we did agree with the FDA was even though we don't need to enroll PI-RADS 5, the FDA would consider the totality of the data and would consider that it covers all of those PI-RADS scores.

But just at a high level, what the study is going to enable in terms of clinical implementation post approval is the objective of halving the number of prostate biopsies that need to be done or that are required to be done, so halving the number of biopsies, while not missing patients with clinically significant prostate cancer that then need to have a biopsy done.

So obviating the need for biopsy in half the population of patients that currently get biopsy, and then in the patients that do require a biopsy, taking it from a template biopsy, which is between 12 and 20 needles, placed transperineally, through a very sensitive piece of real estate to one targeted biopsy.

So we say none and done obviating the need for a biopsy in half the population that today would get biopsy, or one and done, shifting template to a single targeted image-guided biopsy. That's the purpose of BiPASS. And in doing so, we believe that there will be very significant clinical uptake that it will become standard that PSMA PET scan is done as well as an MRI scan before anyone has a biopsy. Does that help, Dennis?

Yes. That's very helpful. And if I can ask just quickly on TLX597. Can you just talk about what you think the next step will be for 597 after the OPTIMAL-PSMA and OPTIMAL-e trials?

We're waiting for really the first chunk of data to read out. I mean our priority right now from a prostate trial perspective is clearly to complete the recruitment of 591. It's our major program and our flagship program. So we've got some data to read out from the first Phase II trial, and we're really looking forward to reading that data out. And then once we've got that in hand, that will inform -- that will be the catalyst to inform the market about what our plans are longer term for that asset.

That does conclude our time for questions, I'll now hand back to Dr. Christian Behrenbruch for any closing remarks.

Well, thank you very much, everyone. Hopefully, that was a useful update. And again, a very strong quarter from a commercial perspective and lots of great clinical outcomes. We look forward to seeing you at the R&D Day in New York in a few weeks' time. And as for this call, I'll leave it there and wish you all a good day. Thank you.

Good morning, and good evening, everyone. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communication at Telix. Thank you for joining our educational webinar on our neurologic oncology portfolio. .

Before we commence, I want to note that today's presentation includes forward-looking statements. These forward-looking statements are based on current assumptions. Actual results could differ materially. We do advise you to read the safe harbor statement.

Today, you'll be hearing from Richard Valeix, CEO of Telix Therapeutics for a portfolio overview; and this will be followed by Dr. David Cade, Group Chief Medical Officer at Telex for a clinical update on our therapeutic and precision medicine candidates in the neurologic oncology portfolio. This will be followed by a discussion with key opinion leaders in the field, Dr. Joseph Pitcher; and Dr. Nelleke Tolboom, who David will introduce more fully during the session. Following the discussion, there will be live Q&A, whereby David Richard will be available to take your questions.

With that, I'd like to hand over.

Thank you, Kyahn. I'm Richard Valeix, the CEO of Telix Therapeutics. As you can see, Telix has one of the deepest pipeline in the rated pharmaceutical industry. But let's focus today on the neuro-oncology portfolio. This is an area where innovation has been stagnant for the past 2 decades. And we believe, based on the clinical evidence generated to date that we are positioned to bring new therapy options to patients and become a leader in this field.

Within our oncology, our lead candidate is an iodine-based compound named TLX-101 therapeutic, which is the subject of a pivotal Phase III trial named IPAX-BrIGHT. David, our Chief Medical Officer, will speak today about this and other trials for this candidate. We are also exploring an asset-based candidate, TLX102 therapeutic. It's an alpha emitter in an earlier development phase. One of the key features of our candidates is the ability to cross the blood brain barrier. Our molecule is designed to overcome this challenge, and we develop a simple IV route of administration, which is a breakthrough innovation considering all the other therapeutic options, which are very invasive. Our key opinion leader will talk more about this today.

As a leader in radiopharma, we are dedicated not only to treat disease but also to diagnose patients. It's what we are used to call the per agnostic approach. And this is the reason why we have developed an imaging agent for glioma, TLX-101 diagnostic expected to be branded as Pixclara or Pixclumi, depending the geographies. This is currently under regulatory review in the U.S. and in Europe. -- while being developed as an agent for imaging and glioma initially, it is also intended to be a patient selection tool to make the patients eligible for our 2 therapeutic candidates.

Next slide. With this slide, I just wanted to show the importance of a diagnostic pair, an imaging agent associated with a therapeutic compound. On the left part of the slide, before treatment, you can see how clear the image with FET-PET, or ICA is compared to MRI, showing a more extensive and active disease. On the right part of the slide, after treatment with TLX-101 therapeutic, the new images illustrated in that case a near complete response, showing the power of diagnostic to see it and treated. More on this later in the presentation.

But let's move on the total addressable market in the next slide. Our non-oncology franchise faces a significant unmet need. Gliomas and glioblastoma represent an underserved patient population that has not seen any new therapies over the past 2 decades. It's also a sizable and growing patient population with increasing diagnosis rates supporting long-term growth. This creates a compelling commercial opportunity for Telx. Our initial focus is on later line patients, more precisely in recurrent glioblastoma. It's the focus of our Phase III therapy study, where we have an orphan drug designation granted.

We pursue also the opportunity to expand into earlier lines of treatment, and we have just completed a Phase I study in this setting. We see the opportunity to expand into multiple indications and broaden the market opportunity, including into another indication lepto managerial disease or LNG, with our alpha targeting therapy. The patient number on this slide illustrates the potential of this complete disease area.

But with that, I will turn over to David Cade, who will provide a clinical update.

Well, thanks, Richard. Much appreciated. David Cade is my name, and I serve as the Group Chief Medical Officer at Telix. I look forward to going into our clinical programs in a bit more detail. Let's go to the next slide. Thank you. Now before I go into our current clinical trials, I think it's important to recap the previous key studies that we've undertaken and completed with TLX101, which comprise the IPAX-1 and the IPAX-Bright studies. Now both these studies evaluated TLX101 in combination with standard of care external beam radiation therapy in patients with glioblastoma.

And of course, both these studies were done in the recurrent disease setting. Now this is a population of patients who have very few effective treatment options available to them, and we clearly need new and better options. And I can summarize these 2 trials very simply, I think. Firstly, both studies confirmed that TLX101 is well tolerated with a quite benign safety profile. And then secondly, both studies indicated encouraging overall survival durations. In other words, when we measured overall survival from the time of first diagnosis, overall survival was in the range of 23 to 32 months.

And then when we measured overall survival from when treatment with TLX101 was initiated, overall survival is in the range of 12 to 13 months. Now both these durations depending on either from time of initial diagnosis or time of initiation of treatment, both of them are very encouraging overall survival durations. Now more recently, we reported the completion of patient enrollment into a third study, which is IPAX -2, which is our study of TLX101 in combination with frontline standard of care in newly diagnosed patients. And while follow-up for IPAX-2 is still ongoing, this study has been particularly pleasing with no dose-limiting toxicities even at the highest planned 10gigabecl dose regimen.

And I look forward to reporting the outcomes from IPAX-2 later on this year. Now let's move to IPAX-Bright and IPAX-2 in a little more detail, which I'll go into in the next couple of slides. So if you go to the next slide. Now here, I think this really nicely lays out IPAX-Bright, which is our registration-enabling Phase III study that's evaluating TLX101 in combination with lomustine in patients with recurrent glioblastoma. Now lomustine is an oral alkylating agent that's been around a long time. It's primarily used for patients with recurrent glioblastoma once it progresses following standard frontline care, which will typically comprise of maximal surgical debulking by the neurosurgeon followed by chemoradiotherapy.

Now lomustine is commonly used when disease recurrence occurs, but there's still no established standard of care. in this disease setting. And hence, we really need quite desperately new options. And as you can see, IPAX Bright is a 2-part study, where in Part 1, we're evaluating 3 cycles of the highest dose of TLX101 at 4 gigaberlles plus lamustine at 90 milligrams per meter squared. Now if this combination is tolerated, we'll proceed quite rapidly with an expansion cohort of another 12 patients before we proceed to Part 2 of the study.

Now Part 2 is where it gets really Dose of TLX 101 that we could give when we layer it on top of frontline standard of care. And as I mentioned earlier, we're very pleased that there's been no dose-limiting toxicities in this study. Indeed, the safety profile has been really quite benign and we've been able to escalate to the planned maximum dose of 10-gig back rules, and I look forward to providing an update on this study in the coming months. Now let's go to the next slide.

Now to round out the picture, and I think that's probably quite apt. I'd like to briefly cover the imaging side of our neuro-oncology portfolio. Now while conventional MRI has long been the standard of care for imaging malignant gliomas in the brain, the purpose of diagnosing and staging these tumors, I is also used to determine whether a patient is responding to a treatment, for example, chemoradiotherapy.

But especially in this setting, when we're using MRI to work out response to treatment, there's some significant limitations with MRI, where depending on the literature that you look at, up to 40% of MRI scans are deemed equivocal. And they can't tell us clearly whether a patient's tumor is growing and progressing on the one hand or whether it's what we see is simply an artifact of treatment or what we call treatment-related change. But as you can imagine, this inability to distinguish between disease progression and treatment-related change that can lead to a delay in treatment or overtreatment or under treatment, which this group of patients simply don't have the time to be able to afford.

Now if you look at these 2 images, you can see how clearly the active tumor contrast on the right-hand side when you compare FURN18FePpit using Pix Clara versus MRI. Pilaris, therefore, a critically important additional tool to support clinical decision-making in patients with malignant gliomas who need definitive decision making. Now let's go to the next slide, please, in combination with conventional MRI. Now these data come from a prospective study evaluating whether the diagnostic accuracy of MRI could be improved by the additional use of fluorine-18 fat PET with Pixclara. In the study, 26 biopsy samples were taken and the diagnostic performance was determined by the area under the receiver operator curve.

That's that dram on the right. That's the technical terminology that we use. So for MRI, sensitivity was 96%, and specificity was only 53% specificity, which is not good enough. The combined use of MRI and Fluor had significantly improved that specificity into the high which is exactly what we want. So Pixclara, therefore, is a very eagerly awaited tool to improve our diagnostic accuracy of gliomas, and it's currently under the review by the U.S. FDA with a target approval date in mid-September. So with that, I hope that gives you a solid foundation for our imaging and our therapeutics pipeline.

And I'm looking forward now to moving into our in-depth Q&A session with Dr. Tolboom and Dr. Pichler.

Well, thank you very much for joining us. David Cade is my name Chief Medical Officer at Telix Pharma based here in Sydney, and absolutely delighted to welcome 2 of the most extended colleagues from Europe. Europe is probably the major contributor to the advancement of research and thinking for the way that we treat patients with malignant central nervous system and brain cancers and 2 of the leading institutions we have clinicians joining from.

So first of all, Professor Joseph Pichler from Kepler University in Linz in Austria. Professor Pica is the leading neuro-oncologist and over many years in the field, a contributor to the advancement of our approaches to the way we treat patients with some in particular. And also joining us is Dr. Nelleke Tolboom from the University Medical Center of untrack in the Netherlands. This is a leading group from the Netherlands. And Dr. Tolboom's research is focused on malignant brand units, but also as a nuclear medicine physician, how we image them and also, you have a very strong interest in pediatric neuro-oncology as well.

So I think I'm delighted to welcome you both. I think given that we've got quite a diverse audience. Let's start with some basic fundamentals. And I think I might direct the first question to Professor Pichler, Glioblastoma is a disease where there's never an average patient. But as clinicians, we have quite average approaches. It's a difficult disease to treat. So could I just sort of ask you if you could lay out the -- some of the basic demographics or the demiology of glioblastoma? And what would -- if you paid the vignette of a patient who was diagnosed with glioblastoma and the way that you would manage them, how does that look?

I will give you a short overview of the current state of gemology a little bit about the standard of care therapy and perhaps some future strategies in this elastin cancer. So here you see that GBM is increasing burden. However, survival rates have not improved about last 2 years. You can see on the graph, we had a little rise up the annual incidents and average Solar is not really good -- it was not really better in the last 20 years. We have spent a 5,000 new brain and CNS tumors every year in the U.S. with 18,000 death per year.

GBM is the most common and most devastating type of break cancer accounting by 5%, all malignant brain cancers in total. So the median overall survival of these patients rise from 2006 to now, to this date only for 15 months at the beginning of the year and rise is a little bit up to 18 to 20 months today, the median progression-free survival is within 1 year. So it's really unmet need to have really effective treatments. And you can see it on the next slide. First-line treatment of the glioblastoma.

Our Maximal safer surgical resection, followed by accommodation radiochemotherapy, using alkylating agents the most used agent is temosalomide. But also with this treatment, we have a progression-free survival about 7 months and recurrence rate is very high in the first 2 years. Upon recurrence in these patients, we have no standard of care treatment. You can reoperate the patient, you can real the patient. You can use other chemotherapies, but nothing really prolongs solar at that date. And in the sales recurrence, the tumors often refractory and it is a positive situation. and imaging modalities right how to diagnose this cancer is the gold standard MRI in the last 30 years, but MRI have some limitations, and we will further discuss these limitations with new treatment in metering modalities with altogether.

So in the next slide, you can see, in summary, the progression of treatment, the progression of diagnosis and the progression of diagnosis with imaging and with molecular pathological diagnosis. We have the radiotherapy and operation in the last millennium treatment was added with temosolomad additional to radiotherapy from 2000 on Bevacizumab was introduced in 2010, but no study shows a prolongation of overall survival. Tumor treating field were added. It's not very wide accepted this kind of treatment, but it has a positive study as a study or planned. Imaging modalities was less Millennium CT than the inclusion of MRI.

Treatment modalities are now more and more added with T Pet, ACI pads, and we will discuss it in the next few minutes. So treatment is always necessarily have right diagnosis. Diagnosis with immunohistology is added now in an integrated diagnosis with the double on classification based on molecule model markers. GBM presents a significant and persistent unmet need for patients treatment because we have no really good option to prolong survival is effective with essential.

So the next slide, I will fair to [indiscernible], if it is okay, David?

Yes. Yes. Look, I think in...

We have a new target and a new treatment option, but the [indiscernible] the structure behind is more explained by [indiscernible] as a specialist for nuclear medicine.

Well, that leads me to a question for Dr. Tolboom is the brain has a special protective apparatus called the blood brain barrier, which not only protects it from undesirable chemicals also the drugs that we want to get to the brain various tumors. As a nuclear medicine position, I think it would be really relevant for you to discuss the blood-brain barrier and the challenge that, that poses and then the unique target that we are targeting. And then I'll have, I think, a follow-up question on imaging as well.

Thanks, David. Well, that's a very interesting question. Like you said, brain tumors or gliomas are tumors from the gliocells from the [indiscernible] and they have -- unlike other tumors in the human body they have an added layer of defense around the blood vessels. So like you said, toxins cannot enter the body, but that means drugs can also not enter the body. So commonly, we use MRI for imaging brain tumors. And what we greatly rely on is on the enhancement that you see on MRI an enhancement on MRI is gadolinium leaking through a leaky blood brain barrier like we see the core of a glioblastoma, so the more aggressive form of brain tumors, for instance.

But around that core, where the blood-brain barrier's leaky, there are also more infiltrative components of the brain tumor, which have a blood brain barrier, so which do not permit leakage of gadolinium or leakage of drugs for that matter. So that means that the brand tumors are very difficult to image cause we don't see infiltrative components and also difficult to treat because -- it's very difficult to treat those infiltrated components, which are protected by the blood brain barrier. And I think that is where the LAT1 and the LAT2 targets really are a game changer because they're on the blood-brain barrier. The brain needs essential amino acids as building blocks and the brain let's amino acids through via the lab transporters.

And that means that if you radiolabel an amino acid, for instance, with amino-acid or with TLX101, the compound your company is using for treatment that it also gets across the blood brain barrier because the brain does not see a difference between a normal amino acid that it needs for building books or the radioactive amino acid. And because the brain tumors have a higher uptake of those amino acids, they also get taken up. the radioactive amino acids get taken up by the brain tumor more, so we can visualize that infiltrative component with the compound, but also treat that infiltrative component with the compound. And that is, I think, where product and the mechanism of imaging and treating disease is so promising for this group of patients.

Dr. Tolboom, I noted that Professor Pichler was showing some of the basic epidemiology of glioblastoma One thing that really jumps out is the abbreviated limited survival duration as researchers and clinicians we need to come up with more options. But in that context, we have to make rapid decision-making in terms of what is the optimal treatment. Could you maybe talk about the conventional imaging, CT and MR -- and yes, in the molecular imaging that in Europe as clinicians, you have broad access to, but then the United States clinicians do not have board access to molecular imaging. So maybe if you could talk about FET-PET what does that bring?

Right. So brain tumors are imaged mainly with MRI. And after the initial diagnosis, patients again sequential MRIs at set time points to see if a treatment is working, if the tumor is stable or if they have recurrent or progressive disease. And while MRI really is the hallmark of imaging for brain tumor imaging. It does a fantastic job. It shows the infiltrative component like we just discussed, but you also have other modalities with MRI and flare sequences also newer options with MRI like perfusion and metabolic MRI.

MRI only shows part of the personal in my opinion. And amino-acid pet really is an additional very valuable tool. It's not in the game to replace MRI, but it does really show really additional value to MRI, for instance, in patients where MRI can sometimes have a problem in distinguishing if a patient is having -- if new enhancement on MRI if that is due to the treatment itself, so due to the radiation and the chemo or if it is in fact tumor progression.

And as you might understand, there is a very -- it's very crucial to differentiate between the 2 because they are treated very differently. And that is where aminoacidet really can aid the diagnostics in patients. So emirate is not out there to replace MRI, but it really is an additional extremely valuable tool for instance, in the follow-up of patients during their treatments.

Yes. Look, that's very clear. Well, I think both of you are trialists, your very significant trials, in fact, contributing to the literature. I might turn back to Professor Pichler. You were the principal investigator on the IPAX-Linz study, named after your institution. But TX-01 Telix, which is 131 IPO, a therapeutic agent when you did that study in recurrent lease. What might stop asking you about the trial, what led you to initiate that trial. And what was the purpose that you were trying to examine?

IPAX-Linz was initiated because I've mentioned it before, we have no standard of care, standard of therapy in the recurrent setting and IPAX-1 was the study first in patient Phase I study with different doses of [indiscernible]. And I want to add some information with a couple of patients additional to this first-in-man study. So we conducted the study and closed it with 8 patients treated with much high doses than in the IPAX-1 trial. We administer [indiscernible] before the [indiscernible] radiation and 2 tapers after reiteration. And radiation therapy was applied fractions of trade. So that was the same as in IPAX-1.

The inclusion criteria comprised patients with recurrent GBM and first or second recurrence that's not different to IPAX-1. And also our reoperation was allowed in this setting. It was also not allowed in the IPAX-1 study. But after reoperation, have to see a residual tumor in MRI or in a as mentioned, Malika, the MRI and the FET-PET have different signatures because sometimes we see no tumor under MRR because the blood brain barrier is intact and infiltrating tumor part but we see it on the FET-PET. And when we see it on the FET-PET, we have a target for you to follow. So we have the option also in operated patients. The primary outcome was a safety and tolerability because of lack of a lot of patients and secondary endpoint comprised progression-free survival and overall survival also.

So I can share some outcomes if you want.

Yes, that's important. Yes, if you could talk about the impact, I mean, it was a small Phase I study. You mentioned 8 patients. What would say the impact was to your outpatients? And what did you -- what should we take away from IPAX-Linz?

I think the impact was we gather more data, additional to IPAX-1 treatment, IPAX-1 treated patients. And also, we got further information on the feasibility of the treatment and also on toxicity of the treatment. And I will state that the impact of the patients is very good because the treatment is very well tolerated. The only for the patient is that they have been isolated for a couple of days. But they have no relevant adverse event or serious adverse veins, only 3 patients experienced adverse event with liquopenia grade 2 or the lymphopenia 3 and 1 thrombocytopenia grade 3. One patients have fatigue and the most other events were very, very mild.

So in this primarily palliative situation of recurrent first or second current GBM patients is very important that the patient has not to suffer from the treatment and we can guarantee with the treatment of IPAX, they don't have to suffer from the treatment side effect. That's the patients planned.

So this is a patient from your study. I think I believe you presented this at the European Nuclear Medicine Meeting last year. Could you give this as a vignette of one of your patients, a case study of the dilemma that you face with this patient that you were trying to address on the study and if you could step us through the case, I think that would be very illustrative.

Yes. You see in the slide that the patients have a recurrent tumor clearly seen on the right image, but also very impressive seen on the FET-PET scan. And when you administer the i0dine, [indiscernible], you see a clearly uptake in the tumor. And this patient have a partial response after this treatment and a good quality of life during the whole until she died due to the tumor. So I think it's impressive when you see that the patients are treatment with fave a very clear uptick, and we see we hit the target, really, we can treat it, and -- but we have to look for the optimum dose in this treatment. We don't know it now.

I think a higher dose than IPAX-1 is necessary for relevant treatment. The combination of the dofolan therapy with the radiation therapy has in my opinion additional effect in enhancing the treatment effect in strand break of the DNA of the tumor. So for the future, perhaps not only the single treatment is utopian is the key of treatment, I think we have to find perhaps some additional component additional treatment combined with this kind of radiation internal radiation.

Okay. Well, I might turn to Dr. Tolboom. As I mentioned at the opening University Medical Center attract is 1 of the leading Western European institutions to million branch humans you've been doing some extraordinary research. But to Tolboom, Ithink you've tread approaching 20 patients. What types of patients do you treat? I believe it -- it includes adults and pediatric patients, and it includes glioblastoma and other forms of malignant brain tumors. So if you could maybe summarize what is your patient case load would like? And maybe you can talk about the types of patients you're treating?

Well, we're very fortunate to be able to collaborate with Telix, obviously, to get our hands on this promising compound. So we have been treating a lot of patients in studies, but also outside of the studies as combat use. So in certain instances where there was absolutely no other treatment for the patients. And we have been treating mainly patients with a glioblastoma. So the most aggressive form of glioma but also indeed to pediatric patients, we're looking into that. We're adjacent to the largest pediatric oncology hospital in Europe. So we collaborate with them a lot. And like Professor Pichler mentioned, the high clinical unmet need for glioma patients, it is as high pediatric neuro-oncologic patients.

So aside from the pediatric patients, we've also treated some patients not with a glioblastoma, so not the most aggressive form of them, but with maybe a little bit less, but still aggressive and fatal glioma. So we've been getting more and more experience on the treatment and also for Nuclear Medicine awards around the world for the theranostic concept is getting very popular. So we're treating a lot of patients, but these are mainly patients, adult patients and also prostate and neuroendocrine tumor patients.

And that is a holding for ball game to these neuro-oncological patients, which take, I think, real teamwork and expertise care with neuro-oncologists and the oncologists in our center and in the center like Professor Picker. So we've been mainly treating glioblastoma but also pediatric cases and higher grade gliomas.

Okay. I think that summarizes it very nicely. Now we -- Professor Pichler talked about Phase I trials, IPAX-1 that's been done and buyback and IPAX-Linz that has been done. Now we'll get on to IPAX-BrIGHT, which is a multicenter international Phase III trial, which we need to understand where IDN-131IPA, TLX-101,T-X might contribute in the future. But case studies in this setting, this is an orphan disease glioblastoma. So case studies remain highly relevant to inform our ideas about research. You reported a near complete response in I believe, a treatment refractory patient, again, just recently -- could you step us through that case study and the relevance of the findings from that case?

Right, right. This is -- I think this is a super exciting case for well, especially for the patient, but I think for the whole field, really, because we have to understand that glioblastomas are such aggressive tumors that even like slowing down the disease progression of disease is -- would be -- is fantastic or stabilizing let alone, having a near complete response that is the bluest all away. So this is a 56-year-old mail who was a treatment refractory. So he had past treatments for his glioblastoma. As you can see in the top row, the MRI before on the left side and then the MRI after on the right side. If you look at the MRI, you see in the left parietal lobe, you see an enhancing mass, and that was his tumor. It couldn't be resected due to the location.

So surgeons always look at the tumor, is it safe to resect or do we cause too much debilitating symptoms for patients. So this patient had dysarthria due to the location of the tumor. He had several lines of treatment that and the tumor was progressing again. Then he came to us and got a FET-PET, which you see in the bottom row. On the left side. And there, you see the intense uptake of the tumor. And what is very interesting is that if you look at the area with high uptake, where the white arrow is, you also see that the uptake is also in the regions that do not show so much contrast enhancement that we see on the MRI like we discussed before, contrast enhancement is leakage over a leaky blood-brain barrier the stones and gliomas have infiltrative components, which make it very hard to target disease.

And as you can see that the FET does come does come there. So that's also where the TLX-101, Telix also will come. So it also treated the infiltrated component. So this patient got treated with 1 cycle and he tolerated it extremely well. I think is the only complaint was maybe a little bit of boredom of being in our isolation rooms. And then he came back and after 4 weeks, he got another cycle. That's what we typically do, give patients 2 cycles. And then in between, we waited a well to see how well he tolerated in. And it's good to realize that this patient got to 5 gigabits, which is much higher than has been given before in case studies, but also in IPAX-1, 2 and Linz.

And then he called lomustine, which is a chemotherapeutic for a while. That's not something that is. It differs a little bit in Europe. Some countries, I believe Germany gives it standard as a second line in Holland, it is offer, but it's not always given. So this patient did receive it, but the lomustine is so toxic that his bone marrow his plate that's dropped. So he was taken off the lomustine again and then patient was still in clinical such good shape after a couple of months that we decided together with the patient and they're treating neuro-oncologists to give him 2 cycles more.

And we followed them up for months and then this is what you see after I have to -- I think after something like 22 months, you see his MRI on the right and the feed in the bottom. And if you look at the MRI, you hardly see any contrast enhancement anymore, which is that alone is something we never ever see. And then to prove that his tumor is in fact, decreasing and that is not just the enhancement going away, which we have seen in the past before with treatments like bevacizumab in other patients, you see that the uptake on the amino acid that is also going down.

But more importantly, this patient is still alive. He's doing very well. His quality of life has increased massively, and his speech problem, so Dysart has also improved a lot. So for us, this is something we would never ever have dreamed of to see in a patient. And even though it's only 1 patient, and this has to be replicated in a large trial like the IPAC Bright for us, this gives us a lot of hope for the future for these patients.

I think that's a very articulate story for this patient. As I said, orphan disease case studies like this are informative that we don't tend to pay a lot of attention to case studies in the common cancer, as you know, prostate cancer for men, breast cancer for women or colorectal cancer, second mice can for both men and women. In this or these types of outcomes are informative and they do contribute to the design of the trials that we must run Phase III multicenter randomized trials. Now both of you are principal investigators on by IPAX-Bright, I might I recall Dr. Pichler, probably 3 years ago now was in lens with you contemplating how we might design a Phase III trial, and it got named IPAX-BrIGHT as all big Phase III trials do. They get a good name.

Could you maybe talk about -- share your thoughts on the design of IPAX-BrIGHT and what we are aiming to learn from running that study, which is now underway and enrolling patients, I might add.

Yes. IPAX-BrIGHT is the next study, I think the next step forward in our recurrent setting because the recurring siting is that we have to most unmet need for effective treatments. And as I mentioned it before, in pax pride, we will combine to treatment modalities because it is combined in this dose-finding first part of the study with Waneta, as Delica mentioned it in the patient before. We know that Lomustine has no really effect on overall survival in the recurrent setting over the last 40 to 50 years. But it's an alkylating agent, crossing the blood brain barrier. We know it. have a little bit more toxic effect on the bone marrow as but it's not very complicated drug in oncology. Cheroncologist is very mild, mild drug, I will say.

So we will combine it because I think term out of actions will be better for treatment. And the mode of action is an alkylating agent different to radiotherapy in double strength base and are also in repair mechanisms because lomustine has a limitation of the of chemo resistance in tumors with unaffiliated MGMT promoter that's chemotherapy-resistant mechanism in glioblastomas affecting about 50% of all glioblastomas. And this calculating 18 has not another good effect in this type of tiers. So -- but in the other side, the 50%, we have an option with the combining for an enhancing effect because also [indiscernible] when it was given only in the adjuvant setting, is that not did effect as it was combined in the concomitant tenosolomide in combination with radiotherapy.

That was the effective part of the [indiscernible]. And so I also think IPAX-BrIGHT is good for the next phase to combine 2 treatment modalities in the recurrent setting.

Okay. Look, I think that designs -- it's a very simple design, isn't it? And I think it's going to answer a fundamental question. You made the point earlier on vesicular that upon first recurrence, yes. And 90% of patients or thereabouts do recur. So pretty much the entire population that we treat with maximal surgical debulking and postoperative chemo radiotherapy. Once we've done that, what is it, it's a median of 7 or 8 months, and they -- 90% of patients do recur. So we need something there. But I do note that the National Comprehensive Cancer Network, the NCCN guidelines in the U.S. recommend a clinical trial which can include unproven agents as being best treatment upon first recurrence.

So clearly, we clearly need new options, and we're hoping that this randomized trial will address that. I've got a follow-up question for Dr. Tolboom. You talked earlier on about using -- well, you talked about the limitations of contrast MRI and sort of 30% or 40% of MRIs being equivocal, and we need FET-PET to adjudicate in that setting. But could you comment maybe on the role of a theranostic approach where we use a 18 FET-PET for patient selection and then 131 IPa for treatment, but for genuine theranostic par there. What is the role for theranostics in gli0blastoma?

Well, I think the beauty of the theranostic treatments with you have the imaging for patient selection and then almost the same compound for treating the disease that you do really see that there will be target engagement in this particular patient because if you need to -- if you use histology, that can be from -- it can be either older from their previous surgery or you need invasive ways to get the histology. So I think this is a very elegant, noninvasive way to determine that the -- you're actually trying to attack is visible in the patient.

And I also think this is a little bit a side step if we look at -- for instance, the Altas disease field where a lot of studies have failed because they failed to incorporate -- well, they incorporated a lot of patients, and then when the amyloid pet came about -- they discovered that actually, in fact, I think 1/3 of the patients did not have Alzheimer's disease so they were treating these massive cohorts of patients that were heterogeneous. I think with the possibility of amino assets you can really make sure that your cohort is really the right cohort for the treatment because we don't want to do a trial where we're, in fact, treating patients who do not have progressive disease at that time, but who have to depression, for instance.

So I think the fair pair the imaging and the treatment is really crucial for noninvasive target selection and making a real homogeneous cohort for a trial.

Yes. So Dr. Tolboom, there's a renowned nuclear medicine position here in Melbourne who describes conventional imaging with CT or MRI is lumpology, the study of lumps and do they get bigger or smaller when we treat them. You're a nuclear medicine position and you have the benefit of molecular imaging. So when you use F-18 FET-PET to select patients or when you use it to determine response to treatment, -- how does that help you in having the discussion with the patient about whether they are a good patient treatment and whether they're responding to the treatment that you offer them?

I think that's a great question, David. I think it takes away a lot of the uncertainty, for instance, with the amino acid pit and what we discussed previously, sometimes it can be very challenging to see on MRI if a patient is progressing or if it's due to treatment-related effects, -- and I'm not saying a menace that is perfect, but it does add another piece to the puzzle and help in kind of taking away a lot of the uncertainties We, as imaging specialists, but also treating physicians like Professor Peeler, but especially the patients have because it's very difficult to get like the result of your scan being like we're not sure what it is, come back in 3 months, and we'll do another one.

And as far as treatment selection, I think the amino acid pit is really helpful in showing the patients exactly where the treatment will go and that we -- and the reasons why we think it is promising. So it really helps in visualizing for patients, a little bit of their patient journey. So it does make a big difference in my opinion.

Yes. I think 1 final question, just to frame it this way is I noted when Professor Pichler showed some of the epidemiology, the 1-year, the 3-year, 5-year survival rate for patients have been stuck in first year. We're probably stuck in neutral, really. We've gotten nowhere for really the last 15 years. I think those rates haven't materially changed. So Professor Pichler, if we take a then, if we look through the theranostic land, is what is an aspirational question, what really excites you about what we might see over the coming 18 months, 24 months as we run a pride, what do you think the potential might be?

My statement on this is the -- there are 5 main reasons for brain tumor still defines us. There's an infiltrative growth, the tumor eternity. -- the tumor macro environment, the blood brain barrier and the treatment resistance to the repair mechanisms after acalating chemotherapy. Simplified, we need a new strategy. In the last 2 decades, all treatment failed. The block at in targeted therapy, multiple pathway blockade, immodetherapy fails, local treatment, also high-end immunotherapy with CAR-T cell fate. The radiopharmaceutical treatments in brain tumor are at the beginning and have potential to change really the abiotic options in this divesting disease. And it excites me in this way that it's had a favorable safety profile. We see the exact release to the tumor target, overcoming the blood brain barrier, and we have an option for monitoring with FET-PET.

That's crystal clear, crystal clear. Dr. Tolboom, you have a passion for your patients, you care deeply and their quality of life. So what again, aspirationally, what would excite you over the coming sort of 18, 24, maybe 36 months as we run IPAX-BrIGHT. A lot of these patients, I do hope all have extended survivals. Time will tell but what are you looking for?

Well, as Professor Pichler also nicely put it, but I think there is so much to gain for these patients, and we're not there just trying to elongate their lifespan, but also doing that with really good quality of life. And I think radioligand treatments like we know from treatments for patients with prostate cancer in patients with neuroendocrine tumors really have the potential to be able, hopefully, to slow down disease progression with really good quality of life so that would be -- that's the Holy Grail for these patients.

And I'm really excited for IPAX-BrIGHT. I think that's to have the first ever theranostic trial in neuro-oncology being run at the moment is really exciting. It's like a milestone for neuro-oncology research. And hopefully, with combined for other amino acid that take other CNS diseases that take up a mini acid pet like other brain tumors or maybe pediatric brain tumors. There could be future trials, combining them also with agents that are being used in these diseases and also looking into other radionuclides.

So in the future, I hope we will have a radioligand therapy that will be given in an outpatient clinic. Patients will get the radioligand and then be able to go home and enjoy their life with their loved ones with only minimal side effects and minimal radiation safety rules. That would be my aim.

I would add something. I also think that we are in the beginning of the treatment with the ligands, perhaps with alpha emitters, we spoke Nelica, because it's an outcome treatment possibility and so we have a lot to do in the next years. And the quality of life in this patient is very important, especially in the pediatric population and also involved in the padretic, neuro-oncology tumor boards. And I think we have treatment options in midline gliomas in pontinglyomas who are never can be resected and that's for the children will be a really good option, I think.

Well, look, Dr. Tolboom, Professor Pichler, I think it's not available really the Netherlands and Belgium and Germany and Austria, your European countries are leaders in radiopharmaceutical development, not just in urological oncology but in neurologic with the NAND neuro-oncology. I think a strat part of that group as well of major contributors in radiopharmaceutical development, I hope. And what really shines through is your ambition for your patients and for advancing what has been a drug development stalemate for 15 to 20 years. And I think collectively, we're going to do that.

You both have massive patient case loads. I well aware of that, I'll be to both your institutions. They're enormous. So I won't keep you friendly patients, you've got a lot to do. I'd like to thank you both. On behalf of the audience for your time and I've learned something and I hope the audience has, too. So thank you very much.

Thank you, David.

Thank you.

We will now proceed to the Q&A session of the investor call with Mr. Richard Valeix and Dr. David Cade. [Operator Instructions] Your first question today comes from [Andy Shah ] from William Blair.

Super informative. I just wanted to dig a little bit deeper into the case study with a complete response. -- for the outside world, we don't have a lot of background information about how commonly you see that in the relapsed setting for glioblastoma. So could you paint a picture for us just in the real-world setting, how common or maybe I should say, uncommon do you see a complete response using the standard of care, just to juxtapose that with 101's potential activity there.

Yes. Thanks, Andy. It's David. Yes, thank you for the question. Essentially, in the recurrent disease setting and I made the point during the call that almost all. So about 90% of patients ultimately recur after maximal safe surgical debulking and postoperative chemo radiotherapy almost all of them recur, unfortunately. When we use a salvage treatment in that recurrent setting, and there is no standard salvage treatment. Complete response is exceptionally rare. So it's as rare as being as close to 0 as 1 can possibly get.

So to have an agent that has clearly activity to be able to deliver either stable disease or partial response or in this instance, again, it was just a single vignette complete response is clearly meaningful, given that the survival duration is approximately sort of 7 to 9 months with lomustine if you pick 1 of the standards, Andy. So we must in a recurrent setting, overall about -- so anything that provides disease control complete response, partial response to the disease. It's clearly important. And that is currently almost almost no patients gap.

Your next question comes from [ David Dai ] from UBS.

And I also want to set on the great presentation, very formed learning more about the neuro oncology approach. So David, just a quick question on the IPAX-BrIGHT Phase III trial, given that there is 2 limited therapeutic as for GBM over the past 2 decades, what levels of benefit would be considered meaningful clinically that would actually change the clinical practice and establish the 101 as the new standard of care?

Yes, David, great question. estates there's 2 parts to the answer. So the first part to the answer is that the last major advancement in the treatment of glioblastoma with a European and Canadian trial. It was an EORTC cooperative group trial in a bit embarrassing to say for all of us in the field, 2005, so 21 years ago that added concurrent and adjuvant temozolomide to postoperative radiotherapy. And in 2005 for stop regimen so-called -- sorry, STUPP regimen became the new standard of care with temozolomide, concurrent and adjuvant added to radiotherapy. And that was done on the basis of a 2.5 months improvement in overall survival, if you got temozolomide versus if you didn't. So I think survival went from something like 12.1 to 14.6 months, so a nominal 2.5-month improvement in overall survival by adding that in the recurrent set.

So that's the one of improvement in survival duration that changes the standard of care, and we've been stuck in that year since since 2005. So the second part of the answer is really what does lomustine give today in this recurrent setting. It gives somewhere overall survival in the range of 7 to 9 months. And as we discussed in the webinar, the 2 trials that we've done, they're small trials, the Phase I trials, backspace and IPAX-Linz, had survival durations in the order of sort of 11 to 12 months. So we're looking at sort of a 3- or 4-month improvement in over survival and IPAX-BrIGHT is aiming to at least be able to identify that at a minimum and ideally model. So it's a long answer but I hope that addresses that, David.

Your next question comes from Laura Sutcliffe from Citi. .

Got a question on the Bright trial and hopefully, I get away with this as just one. Is the output of the IPAX-BrIGHT trial, what you would look to submit to regulators with a view to an indication that just captures the recurrent setting. And can maybe you also just give us some color on this setup whereby you have a dose-finding component as part of a for? Why have we chosen to do it that way? And would you need anything on top of that for any of the major regulators?

Laura, thanks for the excellent question. And I would love to ask Richard to contribute because he's a very experienced drug developer. But maybe I'll just kick off and then hand to Richard. To the first part of your question, we will start in the recurrent first recurrent disease setting because that's where we don't have any standard options, as we mentioned during the call, the NCCN guidelines list Phase I trial as being an option for patients with recurrent glioblastoma.

And obviously, Phase I can include trials of agents that are right at the start of their drug development journey totally unproven, so that's not adequate. We need to improve upon that. And then from there, we typically -- if a study works in that recurrent setting, typically would we would then run future studies that move it upstream and Richard can talk about that because he's done that a lot before.

And then just the second part of your question, we're aiming to optimize the dose of TLX 101, so optimizing the amount of activity to inject and optimizing the dose simultaneously of lomustine, what drug dose to give. And that's the first -- that's a part of Part 1. That's the objective of Part 1. I won't bore you with the details, but that's called a Basin design, and that's what the FDA we've, I guess, been in very deep discussions with the FDA to design the first part of the trial to optimize the dose of the radiopharmaceutical when given with the drug. And that's sort of a hot topic probably the last 18 months to 24 months, picking the right dose for a radioligand therapy to take forward into Phase III.

Richard, do you want to add anything to that about starting in the refractory population and going upstream from there. You've done that a bit.

Yes. Thank you, David. So you're totally right, and you summarized well, when we interact with the FDA, they advise us to go for the last line treatment. As you know, classically, in oncology, that they don't want to let us start earlier. They just want to test the product in the last line setting. That's also the reason why they say that. And as Mr. Pitcher highlight we said a combination therapy will be ideal because we are addressing in IPAX-BrIGHT recurrent glioblastoma, which is the most aggressive type of gliomas concept.

So having 2 compounds and having the optimal dose that was really the recommendation from the experts and from the -- so that's the reason why we start with the last line with this dose adaptation as a part 1 and then after that, the dose expansion, which we authorized to obtain this indication in the marketing authorization. But clearly, we have the ambition to expand the use of the 101 in earlier lines of treatment. And the previous studies that we have conducted with external beam radiation therapy goes in that sense plus additional indications with the alpha such as leptomeningeal disease.

So it's the beginning of the development of this compound, but we had to start from somewhere, and this is the the basic topology to start with the last line treatment.

Okay. So just to confirm, the FDA is happy with this trial design?

Yes, I confirm that we designed the clinical trial following the interactions that we had with them.

Your next question comes from David Stanton from Jefferies.

I'm referring to Slide 12 on your deck around the Pixclara or the potential Pixclara drug. Can you talk to us about the sensitivity and specificity of 93% and 94% that you've talked to there. Is that basically new data that you've now submitted to the FDA...

Dave, the last part of your question dropped you wanted to state the last part?

Pardon me, it seems David is disconnected.

Okay. Well, maybe he did get most of you guys, I think, 85% or 95% of his question now. So let's give it a shot. Yes, the Pixclara, so Fluorine-18 FET-PET will be used as well as MRI or as we would say, as an adjunct to MRI and Dr. Tolboom made the point that F-18 FET-PET is not intended to replace MRI. It's adjunct. And when they are used together, the sensitivity and specificity is over 90%. And so that is part of the clinical data package that was included in the refiling of Pilar to the FDA, where we have the goal PDUFA approval date of the 11th of September. So I think that's the last of the questions. I'll hand back to Richard for any final remarks.

Thank you, David. So perhaps to complete the question from David Stanton, that it's true that the sensitivity and specificity will be amazing combined with MRI and the ambition to start with first indication for the characterization of recurrent lips. -- but we can see also there a fantastic world of opportunities to expand these indications. We had the ambition to move the diagnostic tool Pixclara in the adjuvant radiation treatment planning in glioblastoma and also, more importantly, a reservoir of patients, if I can say like that, in the brain metastasis indication when we have the diagnosis and the evaluation of the brand met that's 100,000 patients a year that will beneficiate from this new diagnostic and monitoring tool.

But let's move to the to the last slide, perhaps and conclusion of the session, if we don't have any more questions.

No. There are currently no mortgages at this time.

Okay. Perfect. So let's look at the key takeaways. Can we have the slides on the screen? Okay. So the key takeaways of the session. I would say that with in Telix, we have this fantastic opportunity to do this diagnostic couple of Pixclara and the 101 compound with Iodine. That's the first -- we are the first company with these 2 compounds under development in such advanced stage. So very proud of that. We can see that even Pixclara is now included in the NCCN guidelines as a recommendation improved, but proud of that.

We are also developing our therapeutic candidates with , as you saw, the beta therapies with Aldin but also with the ambition to move with the Alpha area, the asset in isotope that we are already proceeding in the preclinical stage. -- study and with the ambition to move in 2027 with human with the estate. So that's a novel mechanism of actions. And all the the preclinical data and clinical that are very encouraging. Perhaps something that we did not address during the presentation is the fact that in Europe and more especially in Netherlands, within the center of [indiscernible].They have treated more than 20 patients, which is massive.

And if I have to provide you milestones during the year, let's fix meeting during the E&O Congress, European Association of Neuro-Oncology in October 2026 because we just received the information that we patients from the EAP that will be presented and accepted as an oral presentation by Dr. Talboom and Dr. Brad from [indiscernible]. So that's very encouraging. And the medical community will be exposed to this small cohort of 12 patients.

So as I mentioned previously, we will address multiple indications with these compounds in the oncology thing, which is really 1 of the pillar of the indication that we develop with Intelex. We have a deep radiopharma expertise. We control the manufacturing to the distribution and the recent success story with our compounds for the diagnostic of the prostate cancer has demonstrated that we are well positioned to build a success story also in neuro-oncology after urology. And that's perhaps the last word I wanted to share with you.

Dave, you have something to say, please?

No. Look, I'd just like to thank the audience for their time and attention. I hope it's been a valuable deployment of your time. and that shed some light on both the precision medicine and they are not therapeutics parts of Telix's portfolio. I personally think this is a very exciting set of assets where we have a very opportunity with a proximal event to improve the lives of these patients. So thank you for your time and attention.

Thank you.

Thank you for standing by, and welcome to the Telix Pharmaceuticals Limited Unlocking the Potential of PSMA Therapy: A Next-Generation Portfolio. [Operator Instructions]

I would now like to hand the conference over to Mr. Stewart Holmstrom, Director of Corporate Communications. Please go ahead.

Hello, everybody. My name is Stewart Holmstrom, Director of Corporate Communications at Telix. We're very pleased to welcome you today to our educational webinar to present on unlocking the potential of PSMA therapy and Telix's next-generation portfolio approach.

We can just move to the next slide, please. I ask you to take a moment to look at our disclaimer.

Next slide, please. I'm very pleased to introduce today's speakers. Dr. David Cade, Group Chief Medical Officer at Telix, will present on Telix's PSMA targeting therapeutic portfolio. And then I'm delighted to welcome our guest speaker, Professor Louise Emmett, Director of Theranostics and Nuclear Medicine St Vincent's Hospital in Sydney, a Conjoint Professor of Medicine at the University of New South Wales and Clinical Research Leader at Garvan Institute of Medicine Research and also the principal investigator on the OPTIMAL-PSMA trial that she will present today, along with case studies and perspectives based on her experience with TLX597-Tx.

Following the presentation, Dr. Cade will take questions via the conference line and webcast Q&A function. Professor Emmett, who has been very generous with her time already whilst presenting in Europe, will be available afterwards to respond to questions via e-mail.

And with that, I'd like to hand over to David.

Next slide, please. Well, thank you, Stu. Today, together with Professor Louise Emmett, who is one of the globally recognized pioneers in the development of radiopharmaceutical therapies for prostate cancer, I'm hoping that we'll be able to enable you to gain from our discussion a useful understanding of 3 important themes. And the first of those is we'll briefly discuss the current first-generation small molecule radioligand therapies and where in the treatment cascade, they've established themselves for advanced prostate cancer.

Secondly, we'll also discuss some of the challenges that have emerged in applying first-generation small molecule agents earlier in prostate cancer where patients tend to be fitter and healthier, and why Telix is taking a portfolio approach based on very distinct mechanisms of action with TLX591, which is a radio antibody drug conjugate being developed for advanced metastatic castrate-resistant prostate cancer in the ongoing Phase III ProstACT Global trial.

And with TLX591, which we haven't really talked a lot about previously. This is a highly targeted second-generation small molecule radioligand, which has demonstrated a favorable dosimetry profile with a very minimal salivary gland and kidney dose, but a very high tumor dose, which really makes it uniquely positioned for use in earlier metastatic hormone-sensitive prostate cancer.

And then thirdly, I'm looking forward to Professor Emmett, who will discuss her St. Vincent's Sydney group's rapidly growing experience with TLX597, which Professor Emmett and her team are studying in the OPTIMAL-PSMA randomized Phase II trial, which Professor Emmett presented very recently at the IPCS Congress in Lugano in Switzerland.

So if you go to the next slide, please. So I think this slide really very nicely summarizes on the left-hand side there, how we would typically treat prostate cancer once it's broken free from the prostate gland and it's become metastatic. And what you can see is that for early metastatic hormone-sensitive prostate cancer at the start of the disease journey, we would typically use androgen deprivation therapy to block testosterone and/or would use the newer androgen receptor pathway inhibitors or we may use a taxane chemotherapy, especially if the patient has high-volume metastatic disease.

But then what invariably happens is the prostate cancer learns how to progress despite the testosterone tap having been turned off, which is what we call metastatic castrate-resistant prostate cancer, we see that PSMA-617, which is Novartis' agent Pluvicto, is appropriately established for advanced metastatic castrate-resistant cancer over on the right. And this was established 3 or 4 years ago when the VISION trial showed a 4-month extension in overall survival with PSMA-617 when compared to conventional standard of care.

And from here, of course, a very logical next development of such an agent is to undertake trials in earlier disease settings, which is what the PSMAddition trial sought to do. But what PSMAddition also showed is that there are emerging concerns when we try to treat earlier, healthier patients. And the 2 main concerns really could be summarized as the radiation dose to the salivary glands that tends to lead to dry mouth that then degrades patients' quality of life as well as the radiation dose to the kidneys, which may lead to long-term kidney injury.

So in other words, we're probably overtreating these patients with a first-generation radioligand therapy, whereas what we really need is a second-generation agent that exhibits a very low dose to any of the normal tissues if we're truly going to be able to deploy radioligand therapy widely in early mHSPC.

So if you go to the next slide, I think this really does nicely summarize those points that were made at the ESMO Congress in Berlin last October, where Dr. Tagawa from Weill Cornell, he presented the interim data from PSMA addition and Dr. Azad from Peter MacCallum in Melbourne was the discussant, and he critically discussed the results from PSMA addition and the take-home messages that we in the audience should take away for our clinical practice.

And -- what he concluded were really 4 key take-home messages. The first of those was the PSMA addition is the first randomized Phase III trial demonstrating efficacy of radioligand therapy in mHSPC. And ultimately, the progression-free survival benefit will probably lead to regulatory approval in multiple jurisdictions. But to date, there's been no improvement in overall survival really shown. And to date, lower quality of life has been exhibited with PSMA-617 in this disease setting. So that's a very important point.

Secondly, he reminded us as we sometimes forget that he reminded us that the goal of any cancer treatment is to make patients not just live longer, but also live better, and the discussions view was that this was not achieved in PSMA addition.

Thirdly, he indicated that he wouldn't currently recommend the widespread use of PSMA-617 in mHSPC at this stage. And the final point he made, which is very, very important, was that to deliver the best outcomes in mHSPC, it's going to take a really patient-centric approach focused on avoiding overtreatment while minimizing the impact on quality of life and minimizing those late toxicities.

So if you go to the next slide, please. And so if we took all that we've learned from the last few years' experience gained with first-generation small molecules and say we were to draw up a wish list, if you will, of those characteristics that a second-generation radioligand therapy would need to succeed. These can be summarized, I think, very simply. So firstly, we would absolutely demand a very low radiation dose to that organ that's responsible for clearing the radioactive drug from the body, which for small molecules is typically the kidney or we prefer the clearance organ to be the liver, which is an organ that is actually quite forgiving of radiation delivered to it.

Secondly, we also demand a very low radiation dose to the exocrine glands, primarily the salivary and the T glands.

Thirdly, would also demand a higher and more prolonged tumor retention. Especially given the relatively short retention time that characterizes first-generation agents.

And then fourthly, we want to be able to apply a very patient-centered approach with both dose intensification, which is dialing up the amount of activity that we administer and adaptive dosing, which is administering only when the patient needs it to simultaneously improve both disease control and quality of life, which Professor Emmett is going to discuss -- she's going to discuss these concepts in a bit more detail shortly.

And then finally, we'd ask for compatibility with alpha isotopes like actinium and lead.

Next slide, please. And so with those attributes in mind, let's now move to TLX597 or Lu-DOTA-HYNIC-panPSMA to give it its full name. And what was evident right from the very early Phase I trial that was done by Professor Omar's group was that TLX597 is a highly targeted small molecule agent with a dosimetry profile that exhibits a minimal kidney and salivary gland dose while achieving some very significant PSMA -- PSA reductions in heavily pretreated patients. And you can see this in these 2 patients from Professor Omar study on the left-hand side there that he reported at the European Nuclear Medicine meeting just late last year.

Now today, Professor Emmett's more recent randomized Phase II trial known as OPTIMAL-PSMA, that's about to complete patient enrollment has further demonstrated the very highly targeted behavior of TLX597, again, with really minimal uptake in the kidneys and the salivary glands, while in Professor Emmett study, additionally confirming very high radiation dose being delivered to the tumors, which is exactly what we want.

Now if you think about these properties a little more deeply, they uniquely position the TLX597 agent for the important developmental objectives of, number one, dose intensification and adaptive dosing, which Professor Emmett is going to talk about shortly as well as use in earlier metastatic hormone-sensitive prostate cancer, and Professor Emmett will discuss this concept in a bit more detail as well.

Next slide, please. So I think this is my last slide. And I think it really is articulate in its simplicity. And while I won't spend too much time here, this summarizes our drug development intentions across the continuum of prostate cancer care based on very distinct mechanisms of action that are tailored to both the disease state itself as well as the condition of the patient.

And the way I would summarize it is TLX591, which employs the radio antibody drug conjugate mechanism of action, utilizes an antibody targeting vector to deliver that therapeutic payload, which enables long tumor retention with limited radiation to the healthy organs as we would want and that the short 2-dose regimen with 2 fractions, 2 weeks apart is primarily intended to allow this agent to be combined with the other standard of care agents that the patients is also going to be receiving in the mCRP setting. And that's the intent of ProstACT Global that many in the audience would be familiar with.

Whereas on the other hand, there's a very significant opportunity in mHSPC for TLX597 due to its potentially best-in-class dosimetry profile that makes it uniquely suitable for earlier use in mHSPC as well as the dose intensification to achieve those further efficacy gains.

So hopefully, that sets the scene nicely and clearly. And I think it's time I pass the mic to Professor Emmett, who's going to discuss some of the ground -- what I believe to be really groundbreaking work that she and her group has been doing at St. Vincent here in Sydney. So with that, I'd like to pass to you, Professor Emmett.

Thanks, David. So it's a great pleasure to be here and to be able to discuss OPTIMAL-PSMA, which we've been beavering away at now for about 9 months. So just next slide.

The OPTIMAL-PSMA is a randomized Phase II trial, and it is about -- it's about dose intensification compared to standard of care dosing, and it really originated from this slight frustration, I guess, of the fact that we're dosing 6 doses, 6 weekly, most doses of 7.4 gigabecquerel, and we based that dosing on external beam dose constraints to the kidney. We haven't based it on efficacy. So we've done a number of randomized Phase III trials at the moment now where we haven't had a lot of significant kidney dose, but we struggled with overall survival. We have shorter progression-free survival than I would like to see with PSMA radioligand therapy.

And the question is, are we actually optimally dosing? So OPTIMAL-PSMA is about evaluating the dosing interval and whether we should do short intensified dosing right upfront to attack the cancer cells when they're most vulnerable. And then have maintenance or why I call it mowing the lawn a little bit later. So we're doing 6 doses on each arm over 6 weeks, but we're dose intensifying upfront in just one of the doses.

And it was very nice that we were able to really do some work on Lu-PSMA-597 before the trial started. So with safety lead in with the trial and looked at the dosimetry. Dosimetry is a big part of the trial, and we're doing a lot of translational work as well. But perhaps we can just look at the next slide and just have a look at the dosimetry.

So this is dosimetry that's been derived from the safety lead-in first 12 patients of the trial. So single injection, so first dose of these patients, they had 3 time point dosimetry with the TLX597 and just compared to previous publications of PSMA-617 and PSMA-I&T.

What we see with the dosimetry and it's been done twice. It's been done by our physicist and it's also been done formally by Ascinta Technologies. So I'm happy that these results in the nontarget organs are absolutely 100% correct. The kidney dose is 0.28 gigabecquerel, sorry, compared to 0.58 and 0.71. And then when you look in the lacrimal salivary gram, you've got significantly lower lacrimal salivary grand activity than either PSMA-617 or PSMA-I&T, but we don't have lower tumoral activity. So that's a really nice combination. Low salivary, low kidney maintained tumor, and that's really what you want to see.

Next slide. So when we look here, we've got -- on the left, we've got the 4-hour, 24-hour and 120-hour delayed imaging, SPECT after a single dose of Lu-PSMA-597, 7.5 gigabecquerels. 4-hour image, you can see a lot of background activity. You can see some low-grade salivary gland activity, not very bright, really almost struggled to see the kidneys, but quite nice bright tumoral activity. 24 hours later, tumoral activity looks a bit brighter, salivary gland activity looks a bit less bright, once again, struggling to see the kidneys because there's quite a lot of bowel exclusion with this agent. And then 120 hours, really nice bright tumor. almost can't see the salivary glands at all and definitely can't see the kidneys.

So on your right, similar time point, we're comparing this to PSMA-617, SPECT dosimetry. And you can see those salivary glands are really quite bright and they stay bright up to 160 hours following injection. Similarly with the kidneys, you can see quite bright activity within the kidneys, staying bright up to 168 hours post injection. So I do think that this is a very nice dosimetry, David. I actually think this is optimal dosimetry for a small molecule, right?

Yes. Well, I think Professor Emmett, it would be really interesting to sort of hear a little bit more about what prompted your -- I mean this is very intellectual thinking what you've set out to do in the study. It's one singular question you're aiming to answer, which is does dose intensification, which is really the constant tendering together of the first 3 fractions. So you're dosing day 1, day 3, day 15 very intensively. The underlying thesis that you formed in designing this trial was the upregulation of the PSMA target. So maybe you could talk about the data on that, the literature on that and why you thought that this approach might work.

Yes. So actually, it's the upregulation of the PSMA receptor with DNA damage is an appealing concept and there's some preclinical work on that and some work we did at St. Vincent's. But the other thing is we've got -- the radiobiologists tell us that when we hit with lutetium, it's all done and dusted within a couple of days. And there's some very nice work in lymphocytes that show that you have radiation induced foci for up to about 96 hours. But after that, it's all healed. So DNA damage repair heals at all.

And so 2 things. What I'm really interested in is if we -- instead of just giving one big dose upfront, we split it up and we give it in a time fashion to when the DNA damage is not yet healed, do we get a deeper hit by hitting already damaged cells. That's one thing.

And then Johann de Bono's lab, she and et al a couple of years ago published a very nice work that if you damage the cell -- prostate cancer cell, particularly mCRPC prostate cancer cells with radiation, you actually increase PSMA expression. And that happens in the first few days as well. And so we actually explored that last year, we presented at PSMA Theranostics Conference a series of patients where we did day 1, day 7 dosing with Lu-PSMA-I&T and 2/3 of those patients actually had increased PSMA expression.

So putting the -- wanting to hit while the cell is damaged together with wanting to have increased PSMA expression, we came up with a day 1, day 3 dosing, but then we thought Scott Tagawa has got some great outcome data of day 1, day 15. So we did day 1, day 3 and then day 15. And so obviously, that's a brave trial to be doing because we would clearly be concerned about toxicity. So we have done a series of data safety monitoring Board meetings within the trial to see whether we ran into toxicity at all. But the idea is if we can intensify dosing and time it to the radiobiology and the PSMA biology, can we actually get really, really deep responses in these patients. So next slide.

Understood.

So this is actually the trial schema. It's a randomized Phase II, as you said, it's a 2:1 dosing. So we've got 80 patients in the dose intensified arm. We've got 40 patients in the standard of care arm. Patients had to have metastatic castrate-resistant prostate cancer. They have to have failed an ARPI -- they have to have failed docetaxel or be chemo ineligible for docetaxel, but a lot of patients on this trial have actually failed 1 or 2 lines of chemotherapy that have quite high-volume disease.

And then in the first 35, 40 patients on the trial, we actually started at 7.5 gigabecquerels in the dose intensified arm. So we gave 7.5 gigabecquerels day 1, day 3 and day 15 and then 10 weekly in the experimental arm. And in the standard of care arm, it's 7.5 gigabecquerels, 6 doses, 6 weekly until no longer clinically benefiting, which is essentially standard of care.

And all patients have a PSMA PET scan. So we started off using the vision criteria with the PSMA PET scan. We actually moved to the ENZA-p criteria after the first data safety monitoring meeting. And then we do a repeat PET at 8 weeks on all patients in the trial.

For these patients given your referral patterns from both metropolitan Sydney and regional centers, what is the patient population? What prior treatments have they been exposed to given that in Sydney, Australia?

It's a mix. The vast majority of patients have had docetaxel. A significant proportion of patients have had both docetaxel and cabazitaxel. All patients have received at least one androgen receptor pathway inhibitor, all patients are metastatic castrate resistant. I think we have a very high volume of disease on the trial because we don't have much access in Australia to lutetium PSMA therapy at the moment, we've deliberately made the inclusion criteria of this trial very broad. We take very sick patients. We take super scans. We take patients who are hemoglobins of 80 and falling and we get these patients on to this trial.

So the primary endpoint, because we're looking about whether we can go deeper, whether we're going to be deeper in terms of our responses with dose intensified, the primary endpoint is PSA 90% response rate. I think that's quite a high bar in terms of primary endpoint. But we're also looking at PSA 50% response rate, PSA and radiographic progression-free survival, overall survival. And importantly, safety, quality of life and dosimetry. So we're doing multi-time point dosimetry in all the patients on the trial on both arms so that we get very good data about Lu-PSMA-597. We're going to be able to look at biologic effective dose of dose intensified dosing compared to standard of care dosing.

We've also doing ctDNA on this. So we're doing ctDNA at multiple time points, so we can look at ctDNA clearance. So we're actually clearing cancer cells from the blood using a more intensified dosing than we are with the standard of care dosing. And because Lu-PSMA-597 is so new, the standard of care gives us a great opportunity just to see how it benchmarks compared to other lutetium PSMA agents, small molecules and antibodies in terms of toxicity and effect.

I think an obvious question is, given the extent of prior treatment that these patients in this trial have received, how are they in your experience so far? And I know you've recruited very rapidly, how are they tolerating that dose intensified regimen in the experimental arm? Could you comment on that?

Yes. So it's one of the things everyone thinks you're very brave and looks at you slightly a stance that we're even thinking about doing this dose regimen. And when I first put the patients on the trial, I told them they may need blood transfusions, they were going to feel terrible. They were going to have this, they were going to have that -- it's been very interesting in terms of the toxicity. The toxicity has been very low. We did the Data Safety Monitoring Board meeting with the 8.5 gigabecquerel dose intensified in March.

And so we looked at the first 10 patients who had dose intensified Lu-PSMA-597, and that was after 10 weeks. And I think we had 5 grade -- so we had 5 grade 1 anemias. We had 2 Grade 1 thrombocythemias, we had 1 patient who had grade 1 xerostomia and 2 grade 3 lymphopenia. So it is well tolerated. I will say that with the dose intensification in patients who have very high-volume disease, we do make pain worse in the first couple of weeks. So they get a really big response to this dose intensification at their sites of disease.

We do have to make sure they have a pain plan, and we do put them on dexamethasone for the first couple of weeks just to reduce the fatigue that they might feel as well. That's actually a treatment response effect. So get a bit of pain around the time of lutetium, that's a good sign. No pain is not a good sign. So -- and then their pain is great. They're coming off their opiates. They're feeling very good.

What I really want from this -- so they're great. We're not having any problems on this trial, but what I really want to know is can we make it last longer as well?

Yes. Yes. Understood.

Next slide. So this is just a couple of the early patients. And it's one of the things that just showing what's happening between the day 1 and the day 3 dosing in these patients, and it's pretty uniform. So when we did the first injection, you can see here, it says dose 1, day 1 on the far left, the SUV max the salivary gland was 11, SUV mean 9.4 of the tumor. And this patient got metastatic disease in bone in their mid-thoracic spine, and they've got a series of lymph nodes in their paraaortic region that you can see there.

And then if you go to dose 2, day 3, so this is the SPECT images taken after the second injection, day 3. You can see the salivary gland looks a lot less bright, right? So it's gone not as bright and the SUV max is 5. And then -- but the tumoral intensity has actually gone up. So the SUV mean and the tumor has gone up to 14, the SUV max has gone from 51 up to 124. So we're getting increasing intensity in the tumor, and we're getting reduced intensity in the salivary gland.

And if you look at the next patient, you can see the same thing. So salivary gland activity, dose 1 day 1, SUV max 5.2, dose 2, day 3, it's gone down to 1.8, you almost can't see it at all. So it's super, super interesting that you are reducing salivary gland activity while increasing tumoral activity.

And in this second patient with very high-volume disease, you can see the SUV mean's gone from 5.7 to 7.9, SUV max gone from 25 to 74 and the tumoral volume has gone from 2,379 ml to 3,977 ml. So whatever the mechanism, we're getting a lot more lutetium into those cells with the day 3 dosing.

The question is whether we're getting more dose into those cells than we would dosing them week 1, week 6. And that's one of the big questions of the trial really.

And would you say that -- I mean, this is -- I don't know if you can answer this question, but would you say that there is a correlation between the low radiation dose imparted to the normal tissues that you don't want to hit and the tolerability, the tolerability safety profile of what you've seen? Or can you not come to that conclusion yet?

I don't think -- we'll do all 120 patients and draw that conclusion. We're giving -- we're giving 25.5 gigabecquerels in 2 weeks. And in that data Safety Monitoring Board meeting, we had 1 patient with Grade 1 xerostomia. So I'm super happy with that. I don't know whether that's because we're saturating. There's a different mechanism of uptake in salivary glands to tumor. We know that. And it looks to me like this dosing regimen is saturating the salivary glands, but it's not saturating the tumoral activity day 1, day 3.

So we know if we gave cold PSMA and then gave an injection of lutetium PSMA, we would have reduction in salivary glands and we'd also have reduction in tumor. But perhaps the regeneration of the PSMA expression in tumor is so fast that we've still got saturation in salivary glands in day 3, but we've actually overcome the saturation that we might have had with the injection by day 3 in the tumor, and we've got increased expression in -- either in relation to DNA damage or because we're overlying dose and we've got persistent activity because this agent has got really nice persistence in the tumor cell. Either way, I don't care. It's looking really bright. I can see we're getting a really nice deep radiation dose to all of those sites of disease where we want it, and we're not getting it where we don't want it. So I'm happy with that. That was -- that's cool. Those images are really cool for me.

I like the images, too. Yes, thank you.

Next slide. So this is just one of the patients on the study, and these are 4 our SPECT images actually underestimating the volume of disease of these patients. This is a patient who's pretty classic for us post chemotherapy post 2 lines, obviously, post-op because that's an inclusion criteria, very high-volume disease. PSA is 1,380, hemoglobin 112, platelets 200. So what we have here is the day 1, day 3, day 15 dosing. And these are the SPECT images that are all taken 4 hours after each injection, and then we have the week 10 dosing.

So you can see that in this patient, the day 1 dosing, high-volume disease, day 3, it looks -- the volume has gone up again. Day 15, you get the impression it's not as bright. There's things going down. And then by week 10, there's a marked reduction in the number of sites involved. So a marked reduction in the volume. And you can see PSA has gone from 1,380, day 3 has actually gone up, and that's something that we routinely see. Pretty mixed at day 15, sometimes it's up, sometimes it's down, but down to 40 by week 10. So really nice PSA response there correlating with the really nice SPECT imaging response that we see at the week 10 dosing. And very nice to me the hemoglobin is maintaining itself and the platelets are maintaining themselves. So we're not getting a lot of -- we're not getting extreme hematotoxicity at all in these patients.

Yes. It'd be interesting. I'll ask you at the end, but your view as you go through your view on where the behavior of this peptide small molecule lends itself to future development because you're going to touch on that with earlier use. So back to you.

Yes. So next slide. Yes. I think we're almost there. I mean I -- so the OPTIMAL-PSMA trial is a randomized Phase II. We're at -- I think we are randomized -- we possibly -- I think we randomized the 90th patient today out of 120. We are getting another site on board, but that's essentially 90 patients at a single site at St. Vincent's Theranostics department in Sydney. As you're saying, David, a lot of these patients are rural. They come from all over the place to receive this treatment. So it's wonderful that we've been able to help them with this trial and that they've tolerated it well enough. A lot of patients are getting to the end of treatment. So they're getting all 6 doses, which is also fantastic. The median number of doses in therapy was 4, and that's because patients progressed around that time. About 45% of patients have progressed by dose 3 in the therapy trial. And so to me, that's the thing to be keep them on trial longer and see how long we can keep them on trial, how long we can keep them alive and feeling well.

Yes. Yes. Well, as I talked about earlier in the intro, Professor or Dr. Azad, a colleague of yours from across the border in Victoria down to [ indiscernible ] made that very thoughtful discussion session of PSMA addition and talked about some of the requirements for an agent for metastatic hormone-sensitive prostate cancer. I think it would be very interesting to get your thoughts on the development in that disease setting and your OPTIMAL-E trial that you've already, I think, got IRB approval for.

We do. So I think one of the reasons why we had the baseline PSMA PET and then the week 8 PSMA PET was we're thinking with the intensified dosing, we might be able to stop treatment in some of these patients. And we do, do treatment pauses frequently with -- so they continue the ADT, but they pause treatment with lutetium PSMA until they get first confirmed right, most patients who have a marked reduction in PSA and volume on their SPECT or their PET images.

We haven't -- we've had very high-grade aggressive disease in the patients here. A number of these patients are actually super scans. So we've had good deep responses, I believe. But we haven't paused treatment in any of the patients in mCRPC. But I think in mHSPC, you have much better behaved clonal populations. You have more sensitive disease. It's a combination. It's always combinations that you use. So PSMAddition is ARPI, so androgen receptor pathway inhibitors plus ADT plus lutetium PSMA. And we showed in the ENZA-p trial that if you use 2 effective agents together, your responses are massively deep. Our PSA 90% response rate in mCRPC in ENZA-p was 95%.

So if you're using ARPI plus ADT plus lutetium very early, you're going to get extremely deep responses and a lot of patients will have no disease left. If you just keep treating them, then you're going to end up getting a higher dose to the non-target organs. So I think Lu-PSMA-597 does lend itself well to the earlier space. It's got low salivary gland, low kidney activity. We haven't seen a lot of hematotoxicity yet. But of course, we have to read out the whole of OPTIMAL-PSMA. And so it does lend itself to going earlier. But I think it also this idea of adaptive dosing in the hormone-sensitive space where you treat upfront, then if you lose the target, you stop, you continue the very active ARPI and ADT regimen. And then at first confirmed PSA, you retreat again.

So next slide. I think we've got the OPTIMAL-E concept. So this is OPTIMAL-E. This is the version of OPTIMAL-PSMA accepted in the metastatic hormone sensitive space for patients who've got metastatic disease at diagnosis. You can tell it's designed by a nuclear medicine physician because it's dust full of imaging. And we really want to see what's happening to that target as we go. So there's a screening PET to make sure they've actually got disease. And then the patient goes on ARPI, so an androgen receptor pathway inhibitor, either enzalutamide or abiraterone or darolutamide. And then at day 8 after commencing the ARPI, they have a PSMA PET. And then we commence day 1 and day 3. So we do a dose intensification, 8.5 gigabecquerels of those patients on the trial. We do a 6-week dose. We do a 12-week PET -- and then if there is no residual disease on the 12-week PET with the lutetium PSMA ARPI and ADT on board, we stopped the LU-PSMA-597. So ARPI and ADT would continue until first confirmed PSA rise and then we would start administering again.

If there is residual disease, then we give another 2 doses of Lu-PSMA-597 at week 14 and week 22, and the patient has another opportunity at 6 months, so week 24 to see whether there's -- whether all disease has gone on the SPECT as well as the PSA -- around the PET as well as the PSA. And if it hasn't, they get another 2 doses. So this is what we call adaptive dosing. We're trying to treat when the target is present stop if it's not present and then recommence again the minute target starts to come back. And we look at target coming back based on PSA rise.

So the question is how long can we go in some of these patients with very well-behaved disease with a dose intensification upfront with the lutetium PSMA and then stopping if they've got well-behaved disease. Is it years? I hope -- I really hope that, that's years before that clonal population comes back. In the ENZA-p trial, which we did a similar thing, we did a PSMA PET so that we could start and stop treatment, some of those patients only got 2 doses, and it's 6 years now, and they still have no measurable disease. So can we treat multiclonally and actually eliminate whole clonal populations for these patients, potentially cure.

Yes. So in your mind, what would you want to see? Obviously, OPTIMAL-E in metastatic hormone-sensitive prostate cancer is really the first proof of concept with dose intensification and dose adaptation so that we don't overtreat blindly a patient that negatively impact the quality of life. What would you want to see from such a study if you were to say, right, based on achieving this outcome, this warrants a registration enabling pivotal trial in this early disease setting?

Okay. So I hope we get a number of patients with reasonably high-volume M1 disease in this small study. I hope that we see that the ARPI and the ADT and the lutetium PSMA are working extremely well together with the dose intensification such that when we get to week 12, 3 months, I'm hoping we have a very high proportion of patients who have a PSA of less than 0.2 and nothing left on the PSMA PET. A lot of the benchmarks for overall survival in mHSPC is around the week 24 mark with a PSA of less than 0.2.

What proportion of patients can we get to that? So if you're just ARPI and ADT and you are using and you're not using lutetium PSMA, that's about 68% of patients you would expect to have a PSA of less than 0.2 at 6 months.

What proportion can we get to without inducing a lot of toxicity just by dose intensifying upfront and then giving patients an opportunity to de-intensify their treatment and go back to the ARPI and the ADT again. And then how does our quality of life compare, say, to 6 doses upfront. There are other trials that are doing this. [ MPP ] has got a very interesting design. It's using -- it's giving baseline, it's giving day 1, day 7, 7.4 gigabecquerels of Lu-PSMA-617 with ARPI and ADT. And then 6 weeks later, it's giving day 1, day 7 again and 6 weeks after that, it's giving another day 1, day 7.

So dose intensification is happening at day 1, day 7, not day 1, day 3. So I think they're beyond the window of the DNA damage. And then they don't have the adaptive dosing design. And I think the adaptive dosing design is something that patients want -- they will want that. And I do want to know whether it works. Certainly, in the studies that we've done in the castrate-resistant setting, we've see no disadvantage to stopping treatment with losing the PSMA target. Patients feel well. They're not coming in for continued treatment. They don't have the associated toxicity. They don't get the very dry mouth. Potentially, we're avoiding renal toxicity, and then we're treating when they really need it when the PSA starts to rise again and the clone is on the move.

Yes. That's very clear.

I think it's interesting. We've got different ways of doing it. But if we got to week 24, all of our patients had a PSA of less than 0.2 or 95% of them had a PSA of less than 0.2 and 70% of them have been able to stop treatment because they didn't have anything left on their PSMA PET. I think that would be amazing. We'll see.

Yes. You say that would be your benchmark for saying, right, it's pivotal trial time. Yes. Understood.

Well, that's my benchmark. Obviously, other people will have different benchmarks, but I would be pretty happy with that.

Yes, very clear. Very clear. Okay.

I just want to say one thing, David. And that is we're so grateful to do this trial. Our OPTIMAL-PSMA has provided treatment access to many men across New South Wales in Australia. They are very grateful. I'm grateful that Telix has provided this access to this drug. It's been fantastic. But I just want to shout out to my team. Putting 90 patients on as a single site with a randomized Phase II trial has been heroic, and I really want to say thank you to them.

No. I think Professor Emmett, that's a critically important point. I've never seen a single center trial enroll at the rate that you've been able to do. So you and team and your patients are truly something out of the ordinary. Thank you.

Next slide.

Okay. So look, on behalf of those who have dialed in to the webinar, I'd really like to thank Professor Emmett, who's, I think, evidently doing some of the most evolved thinking in prostate theranostics at the current time. These are concepts that take a lot of CTU cycles in an academic brain. And I think we're seeing that a lot of thinking is going into this, Professor Emmett.

So I hope today's discussion has gone some way to look, clearly articulating Telix's portfolio approach based on 2 very distinct mechanisms of action, TLX591 in metastatic castrate-resistant prostate cancer, but now TLX597, which is exhibiting some best-in-class small molecule distribution and dosimetry and tolerability characteristics that we believe make it really uniquely suitable for achieving the requirements for metastatic hormone-sensitive prostate cancer that was so well articulated at ESMO last year, i.e., that the goal -- number one, the goal of any anticancer treatment is to make patients live longer and live better. One without the other is not sufficient. And i.e. that to deliver the best outcome in metastatic hormone-sensitive prostate cancer. It's going to take a really patient-centered approach, which Professor Emmett has really, I think, driven home about not overtreating and adaptive dosing, focused on avoiding overtreatment, focused on minimizing the impact on quality of life and focused on minimizing late toxicities.

So with that, I'd like to thank you, and I'll pass back to the operator, and we'd be very happy to take any questions from the audience.

[Operator Instructions] Your first question today comes from David Dai from UBS.

So just on the safety, it looks like dosimetry of bone marrow is correlated to tumor lesion, whereas patients without extensive bone lesions have limited dosimetry of bone marrow. So based on this data, how should we think about the potential hematological toxicity for TLX597, especially in early line hormone-sensitive prostate cancer patients?

Yes. Thanks, David. Great question. I think as you've seen, Professor Emmett presented the preliminary dosimetry, and she was at pains to explain that, that was in the first 12 patients that were enrolled to the trial. Ongoing dosimetry work is being done. But it's very clear that the dosimetry is at a multiple PSMA-617. It's a multiple of that agent in the tumor lesions and it's a percentage or it's a fraction of relative to that agent in the nontumor compartment. And that's the salivary glands, that's the kidneys and that's the bone marrow.

So Professor Emmett has not extensively reported on the bone marrow dose, but it is similar to the kidney and salivary glands, very, very low. And that's why the hematological toxicity with small molecules as a class of drugs, but in particular, with this second-generation agent, the bone marrow dose is also very, very low. And that's what's correlating with the low clinical expression of hematological toxicity. So it's a very consistent profile, David, across the tumor compartment and the non-target normal tissue compartment, whether it's salivary gland, kidney or bone marrow. Does that answer the question?

Yes, that's really helpful. And so maybe just kind of follow on the dosimetry. So I just want to kind of follow a little bit more. Just based on the SPECT biodistribution data, it looks like there is some dosimetry in GI. So maybe just talk a little bit more around what do you think potential GI tox look like, especially the constipation or diarrhea and vomiting that we're seeing Pluvicto. Do you expect this to be replicated in PLX-591 as well or 597 as well?

Well, we don't, no. And the reason we don't is that this is a -- we are developing -- just to be clear, we're developing a new radiopharmaceutical. It is not in any way a generic version of Pluvicto. So it's a new -- it's got a new structure to it. It's basically being designed with a different linkage to Pluvicto and PSMA-I&T and the other small molecule agents that fundamentally alters its chemical and its physiological properties. Unfortunately, I can't really disclose more than that, but those altered chemical and physiological properties govern its biodistribution, which is essentially where it goes. And ultimately, where it goes governs the dosimetry, the radiation absorbed dose that it physically imparts.

And so all of the off-target or off-tumor tissues are touched by this asset very, very minimally, and that includes the GI tract as well. So the adverse event profile that Professor Emmett has observed in her 90 patients that she reports to her independent data monitoring committee have had very low constitutional side effects, fatigue, nausea, vomiting relative to the other small molecules.

Your next question comes from Andy Hsieh from William Blair.

Thanks for answering a very important perhaps long overdue clinical question about dose intensity and optimization. So I have a question about the patient enrollment criteria. I think for the OPTIMAL-PSMA, the enrollment criteria was VISION and then transition to more ENZA-p. And so maybe for the first part, I'm wondering if you could talk about why ENZA-p enrollment criteria is enriching patients who will be likely candidates for intensification.. AND also the rationale for the OPTIMAL-E, it seems like it went back to the VISION study. So maybe kind of the rationale behind that enrollment criteria.

And then maybe a quick one -- so for docetaxel -- sorry, not docetaxel, for dexamethasone usage, I believe that dexamethasone also reduces PSA. So I guess when you look at the PSA reduction down the road, I'm curious how you would interpret the data delineating between the 597 contribution also the dexamethasone contribution.

Yes, Andy, basically characteristically solid question from you. So the first question, just to restate it is you asked about in Professor Amit's current on foot OPTIMAL-PSMA trial, which is enrolling 120 patients is the target, and she's done, she's enrolled 90 of the 120. During the trial, she increased the PSMA positivity criteria where she started with the VISION criteria and she tightened the criteria to the ENZA-p criteria, which is a study that she was the principal investigator on.

Now the primary reason she did that was that these patients in Australia are very late stage, so metastatic castrate-resistant prostate cancer, very heavily pretreated, and they have failed or sorry, progressed while on or become intolerant to all of the conventional therapies, which is primarily and taxane chemotherapy, mostly cabazitaxel and docetaxel.

So these patients are very heavily pretreated. And what Professor Emmett wanted to do was to evaluate in this trial whether she could -- she started with a dose intensified regimen. She wanted to further dose intensify, which she did during the trial with the permission of IRB. She went from 7.5 to 8.5 gigabecquerels. So she inject -- she is now injecting a much higher amount of activity at each injection and she's constant tendering the first 3 injections together, if you will, on day 1, day 3, day 15.

So that's a very dose intensified regimen. And what she wanted to do was make sure that with that heavily dose intensified regimen and in the population of heavily pretreated patients that she was making sure that they were highly PSMA positive before they're enrolled as a means of making sure that they were appropriate patients. So that's why she's done that.

In terms of what this OPTIMAL-PSMA trial has shown. It has shown that this molecule is -- it really facilitates 3 objectives. Number one is dose intensification and dose adaptation, which is only treating when the target is present and not overtreating when it's not present. Number two, this has shown that the off-target deposition in the normal tissues uniquely lends itself to the metastatic hormone sensitive prostate cancer setting, which is what this trial OPTIMAL-E will evaluate. And then thirdly, if you think more over the horizon, it lends itself to use with an alpha isotope again, because of the low deposition in the kidney in particular. So that slide Professor Emmett has already planned and got approval for OPTIMAL-E, which is the study she talked about, Phase II trial in 20 patients that is combining this agent with conventional androgen deprivation therapy and ARPI.

Now I can't really comment on really the role of steroid -- concurrent steroid. But she will look at the 4 ARPIs. She'll start with darolutamide and enzalutamide and then expand this trial to apalutamide and abiraterone. So all 4 will be studied and then we'll be able to answer that question once those data are in hand. So it's a detailed answer to a very thoughtful detailed question, but I hope that addresses it, Andy.

I think we've got time for a couple more questions. We've got about 2 or 3 minutes to go.

Your next question comes from Melissa Benson from Barrenjoey.

I just wanted to kind of step back and understand, I guess, the rationale a little bit more about the 2-product strategy. If it is kind of focused and it seems like it's based on this reduced salivary uptake, low renal clearance, those are kind of both attributes of 591, obviously, because of its antibody in nature. So trying to understand, is it perhaps that the heme tox profile is less acceptable in kind of earlier stage hormone-sensitive disease and that's kind of part of the rationale. But also, is there anything that -- I remember you had the prostate TARGET trial with 591, which was kind of in that earlier like a BCR setting, but some of those patients are effectively hormone sensitive. Is there anything you learned in that, that's kind of guided this need for kind of a 2-product bifurcation?

Yes. Thanks, Melissa. And I think it's -- that's an important question, but it warrants a thoughtful answer. And I think the key point is that we at Telix fundamentally focused on the patient and a focus on the patient requires a focus across the entire disease journey or spectrum. And you can see that in the prior composition of the therapeutic portfolio for prostate cancer. It includes TLX591, but it also includes the development of TLX592, which is actinium, an alpha therapy, which must follow lutetium, it can't go ahead of lutetium. And then after alpha, an agent for bone pain, which is a sort of a prepalliative stage of the disease journey.

So we have -- we continue to develop 591. It's uniquely positioned as a radio antibody drug conjugate for metastatic castrate-resistant prostate cancer. And I think we've its unique virtues in a very detailed kind of way. It's the long tumor retention, it's the prolonged radiation dose deposition and the fact that it is able to be given as a 2 fraction, 2-week apart dosing regimen really lends itself to be intercalated or combined with conventional standard of care that a patient is going to get. So we're asking the question, can we layer on top of standard of care a radio antibody drug conjugate.

From there, though, we have looked upstream to mHSPC. And we have really thought deeply about the findings of PSMAddition, and we have been thinking about this for a long time. And we don't believe that just treating blindly with 6 fractions when the target life disappear is in the best interest of the patient. So we believe that in that early disease setting, a mandatory condition is that you do not do 2 things. You cannot adversely affect the patient's quality of life by having significant off-target effects. And secondly, you cannot injure critical organs like the kidney and have long-term toxicities because these patients, we are aiming to help them live a long time, measured in years. So we cannot be allowing them to live for years, but with renal injury and potentially renal dialysis as a consequence.

So that's why it requires a very patient-centric approach and a fundamental rule in medicine is to do no harm, first of all, do no harm. So that's why we think an asset like this is intended for metastatic hormone-sensitive prostate cancer in that early metastatic setting. That's what I would want if I was a patient.

So I hope that makes sense, but that's our view of the world. And I think it's a very thoughtful view of the world. And I think you can hear the sort of ambition that Professor Emmett hands in taking this upstream to where she's currently studying it.

I hope that answers the question. I think we're probably at time. But if there -- I just apologize if there's any other questions that we haven't been able to get to. We would be very happy to have those triage to our Investor Relations team. And Professor Emmett was at pains to say she'd be delighted to respond to any questions. It's 2:00 a.m. in Europe at the moment. So we can't ask her to do it right now, of course. But within sort of the next day or 2, she'll be very keen to respond.

So I'll hand back to the operator with that. Thank you to the audience for dialing in, and thanks for your attention.

Thank you. That does conclude our conference for today. Thank you for participating. You may now disconnect.

Thank you for joining us today. I'm Robert Burns, the Managing Director and Senior Biotech Analyst at H.C. Wainwright. I'm joined today by Chris Behrenbruch, the CEO of Telix; and David Cade, the CMO of Telix. Gentlemen, thank you for joining us today.

Thanks very much. Good to see you, Robbie.

Awesome. So why don't we just dive in?

For those who may be unfamiliar with Telix, can you give us a brief overview of the company and give us a recap of your 2025 earnings that led to a strong year-over-year growth as well as the disease areas that you're focused on?

Yes. Thanks. So we're a fully vertically integrated radiopharma company specializing in oncology. We have a portfolio of focus in urologic oncology and neuro-oncology in particular. We are a commercial stage company. This past year, we did just over $800 million in sales, primarily around our U.S. prostate cancer imaging franchise. That's our -- we have two approved FDA-approved products in that space and very active product portfolio on the therapy trials, which I'm sure we'll get to at some point as well.

But in terms of commercial performance, we've just put out our guidance for 2026, targeting the mid-900s in revenue. And really reflective of, I think, a very solid growth in the prostate cancer imaging space globally, but particularly the U.S. as well as the launch of our second prostate cancer product, which got passed through in October of last year. So that's putting a fair bit of momentum into our commercial operations as well. So I'll pause there. Hopefully, that's a good snapshot.

Yes. No, it definitely was. I sort of wanted to hone in a little more on the revenue guidance that you provided. So I know it's around $950 million to $970 million in revenue for 2026, with roughly a 25% growth in the Precision Medicine business unit. When we think about the growth opportunities for the PSMA franchise, where do you see significant upside for that agent as well as the new launches in brain and kidney cancer, specifically Pixclara and Zircaix.

Well, our guidance doesn't include any unapproved products. So it's -- so when we get approval for Pixclara, which we've just resubmitted just this past week and Zircaix is not too far behind. As you recall, we had a CRL for both of those programs last year. Then we will revise our guidance accordingly. We still expect to resubmit Zircaix obviously this year and hopefully launch it this year as well. That product has a breakthrough designation. So pending the review of the CMC issues we had with the FDA. We expect to get that program back on track. For the prostate cancer area, I would say there's sort of three drivers for the business. First of all, there is the inherent growth still in PSMA. We think that's 5% to 7% a year based on the fact that there's still white spaces in the market. There's still referral urologists that are getting up to speed on the value of PSMA. It may surprise you to know it. But CTs and bone scans are still prescribed and obviously, practice of medicine has changed.

And maybe David can elucidate a little bit more how that practice is changing. We also see urologists taking more and more of a front line interest in PSMA imaging. So we're seeing -- I think in the steady state, call it, 3 to 5 years out, you're going to see 25% to 30% of the market for PSMA imaging actually directly controlled by urology. I think that's an emerging sort of category of PET scan or user/owner/stakeholder.

And I think the second tailwind on the PSMA landscape is really around having a second product that's got passed through. Gozellix is a very innovative product. It offers some real clinical and distribution benefits. And by having a product segmentation strategy or market segmentation strategy for prostate cancer. We really target commercial and hops payers very differently. And I think that gives us a commercial advantage that will translate into revenue.

And then I think the third one is we have a significant Phase III trial running this year, which is the BiPASS biopsy study. This is an opportunity to significantly grow the TAM, the BiPASS study stands on the shoulders obviously, of great work that's been done in academia, particularly the PRIMARY2 study that was recently presented. We actually wanted to take that study to the FDA -- actually took that study to the FDA for -- sorry?

We lost you for a second there.

I'm really sorry. Can you hear me now?

Yes.

Well, let's continue. I'll continue for a second, and then we'll just pause and do an audio catch-up. But basically, the PRIMARY2 study, we actually took that study to the FDA, and it does require some tweaks for it to be a label indicating study. So -- but there's a very important education process that's going on in the process of executing that study. And I think that builds further momentum into where prostate cancer imaging can be used. So I'll pause there. Hopefully, you've got some of that. But yes, there's a lot of -- there's a lot to look forward to in prostate cancer imaging in '26.

So one of the things I'm curious about is if the BiPASS study actually succeeds, what does that mean for the market expansion potentially in terms of the number of scans that you might be eligible to garner?

Yes. Dave, why don't you have a chat about the clinical consequence and maybe what that means in TAM.

Yes, sure. Robbie, it's a very important question, and it was really brought to us by our clinicians themselves. Essentially in the United States, we just focused on the U.S., there's north of 1 million biopsies done for the -- to try to establish the diagnosis of prostate cancer a year. And I emphasize the word try because a very significant proportion of those somewhere between 750,000, maybe 800,000 of those don't yield tissue that can be decisively ruled by a histopathologist either being prostate cancer. So the yield from the biopsy is low.

And as a consequence, there's a very significant number, maybe 250,000 men that actually decline a prostate biopsy when they probably should. So there's a lot to improve. Now the way it's usually done is with an MRI scan. And I won't bore you with all the details, but the MRI scan is scoreboard according to a 5-point scan, which is called the PI-RADS system, 1, 2, 3, 4, 5 where 1 is a very normal scan. Typically, we don't get a lot of PI-RADS 1s in the men that we -- in the age group that we expect to have prostate cancer. That's like a very normal scan. PI-RADS 5 is prostate cancer. So there's an area in the middle PI-RADS 2, 3 and 4, particularly PI-RADS 2 and 3, which is a very significant group where the MRI is unresolved. It doesn't indicate to the urologist where to biopsy from.

So we typically end up doing what we call a template biopsy, which is sort of a row 4, 4, 4, 4, 4 so basically somewhere between 12 and 20, maybe 12 and 24 needle cores for the biopsy, and even yet it doesn't yield the results. So what there is a huge opportunity to do and the results of this study in this BiPASS study are already showing us is that with the Gallium PSMA PET scan added to the MRI it can either direct using that imaging where the biopsy should be taken. So instead of doing 24 core biopsies. It can be image-guided and 1 needle core can be taken.

Or on the other hand, if the Gallium PSMA PET scan is negative, no biopsy needs to be taken at all, and the patient can be reassured and put on to active surveillance where their PSAs monitored and they come back and are simply non-invasively scanned at a later date, 6 or 12 months' time. So for lay people, and this is not a lay audience, but for the lay people, I explain it this the one and done or none and done, which is a major deescalation of what we typically do today, which is very unsatisfying with that low yield of diagnosis. So you can see with that utility that opportunity is very significant, as Chris described, and that's probably an explanation of why this BiPASS trial is enrolling so rapidly, possibly even ahead of plan, which, as you know, doesn't happen with trials all that often.

Yes. So just to summarize, we're talking about sort of an estimated 750,000 to 800,000 scans with -- at the way that, that clinical evolution takes place. And then what it also does is it affords the question to be asked in the future, should PET follow MR or, in fact, should PET lead MR, and that will be something that will come out as there's more experience with clinical practice and combining the two modalities.

Yes. At least for me, as a male, it seems like I would definitely prefer to have the added on diagnostic imaging rather than having to take these numerous core biopsy samples, which are frankly onerous.

Yes. Well, and also it's just a cost. I think it's a cost issue. I mean if you look at the health economics of replacing biopsy, not just the cost of biopsy and the practice demands but also the morbidity issues associated with it. It's going to clearly save the health care money -- health care system money. And as you know, it does patients care about this. And in fact, it's hard to know the exact number, of course, because it's an estimate, and literature varies fairly widely.

But there's estimated to be 200,000 to 250,000 men that simply don't participate in the process because just don't want stuff near their nether regions. And if we can -- I'm putting that as diplomatically as I can. And so I think that if we can make patient compliance better and patient engagement better, that's going to have a big consequence on detection rates. So I think it's very positive.

I would certainly agree with you that -- why don't we move on to your therapeutics pipeline now? So you recently reported initial data from Part 1 of the ProstACT Global trial, which is our Phase III trial, mCRPC. Can you provide an overview of that trial design? And remind us what you reported in terms of safety as well as dosimetry and what impact that has on Part 2?

Sure. Look, when we took the protocol to regulators, not all regulators had the same viewpoint on it. We had a number of sophisticated regulators that were quite okay based on the data that we had of going straight into ProstACT Global, which is a randomized Phase III trial across 3 different treatment cohort. So it's a standard of care plus versus a standard of care alone randomized study. The 3 different treatment arms are enzalutamide, abiraterone and docetaxel combinations. And we've selected those because those RP switches and taxane reflect sort of consistent global standard practice in first and second-line metastatic prostate cancer. When we went to the agency, they felt that we were a little bit light on the combos with the RPs comparatively. And we went in with a view that enzalutamide and abiraterone are a class, and we had some data to support that assertion, but the FDA wanted to see a bit more.

And that's where the genesis of the Part 1 study came out. So it's really to reinforce that there's no particular delta between the different treatment arms, particularly the RPs. I mean we had some combination data with docetaxel. We showed that it was tolerable in combination with docetaxel, but we had -- we were a bit lighter on than the FDA wanted with the RPs. And so that's why we've done this additional study. We've, as you know, just put the results out. Maybe I'll make an initial comment, and then David, if you want to chime on anything. But the purpose of the study, as you know, was safety and dosimetry. We were really looking on a cross-cohort basis. There's always been a lot of speculation around the asset, around safety and particularly hematologic AEs. And what we hope that the data shows sort of fairly definitively is that these are well-tolerated treatments.

The 591 layers very nicely on top of those different combinations. What the data shows is that we do have hematologic toxicities. It's the main toxicity associated with it, but it's transient and self-limiting and reverses very rapidly even when the adverse event is a higher grade adverse event. And that's counterbalanced by the fact that the patient-centric AEs are very benign because we don't have salivary gland, exocrine gland uptake. We don't have renal excretion. And so we think on the balance that it represents a very compelling risk benefit. That's what's demonstrated in the safety data. And now we'll be taking that combined with the dosimetry, which is, again, very favorable, particularly compared to current solutions that are in routine clinical use. We'll take that to the agency with the expectation that we'll be able to move to Part 2 and dose patients into Part 2 in the United States in the fairly near future.

Awesome. One of the things I'm sort of curious about as well, what are the next steps in terms of opening up enrollment within the U.S.

Yes. So I mean we did recruit patients in Part 1 in the U.S. So we do have sites that are sort of in the program. We will, of course, be adding a bunch more that are particularly focused on the Part 2. It is a global study. So we have regulatory approval, I think, now in 7 or 8 countries. We are actively recruiting patients in Canada, Australia and New Zealand. We've got U.K. just coming online. So we are rolling out the program globally. I expect that we'll get U.S. patients subject, of course, to what the agency says into the study around midyear, maybe early Q3.

We expect about 20% of the study to be recruited in the U.S. And yes, obviously, it's critically important to get U.S. patient experience for the study. So yes, it's a high-priority study. We're really pleased with the data. I think it sort of finally benchmarks once and for all the profile of the drug. And unfortunately, when we deal with targeted radiation, cytopenias are a common side effect, but the fact that the management of those AEs are so straightforward that was the clinical experience gives us a pretty clear platform for discussion with the agency. I don't know, David, do you want to add anything just from a medical perspective?

Yes. We took a lot of patient input into the design of the trial, a lot of FDA input into the design of the trial. I think fundamentally, the Part 1 results do demonstrate the feasibility of integrating TLX511 with a contemporary backbone of different global standards of care as mentioned, just what the prevailing practice in the United States, which is predominantly RP Switch, but also outside of the United States, both Europe and in Asia, which is primarily moving from an RP to docetaxel.

So it really is, as the name of the study says a global trial. So we would see -- should the trial meet its primary endpoint, it would lead to simultaneous filings, not just in the United States and Europe, but ultimately Japan, China, South Korea and so forth. So that's why we designed it that way. I think it's a very pragmatic trial. And as Chris mentioned, the next step is to take those data. They're exactly what the FDA asked for, and we'll take it back and present it to the FDA seeking an IND amendment to start to put U.S. patients into Part 2, which is already enrolling elsewhere.

So talking about Part 2 of the trial, what is the sort of enrollment trend that you're currently seeing for that portion of the trial?

Yes. I mean I can initially comment. So the trial is certainly picking up steam compared to the Part 1 study. The Part 1 study took a long time because it was a very technical study. It required a lot of SPECT Imaging, a lot of patient visits. So we had limited it to -- because of its technically demanding nature, we had limited to a number -- limited number of sites. Now we've added, of course, a lot more sites for the Part 2. And so that's a natural accelerator. Also, the protocol in Part 2 is just much more streamlined. There's a single time point PET imaging for patient selection. It's much more like a clinical treatment protocol for conventional PSMA RLT therapy. So we do expect to see a pickup. And obviously, having some data out as well from Part 1 is quite motivating, I think, for investigators to kind of get on with the study with a sort of clear understanding of what they're dealing with and how they manage patients going forward. So we've seen good pickup.

The goal this year is we have based on an event-driven process, obviously, on 25% of events, so around 80 patients. We expect to report out a futility, an interim futility. We've discussed that with a number of regulators, but particularly with the FDA. We don't have -- obviously, because it is event-driven, we don't know when that's exactly going to drop, but we would imagine sometime around Q4 or Q1 next year. And that will be the next sort of milestone on the study as far as the Part 2 randomization goes.

Well, I'm certainly looking forward to that data. One of the other questions I also have, I note that you also have TLX592, which is -- which utilizes an alpha emitter versus the beta for 591. How are you thinking about the sequencing of those 2 agents within your portfolio and the treatment paradigm specifically?

Yes. Look, we're exploring a number of things on alpha. We haven't locked down finally what our PSMA strategy is really going to be in alpha. 592 is a fairly very early-stage asset. We have done some human studies with 592, but they were done with PET imaging as a surrogate. As you know, actinium is quite tough to image in humans. It can be done, but it's not sort of that straightforward. So what we did is we did targeting and biodistribution studies with PET -- with copper 64 as a surrogate, not that we have the intention to develop it commercially, but to get a sense in a benign way of really what the pharmacology of that agent is like, and that looks quite promising. So we are getting ready now to do the first-in-human actinium studies with that agent. We're starting off in very late-stage patients that have typically progressed on lutetium therapy. So that's where we'll get initial clinical experience with that. But the value proposition of 592 is really twofold.

First of all, it doesn't have exocrine gland uptake. So one of the real challenges with small molecule delivery of alphas has been salivary and lacrimal gland ablation and not typically transient, usually fairly -- well, more serious, I would say, in terms of grade than what we typically see with a beta emitter. And then secondly, we've had discontinuations of programs recently for renal toxicity with renally excreted alphas. Again, that will vary from program to program. But generally speaking, alphas don't have much business ending up in your kidneys. The liver is a far more radio-resistant organ. And so the attraction of 592, it's somewhat derived from 591, hence, the sort of naming convention is that it is also hepatically excreted like 591. It has very little renal excretion.

And so the expectation is that it's a better suited moiety for targeting alpha emitters. And I guess we'll find that out in due course. We, of course, we dabble in small molecules. I mean we want to understand the field. We have a fairly active R&D program looking at alpha emitters with small molecules as well because, of course, the advantage with smaller formats, and we look at small molecules, we look at small proteins. We have a protein engineering team in Los Angeles that looks at smaller formats. Of course, the advantage is that as we move into earlier lines of therapy, and I think the sweet spot for alpha is honestly not treating late-stage advanced bulky cancers. It's not really what the radiobiology of alpha is optimal for.

I think if we -- I think alpha will have its sweet spot one day in targeting that very low burden of disease in the early metastatic, perhaps even hormone-sensitive space, that's where alphas will be fantastic. And then tumor penetration is really going to matter. But also those patients are going to live for a very, very long time. And so we've got to be confident that when we're parking an alpha emitter, particularly with respect to clearance organ that we are not creating something that's going to be a major downstream multiyear risk for the patient. And I think that's where the field has quite a bit of evolution to still undertake.

Yes. When you think about the alpha emitter space, obviously, you have actinium as well as 212PB or lead. There are a few players within the lead space. Obviously, ARTBIO is one of them, advanced cell prospective therapeutics. How are you thinking about the utilization of lead specifically with the small molecule components?

I mean, look, there is a sort of a heuristic in radiopharma that your pharmacologic half-life and your radio biological half-life should sort of somehow be similar. Of course, we also ignore that heuristic quite often. I mean lutetium PSMA products that are out there today in commercial use or even in late development are obviously violate that. You have a small molecule that has some hours of resonance time and then you put lutetium on it, which has a multi-day half-life. So we're obviously -- we're not very dogmatic about it in practical reality. I think that the challenge with the short half-life alpha emitters is really when you're dealing typically with a small molecule, you're dealing with something that's under the threshold of first pass renal clearance. You have to manage the design of your molecule very carefully around kidney metabolism.

And if your alphas end up in sort of prolonged glomerular retention, you're not going to really have a great outcome for the patient. And so you want those decay events to happen quickly with a small molecule because typically, it's not targeting a lesion for very long before it gets washed out. But on the other hand, you also want to make sure that those events are not taking place in your kidney. So we've had -- we've seen in the last few months, we've seen discontinuations of programs because that balance between imparted energy to the tumor and excretion is not really balanced.

No, I completely agree with you there. When we think about the mCRPC space more broadly, obviously, there are a few other modalities that are targeting PSMA. T cell engagers are a great example of that. We've seen data from GenX as well as Amgen. How are you thinking about the deployment or physician preference for a radiotherapy over a T cell engager...

Yes. I think it's a really important question. And I sometimes feel that the nuclear medicine community, we sort of ignore these questions at our peril. So part of the answer to that is how we've tackled 591, which is really -- because it's a short duration of treatment, it's much more appealing for a medical oncologist to refer a patient. They're not handing over a patient to an authorized prescriber in nuclear medicine or radiation oncology for 40 weeks of therapy, right? So it's more -- and in fact, if you look at the global design, what we're trying to do is really layer 591 on top of kind of routine standard of care so that the patient management dynamic sort of status quo.

And we've seen nuclear medicine products fail in the past because there hasn't been parking clinical efficacy aside, there hasn't been adequate motivation for a referral physician to just hand over a patient to another specialty. So I think that is particularly in the U.S. context, I think that is a real kind of just practical challenge. And yes, we forget, and you're quite right to raise it, we forget kind of ignorantly that MedOnc has a lot of opportunities to prescribe innovative new drugs to patients. There's a lot coming down the pathway. You made a couple of great examples. We're seeing next-generation androgens. We're seeing PARPs. We're seeing all kinds of other things impact standard of care in prostate cancer.

And I think that the short answer to your question is really that radiation is incredibly valuable as a pillar of therapy of durable treatment response in metastatic prostate cancer. And you have to think about radiopharmaceuticals as the sort of migration from a box from traditional linac-based approaches to systemic approaches, but it's really the evolution of radiation oncology. And I think that managing prostate cancer, as we all know, it's about therapeutic drugs, it's about surgery and it's about radiation. And so I think that PSMA-targeted radiopharmaceuticals have a very natural role alongside potentially other immunomodulatory strategies in prostate cancer. So I think they're actually complementary. We see radiation as a driver of immune response in all kinds of cancers. We haven't seen a lot of success stories on the immunology front in prostate cancer so far on the immuno-oncology. And so I actually think that radiation can drive more success in this space. But yes, there's a lot to think about as the field evolves.

No, I completely agree with you there. Thank you for those insights. Why don't we shift gears now to TLX101, which is currently being evaluated in the IPAX-BrIGHT study, which is a Phase III trial in brain cancer. Can you talk a little bit about how that trial is designed, what the status of it is as well as the market opportunity there?

Dave, do you want to talk about IPAX-BrIGHT, more your wheelhouse?

Yes, sure. Maybe I'll open, Chris, and you can add some comments. But Robbie, IPAX-BrIGHT, as you said, it's a Phase III trial of our Iodine-131 amino acid asset, which is relevant because you need a small molecule to cross the blood-brain barrier. This asset targets the LAT1 large amino acid transporter, which is expressed in glioma tumors. We've got a number of studies that are sort of precedent studies, IPAX-1, IPAX-2, IPAX-Linz, which is an investigator-initiated trial that have demonstrated meaningful tumor control and some extended survival.

So I'd caveat that because these are Phase I trials, but survivals from time of diagnosis in the range of 23 to 32 months. So these are meaningful survivals given the median survival is typically the order of 9 to maybe 15 months in that population. Essentially, IPAX-BrIGHT is our Phase III trial. And this study, again, has a Part 1 and Part 2. I won't bore you with all of the detail, Robbie, but Part 1 is a Bayesian design, which aims to optimize the dose of TLX101 and to optimize the dose of Lomustine, which will be the control arm. So there's 2 agents and the FDA requires us and other sponsors to spend a fair bit of time at the front optimizing the dose magnitude and the dose schedule. So that's part 1, optimizing the dose of 101 together with Lomustine and there's a Bayesian design that does that. Once we get to the optimized dose, there will be an expansion cohort.

Then we get to the exciting bit, and it's a familiar theme, Part 1 and Part 2 of ProstACT Global, we talked about but IPAX-BrIGHT has a similar schema where Part 2 is a randomized Phase III design where we will randomize patients to the conventional therapy, which is typically Lomustine, that's in the guidelines like NCCN guidelines versus Lomustine, again, which is having 101 layered on top. So the question that is being asked in this trial is can we take a conventional standard of care and add a radioligand therapy on top of that to improve upon the standard of care. And in this setting, it will be overall survival. These patients have a limited duration upon recurrence. This population is patients with recurrent glioblastoma and overall survival is the primary endpoint of this trial.

Can I just make a quick time. We are...

Please.

We've been getting monotherapy data, IPAX-BrIGHT. IPAX-2 study was monotherapy data. We have done a dose escalation study, just to be clear. So we have an idea of what we're targeting in terms of dosing regimen. It's -- as David noted, it's about layering that now on top of standard of care where the extra run-in piece is required. So when we've done prior studies, including quite a bit of compassionate use experience in Europe, patients have typically been receiving whatever standard of care is available, whether it's Temozolomide, Lomustine, adjuvant radiation therapy, additional surgical. I mean it's been the whole heterogeneous hail Mary of recurrent glio research or clinical management. But now it's really about locking that down into a slightly more constrained study. And so that's really what that run-in part of BrIGHT. It's not about to validate dosing because we've done that, but it's about really ensuring that the dosing assumptions that we have on top of standard of care -- on top of a prescribed standard of care hold up as we go into Phase III.

So I have to say Dave's team has done a phenomenal job from a KOL engagement perspective. We've got a bunch of sites in Europe now that have been working with the asset for a long time. I've done a lot of patients, had a really positive temperament towards the asset have seen really good disease control and treatment responses even in some cases, which we don't see in this patient population very often. So it's a very gratifying to have so much investigator momentum and interest in the study from top-tier European neuro-oncology sites is very gratifying. And we're really looking forward to rolling this out to U.S. patients this year as well.

One of the interesting assets that I also find fascinating in your pipeline is CLX250, which is being evaluating clear cell renal cell carcinoma. I'm curious where that -- what's the status of that trial that's ongoing? And from an early standard activation perspective specifically?

Yes. I'll make a few comments and then Dave, perhaps you chime in. I have to tell you this program has been very challenging because of the constant change in standard of care. I mean, kidney cancer moves so fast. And it's actually really gratifying. If you take a step back and look at the field overall, we've made huge strides in kidney cancer over the last decade. It's become a very immunotherapy-centric study. We are seeing new combination therapies evolve that are providing fairly incremental, but steadily in the right direction, survival benefit for patients. And I think the 2 cornerstones today as we see it evolve is really the immunotherapy combinations, whether that includes or doesn't include things like TKIs or cabozantinib or whatever.

And then on the other end of the spectrum, we've obviously seen the emergence of belzutifan in the last-line setting. And so what this has done is we've been developing our sort of Phase II strategy around this asset. We've been taking multiple approaches. We've been looking at combo immunotherapies in first and second-line setting and how to layer in kind of more traditional treatments. And we continue to do research in that area. But what we have decided is that there still remains an unmet need in last line rapidly progressing patients. We don't feel that, I mean, belzutifan has emerged as a new standard of care in that setting, but it's not. I don't think it's -- I don't think anyone believes that it's a very overwhelming solution. And so I think whilst it's good to have a new option in that patient setting, and there are a lot of patients that progress off immunotherapies, I think we can do better.

What we learned from this initial work that we did in the space is that we can resensitize patients back to immunotherapy to an extent with radiation. And we have some fairly compelling monotherapy data. And so what we have done is we've gone back and said we're going to do a, call it, a VISION trial style study in last-line progressing metastatic patients and then start to work upstream in parallel with the immunotherapy combination. So we have, for example, a study that's open at the moment, that's combining immunotherapy checkpoint inhibitors with targeted radiation that's being run at MD Anderson.

So we have these sorts of studies, which are really about preempting and planning a little bit what happens when we move upstream from that monotherapy advanced metastatic signal. So that's the current plan today. That's what the LUTEON trial is designed to do. It's to really -- to look at that last line setting where there really isn't a lot of treatment options. It's a traditional place for nuclear medicine to be. And then once we get that monotherapy efficacy confirmation because we have some pretty nice data that shows disease modification and stabilization in that patient population, progression-free survival, prolongation, then there's an opportunity to move up into the earlier lines with combination immunotherapy. Dave, do you want to add anything?

Yes. Thanks, Chris. Robbie, you'd be familiar with this, but I just want to highlight the need. There are -- we've had a major advance with immunotherapies over the last decade. And those patients who enjoy a response, that's great for them, but it's only -- it's a 30%, maybe 40% of the population that you expose to an immunotherapy agent in advanced kidney cancer that get a response. So there's a large group that when I talk to patients about this, they often say things like what if I blow through and just go straight through because I'm not one of the responders. And they're the ones that are really worried about needing something else. So there is a large subset that end up in the treatment refractory end of the journey very quickly. And that's why we need assets like this to be developed and...

And also why we need the imaging as well. And just the same way as we're seeing PSMA playing a huge role in patient selection and longitudinal patient response assessment in prostate cancer, we already see the same demand for renal cancer. There's no doubt that the Zircaix product, which we still expect to launch this year -- that's the true companion imaging agent to 250. It's actually the same targeting agent. It's actually, we are able to do predictive dosimetry with the zirconium agent for the lutetium product, which is really exciting. That's the first time that we've had that in our portfolio because, as you know, prostate cancer imaging has really centered around small molecule imaging. But with renal cancer, particularly for primary staging, we want to keep the ureters nice and clear. We don't want bladder. We don't want kidney. We don't want anything. Basically, from the belly button downwards, we don't want any -- we don't want to see any of that.

And so that's why a hepatically excreted agent very compelling for imaging. But ultimately, that asset is not going to get just used for indeterminate renal masses and primary staging and maybe evaluation of reoccurrence. But ultimately, it's going to get used for looking at treatment response. and to try to determine, as David says, when is the patient really truly progressing and to try to get ahead of that and not subject the patient to prolonged toxicity from immunotherapy if there's something that -- or cabozantinib or belzutifan, if there's something that you can do if you can move them on more quickly and still preserve some capacity to respond.

Thank you for that. One of the things I'm also sort of curious about because I know we're running up on time, so I'm going to make this succinct. When we think 5 years down the road, 5, 10 years for Telix into the earlier-stage pipeline, how are you envisioning the mixture of validated targets versus more novel nuanced targets as well as beta versus alpha emitters? And what do you think is the most underappreciated aspect of Telix?

Well, that's all of us underappreciated our current market cap. I think we're trading at a poultry multiple of our commercial business, but I think you'd be disappointed if the CEO didn't say that. So I'm just meeting my obligations there. But I think at the end of the day, look, I'll be the first to admit. Some of our portfolio has fairly well-trodden targets like everybody does, but we think we're taking a differentiated approach from a pharmacophore perspective. Our focus on biologics is quite unusual, mostly because biologics are harder. But the selectivity and the engineering that you get on a protein gives you all kinds of strategies for PK modification and changing your biodistribution.

And so it is more complicated. It takes longer, but it also gives you a lot of really great control and flexibility over where you steer radiation. And I think one of the things when you look at Telix's pipeline, whether you like our targets or you don't like our targets or whatever, is we choose the right radionuclide for the biological problem that we're trying to solve. And I think that, that's really important. So we do have the appetite to say, all right, this is the cancer biology we're dealing with. This is the radiobiological mechanism of action we're hoping to achieve. And here's how we're going to steer it within time and energy constraints, this is how we're going to steer that radioactivity to that -- with that particular goal in mind.

Now we are -- as you noted before, we are -- we do work in Lead-212. We do work in actinium. We do work in astatine. If you want to get something across an intact blood-brain barrier, chelators and radio metals are pretty challenging. charge matters. Pretty tough to do, but radiohalogens have lots of potential. So we have, for example, a near-term first-in-human study with an astatinated amino acid, which is for looking at leptomeningeal disease. That's a really beautiful example of where you have a widely disseminated -- relatively small metastases. It could be a great opportunity for an alpha emitter, but you still need to have things that have a more favorable CNS biodistribution. So you need to think about your radio labeling strategy there as well.

So those are the sorts of thoughts that we have as we develop the earlier-stage pipeline. Some of our first-generation products were either small molecules that people relatively well understand or antibodies, full-length antibodies. I think that the sweet spot somewhere in the middle where we're dealing with smaller formats potentially that have better tissue penetration, but are still steerable to more radiation-resistant clearance organs. Internalization still matters even with alpha emitters, receptor-mediated internalization is different than binding to the substrate of a receptor and having some transient on-off effect. So I think there's a long way to go. I think what we really see now is the first generation of pharmacophores, and we've been -- we've had some great successes for the field, but there's a lot more that we can do to optimize the pharmacology of radiopharmaceuticals for the types of isotopes that we're interested in delivering to patients.

So I think that's the science lens of the company. And fortunately, we're in a great position where through some M&A and through some organic investment, we've been able to build new capacity. And in fact, this year, you will see the beginning of a couple of very novel targeting agents, including with novel targets that will come out and go into first-in-human studies where you'll see the fruits of that labor materialize.

Well, I'm definitely looking forward to all of the innovative science and data that's going to be coming out of Telix, both this year and in the future. Gentlemen, thank you for taking the time to have this insightful discussion with me today.

Yes. Thanks. I'm sorry about the audio. I hope it came through reasonably well, but I always appreciate the opportunity, and you always ask great questions, Robert. So thank you.

Awesome. Take it easy, Chris. Nice to see you again, David.

Thanks, Robert. All right. Bye-bye.

Good morning, everybody. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communications at Telix. And we're very pleased to welcome you today to our investor call and webcast to present the results of the ProstACT Global Phase III study, Part 1 safety and dosimetry lead-in.

I'm just looking to the next slide, just ask you to take a moment to have a look at our disclaimer.

In terms of -- and then moving to the next slide. Very pleased to introduce today's speakers. Dr. Christian Behrenbruch, our Managing Director and Group CEO, will make some brief introductory remarks. Our Chief Medical Officer, Dr. David Cade, will present the data. And then I'm very pleased to welcome our guest speaker, Dr. Pedro Barata, Medical Oncologist with the University Hospitals Seidman Cancer Center and Associate Professor of Medicine at Case Western Reserve University School of Medicine in Cleveland, U.S.A. and also a ProstACT Global Steering Committee member and investigator on the trial to also share some case studies and his perspectives.

Following the presentation of the data, we will open the call up to questions from analysts. These -- through the conference call line, these will be focused on the clinical data. For the questions that we don't get to or questions on the webcast, we will respond to you at the conclusion of the call if we can't get to your question. With that, I'd like to hand over to Chris.

Thanks very much, Ky. I'm going to actually hand over to my clinical colleagues in relatively short order, but I would like to make a few brief introductory comments. We are delighted to present the results of the ProstACT Global Phase III study Part 1, and we thank for your patience as we closed out the study and completed the data and dosimetric analysis in preparation for engagement with the FDA.

As a reminder, this Part 1 study is a specific requirement of the FDA in order to proceed to Part 2 in the United States.

ProstACT GLOBAL is a highly innovative trial that is designed to integrate with current standard of care in the castrate-resistant metastatic prostate cancer setting, including in combination with androgen deprivation or RP switch. RP switch is the preferred standard of care in this patient setting in the United States. However, the study design also reflects the fact that in many parts of the world, patients still receive chemotherapy following treatment with an initial RP, largely due to its cost effectiveness. As such, both approaches are permitted in the study.

The data that is presented today confirms the safety profile of TLX591-Tx in the combination therapy setting. And while an important milestone for investors is not an entirely unexpected outcome given that we had an independent data safety review committee grant clearance last year to progress to Part 2 randomization in the ex-U.S. jurisdictions where we already have regulatory approval to proceed.

Having now formally closed and read out the study, this enables us to go back to the FDA to obtain an IND amendment to include American patients in Part 2, subject, of course, to agency approval. As a reminder of the purpose of this gating study from the FDA perspective, the agency is looking for us to demonstrate safety, dosimetry and feasibility of the combination therapy and particularly the comparison between the different RP combos. As you will see, the data indicates that TLX591-Tx can be integrated with standard of care, both RP and taxane with no observed drug-drug interactions and no new or unexpected safety signals. Drug is well tolerated on top of standard of care in all 3 treatment arms. Additionally, and this is very important, based on the adverse event profile and specifically recovery from treatment-related AEs, there would be no impediment to patients receiving further treatment upon progression, including, if required, taxanes.

We're now focused on enrolling Part 2 of the study globally as quickly as possible. Part 2 has quite a different recruitment cadence in Part 1 due to the more streamlined nature of the second part of the study. It is our belief that in the not-too-distant future, combining TLX591-Tx with standard of care in the first- and second-line metastatic setting, will give physicians new options to treat patients and potentially better outcomes after failing first-line therapy.

Finally, before we move to the specific study outcomes, I want to acknowledge with gratitude the patients, their families and our clinical collaborators that continue to support this important trial. I'd like to especially acknowledge one of our key investigators, Dr. Barata, who joins us today as a speaker alongside Dr. David Cade, our Chief Medical Officer. And with that, I will hand over to the clinical team to go into the detail of the study outcomes. David, over to you.

Thank you, Chris. If we go to the next slide, today, together with Dr. Barata, I'm going to take you through the outcomes from Part 1 of our Phase III ProstACT Global study, in which we set out to evaluate the safety and the dosimetry of our lead prostate cancer therapy agent, TLX591 in combination with the androgen receptor pathway inhibitor agents, either abiraterone or enzalutamide or the chemotherapy agent docetaxel, which we evaluated in 3 separate cohorts of patients.

In essence, really all of the Part 1 study objectives comprising the safety of the 3 combinations, very clear pharmacokinetics and a favorable dosimetry were achieved. Specifically, I'm delighted to see that there are no new safety signals that were identified, and the hematologic or the blood events were both transient and manageable as we'll go through a little bit more detail later in the discussion.

The tolerability -- the tolerability of TLX591 plus RV or docetaxel given sequentially following TLX591 was supported by the dosimetry and the low grade of non-hematologic events. The lesion dosimetry demonstrated very meaningful uptake in the lesions, and there were no significant differences in the absorbed dose profiles across the 3 cohorts of patients that we studied. And then finally, there were no adverse drug interactions observed in any of the TLX591 combinations. So if you put this together, fundamentally, these Part 1 results demonstrate the feasibility of integrating TLX591 with contemporary backbone standards of care globally is a feasible approach to undertake.

So if we go to the next slide, as a brief recap of Telix's therapeutic candidate, TLX591, is a highly differentiated PSMA-targeted radiopharmaceutical that employs a monoclonal antibody to very selectively target prostate cancer-expressed PSMA while avoiding the PSMA that is natively expressed on some of the normal tissues. And what this does is it enables a very precise delivery to the cancer tissue, which is where we wanted to go of that radioactive payload. Now this approach really addresses a number of clinical needs that we need to address, particularly a 2-dose 15-day schedule that enables a much more feasible integration with standard of care, either RP or chemotherapy agents that we otherwise want to continue to offer patients. A very low radiation dose is imparted to the salivary glands and the kidneys, which are the 2 main organs that may be injured when we use small molecule agents as well as a very transient and manageable hematologic profile that we'll get into a bit more detail later on. There's very specific internalization and thus a prolonged retention within the prostate cancer cell, which is clearly evident on some of the post-treatment imaging, which Dr. Barata will show a number of case studies on. And then finally, there are some really potential real-world advantages from the lower administered activity at lower radiation doses being directed at the normal tissues, particularly in the kidneys, which may, in future, enable the patient to have additional forms of radiation therapy if necessary.

So if we go to the next slide, this slide really nicely illustrates the fundamental differences between TLX591, which is a radio antibody drug conjugate, and a first-generation small molecule radioligand therapy, for example, Pluvicto. And I think the key takeaway here is that the dosing schedule is markedly different with TLX591 being dosed as 2 fractions 2 weeks apart compared to up to 6 fractions every 6 weeks with the small molecule. And so what this means is that the total amount of radioactivity that has to be delivered to a patient is much less with TLX591. And this is because the antibody delivery vector is specifically immunoreactive with the tumor-expressed PSMA type following, which it internalizes into the tumor cell and maintains a prolonged retention, which the imaging shows.

All with pictures. So on the right, you can clearly see the biodistribution and the clearance of the 2 different approaches and the advantage of the radio antibody approach where the liver, which is a relatively radio-tolerant organ, is the primary clearance organ followed by the large bowel and ultimately fecal elimination.

The other image obviously shows the small molecule, on the other hand, which is primarily cleared from the blood circulation by the kidneys, which really does so welcoming the radiation, followed by the bladder, which you can see very clearly and ultimately, urinary elimination. You can also see significant off-target uptake in the salivary glands, which leads to dry mouth, which can be quite problematic, leading to a reduction in quality of life in quite a significant proportion of patients.

So if we go to the next slide, let's move on to the study design, and I'll summarize the patient population. Go to the next slide, please. Now here, you can see why we designed ProstACT Global, the study the way we did. It's a very pragmatic study design that aims to evaluate whether adding TLX591 on top of standard of care can improve progression-free survival and overall survival. And what it does, as Chris mentioned at the outset, was that it aims to accommodate the different backbones of standard of care that are most commonly used by and are familiar to oncologists either within or with outside of the United States. So specifically, this chart of the world indicates that in the United States, when a patient experiences prostate cancer progression while receiving their first RP drug, the predominant clinical practice is then to switch the patient on to a second RP drug; very, very established practice in the United States. Whereas outside of the U.S., the more common practice, and this is reflected in the clinical practice guidelines, both in Europe, such as ESMO and the EAU guidelines but also those guidelines in China and Korea and Japan and elsewhere, the prevailing practice is to switch the patients on to a chemotherapy agent. The most common one of those that's used is docetaxel.

If we go to the next slide, this is the overall design of ProstACT Global, the Phase III study and its current status, which is very nicely summarized on the top right. And as you can see, Part 1 -- sorry, Part 2, which is the randomized treatment expansion is enrolling 490 patients, and that enrollment is occurring currently in Australia and New Zealand and Canada following the independent data monitoring committee review in October of last year, but the study also now has the regulatory approvals, enabling Part 2 to commence randomization of patients in China and Japan, Korea, Singapore, Turkey and the United Kingdom. So that's underway at the moment.

Part 1, back to Part 1. So Part 1, which is now complete, was a prerequisite of the FDA that was required by the FDA before we were given permission to commence Part 2 in American patients. So we're really encouraged by the data from Part 1, and we look forward to engaging with the FDA with these data at the earliest opportunity while continuing to obviously enroll into Part 2 in those regions where the study has been approved to do that.

Now if we go to the next slide, this is a brief consult -- what we call a consult diagram that really outlines what has occurred so far in Part 1 as we've completed Part 1. And you can see that there were 57 -- starting at the top, you can see that there were 57 patients screened. 36 patients who each progressed while receiving a prior RP agent were deemed eligible, and all 36 of those eligible patients received 2 doses of TLX591 as planned according to the study protocol. Then you can see the breakout below that. 11 patients were allocated into the abiraterone cohort, 11 to the enzalutamide cohort and 14 to the docetaxel cohort. I think it's a very positive sign that there were no treatment-related deaths on study, and 32 of those 36 patients enrolled remain alive as well as 26 patients that continue on the study as of the time of the data cut back on the 12th of January.

So let's move on to what these patients look like. Next slide. These are the demographics and prior treatments of those 36 patients that we enrolled for Part 1 at baseline. And I think in summary, really nothing is especially remarkable about the demographics or baseline characteristics of the patients that were enrolled to Part 1 of the study. As you can see, the majority of patients in Part 1, almost 3/4 were receiving second-line therapy in this study, and the median age was 77 years which is somewhat older compared to other studies where the age is typically around 70. For example, in VISION, it was 71. So this is a relatively advanced group of patients.

In terms of prior treatment, most patients, just under half of them, had enzalutamide as their prior RP agent. And most patients, almost 3/4, have not had a prior taxane chemotherapy agent in the earlier metastatic castrate-sensitive setting. So when we look at some of the prognostic factors, a subset of which are on the right, the median PSA was similar to other studies and the ECOG performance status was good. So in Part 2, as we proceed to enroll and ramp up enrollment to Part 2, maybe we'd expect the age to come down slightly, but otherwise, it will be a very similar set of demographics in the second part of the study.

Next slide. So let's now look at the safety. Next slide. So the primary objective of Part 1 of ProstACT Global was obviously to assess the safety of TLX591 when either administered concurrently with standard of care, abiraterone or enzalutamide, or followed by standard of care docetaxel chemotherapy. Overall, the 3 cohorts demonstrated an acceptable safety profile with no new safety signals when compared to the prior studies, including the most recent ProstACT SELECT study. You can see in the table on the right, the most common treatment-emergent adverse events comprised fatigue and nausea and dry mouth, and almost all of these non-hematological adverse events were Grade 1 or Grade 2. In other words, they were mild with the exception of 1 patient who had a Grade 3 dizziness event.

The hematological adverse events, as we would expect, comprise Grade 3 and Grade 4 thrombocytopenia, which is a reduction in the platelet counts on the lab test, which occurred in 14% and 31% of patients, respectively, as well as Grade 3 and Grade 4 neutropenia, which is a reduction in the neutrophil count, which occurred in 22% and 25% of patients, respectively.

I think it's important to say that these hematologic events were certainly in line with the profile that we would expect for this class of radio-antibody drug conjugate, and they were transient and manageable as we'll discuss in a bit more detail on the next slide.

So next slide, please. So the question that comes up, of course, is when you have a hematological event are what happens. And as I mentioned in the prior discussion, the hematological events are the main adverse events of interest for this radio antibody drug class of therapy. Now in terms of thrombocytopenia, which is the most important of these events, as you can see here, the platelet counts were very consistent across the 3 cohorts with the near or the bottom point in the platelet count occurring very consistently at an average of 43 days, which is about 6 weeks after the first dose of TLX591. But what's most important is what happens from here. So from the nadir, you can see that the platelet counts recovered to Grade 1 or better than an average of about 15 days after the lowest point. And from there, they continued to revert back to the normal range in the majority of patients. Importantly, no patients experienced any febrile neutropenia related to TLX591, which is a relatively common adverse event that patients may characteristically experience from conventional chemotherapy. So in summary, the hematologic adverse events, which are very well characterized and understood from prior clinical studies with this agent were self-limiting and they resolved spontaneously without intervention in the majority of patients in Part 1. So this is very encouraging.

Let's move on to, next slide, please, the dosimetry. Next slide. So while safety was the primary objective of Part 1 of ProstACT Global, the main secondary endpoint was to assess the pharmacokinetics, biodistribution and the radiation dosimetry of 591 when administered concurrently with those standards of care. Overall, the 3 cohorts demonstrated a very predictable pharmacokinetic profile. And if you think about where you want the radioactivity to be, you either want it circulating in the blood pool so that it's available to be taken up by the tumors or you want it in the tumor lesions themselves or you want it in the liver as the drug is cleared from the body as we saw in those earlier images. Now the importance of these 2 graphs, and I'll explain them to you, is that the graph on the left demonstrates the blood radioactivity concentration, which, as you can see from the curves, is sustained but declining over time. In the right-hand graph, what we see is essentially the reciprocal of that, which I think very nicely demonstrates the tumor radioactivity concentration, which increases early and then is sustained over time through the antibody-specific binding, its internalization and its prolonged retention on site within the tumor. These exposure and watch kinetics were very clearly consistent across the 3 cohorts, as you can see by the oversitting of the lines, which indicates that there was no evidence of TLX591 interacting with any of the RP drugs when we co-administered those agents with TLX591.

Next slide. Now let's move on to the normal organ dosimetry. This is very important. So this is those organs that we want to keep the radiation away from. And as you can see very clearly, this part of the study confirmed that the radiation exposure to those normal organs was very low and certainly well below safety limits that have been determined from the external beam radiation and the radioligand therapy literature. And a particular note, you can see that with TLX591, there's a very low radiation dosing part to the kidneys and the salivary glands, which are the 2 normal tissues that small molecule radioligands tend to hit the hardest. And this reduces the risk of developing kidney impairment or dry mouth, each of which may very significantly impact patient quality of life, both during treatment and in the out years to come.

You can see on the right-hand side of this chart, the liver, as I highlighted earlier with the images. The liver is a very -- a relatively radio-tolerant organ. So it makes sense that this is the primary clearance organ and therefore, it receives the highest dose, which it is capable of doing. And then from there, the activity is cleared from the body via the right colon, the left colon and the rectum, which is sort of downstream of the liver and ultimately via fecal elimination.

Next slide. And then finally, Part 1 studied the lesion dosimetry, which, again, was highly consistent across the 3 cohorts of patients and it showed that following the administration of 2 doses of TLX591, 14 days apart, there were consistent and meaningful physical radiation doses imparted to the tumor target lesions across all of the main anatomical sites of disease, the 3 main ones being the skeleton, which is where prostate cancer goes, the lymph nodes and the soft tissues. I do think it's important to note that while these radiation doses are meaningful, radioantibody drugs possess a different mechanism of action compared to small molecule ligands. And as a recent dosimetry think tank at the ASCO meeting concluded, it's important to be mindful that tumor dosimetry is measured differently from trial to trial. And while it's available for go/no-go decisions in radiopharma development, we ultimately still rely on [ subjective ] clinical measures of efficacy, such as PFS and OS, which, of course, what ProstACT Global Part 2 is already underway to evaluate.

Now we are -- I would like to hand over to Dr. Barata. We're very fortunate to work with investigators of the caliber of Dr. Barata. And Dr. Barata is going to take us through a couple of typical patient cases from Part 1 of this study. So Dr. Barata, over to you.

I appreciate it very much, David. I hope you and everybody can hear me okay. Pleasure to be here with you all.

Can you show me next slide, please? So we have a couple of cases here, part of this component of the study for you today. And what we're looking at is actually our first patient case. So this case in brief kind of illustrates a 64-year-old patient known to have metastatic prostate cancer involving the lymph nodes who got treated with TLX591 in combination with abiraterone. So just for context, this patient had evidence of mCRPC, so construction-resistant disease, previously got treated with enzalutamide and ADT, and the investigator decided to choose abiraterone as standard of care along with TLX591 and end up enrolling in that cohort.

So baseline gallium PSMA PET did show disease in the lymph nodes, as you can see here on the left, including subcarinal, pera tracheal, abdominal, pelvic lymph nodes. So extensive nodal disease, if you will. He did receive a single dose 177 lutetium-0711 at approximately 27 80 mgl and then was followed by a serial PT to evaluate biodistribution. I think what we can see is here early images at 4 and 24 hours show kind of an expected distribution of the rather label antibody within the vascular compartment and also the liver, which does reflect what David presented before, that systemic circulation and hepatic clearance. Importantly, by 96 to 168 hours, we do see a clear uptick and which I think demonstrates effective targeting of those PSMA expression lesions. I think it's relevant to note the persistence in the signal even at 360, highlighting, I think, to me, the prolonged tumor retention of these antibody-based radiopharmaceutical. So I think this prolonged residence time, I guess, supports this radiation delivery to tumor sites. And I think it can reflect the potential advantage of this approach compared to small molecule, for example. I should note that this patient remains on study at 279 days at the time of data cutoff, and this was last January 12, 2026.

Thank you. Can we move on to next slide?

So I'm going to show you a little different case. This is an older patient, 83-year-old patient, also known with mCRPC, predominantly bone disease as shown in the baseline gallium PSMA PET that includes the disease in the vertebra as well as in the ribs. This patient was also previously treated with ABT and enzalutamide. And the investigator determined that the patient should receive docetaxel at standard of care following TLX591. So patient did receive TLX511, approximately 28 90 [ mg per kl, ] and again, serosity imaging in that context. So as with the previous case, we see early images there demonstrating the same type of distribution, which is, again, consistent with the pharmacokinetics and of the monoclonal antibody base radiopharmaceutical. And by 96 hours and beyond, we do see a clear localization of the radio tracer in the skeletal mets, which I think confirms the uptake of the sites of the PSMA-expressing tumor in the bone. It's also relevant one more time to note that we do see activity detected through the 360 hours, which again demonstrates this prolonged tumor retention and sustained radiation exposure. This patient also remained on study at 160 days at the time of the data cutoff, same day, January 12, 2026. And in this context, I think it's important to highlight the feasibility of sequencing TLX591 with docetaxel while maintaining effective tumor targeting and favorable biodistribution.

So 2 cases, one standard of care, abiraterone, the second standard of care docetaxel received sequentially. Both cases, patients were -- remain on study at the time of data cutoff.

Thank you. And please show me the next slide. I'll give it back to you, David, thanks so much. Happy to take questions.

All right. Thanks, Dr. Barata. Next slide, please. So let's summarize and then we'll move on to -- we're very happy to take questions.

So to summarize, Part 1 of ProstACT Global really has confirmed for us that TLX591 plus the most common standards of care has an acceptable safety profile. It's got favorable normal organ and meaningful tumor dosimetry. In particular, I think these findings were consistent across the 3 cohorts. That's a very important finding across those 3 cohorts that we studied. As expected, there were no new safety signals identified. There were no drug adverse interactions and that was shown very clearly in the behavior of the agent when it was combined with the RP agents. And a low radiation exposure to the salivary glands and to the kidneys are very important and I think attractive features of this agent, which really support and explain its tolerability amongst the patients that have received the agent, the 36 patients in Part 1 of the study. So really, we're very encouraged by these data from Part 1. I think they're sound, and we do look forward to engaging with the FDA at the earliest opportunity, while, of course, at the same time, ramping up enrollment into Part 2, which is the exciting part of the trial, the randomized treatment expansion in all of those regions where the study has already been approved.

So I'd like to thank you for dialing in. Thanks for your attention. I hope that's been informative. And we are very happy to take any questions.

Your first question comes from Andy Shah from William Blair.

So maybe a couple of just quick ones for Dr. Barata, if you don't mind. Just from a patient baseline characteristics, I noticed that the visceral metastasis rate is about 36%. Can you comment on that, whether that's kind of high compared to other prostate cancer studies like a PSMA-4 or VISION study? And also before the -- diagram, it seems like the screen failure rate is also a little bit high, about 37%. So I'm curious about what the most common reason for not meeting eligibility. And I have a quick follow-up in terms of maybe absorbed dose.

David, I'll defer to you if you want me to address the VISION question first or vice versa, I'll defer to you.

Yes, Dr. Barata, you go ahead, and I can add a little bit of color to it as well.

Of course. So thank you for your question, really relevant. And I think you're quoting several data sets, trial and real-world data regarding the prevalence of visual disease, right, which usually lands in up to 20%. So you are right, when we compare things, the number needs to be higher. But my interpretation is twofold. Number one, I think it's an advantage of this design is the ability to offer chemotherapy as part of the cohort here, which is different from other studies. What that means is this tells me that the investigators around the world were very comfortable offering this protocol because they have the option of going with chemotherapy, which is a standard of care in many parts of the world, particularly for patients with aggressive disease such as visual disease.

And the other piece is definitely the sense from investigators that if you have a positive PSMA as a tracer, even though you have visual disease, you do believe that radiopharmaceuticals play a role. So in my opinion, the higher rate than expected, it's a good thing for this particular study design because it reinforces the opportunity to run this study in the context of more or less aggressive disease. But to your point, in the context of more aggressive disease as well. So it does play relevance in both scenarios -- in a scenario of a crossover to a different RPI or the scenario of going with the chemotherapy. So a fantastic point that you raised.

Yes. Maybe, Andy, look, you've got a very sharp eye. So I'll answer the second part of your question. Just to repeat it, you asked in the -- diagram why was a significant number of patients excluded 57 screened and 36 enrolled. It's an excellent question. So primarily, that's because of the 21 patients excluded, 18 of them didn't meet the eligibility criteria. And within that 18, the vast majority were because there's a baseline independent radiology review that looks at the PSMA positivity of these patients. And so obviously, you want to have a high PSMA positivity, in other words, a high expression of the target because they are the patients that ultimately stand to benefit from therapy, whereas those patients with a low PSMA expression are very likely to respond. So we select patients quite heavily on that basis, and that's why patients that don't have high PSMA expression read out and thus excluded. Does that answer the question, Andy?

Apologies. Andy has dropped off the line. Your next question comes from Laura Sutcliffe from Citi.

Since Andy just dropped off, I might follow up to his question first. Do you envisage that initial baseline screen in any way becoming part of who is eligible for this in the future? So would you be cutting down your eligible patient population by the end of required PSMA expression level? And then I'll come back with another question.

Yes, Laura, look, that's a great question. And the answer is yes. So in the entry criteria into the study, patients have to have lesions or at least 1 lesion that has PSMA positivity that is twice the liver. So that is a requirement to enter the study. And that's for sensible reasons because PSMA positivity is sort of -- is an indicator of how much the radioligand therapy, the radioantibody drug conjugate, will go to those lesions. So if the patient has a very low PSMA positivity, there'll be much more off-target uptake and won't hit the tumor target. So that's why that is set. That was used in the VISION trial. We've increased the requirement for PSMA positivity in the study. And typically, the eligibility criteria guide the ultimate label discussion with FDA. But that's a matter for that discussion in the future.

Okay. And then my other question is just you've broken down in your presentation the dose absorption characteristics of the 3 groups, and they're quite similar, but the safety profile is not broken out by cohort. I was just wondering if you could comment on how the groups differ and in particular, any differences in Grade 3, 4 adverse event rates between the groups?

Yes. Look, they're actually very similar across the 3 groups, very, very similar. The most important adverse event is the hematological adverse events. And of those, the most important of those is the thrombocytes. And you can see that those 3 curves for the platelet decline to nadir and then recovery from nadir back to grade 1 and then beyond that, recovering back to normal. Those 3 curves, when I first saw them, I was very pleased to see that they almost sit on top of each other. So that behavior for thrombocytes, platelets, but also for neutrophils is very consistent across the cohorts, and it's the same for all of the other non-hematological toxicities as well. So Laura, that will be -- the FDA will want to see that. That will be a detailed discussion with the FDA, but they -- across all 3 cohorts, they're very, very similar.

Your next question comes from Tara Bancroft from TD Cowen.

This is Nick on for Tara. Given these data, what is your level of confidence that patients who remain on drug to experience longer RP FS than Pluvicto does in the PSMA 4 trial at 12 months? Or do you believe there is a different bar to use for ProstACT Global given the combination approach?

Yes. Look, the statistics of this study basically required 9 months versus 6 months, but that's not an assumption of efficacy, of course. That's just simply for the statistical planning for the sample size based on an assumed treatment effect. So that's the assumption for the sample size plan. Now that's not to say that's what we'll demonstrate. But obviously, there needs to be a meaningful progression-free survival and a meaningful overall survival. And that will be first gauged. So we don't have any reading on that at the moment. That will be first gauged as an exploratory endpoint from Part 1, progression-free survival and radiographic progression-free survival are exploratory endpoints. And we anticipate that they will probably be available later in the year, second half of 2026. Obviously, that's a time to event, which is guided by how the patients perform. And so longer for each patient is better, and that obviously pushes that out. The next inflection obviously, is guided by the interim analysis of futility, which is a preplanned inflection after 81 progression events. So that's where we're headed.

Your next question comes from Shane Storey from Canaccord Genuity

David, I'm going to continue just there with that statistical route, please. I anticipate that we'd probably see quite different activity and maybe effect sizes between the 3 controls in the second component of global. So just curious about how that might be handled. And maybe another way of asking that is whether any of the individual standard of care arms might themselves be powered for that primary endpoint, please?

Yes, Shane, that's a well-directed question. There's no -- there's an assumption of no significant difference in the effect size between the RPs and the sequence docetaxel. However, per the protocol design, and this is obviously up on clinical trials, there's -- these are stratification factors between whether they were elected by their investigator to have either RP or chemotherapy. That's a stratification factor, which means that both sides will be balanced. And that's how bias is dealt with. And yes, really, I think that answers the question, hopefully, Shane.

No, it does. So they're stratified first and then randomized second.

They are. Yes. So stratification balances out to make sure that there are more patients in one arm compared to the other getting chemotherapy or RP. And that's how that bias is mitigated pretty conventional sort of statistical approach.

I've got a couple more just back to this morning's data. You mentioned the, I guess, homogeneity of the safety sort of across the different cohorts. Could you speak maybe to a little bit more detail on the management of the Grade 4 hematologic events? I wondered whether in any of those situations whether transfusions and growth factors are necessary, please?

Just take myself off mute. All of those thrombocyte declines were self-limiting and resolved spontaneously. Two patients received platelets and 2 patients received red cells. But that's very, very similar to prior studies. 2 patients received platelets, 2 patients received red cells. Now that's pretty consistent as you would expect in patients receiving chemotherapy or receiving other cytotoxic agents or radiation therapy as well. So there's not really a difference in the rate at which blood products were received compared to studies.

And my last question, David, but my last question really, and I know it perhaps might go a little bit beyond the duration of interest that we're dealing with this morning. But maybe some comments on how many cycles of docetaxel those patients went on to receive after 591. I just want to kind of rule out the idea that there are any sort of serious deviation from the dosing protocol for docetaxel.

Yes, sure. And that's a relevant question, Shane. So in standard practice, when we use docetaxel, the median number of cycles that a patient with prostate advanced prostate cancer would get is typically 5 to 6 cycles. Now in this study, we're very confident that we've got enough patients receiving enough chemotherapy to take to the FDA. That's what they asked us to show. We didn't go into any detail on that because that is really a question of treatment intensity. Now treatment intensity, the number of cycles that the patient gets, is not obviously an endpoint of Part 1, and it's typically discussed, as you know, when we get into efficacy discussions. And so you will see that in the Part 2 results, but it's not an endpoint and not that relevant for Part 2. But we're very confident we've got enough data to -- on the docetaxel cohort to take to the FDA and have a meaningful discussion.

Your next question comes from Dave Stanton from Jefferies.

Just a follow-up on the previous question from Shane. So can you perhaps outline to us the next steps and potential time lines for that for FDA engagement?

Yes. Look, I'll also invite Chris to comment on that as well. But yes, look, I think these data, Dave, the data these clinical data are exactly what the FDA prescribed us to collect. We've now completed that. And it is -- I think we're overwhelmingly encouraged by these data, and we're really keen to put it in front of the FDA. Chris, I might ask you to sort of add any additional color to that, that you would like to add?

No, I don't. I mean we -- this is the first time that we've had the completed CSR from the study, which is why we've disclosed it in a timely fashion, and the team is working really hard to get the package in front of the FDA in a timely fashion. So it's a high priority to get U.S. patients into the randomized Part 2.

Understood. And perhaps just in the real world, can you talk to potential treatment options for TCP, Grade 3 or Grade 4 that a clinician might look to use and how to mitigate any -- that decline in a Grade 3 or 4 situation in the real world. Perhaps it's a question for Dr. Barata.

Maybe Dr. Barata, you'd be welcome to answer that question of Dr. David Stanton.

I appreciate that. I think I was having some trouble hearing the question to the end. I think real-world management of significant side effects. Is that what I heard or -- I'm sorry?

Particular -- in particular, Grade 3 and Grade 4 thrombocytopenia, please. How would you manage that in the real world to get patients through?

Got you. Got you. Yes. So I think what we've done in the protocol is pretty much aligned what happens in real world. So I can tell you that most of the time, unless you have below 10,000 platelets where transfusion, platelet transfusion is recommended because you can develop spontaneous bleed, numbers above 10,000 usually are the close monitoring with repeat labs on a regular basis and observation is what we tend to do. So the protocol in terms of managing and watching the numbers on a regular basis, repeat labs is what we would do in clinical practice, and that the periodosity or the schedule of those checks, lab checks vary. Some folks will do a little bit more often, others every week to every other week. So I would say the protocol gives you that flexibility. So what you're seeing here, it's really pretty much what we would have done in real world outside of clinical protocol.

I'll just add to that. It's certainly not an acute event. So we know the behavior of the platelet profile. And most patients in the study, as you can see, I think it's in that graph very clearly articulated that they get just below Grade 1. So Grade 1 is between lower limit of normal and 75,000 platelets. Patients spend a very, very short fleeting time below Grade 1 and then they recover. Almost all of them despite themselves back to Grade 1, which is sort of you're an MDI as well, but Grade 1 is obviously the safe zone. In fact, Grade 2 is quite safe as well, but they get back into the Grade 1, very safe zone very quickly by themselves. And then from there, most of them recover pretty quickly. So it's really, really predictable, and it's only the outlier patient that might need hematologic support with units of platelets or red cells. Now obviously, red cells declining is very, very common in radiation therapy and chemotherapy. Anemia is one of the most common side effects, but it's not characteristic with this agent.

Your next question comes from Melissa Benson from Barrenjoey.

The first one, just a quick one on the non-hematologic events, just the dry mouth or Grade 1. Should we think of that as really attributed just to the ARPI combination contribution?

Look, as I mentioned, all of the Grade, all of the dry mouth events were Grade 1, Grade 2, in other words, mild. They were very short duration as well. Now attribution is performed by the investigator. All of the attribution for dry mouth was not attributed to TLX591. So it was not attributed to TLX591. The occurrence of it has not been specifically attributed in the study. So just the investigator basically says that it's not attributed. So I guess the encouraging thing is that, yes, none of the patients had Grade 3 or Grade 4 dry mouth and none of the patients had Grade 3 or Grade 4 dry mouth that was permanent, which it characteristically is with small molecules, always Grade 1, always Grade 2 and always thinking.

Great. And just one further. You've spoken to FDA next steps. Later last year, you mentioned that you need to file a CTA with the European regulators to kind of open Europe sites. I guess just help us understand, I guess, next steps there. Are you kind of waiting first to FDA and then you'll file with Europe or that's kind of a parallel process?

Yes. Thanks, Melissa. Yes, FDA was the regulator that said we want to see Part 1 done and bring it back to show us, and we'll have that discussion for an IND amendment. European regulators did not specifically ask for that. But of course, the regulatory authorities in Europe and the United States communicate. In fact, all global regulators communicate on a regular basis. So when the European authorities saw that the FDA wanted Part 1 completed, the European agencies also wanted to take that approach as well. So now that we've got it, it will be going to the European authorities seeking permission very similar to the FDA's approach to open the study to Part 2 in the European sites.

Your next question comes from David Bailey from Morgan Stanley.

Just the SELECT trial was RP only and in this one, you've added docetaxel. So it's a broad question. You've kind of answered it already. But how would you expect adding docetaxel to impact the hematologic events? And is there anything from a data perspective between ProstACT Global and SELECT that you think might be explained by adding docetaxel into the treatment arms?

Yes. Good question. David, in Part 1 of the study, docetaxel is not given concurrently, as you know, docetaxel is nominated by the clinician, and it's started after 591, typically within a 10-week window. After 591, second dose has been given. Now there are patients that have had many cycles of docetaxel in this study. There are patients that have had the sort of median number of cycles and so forth. And as I said earlier, we've got enough to -- we believe we've got enough of that data to take to the FDA and have a very meaningful discussion.

A lot of patients don't -- when they're feeling great after a therapy, they don't want to start docetaxel. So a lot of patients will actually decline it. I would like to invite Dr. Barata to maybe comment on how his patients view docetaxel versus RP and their willingness to start it. Maybe Dr. Barata, you could comment on that.

Right? That's a fantastic question and a fantastic point, David, that you raised. So I think it's common -- it's known to all of us that patients don't love chemo, right? They're looking for nonchemotherapy options. Perhaps that's one of the reasons why there's so much ARPI switch is done at least in the United States, where we can actually do it.

So from that perspective, when you give a therapy that works and you're doing well on it, you would expect or you will expect some pushback from patients and quite honestly, also from providers, right, because they don't feel as strongly regarding bringing the chemo right now as per protocol is defined versus upon progression. It's almost like you're buying time, you have tumor control. So the more you have an active agent, that provides you tumor control, evident in scans, PSA, patients doing well. Actually, I would argue, it would not be residual. The amount of patients who say, you know what, give me a break, I'm doing well, cancer is not progressing. Can we do it at a later time. So I would anticipate in these kind of designs, the amount of people who ends up not getting the sequential intervention without progressive disease is not necessarily a bad thing. It can be a consequence of patient preference because he has that ability to push back because tumor is not getting worse. So we do see that in clinical practice. And so it's something that, on one hand, we're assigning it to chemo because we think it's aggressive disease. We want to do chemo. On the other hand, if TLX511 is effective, some of the patients very likely can push it back for a later time.

David, I'll just add to what Dr. Barata said. I think we've articulated the purpose of Part 1 of the study. FDA wanted to see specific information on the priority combinations of RP plus TLX591 when they're intended to be given together or 591 sequenced with docetaxel following. Prostate SELECT, you might recall, I don't expect you to during all of these details, you got other things that you think about no doubt that Prostate SELECT, the primary objective that as the title of that study said was to demonstrate that gallium PSMA TRACE indicated where lutetium rozopanimab therapy was likely to go. So in Prostate SELECT, we didn't specify that the patients had to have an RP or a chemotherapy agent. We allowed it that the vast majority of patients in that trial were treated as monotherapy with 591.

Your next question comes from David Lowe from UBS.

Just going back to Slide 15, we saw enzalutamide group showing platelet count continuing to decline after 150 days. Just wondering what -- how we should understand that? And do you think that platelet count is manageable after day 350?

Yes. Thanks for the question. That sort of decline, if you look at where it's happening in the platelet count, it's a long way out to the right. If you look at the sort of, I guess, the scale on the bottom, the patients heading out up to a year and beyond. So really, in this advanced metastatic castrate-resistant population where they're being treated, as I mentioned in the baseline demographics, they're being treated as second-line patients, the median age of 77, this is a pretty advanced group of patients. So that lab profile is certainly not uncommon in the broader population of patients.

Now whether it's any more marked with abiraterone or not, I don't think these data can conclude that for us, but that behavior of that decline sort of out beyond 250, 300 days is pretty characteristic of what you see to the blood counts if you took them and sent them to the lab in the average patient who was off study. Maybe Dr. Barata, you could comment in your own clinical experience, what happens to the lab counts after long exposure to abiraterone?

Yes. No, that's a fantastic point. I would argue as well. You have 25% in the baseline patients previously exposed to taxane-based treatment, right? Elderly population, median age, close to 80, 77, which is definitely higher than the overall population, if you will. We do see some cytopenias with ABT and ARPI. So I don't -- and if you look at the numbers, the numbers is definitely within the safe zone for us to definitely consider subsequent therapy. So it wouldn't got our eye in terms of concerning at this point with such a good -- I mean, a follow-up of the year, as David alluded to, it's kind of reassuring thinking that they got therapy a long time before this last cutoff. So that's, in my view, it's aligned with what we would anticipate for this patient population.

Okay. Just the other one I had, with the next steps with the FDA, what are your thoughts on what the safety criteria might be to proceed to that 2?

Really, look, I think this will be the last question, but it's an important one. The FDA were crystal clear. FDA wanted to see safety on the concurrent use of TLX591 plus very conventional agents in the U.S., which are primarily abiraterone or enzalutamide or if a clinician like Dr. Barata wanted to provide docetaxel after TLX591. They were 3 dosing regimens that the FDA was crystal clear on. It was prespecified by the agency go away and do 10, 10 and 10. We've actually done 11, 11 and 14. So we've done a little bit more than what the FDA asked for. But that was prespecified, pre-agreed with FDA, and we look forward to taking it back.

The only other thing that the FDA would want to make sure is that the agents don't preclude subsequent treatment with chemotherapy, and we've got that data as well, and we look forward to presenting that to the FDA. So we've done what the FDA agreed, all prespecified, and we're about to take it back and show it to them.

So I think that's -- yes, thank you. Great question. I think we're out of time. I'll hand back to the operator.

Thank you. Yes, that does bring us to the scheduled finish time. I'd now like to hand back to David for any closing remarks.

I'd like to acknowledge the -- obviously, the patients that have come into this trial, all 36 of them, including the 57 that were screened, but of course, dedicated clinicians that we are thrilled to work with like Dr. Barata, very esteemed investigators across North America, Europe and Australia and New Zealand. I'd like to thank those for dialing in. I hope it's been informative to you. So thank you very much.

That does conclude our conference for today. Thank you for participating. You may now disconnect.

Good morning, good evening or afternoon, depending on where in the world you are. My name is Ky Williamson. I'm SVP of Investor Relations and Corporate Communication at Telix.

Very pleased to welcome you all today to our webinar with some key opinion leaders and special subject matter experts to discuss a physician's perspective on innovations in PSMA PET CT imaging for prostate cancer.

Today's format will be a moderated panel discussion hosted by Dr. David Cade, MD, Chief Medical Officer -- Group Chief Medical Officer at Telix. I'm very pleased to welcome our speakers. We are joined by Rodney Hicks, Professor of Medicine at the University of Melbourne and Monash University, Founder and Executive Chairman and Chief Medical Officer at the Melbourne Theranostic Innovation Center. and by Dr. Paul Yonover, Chief Data Officer and Director of Clinical Navigation at UroPartners, a division of The Specialty Alliance, Chief of Urology at Ascension Saint Joseph Hospital from Chicago. Thank you for joining us. And last but not least, Darren Patti, the Telix Group Chief Operating Officer.

Today's format will be a moderated panel discussion, as I said. [Operator Instructions] If we can't answer your question during the session, we'll follow up after the call if necessary.

With that, I would like to hand over to David Cade.

Thank you, Ky, for the very gracious introduction and very excited to be here today to discuss what I think is a critically important topic, which is the future of prostate cancer imaging.

We are joined by 2 of the global leaders in the field, Professor Rod Hicks, who is an esteemed nuclear medicine physician and Dr. Paul Yonover, who is a leading surgical urologist based in Chicago.

We're going to cover 3 very important themes today, namely the current clinical landscape of how we image prostate cancer. We're going to also cover the supply chain, which is an important consideration, as we aim to serve patients across geographic expanses. And I think most excitingly, we're going to address a key question, which is what are our needs for the future. We've made some very significant advances in the last 5 years, but where will we go over the next 5- to 10-year period.

So to kick things off, I'm going to ask Professor Hicks. Professor Hicks, you installed the first PET/CT camera in this country in Australia and one of the first in the world at the Peter MacCallum Cancer Center in 2001. It's almost a quarter of a century ago. And then you commenced our specialized PSMA PET imaging and therapeutics, which is what we call today theranostics at Peter Mac around 2015. So that's over a decade ago. So could I start by asking you to provide an overview of PSMA PET imaging and some of the key data that supports Gallium PSMA PET and how Gallium PSMA PET has changed the way we manage men with prostate cancer. So what really matters to physicians today.

I think we've seen over the last decade, David, a really strong clinical support for the use of PSMA imaging in the urology community at 4 different stages of the process of diagnosis and therapeutic planning.

In the diagnostic setting, although MRI has a pivotal role in localizing prostate pathology, it's a technology that is firstly very difficult to read. The MR radiologists, who are good at prostate, they are, in my mind, the idiots of the [indiscernible] imaging world to bring together an incredibly complex set of images to make a diagnosis.

And they use a scoring system called PI-RADS, the prostate imaging radiology diagnostic score, which I sometimes tongue-in-cheek renamed the poorly informative, really accurate diagnostic score because it's really very observer dependent. Men hate prostate MRI. I can tell you that, and there are many who can't have it.

And in that setting, PSMA has a very high acceptance by the patients. It's got a very good sensitivity for the detection of disease. And it also moves on to the next phase when you've already made the diagnosis of prostate cancer on clinical grounds and biopsy. it's excellent for staging the disease. It has a high true positive rate, high diagnostic performance with diagnostic micro metastases down to very small levels.

And that becomes particularly important in the next phase, which is in the biochemical recurrence after definitive treatment, the PSA hasn't gone away. We know they have disease. We have a very sensitive and specific biomarker for the presence of residual disease and that biochemical recurrence, we can see disease down to very small levels with PSMA PET scanning.

The next level is after patients have developed metastatic disease, determining their therapeutic pathway and particularly selection for radioligand therapy theranostics, the pathway of -- if you can see it, you can treat it and high PSMA expression is [indiscernible] for selection of those patients.

And the last phase, and this is something that's just coming along and recently been incorporated into the prostate working group for assessment of response to therapies is the use of PSMA for monitoring therapeutic response. The principle, if you can't see it, you can't measure it, you can't monitor it. And at all stages, we've been able to show that PSMA outperforms CT bone scan. So why would you use a technique that can't see the disease in the first place to monitor that disease. So it's really having a fundamental role at all stages of the evolution of the prostate cancer spectrum.

Thank you, Dr. Hicks. Now if we go to the next slide, please. Dr. Hicks, this is the most recent Phase III study. So it's a Phase III study of Gallium PSMA PET. In fact, this was in a Chinese population that's a pivotal registration trial intended to see Illuccix approved in China. That's in 140 patients. And really, this is a very positive Phase III trial. The results came out recently a couple of months back. And really, the headline results was that it showed that there's a very high positive predictive value of gallium PSMA PET across high to very low PSA strata. And it also showed very high positive predictive value across different anatomical locations of disease in Chinese men. So did these results surprise you? Or are they otherwise what you would expect?

Yes. They don't surprise me at all. I think we've got now a very large body of data from around the world with a whole variety of different quality of imaging technology that have shown very high positive predictive values and pathologically validated studies as well, demonstrating a high positive predictive value.

The area, I guess, that we're seeing the greatest impact, however, is actually below in those very low PSA levels, where traditionally people haven't been doing it. The whole point of doing PSA after biochemical failure is to identify a subgroup of patients, who are potentially salvageable by local regional therapies. And so we've seen our population, referral mix move increasingly to below PSAs of 0.2.

And in that population, we see, firstly, with the protocols and the technology that we use a very high detection rate of disease, but more importantly, a much lower rate of disease outside the prostate bed that could never have been controlled by local regional therapies, which often applied now empirically in that low PSA level.

Thanks, Dr. Hicks. If we go to the next slide, really leads me on to a technology question. Dr. Hicks, you were -- you've installed, I think, one of the first Siemens Quadra whole body PET/CT cameras in Australia at the Melbourne Theranostics Innovation Center, which you established a number of years ago. I think a fundamental question, this is a truly fundamental question is where will the next major innovation come from in the way we image men with prostate cancer? Do you think it's better tracer drugs? Or do you think it's the evolution of the capital equipment, the cameras? What's your perspective on this?

I think it's a bit of both, David. The performance of PSMA has been excellent with what I would consider last century technology in many ways that people were using analog, sometimes time-of-flight, sometimes non-time-of-flight cameras, which have rather low sensitivity for the detection of disease.

The advantage of the Quadra having a field of view of over a meter and very high time-of-flight resolution and very sensitive digital detectors is that it's about tenfold higher than the best digital camera that Siemens themselves make, which itself is about twice as sensitive as most non-digital time-of-flight cameras, which are themselves twice as sensitive as analog cameras without time-of-flight. And so you're getting somewhere between 10 and 40-fold higher sensitivity. And that makes a big difference in terms of the signal to noise, which is particularly important to detecting small volume disease.

So this is a patient who was planned for salvage pelvic radiotherapy on the basis of an elevated PSA of around 0.4 thought to have perhaps a false positive in the rib. We do see some false positive uptake in rib lesions and with any of the PSMA agents more with some than others. But this patient was still going to have an attempt at cure or at least delay of need for systemic therapy by pelvic radiotherapy. And they came to us for some therapeutic radiotherapy planning and had PET imaging on the Quadra.

The image on the left in red, it was the conventional scan done outside our facility, a 32-minute scan on a standard field of view digital camera. And the images on the right are the same acquisition, but then passed into shorter and shorter aliquots of the acquisition time. Our standard acquisition is 4 minutes for that partial body, but we've processed it down to just 30 seconds of that acquisition.

And you can see that what was perceived to be local retinal disease clearly isn't. There's widespread disease. This patient never would have benefited from pelvic radiotherapy. But more importantly, around the pelvis, we can see with late diuretic imaging, post-diuretic imaging, there's almost no or very low activity in the bladder, but there's no evidence of recurrence in the prostate bed.

All of the toxicity from radiotherapy comes from irradiating the prostate bed. And in this patient, not only was it not necessary, but because there was disease outside the pelvis, there was no potential long-term progression-free or overall survival benefit in this particular patient. So huge impact on patients.

So that idea of the reasons we don't see disease, 3 reasons: too small, too close, too close to the bladder, too close to the major blood vessels, waiting longer, imaging later allows clearance of blood pool, and you can see very small nodes close to the blood vessels or too little expression of the target.

Technology helps with too small, the Quadra and other extended field of view digital PET scanners are going to make a big difference and AI processing of those data are going to make a further jump in the improvement in the sensitivity.

To close, it's about technique, imaging before the urine gets in the bladder dynamically, which we routinely do in our biochemical recurrence or imaging late post diuretic. And again, more sensitive scanners allow you to go longer into the decay scheme and still have high statistical quality scans.

The last question is too little target, you need different tracers, new PSMA tracers aren't going to make a big difference if the target isn't expressed anyway.

Maybe just while we're on that topic, you could touch upon the loss of the PSMA target from a prostate cancer and what other tracers might be required to hit other alternative targets that are manifest on a prostate cancer cell.

There's sort of 2 different scenarios wherein PSMA is not expressed. The most important one is where the disease becomes highly differentiated and disorganized and loses the basement membrane, where PSMA is expressed. And that's Pattern 4 -- sorry, Pattern 5 Gleason score.

And so that gets into the very high isotope grade group, so particularly grade group 5, where either 4 plus 5 or 5 plus 4 or 5 plus 5, depending on the proportion of that classification of 5, which often lacks PSMA you'll get very low uptake. 4 has high generally PSMA expression. 5 has -- can have none.

And if there's a high proportion of Patent 5 disease, those cases can be relatively negative on -- in terms of expression on staining. And so those patients, they're genuine card-carrying cancers that use glucose and FDG PET has been shown to be very, very useful and an adverse prognostic indicator. I actually believe they're the subgroup of patients, who benefit most from chemotherapy.

So if you've got one of those very high Gleason score in a negative PSMA, I think it's really important to do an FDG scan in those.

At the other end of the spectrum, as you get into clinically significant prostate cancer that transition from 4 -- sorry, from Gleason 6 to 7, for example, some of them have relatively low PSMA expression, particularly if the percentage of Pattern 4 is relatively low. And that may have prognostic significance, but there are other targets that are overexpressed in that group and particularly GRPR sensitive, which is the gastrin-releasing peptide receptor.

And I think there's some exciting work going on in that area of new tracers that may have both diagnostic and therapeutic applicability in terms of target. But there are other targets that people are obviously looking at both stromal as well as epithelial that may be important.

Yes. Thanks, Dr. Hicks. I mean it's evident that you're operating at the bleeding edge of technology and camera equipment and that's really manifest itself in the success of your theranostics practice in Melbourne.

I'd like to now transition to the surgical perspective. Dr. Yonover, you're a very busy surgical urologist at the largest private urology practice group in the world based there in Chicago. So we've gone from Melbourne to Chicago just now. You're also effectively a business owner in which your practice currently has 4 PET/CT scanners. And I believe you're investing very heavily with your partners in more cameras. Your practice group currently sees and images over 1,000 patients a year in providing a PET/CT scan and you treat those patients under your own care. So how has PSMA PET imaging changed your practice? And what's important to you in your U.S. high-volume practice setting?

Sure. And thank you very much for having me. It's a pleasure and certainly an honor to be with somebody like Professor Hicks. So thank you, Dr. Cade.

Yes. So I represent, I think, a growing sort of segment of the U.S. health care system. I'm in a private practice, essentially single specialty group. We're now fairly massive. We're national. So those scanners that we're putting up are in towns like Detroit, Michigan, Philadelphia, Chicago, New York, et cetera. I think by 2026, we should have 13 or 14 scanners up. And that's with the idea that a large group like us in the United States is sort of a closed ecosystem, at least that's what we aim to be.

And that -- and PSMA PET molecular imaging really plays a sort of an integral role of that because we're part of the gatekeeping. We're the ones who screen for prostate cancer. We diagnose the patients. We have our own pathology lab. We have our own in-office dispensary because we deliver those therapeutics. We also have our own linear accelerators. So we deliver the radiotherapy, brachytherapy, we do theranostics. So we really try -- we've attempted to have a relatively closed ecosystem, where we're really going from cradle to grave, if you would.

And molecular imaging has had a massive -- I mean, it's hard to overstate from a clinical perspective from prostate cancer as a clinician, the impact it's had just in the last 4 or 5 years when it's really come to fore here in the United States and how it's been disruptive in a good way, right?

Right now, we're seeing it in the -- of course, in the diagnostics space, in the therapeutic space and of course, in the advanced prostate cancer space, what we're looking towards, what we are hoping for is expanded indication, getting a lot more clinical data and an expanded indication so we can bring molecular imaging, Gallium PSMA PET into the pre-diagnostic space in the screening space, in the active surveillance space and the focal therapy space.

And of course, as Dr. Professor Hicks alluded to, response to therapy, right? When a patient goes for radiation therapy, all we have really is following serial PSAs, conventional imaging doesn't do much and having some assessment of response will be sort of key.

But your question was how is it impacting us as a business owner, right? Because it's impacting me as a clinician, how do I approach my patients, the confidence I have in being able to truly understand do they have localized disease? Do they have locally advanced or metastatic -- cold metastatic disease? What's the volume of their disease, PSA as a biomarker, we could have hours of conversation just about that.

But the impact on a -- such a large group as ours, the operational economic impact, right, profound, right? It's actually becoming integral to our business planning. And because having access to our own scanning lets us control things, which is a good thing most of the time. quality control, we can stay ahead of things as far as technology, and we can, of course, leverage this from an economic perspective.

But as a large group here in the United States, large private groups outside of academia is actually probably one of the largest sources of clinical research, clinical trials. We have a lot of very busy, very sophisticated clinical trialists.

And so it's sort of that 3-legged stool, right? There's a clinical piece to this that is immediately, tangibly impactful both to the physician and to the patients that we treat. It is certainly impactful to a large for-profit company like ours, where we're looking to the economic benefits of having this in our ecosystem. And then there's the clinical research piece. So I would say that's having access to PSMA PET scanning really has been quite disruptive to all 3 of those pillars.

Yes. Thanks, Dr. Yonover. What I'd like to do is maybe delve a little bit deeper on 2 elements of what you raised, namely the business model, but also the clinical research that you contribute. So we'll just address those. Maybe you could talk a little bit about the requirements of a high throughput 6-day a week business model where you're clearly investing very heavily in camera capital equipment. What are the requirements of that and the requirement to have reliable clinical efficiency?

And then we might talk about some of the patients that you might even have seen today on BiPASS, which is a rapidly enrolling trial that you and Dr. Hicks are both co-investigators on?

Right. So I mean, I can't again overstate the importance of efficiency. This is the word as a business owner, right? Anything that kills efficiency is something that's sort of an enemy to our mission. And so we've had to spend a great deal of capital, both tangible capital as well as just labor on operationalizing a high throughput system, right?

We have a massive footprint. So just our subpractice here in Chicago has a massive geographic footprint. And so we've got patients. It's a spoken wheel sort of referral. We have one scanner. We're hoping soon to have another just locally. And -- the coordination of care, quite considerable.

These patients are of various ages and capability as far as transportation and mobility and getting patients scheduled, getting the prior authorizations and the other issues with insurance that we deal with here in the United States, getting a patient there, getting them scanned, getting them home, getting the scan, getting the data.

I mean it's a -- when we're doing just on our 1 camera, 1,000 to 1,200 scans in a year, then of course, there's force multipliers, right? As you get bigger, those small changes in efficiencies you bring up, anything that can hinder efficiency is something that's something we try to eliminate, right?

So we have to get a lot of patients through. It's logistically quite challenging. It's -- we have here in Chicago O'Hare Airport. And it's nothing short of that, right? So no-show rates are a big problem that we want to eliminate, right? And it's same-day scanning. That's really the only way we can really truly achieve sort of our high throughput.

And from our perspective, right, we are always looking for optimization, right? Any business, whether non-profit or profit driven should always be looking for optimization. We've made a choice to go with gallium-based isotopes in our scanning protocols. And as Professor Hicks so eloquently sort of pointed out and just demonstrated, right, the optimization opportunities are in our technologies, our techniques, our acquisition protocols, the application of AI-assisted interpretations.

That's what as a group, we're going to be looking to as we scale and as we try to get that 6-day a week. I hate the visualization, but we got to pack them in, right? That's a group like us, that's what we have to do here in the United States. That's -- those are the -- we're under the same economic pressures as anybody else. And so, we have to live within the physics of gravity and the physics of economic pressures.

And so we obviously don't want to cut any corners clinically quality-wise, we want the very best. We want the very cutting edge for our patients. But we need to do that in the most cost-efficient way in a way that's not going to be disruptive to our overall very complex ecosystem that we've built. So we're looking towards those improvements in technology that Professor Hicks went through so that we can get better scans.

And in the same vein of trying to provide cutting-edge, high-quality care, we are participating in the BiPASS study, which I have great cautious optimism that based on already published data, but also just from my clinical experience, that if you're able to bring in a PSMA PET into the pre-diagnostic screening space, Professor Hicks, of course, made me laugh about his descriptions of the PI-RADS reading system as a clinical urologist whose job it is, is to find prostate cancer and only find clinically significant prostate cancer and only treat appropriately. The advent of MRI 3, multiparametric 3 Tesla MRI was a huge advance, right?

We all understood and we were sanguine about its shortcomings, but it was -- really came to the fore in essence of a vacuum. And it was game-changing, a little bit of a trite saying, it was game-changing, but we were fully aware of MRI negative -- MRI-invisible disease and sort of the ambiguities of a PI-RADS 3 lesion.

And so we've already gotten the sense that a PSMA plus an MRI, they're very complementary. They're actually not exclusionary. They're complementary in many respects. There are 2 different modalities and prostate cancer is a heterogeneous disease, PSMA expression. We're just at the surface of understanding the biology of PSMA expression.

And so if on an MRI, we can image and understand the ADC and the other areas, where the prostate -- how it looks under MRI imaging. And then we're able to use a molecular target like PSMA PET. You put those 2 together, you look for congruence -- incongruent areas. It should in theory, and I think it will bear out, be able to allow someone like myself to have a more effective biopsy, a higher yield and/or -- and sort of the other aspiration is biopsy avoidance, right?

If you have great clinical data, particularly given the pretest probabilities, some of the clinical parameters, if you have a negative MRI and a negative PSMA PET scan, the hope of the BiPASS trial and other data is that perhaps we can avoid biopsies in certain patients. It will also be interesting to apply that in the active surveillance space.

And my hope is on that end, right, to be able to avoid biopsy in certain patients of mine, but also be able to do a better biopsy for patients of mine, where I'm able to have a higher yield that's more efficient. And then if I have a biopsy that tells me a little closer to truth what's going on in that prostate, that's where I can help guide a patient make better therapeutic decisions. Is a prostatectomy or radiotherapy or metastatic-directed therapy, systemic therapy, clinical trials. When you're getting closer to truth, right, you can actually just make better decisions.

And so that's -- I did 2 BiPASS biopsies today. These were 2 gentlemen's actually who had negative MRIs, and they had minimally avid areas of disease, one that I'm suspicious, I covered it pretty well on the biopsy. And it's an area actually that I would not have ordinarily gone and biopsied on a normal template transperineal biopsy on a negative MRI.

So obviously, I'll be very curious on my own experience. I'm also obviously going to be very curious about the readout of BiPASS when it's available. But I think there's really no doubt that the data that comes out from the BiPASS trial is going to be highly useful. There's just really no doubt about that, particularly based on some of the stuff that's come out of Australia already in that space.

So I'm -- and as a business owner, right, I'm looking for -- I've got a scanner, I've got a tracer that works beautifully. I'd love to find more applications in the screening space, in the advanced therapeutic space and in that response to therapy space.

Yes. Dr. Yonover, thank you very much. Look, that's a very comprehensive overview. I think to summarize, as a surgeon, your raise on [ detra] , if you will, is to do a complete cancer surgery on a patient and make sure that you have cleared the patient of all prostate cancer.

You've also made the point that you've got a lot of patients to serve. You've got an extraordinary high throughput clinic with your partners and you've got a significant requirement for PET camera uptime to make sure that you aren't seeing those assets not run to their full extent.

So that really moves us on to the second theme, which is supply chain and making sure that the ability to use those cameras to image patients to be able to take them to surgery is maximized. So we'll move across to my colleague, Darren Patti. Darren, prior to becoming the Chief Operating Officer at Telix, you were instrumental in the leadership team at Sofie as well as before that [indiscernible] PET trace and manufacturing business as well as their radiopharmacy networks in North America.

Today, we've got 2 isotopes, obviously, Gallium-68 and Fluorine-18, effectively serving the PSMA PET market. Perhaps, Darren, you could start by talking about the supply chain for gallium and how that's supporting the broader patient access as well as production flexibility, which is what Dr. Yonover just talked about.

Yes. Thank you, David. Yes. When you look at the gallium landscape, you find that there's really a -- what we have now is a mature and robust supply chain. Now that we have multiple commercial products on the market for a number of years now, this has really given opportunity for the gallium isotope supply chain to mature.

And because of this, I think there's a few notable things to call out. And this includes that now we have multiple generator manufacturers that have demonstrated consistent, reliable access and delivery. And this is something we expect to continue to expand with additional product offerings in the future.

Additionally, the beginning to end supply chain of generator production has become more vertically integrated with various manufacturers. So that further ensures uninterrupted supply. So that includes starting material germanium that's needed for the generator manufacturing

And then we talked about the flexibility and access and then just the inherent nature of having a generator on site or nearby essentially provides on-demand access, and that really affords the kind of ultimate flexibility for patient demand and access.

And then finally, with newer generators having higher capacity, this availability in the market further drives that flexibility and additionally provides greater access. So we've established that we have a very solid and consistent gallium generator supply chain that's available for patients.

So -- but now we can take a look and augment that or scale that even further now that we have commercially available cyclotron produced gallium methods. So that really allows us to ratchet up isotope production even further.

And this includes things like the ARTMS technology via the QIS system, and this allows large curie amounts of gallium to be produced. And again, this is using a very secure end-to-end supply chain, so we know it's reliable.

And so when you sum up the parts on the isotope side and then couple it with a higher capacity kit as an example, like Gozellix, you really have that higher flexibility solution that can easily scale to meet patient demand.

So on the next slide, it's just really an illustrative example of when you look at the over 250 partners that are producing Illuccix and Gozellix on a daily basis and then you add on capacity afforded by Gozellix in conjunction with high-capacity generators or cyclotron produced gallium, and you can see how it really opens up access with the associated flexibility to a very broad customer base

So I think the take-home message here is that with Illuccix and Gozellix, paired with an extremely reliable gallium generator supply chain, including generators of various sizes, and the option for a high-scale production via gallium production on a cyclotron using something like the ARTMS technology, there's a flexible option that can be tailored to a specific market need. And I think that's a very unique offering.

Yes. Thanks, Darren. I think obviously, let's put it this way, gallium and fluorine have been workforce isotopes over the last 5 years during the advent of PSMA PET. There are also exotic isotopes, if you will, copper, zirconium and others. So now we possibly have 2 providers aiming to bring copper-based tracers to the PSMA PET market.

In your view, I mean, you've got over a decade of experience in meeting demand and doing so with very high reliability. Are these providers with copper going to be able to replicate or meet the reach of the existing gallium and fluorine supply chains? What's your view on that?

Yes. So it's a really good question, David. And obviously, supply chain success is a prerequisite to deliver commercial success and patient access, right? So -- and we saw some of those challenges early on in the gallium market. And as time has progressed, the market has grown to meet that demand.

And I think we're a little bit early in that phase with copper. There's just some product attributes that make it a little bit different to look at as well. You have a longer half-life. So conceptually, you can have more centralized manufacturing, but that doesn't come without fair logistical risks and limitations as well. So in my view, it's still better supported with maybe a more regional model.

But to your point, that's -- there's up-and-coming products, but I don't feel the -- really the supply chain is quite there yet, and that's from starting materials all the way through finished product.

So with the gallium, it's truly something we've seen that's battle tested and really pressure tested through -- in a high capacity and high demand mass market. So I think it will take some time to get there. There's emerging technologies and things that are being done, but that's going to take some time to develop further.

Thanks, Darren. Well, let's assume they do get there. I might direct a question back to Professor Hicks. Professor Hicks, in your mind, in your experience, given the background of what you described was possible with improved camera equipment. Is there a role for new or novel isotopes? And if so, what might they be? Are they niche roles? Or can you see a broader application?

Yes. I can talk, I think, to some extent around the copper development because the agent that's currently in clinical trials, the bisPSMA was actually developed through my lab in collaboration with Professor Paul Donnelly from the University of Melbourne, and we did a lot of the preclinical and some of the earliest imaging of that agent.

And the advantage in the preclinical model was we saw as a companion for the therapeutic application of copper 67 that the long half-life of copper 64 of 12.7 hours allowed you to get a time activity curve that could do predictive dosimetry for the first time, a long enough uptake and clearance curve to estimate the dose that would be delivered to tumor into normal tissues.

And we saw a major advantage in that, particularly in the patients who are a bit borderline for selection of PSMA-targeted therapy where the intensity of uptake is not particularly high, and you worry about the therapeutic index between radiation delivered to tumor versus to normal tissues like salivary glands, like the kidneys.

So we certainly thought there was going to be a significant advantage there that the ability to image late would allow that issue of being too close to blood vessels or bladder would be addressed to some extent by late imaging.

And from that point of view, the long half-life being able to image at 24 and we've imaged here out to beyond 48 hours, which on the Quadra because it's so sensitive with copper, you can go very, very late in your imaging protocol.

But it's -- if you look at the sensitivity of the gallium PSMA and the convenience that in most patients within 1 to 2 hours, you've got all the information you need for therapeutic pathway planning. I was struck by what Paul was saying about how it's impacting management.

Before PSMA and even with multiparametric MRI, surgical planning and medical therapy planning, radiotherapy planning was treatment by Braille. You were treating completely blind. And by -- the real impact is not just simply the positivity negativity, it's where the disease is that's critically important.

We found that between 30% and 40% of even pelvic confined nodal disease is outside traditional empiric radiotherapy treatment volumes. They're not areas that surgeons like to go, but they can go if they know that the disease is there. And so it's making a huge impact on that planning piece.

And so I think that these agents are going to have a role. And increasingly, people are also using tracers for radio-guided surgery, where you use a probe on a robot often increasingly as well as optical imaging, and this is work that we're doing with Telix, as you know, David, to combine radioisotope and optical probes for imaging-guided surgery, the macroscopic planning with the PET scan, the microscopic at the level of the operating microscope and robot.

Yes. Thanks, Professor Hicks. I might just move to the final sort of theme, which was do we need a new tracer. And I might direct this question to Dr. Yonover. Given the discussion up to now on the current clinical landscape and the supply chain aspects that Darren covered of the U.S. PSMA PET market. In your practice setting, a very large or the largest private urology group in the world, let me pose a question to you. Do you need a new tracer? And if so, what for? And what might be the necessary conditions in which to implement it? Does it have to be same day? Or can you accommodate second day, third day, fifth-day imaging? How would it work in your practice?

Well, in a short answer, no right now. In 2026, particularly because we've already created a business plan around gallium scanning, right? The bar would have to be set extremely high for us to not only change and adopt a new isotope, but if that comes with a whole different logistical landscape, right?

That -- those logistical challenges, while not insurmountable, certainly are a barrier that would give us pause. And for those -- from that pure business model perspective, I know that it would be very challenging and it would create sort of -- it would create a big problem for us.

And so I go back to -- we hope to optimize things with technology. I'm -- as a clinician and a business owner, I'm much more interested in novel targets because I know I've seen it myself with my own patients, the shortcomings of PSMA targeted imaging, both in the theranostic space, of course, but in the newly diagnosed space. So I think that's what we're going to be looking for in sort of a short answer.

The other thing from the clinicians and certainly, Professor Hicks could speak much better to this than I, but these tracers are not interchangeable. This is not -- we have -- as a clinician, as a non-nuclear medicine doc, as a urologist, we've had to ingest all of the molecular imaging and most of that is gallium-68-based literature over the last 5 to 10 years, of which there's a great depth and breadth.

And any new tracer is going to have to not only show clinical utility, it's going to have to show not only change in management, but it's going to have to show the impact on outcome, right? And that takes quite a long time.

And until we see that proof, right, it would be hard for us to justify from a logistical challenge, a business challenge to make those sorts of leaps. I see -- and again, just from the clinician's eye, not as from an expert in isotopes, but I see something like copper as a niche product, right?

There are instances, where our gallium 68, which I see sort of as our daily workhorse. There are going to be times, where I think it's probably going to be useful in that space. But I'm personally much more interested in different targets than I am in different isotopes.

Thank you, Dr. Yonover. Look, I think that's a very comprehensive answer. And I think we will conclude the formal session there and move to questions-and-answers. So I would like to, on behalf of the audience, thank Professor Hicks and Dr. Yonover and my colleague, Darren Patti, who are really sort of apex predators right at the top of their fields, as I think you can determine from some of the discussion.

I will now -- perfect timing, it's 10:20 here in Sydney. I'd like to leave 10 minutes at the end for questions-and-answers, and I'll do my best to direct the question to the appropriate respondee.

What I'm going to do is I'm just going to go through the questions as they come in. The first one is there's a lot of noise around BCR sensitivity. I think what that means is that people are asking questions about the sensitivity of different tracers in the biochemical recurrent setting.

On the weekend, we saw POSLUMA head-to-head versus PYLARIFY. In a few weeks' time, we'll see full data from copper versus gallium. That's obviously at the EAU conference. What are those strengths and weaknesses of head-to-head study designs in the BCR setting? I might direct that to Professor Hicks, if you --

Yes. I think it's a really important question of what are the selection criteria of the patients entering into those head-to-head. I think the data actually has been already presented around the gallium PSMA 11, the Illuccix versus the copper agent of Clarity that my colleague here in Australia, Professor Louise Emmett presented at [ EUA ] (sic) [ EAU ].

If you look at the data, and this was in a group of patients, where I think the median PSA was about 0.4 with an interquartile range between 0.3 and 0.6. If we go back to that data that you present from the Chinese study, the positivity rate in that series for that range was over 90% in Louise series, it was 28% for Illuccix, which is just completely out of keeping with that data, but also out of keeping with her own data in 3, I think, published studies, where she's published her results with Illuccix, where in that sort of range, she was getting well over 50%, closer to 75% of a positivity.

And to me, that speaks to the potential of this group being subject to a selection bias that because they have the Illuccix first, and I suspect they either had negative or equivocal scans or their PSA was out of keeping with the level of disease detected on their scan and remembering that, that scan was done probably around 45 to 60 minutes, not at 60 minutes, not beyond 120 minutes, not with diuretic, not with dynamic imaging.

And so they're the very group of patients, where the technique and the technology is going to make the biggest difference in detecting them. And of course, if you then have late imaging in those patients, you're going to see more disease.

But how much does it benefit you to go to 24 hours when we know that the uptake kinetics really plateau off at about 3 hours. And if you can image at 3 hours going to 24 hours or you lose the statistical quality in your image.

The other limitation of that approach is that because of the long half-life, we're restricted in how much we can inject into a patient. The administered activity for copper within the radiation guidelines are much less than for gallium and also for fluorine, which have a much shorter half-life.

So you're starting from a lower statistical background and imaging later. And so there are significant offsets as well as the supply chain issues that Darren brought up that I think are going to really mean what Dr. Yonover was talking about. There is going to be a place for this and it's in exactly the kind of patients that I think Louise is may be inadvertently preselected those who have a negative scan on a conventional PSMA agent or the extent of disease just doesn't seem in keeping with the PSA level that's extent in that patient.

Yes. Thanks, Rod. That's a very comprehensive answer. We are being very egalitarian here because this is obviously a surgical question for Dr. Yonover, which is nice to see. Thank you to the questioner. The question, would PET-guided biopsy reduce the number of cores required and the number of cores required to calculate the Gleason score and does higher yield mean the ability to acquire more cancer cells per core due to PSMA PET guidance. How would you tease that out, Dr. Yonover?

That's an excellent question. I'm still -- that's sort of to be -- I don't mean to be cute, but I think that's to be determined, right?

One of the things in our MRI fusion experience, meaning we -- our MRI experience of whether we do a template biopsy, basically a systematic biopsy, where we're taking cores from various regions and then also targeting the region of interest. That is, I wouldn't say controversial, but that's batted back and forth. And I think we're going to be facing the same sort of conversation with PSMA.

I don't know if the number of cores will be reduced. It's not really impactful as far as morbidity. The number of cores taken don't particularly increase risk of infection bleeding or patient discomfort, to be honest. It's more of biopsy, no biopsy. Once you're starting to biopsy, that impact is de minimis.

What I'm more interested in from a yield perspective is the reduction of occult disease, right? We do an MRI fusion biopsy. We think the patient has a Grade Group 3 disease. Thankfully, we have molecular imaging now so that I can avoid therapeutic futility. We know if the nodes are likely to be positive. We certainly have ruled out metastatic patients so that we take the patient to surgery. We're confident that at least they don't have metastatic disease.

And lo and behold, what we want to reduce are the surprises in surgery, right? We want to know going into surgery, what is the most likely grade group and where it is? Is there SV involvement? Is there extra capsular invasion so that we can do a wide dissection on that side. Those are the things that we're hoping that PSMA plus MRI, we're going into surgery with more certainty. That's where I'm hoping for higher yield.

The other area, right, is if there is -- and this gets into a little wonky into the biology of prostate cancer, but if you have, say, Grade Group 5 non-PSMA excreting disease, right, that has some neuroendocrine features, that may not be responsive to the radiosensitivity of that disease, it may not respond, right?

The advantage of surgery is that it's agnostic to the biology. If it's localized and you take out the prostate, it's gone. If you go for radiotherapy, you have to apply various levels of boosting, radiotherapy, systemic therapy and the response to radiation is variable because we know the heterogeneity of prostate cancer is variable.

And then if I may, just for a moment, from a surgical perspective is focal therapy has been underutilized, and that's partly because surgeons like myself are very reluctant. We know it's a heterogeneous disease, where we always want to avoid missing disease.

And if I have a higher yield, more accurate biopsy, particularly if there's congruence between my molecular image and my MRI, I think the field of focal therapy will start to bloom, which is going to be an advantage, particularly for our younger patients if we can go into focal therapy with more confidence.

And that confidence is borne out from a better biopsy. That's a long-winded answer to your short question, but hopefully, that's the promise of where we can get from the intraprostatic findings of Illuccix.

Thank you, Dr. Yonover. I think Professor Hicks you --

I just wanted to add a very quick thing to that. There are areas, where I think both MRI and biopsy are very difficult. One is the anterior fibromuscular stroma, which can be hard to get to with the biopsy needle. And it's also a more difficult area to interpret on MRI.

And we've seen a very significant impact of PSMA in that particular area, identifying the other areas right up at the very base, close to the bladder where the needles -- they're a little bit reluctant to go so high. And we've certainly seen cases where biopsy negative, but strongly positive on PSMA because they -- it's just a sampling error. And so I think that there is a big advantage there.

We've -- I think, today doing our 51st patient on the BIPASS study. And the fact that this has been run by the Australian Prostate Cancer Center Urologist shows that their enthusiasm for this technology as part of their diagnostic workup because not only do you get a better assessment of the extent of disease within the prostate, at the same time, you're getting staging information, not only about the pelvis, but about the whole body. And in the higher PSA, higher-risk patients, there's a significant yield of staging information, not just diagnostic information.

And that's efficient for a large practice like us, right? That efficiency, the "one-stop" shopping, right? The number of visits a patient -- if we can cut down on the number of patient visits if we can -- part of our business model is navigation, right, navigating these patients. And that's one of the reasons why we've adopted molecular imaging internally and just helps us navigate these patients.

And what Professor Hicks is talking about, I'm glad to see that the enthusiasm I have no doubt would be in Australia would be as great as it is here in the United States about getting PSMA PET in the pre-biopsy space. I think there's just --

I don't want to scare you, but last year, we did over 5,000 PET scans with a single PET scanner and approximately half of those were PSMA scans. So it's going nuts.

All right. Thank you very much, Professor Hicks and Dr. Yonover. We've got time for one more question. We will take any residual questions and answer them separately. This is for Darren. Darren, could you please address the breakdown between cyclotron produced versus generator-produced gallium PSMA. And could you possibly talk about the scale-up of gallium production, as we anticipate the scanning volume to potentially double by the early 2030s, which is sort of 5-odd years from now?

Yes. I think that's the scale-up is where the cyclotron production really comes into play, right? So right now, the majority of the gallium production, the vast majority is done via generator-produced gallium.

And I think there's always going to be a place for generator produced gallium, right? So there's really not a one size fits all. But the cyclotron technology gives us, as I mentioned earlier, that opportunity to really ratchet up the amount of activity we can make.

So you're talking going from 50, 100 millicurie generators to curie amounts of gallium on a solid target system via cyclotron production. So you're talking 10x to 20x the amount of isotope. So that really opens up a lot of flexibility in terms of how radiopharmacies and those producing finished drug product can address the market.

There could be a fractionation of the isotope feathering out to other centers, just opens up a new world of opportunity. And something like that is cyclotron produced gallium is something that really does move the needle to meet that surge in demand.

All right. Thanks, Darren. Well, we are just over time. I would like to, on behalf of the audience and all participants, thank Professor Hicks from Melbourne, Dr. Yonover from Chicago; and my colleague, Darren Patti, who's also in Chicago. Colleagues, thank you very much for your extraordinary insights. I've learned a lot today, and I believe the audience will have as well. So thank you kindly, and I appreciate the audience dialing. I hope it's been valuable for you. Thank you.

Good day, and thank you for standing by. Welcome to the Telix Full Year 2025 Results and Investor Webcast. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Kyahn Williamson, SVP of Investor Relations and Corporate Communications. Please go ahead.

Thank you, and thank you to everybody for joining us on this call this morning, this evening, wherever you are in the world. We launched our annual report and full year results on the ASX about 30 minutes ago. We also have the slides on the screen via webcast for you to see today. I'm just going to take you through a brief introduction and some disclaimer statements before handing over.

If you just move to the Slide 2. Very pleased to have on the call with us today, Chris Behrenbruch, our CEO and Managing Director; Darren Smith, our CFO; and Kevin Richardson, our CEO of the Precision Medicine business. I should also mention that we have Dr. David Cade, our Chief Medical Officer, on the line for the Q&A session. We'll be running through today our strategy, financial results, and update on our Precision Medicine and Therapeutics business.

If you can move to the next slide, please. I am required just to give you an excerpt from our forward-looking statement disclaimer statement. So please note that on today's presentation includes forward-looking statements, including within the meaning of the U.S. Private Securities Litigation Reform Act of 1995 that relate to, among other things, anticipated future events, financial performance, plans, strategies, and business developments. These forward-looking statements are based on current information, assumptions and expectations of future events that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our filings with the ASX and SEC, including on our half year annual report. You are cautioned not to rely on forward-looking statements, which are made only as today's date, and the company disclaims any obligation to update such statements. Please refer to the disclaimer slide in the presentation for further information.

With that, I'm very pleased to hand over to Chris to kick off the call.

Thanks very much, Kyahn, and I hope that my audio is nice and clear, and I certainly appreciate the introduction. Before Darren Smith, our Chief Financial Officer, goes into the numbers, I thought a bit of strategic framing would be useful for investors to understand where the company is heading and, of course, our key accomplishments in 2025.

Next slide, please, Slide 5. Over the last 12 months, we started to put the depth and execution around what has been a multiyear corporate development strategy. It's useful to think of Telix as a platform with these 5 major segments, as illustrated on this slide.

Moving from left to right, first up of key focus is our therapeutics pipeline, which has grown significantly and now features 3 programs in pivotal studies, as well as several high potential earlier-stage programs in rare diseases. I'm going to come back a little bit towards the end of the presentation on this topic.

Because of the explosive growth of activity in the radiopharma landscape, we have also pivoted to some extent to an internal innovation model alongside our business development activities. Clearly, when big pharma is willing to pay $1 billion for an asset that has been in a few mice, there's clearly an incentive to do in-house innovation. And so we now have a significant set of technical and clinical capabilities around fundamental R&D and discovery technologies.

In the middle of this vision and the engine room of the commercial business today is what we call the Precision Medicine business. This is far more than just an ATM machine that throws off a couple of hundred million of cash each year. It's a strategic validation of the targets we develop our therapeutic drugs for. It is more robust and streamlined clinical trials because we can see where our drug goes, and it's an early opportunity to build deep relationships with the physician stakeholders that underpin the future of the business.

Fourth, one can obviously look at sales and a commercial team simply as SG&A. We view it as building a specialty sales organization that very few companies have. Selling nuclear medicine is not selling a vial or a blister pack. It involves selling complex clinical workflows. And as our product portfolio expands, this is a strategic differentiator because it enables us to build depth with key referral physicians and drive preference towards our product.

It's also fair to note that in the major markets, this is a significant financial investment that most of our competition, both present and emerging, cannot afford to undertake. Lastly, you can develop all the great ideas you want and convince people to buy them, but if you can't deliver them reliably every single day, you aren't going to succeed.

In most industries, vertical integration is probably wasteful and doesn't offer much of a moat. In radiopharmaceuticals, where you are dealing with products that have shelf life of hours to days at most, there's a huge amount of market share ownership dynamic, intellectual property, and customer differentiation in how you deliver. This is why we have invested over $0.5 billion in the last years to better control our destiny and pave the way for high-value therapeutic products.

Next slide, please. To do all these things, you need cash, and we have a very high-growth business that made a step change this year, both through organic growth of our Precision Medicine business and through acquisition. We expect all of our revenue streams to continue to diversify and grow in 2026 and beyond, and Darren will cover this off on guidance later in this presentation.

Kevin is also going to frame this in terms of the core growth of the Precision Medicine portfolio, which is extremely exciting. The key point is we have a hyper-growth business, and it generates the cash we need to aggressively expand, further diversify our revenue and dominate the field.

Slide 7, please. This slide puts the whole strategy into perspective. As I've already said, to deliver on our bold vision for being the dominant player in radiopharma, we need a cash-generative business. We have one, and we grew it significantly this year with revenues exceeding USD 800 million or over AUD 1.2 billion for anyone that prefers their green back surge with shrimp on the barbie.

Our margins have remained extremely stable despite competition, and this excellent commercial performance enabled us to invest $0.5 billion into growing our product pipeline, funding the best commercial team in the industry, and building our infrastructure and supply chain. Think about that. $0.5 billion to grow the future value of the company from earnings without shareholder dilution. Telix is a very unique and valuable story.

Moving on to Slide 8, please. Before handing over to Darren, I thought it would be useful to give you a condensed view of our priorities for 2026. I get a lot of feedback that Telix is complicated, but it really isn't. This year is about doing three things and hopefully doing them better than we did last year.

One, we are going to continue to grow our core business around our approved products. We actually did get a new and innovative product approved by the FDA last year in Gozellix that also leverages the ARTMS isotope production acquisition. The launch of Gozellix has been successful and is not only growing our ASP and market share, it will pave the way for many future products through both the RLS network and partner distributors with Zircaix being the next prime example of this technology platform.

Two, we have 2 new products to launch, Pixclara, which is known as Pixlumi in Europe. This is for glioblastoma and Zircaix for renal cancer. We understand the disappointment that these did not get approved last year, but this is the price of being at the forefront of innovation in new technology areas.

While people are well aware, it has been a tumultuous period within the FDA itself, we also made certain we took valuable learnings from the experience. We have made extensive changes to the management team. We boosted our regulatory affairs capabilities, and these programs are in good shape for resubmission and approval this year. They are highly anticipated products and will become significant revenue streams, and we have not taken our foot off the gas pedal in terms of market readiness for these products. We are preparing to launch, and I want to make that very clear.

Last of all, we have several very high-value clinical programs. This is not an exhaustive list. In fact, we have over 30 sponsored and collaborative studies running from early stage to pivotal trials. But these are the ones that are going to generate the greatest commercial and financial inflection points this year and are the priority in terms of our resources and R&D investment.

I note that 4 out of 5 of these studies are pivotal or Phase III studies. We have imminent data point coming out on ProstACT Global, which we will take to the FDA to gain clearance to commence Part 2 in the United States. I remind you that the study has already progressed to randomizing patients ex-U.S. for Part 2 of the study and talk a little bit about this later in the presentation.

Our BiPASS biopsy study will complete enrollment this year, and we expect to generate significantly enhanced revenue in 2027 as a consequence of this Phase III study.

Our current late-stage clinical studies pave the way to our first therapeutic commercial inflection point likely in 2028. So these are not distant thoughts. They are all near-term catalysts. And I will come back at the end of presentation to some of the broader sets of upcoming catalysts.

Now Darren, over to you for the numbers.

Thank you very much, Chris. We have today reported a 56% growth in revenue to $804 million. This is in line with our revenue guidance. Notably it's our third consecutive year of double-digit revenue growth. Revenue from Precision Medicine business year-over-year.

Can I just ask, I think that the... [Technical Difficulty]

Please check your mute button.

This year -- sorry, can people hear me now?

Yes, we can hear you.

So this is in line with our uplifted full year guidance. And notably, it's our third consecutive year of delivering double-digit growth -- revenue growth. Revenue from our Precision Medicine business increased 22% year-over-year with EBITDA improving 25% to $216 million, driven by strong demand of Illuccix and the launch of Gozellix.

The Precision Medicine commercial performance permitted Telix to self-fund and derisk our investment into our R&D pipeline and commercial infrastructure to drive future growth. Further, 2025 was a year of significant investment, yet we maintained a solid cash balance of $142 million. We achieved this while exercising disciplined cost management.

Next slide, please, which is Slide 11. Thank you. We've added this slide for our non-account investors. As at a glance, this slide presents the strength of our business model. The left side of the chart shows our revenue sources and their materiality. The middle of the graph highlights our gross margin in the green and that 94% of the GM is generated from our Precision Medicine business. That is approximately $400 million.

As you can see, about half of the gross margin, the red flows om right are invested into our commercial sales and marketing capability, our global supply chain and our corporate functions. But more importantly, flowing right at the top half of the gross margin is approximately $200 million. That's 25% of revenue. And with this, we decide to either invest it in our development pipeline to create future value or recognize it as operating profit. So as business models go, a business that throws off 25% of revenue as operating profit to reinvest in value creation or the bank is pretty damn attractive.

Now moving to our traditional P&L. I've spoken to most of the financial highlights on the previous slides, but will take some time to talk to further highlights. The group's gross margin of 53% remained consistent with the first half performance. We invested $157 million into product development, in line with 2025 guidance and mainly focused on our late-stage pipeline.

General and administration expenses decreased to 12% of revenue from 17% last year, reflecting the efficiencies of scale achieved as the company continues its strong growth trajectory. As a result, we posted an adjusted EBITDA of $39.5 million, in line with market consensus.

Now moving to our next slide. Telix Precision Medicine business is clearly our cash machine. Its financial metrics demonstrate its excellent performance. Precision Medicine delivered an additional $113 million in revenue, representing 22% year-on-year growth alongside a 28% increase in operating profit and a 25% increase in its EBITDA. This demonstrates the high-growth business with capacity to generate significant funds to invest in long-term value creation.

Sales and marketing investments supported the launch of Gozellix, the geographic expansion of Illuccix and the launch readiness activities of Pixclara and Zircaix. As a side comment, if this was a stand-alone business growing at 20% plus per annum on an extrinsic value basis, it would be worth up to 8x revenue. This is a huge value creation for shareholders.

Now moving to our next slide, in Telix Manufacturing Solutions or TMS. We've provided this level of detail on TMS in our half year results for two reasons. Firstly, to give investors and analysts clear visibility into the financial impact of the RLS acquisition; and secondly, to provide transparency into the cost base of the remaining TMS business, helping with financial modeling.

As you can see, RLS delivered positive EBITDA for the first 11 months post-acquisition. At the remaining TMS facility, we increased investment compared to last year to permit us to advance operational activities facilitating clinical and commercial supply. As we now close out the full year of having RLS in the business, we will revert back to reporting TMS as one segment for commercial and competitive reasons.

Now moving on to cash flow. As you can see in this cash bridge, Telix continued to generate strong operational cash flows, which we then invest into our pipeline. In 2025, Telix generated $206 million from operations, enabling the investment into progressing the R&D pipeline.

Excluding our last contingent consideration earn-out payment of $52 million for Illuccix, we produced a net positive operating cash flow of $35 million. I reiterate that our investment into R&D is discretionary and can be flexed depending on our commercial performance, permitting us to effectively manage our cash position. Additionally, Telix utilized cash on hand to support targeted strategic investments such as RLS, ImaginAb, and in our FAP asset. As a result, we ended the year with a prudent cash position of $142 million.

Next slide, please. As we prepare for our next phase of growth, we continue shifting allocation of R&D investment into our therapeutic pipeline. In 2026, R&D investment is planned to be in the range of $200 million to $240 million, with the largest allocation directed to the therapeutic development. This highlights our focus to transition to a high-value therapeutic business. I'd like to take the opportunity to reiterate our investment strategy.

Over the next 2 to 3 years, we expect to grow revenues by advancing assets from clinical development to commercialization, expanding indications and geographic reach. We will invest the funds from this commercial growth into our portfolio and ensure that we have the capabilities, infrastructure, and readiness to deliver on our therapeutic programs.

Our focus will remain on reinvesting revenues back into the business over the next couple of years rather than optimizing near-term earnings per share. We are committed to building long-term value. We believe prioritizing earnings too early can impede the strategic investments required to fully unlock the potential of our pipeline.

Next slide, please. Telix has a disciplined capital allocation approach that is aligned to our corporate strategy, and it has matured a great deal over the last 12 months. We have previously spoken about our 4 areas of focus, and they are investing into our R&D, optimizing our commercial performance, strategic growth opportunities through M&A, and supply chain resilience and production capacity. We believe these 4 areas of focus will underpin our growth long term. We have continued to deliver on our strategy in a disciplined way, ensuring that we have a prudent cash buffer on the balance sheet.

Next slide, please. Looking forward, we see strong momentum heading into 2026 with another year of roughly 20-plus percent revenue growth anticipated. Our full year 2026 revenue guidance is set at $950 million to $970 million, and this is based on current approved products in approved jurisdictions. This range does not include revenue contributions from pending product approvals, which will be incremental. This growth implies up to 25% growth in our Precision Medicine business and a full year of RLS revenue.

Our corresponding R&D investment will be in the range of $200 million to $240 million and will be dependent on the achievement of certain clinical outcomes and development milestones. In conclusion, we delivered another year of double-digit revenue growth, made high-value strategic investments across the business, and maintained a prudent cash position.

Looking ahead, 2026 is set to be an inflection year with numerous important milestones. Our revenue guidance reflects the confidence we have in the business, and we remain committed to disciplined financial management throughout 2026.

I'll now hand you over to Kevin Richardson, Precision Medicine CEO. Thank you.

Thank you, Darren. My first slide, please. Last year, our Precision Medicine portfolio delivered $622 million in revenue, up 22% year-over-year. Importantly, we delivered sequential growth every single quarter. That includes Q3, our most challenging quarter, which was the first full quarter following the expiration of Illuccix transitional pass-through status and the transition to MUC, MUC or mean unit cost reimbursement for a subset of Medicare patients.

Q3 allowed us to see the full impact of that change on the business. Even in that environment and despite ongoing competitive pressure, we still delivered 3% quarter-over-quarter dose growth and 1% sales growth. That performance speaks to our disciplined approach to business fundamentals and the strength of our customer-facing team.

We continue to gain share based on clinical differentiation and operational reliability, our PSMA agents demonstrates fewer indeterminate bone lesions and higher inter-reader agreement compared to F-18 assets, driving confidence in clinical decision-making. We pair that clinical value with highly specialized commercial organization that engages customers every day and consistently differentiates Telix in the market.

Our reputation as an innovator also positioned us for a successful launch of Gozellix. Gozellix was FDA approved in April of 2025, and transitional pass-through status became effective in October, enabling a transitional pass-through supported full launch in Q4 of 2025. We are very pleased with the early uptake and our 2026 full year guidance underscores our strong conviction in the growth outlook for our Precision Medicine portfolio.

Today, we are the only company with 2 PSMA agents on the market. This dual product strategy is a competitive advantage, offering different types of customers meaningful choice across economics and scheduling flexibility while reinforcing our commitment to meeting diverse clinical and operational needs. In short, resilient growth, clinical differentiation, disciplined execution and a platform built for sustained growth.

Next slide, please. What does it take to win in a maturing PSMA market? Winning in a mature PSMA market is no longer about being first. It's about executing at scale. Clinical credibility is nonnegotiable. Products must deliver consistently high image quality, strong inter-reader agreement and reliable detection at low PSA levels across all patient types. Incremental claims aren't enough. Confidence in clinical decision-making is what sustains adoption. Workflow integration matters.

In a high-volume market, solutions must fit seamlessly into established clinical pathways, enable same-day imaging and support high patient throughput without disrupting nuclear medicine operations. Reimbursement sophistication is a competitive advantage. Success requires multiple product strategies that give customers economic flexibility while navigating complex and evolving reimbursement frameworks over extended period of times.

Commercial infrastructure is a must. This is a contract-driven market that demands experienced field teams, market access expertise, compliance rigor, and long-standing customer relationships. These capabilities take a large investment in years, not quarters to build. Supply chain excellence separates winners from participants.

Reliable, flexible dose production and delivery at scale, supported by high service nuclear pharmacy last mile experts is critical. There is no proven shortcut to mass market large volume coverage.

Sustained investment fuels durability, indication expansion, life cycle management and camera technology advances all require ongoing clinical and operational investment to maintain leadership. In short, leadership in PSMA is earned through clinical trust, operational reliability, commercial scale and disciplined investment, not novelty.

Next slide, please. We continue to execute our strategic plan to grow the Precision Medicine business by expanding our product offering, expand our indications on those products and expand the geographies where we market those products.

Global expansion is a priority for Precision Medicine here at Telix. Illuccix is now available in 17 countries with reimbursement secured, and we hold marketing authorizations in more than 24 markets. In 2025, we focus on country-by-country access. In '26, we pivot to driving uptake, particularly across key markets, including the U.K., France, Germany, Italy, and Spain.

In China, we delivered strong Phase III results with 94.8% positive predictive value, including patients with very low PSA levels. We submitted the NDA to the regulators with our partner, Grand Pharma. And with prostate cancer incidence rising and PET/CT infrastructure expanding rapidly, China represents a significant growth opportunity.

While in Japan, our 105-patient Phase III study is progressing well with the first patient dose. This positions us well in the world's second largest pharmaceutical market where prostate cancer remains a leading cause of mortality.

New products and new indications enhance our ability to take share and grow the market and Gozellix is off to a strong start, and we are focused on accelerating commercial momentum in 2026, and you can see that is reflected in our 2026 guidance.

BiPASS is a Phase III study that represents the next wave of innovation, combining PSMA imaging, Illuccix or Gozellix with MRI to improve diagnostic accuracy and potentially reduce or eliminate invasive biopsies. This is about moving earlier in the care pathway, reducing patient risk, lowering system costs, and expanding the total addressable market to include frontline biopsy candidates.

We believe moving to the front line where patients are diagnosed will give us a competitive advantage, both as the lead PSMA in diagnosis, but also in sequential scans that happen later on in the patient journey as physicians want to see consistency scan to scan.

For Zircaix, we've completed 2 Type A meetings with the FDA and believe we have full alignment on key resubmission requirements. We are now focused on completing the agreed deliverables and documentation required for the resubmission. With breakthrough therapy designation, supportive ZIRCON-X data and the inclusion in major international guidelines, this remains a top priority for approval and launch this year. This is a really exciting and highly anticipated product.

Moving on to our neuro platform. We are pursuing complementary submissions in both the EU and the U.S. TLX101-Tx was filed with the European regulators recently, and the U.S. submission will follow closely.

As a reminder, the FDA has granted both orphan drug and fast track designation for Pixclara. Our commercial, medical, and supply chain teams are launch ready. Our expanded access programs serve patients and our customers very well, and they anticipate commercial use of Pixclara.

In short, we built a global commercial platform, delivered successful launches, taken share, penetrated the available market and advanced multiple late-stage assets in high unmet needs markets. We are entering our next phase of growth with momentum and discipline.

Next slide, please. So what does this strategy mean in terms of financial impact? Our current baseline business with some further life cycle management, which we've talked about, should be able to sustain a 15% to 20% annualized growth. This partially reflects the growth of the field overall, as well as our ability to continue to capture market share as the size of the market expands. The recent addition of Gozellix certainly derisked this.

With indication expansion in prostate cancer alone, particularly a major opportunity in the BiPASS study, this growth over the 5 years can be closer to a 30% CAGR. And then when you add in Pixclara and Zircaix, this growth rate defensively looks more like 40% compounded annual growth, especially with metastatic indication expansions that further drive procedural volume.

In short, our current product strategy, which is fully baked from a clinical perspective, just needs to clear a few more regulatory hurdles as it represents future upside for the company. It is a direct consequence of the market presence we are building, the depth of our pipeline and the quality of service we are able to deliver to the patients. This is really an exciting business with a bright future. The growth in Precision Medicine gives us the ability to finance the growth potential of our Therapeutics business.

On that note, I'll hand it back over to Chris, to give you a bit of perspective on that.

Thanks very much, Kevin. Great update, and congratulations on all the success that your team had this year. It was a really remarkable year of accomplishment.

So moving on to Slide 25, please. In a way, this slide is a simplified version of my opening slide, a highly profitable cash-generative business that would garner, as Darren said, a very healthy revenue multiple. It was a stand-alone business, but it's our engine room. And the future growth trajectory of the business will come from how that cash is invested.

Kevin has already shown you very clearly, I think, how the Precision Medicine business alone can grow expansively over the next 5 years based on clinical, regulatory, and commercial inflection points that we expect to achieve this year.

So again, I just want to reemphasize the point that the growth trajectory that Kevin has talked about comes from events that will be completed this year. I think it's also important to reinforce our commitment to manufacturing and supply chain. But in the context of our Therapeutics business, it's more than just reliable and on-time dose delivery. It's about R&D cost and efficiency and perhaps most importantly, intellectual property capture.

We've learned over the last decade that when we use contract manufacturing organizations, do product scale up, that we simply educate the ecosystem in a way that potentially empowers competition, and we no longer wish to do that. So especially, as our therapeutics go into late-stage trials, this has become an important strategic objective of the company.

To be clear, we still use CMOs, but where there's key IP around platforms, targeting agents and certain key isotopes, we are increasingly tackling this in-house or with selected partners.

Moving on to the next slide, please. And this slide shows the reason why. As I've said, Kevin has already talked about what share of the Precision Medicine side of the business we think we can tackle over the next 5 years or so. And on a TAM basis, it's actually pretty conservative. But the therapeutics opportunity is about 3x or 4x bigger for the targets and indications that we are already pursuing. This doesn't even capture the potential for indication expansion into new disease areas that some of the pan-cancer targets we are developing, like carbonic anhydrase IX and FAP can potentially expand into. So it's a really bright future for the theranostics strategy.

Moving on to Slide 27, please. Over the last 5 years, we've built a very strong pipeline with some key disease focus areas, and you're going to increasingly hear us talk about these disease areas as multiproduct concentration areas, frankly, much as we have done with Gozellix and Illuccix on the Precision Medicine side of the business.

Indeed, to tackle some of these major unmet clinical needs, it's going to, in some cases, require a multi-asset approach at different stages in the clinical development or in the clinical patient journey. And so -- and also well-considered combination therapies with standard of care medical oncology. This is evident already, for example, in the design of the ProstACT GLOBAL and IPAX-BrIGHT studies. There are three particular attributes of our pipeline that I'd like to specifically comment on.

Firstly, by taking a theranostic approach, we built a very deep relationship with the referral and prescribing physician in each of these disease areas. This is a competitive advantage, and this relationship depth has already started with our existing commercial product portfolio and will only intensify over the next 12 months. Investors often view the Precision Medicine and Therapeutics business areas as adjacent, but they are clearly not.

Secondly, while we have some very high potential early-stage programs, and this has not exhausted this list because we have a pretty decent preclinical portfolio coming in behind, we have 3 late-stage programs in prostate, renal, and glioblastoma that will generate significant data over the next 12 months.

Based on the current valuation of the company, these programs are essentially a free option, but we think that the data and clinical basis of these programs are very compelling. Most importantly, while 2026 and 2027 financials will reflect the commercial expansion of the Precision Medicine business, 2028 is our commercial launch year for our Therapeutics business. So it's not far away. This is why we have so much execution focus on the [Technical Difficulty] targets, learning about disease extend, exploring new patient populations and ultimately increasing the market size and market share.

For the therapeutics, when they become available, the Precision Medicine business will pave the way. And so notwithstanding a few challenging but also educational regulatory speed bumps we've had, our commercial imaging gives us the skills and confidence that we can deliver on the therapeutic programs in the future. We've learned a lot this year, especially last year.

Can you hear me, okay? All right.

Moving on to the next slide, please. As I noted earlier, we have many different clinical studies running, some company-sponsored, some in collaboration with key opinion leaders around the globe. But the 4 major trials to watch this year are outlined here. I'm not going to go blow by blow on these because this is an earnings call, but I think it's important for shareholders to understand where the research priorities are and what the development goals and catalysts are. We are collecting a ton of patient data this year, and it's very exciting to have 3 programs in pivotal studies. This is important for patients and important for shareholders, and it's taken a lot of work and investment to get here.

Moving on to Slide 29. Of course, front of mind for patients and shareholders alike is the ProstACT GLOBAL study. The study is now recruiting into Part 2 randomized part of the study ex-U.S. and is ramping up very nicely. Unlike Part 1, which is a safety dosimetry run-in study that the FDA required in order for us to include U.S. patients in the randomized part of the study, Part 2 is very streamlined and straightforward. Part 2 commenced recruitment last year following an independent data safety review that determined that Part 1 data met prespecified safety criteria to progress. We will be shortly releasing the details of the Part 1 study concurrent with our submission to the FDA to request approval to add U.S. patients into the study. We are looking forward to getting these results out into the market and to show the great progress we are making, particularly given the unique combination therapy design of the ProstACT GLOBAL study.

To remind you, the data we will be putting out from Part 1 will be safety data on the 3 standard of care combinations in the global study, as well as comparative dosimetry data, which will be very interesting to see, particularly for the 2 different androgen deprivation therapies used in the study. So this is coming soon.

Moving on to Slide 30. Before I wrap up with a summary of the catalysts, I thought I would share a montage of patient case studies to really tie together the company's strategy and to illustrate how integrated the Precision Medicine, Therapeutics, and Manufacturing businesses are.

In short, why we are here. This slide illustrates 4 patients in 4 different cancers, all of which are advanced, extremely difficult-to-treat cases. Every day across the entire portfolio, we see examples of where our development and commercial pipeline changes lives. Sometimes it's a better understanding of the extent of disease. Sometimes it's a profound disease modification, such as the metastatic prostate and breast cancer examples on this slide. And at times, it's the glioblastoma or the kidney cancer patient that has stabilized disease or enough reduction in pain to be able to return to work.

These are the real outcomes from our research, and they deliver profound and life-changing outcomes for patients. This is what motivates us and why we believe that investing our hard-earned cash into this future is so important. The technology works and will get better as we learn more and get more clinical experience.

I'm also obliged to point out that for the most part, what you're seeing here are images created with the companion diagnostic imaging agents that we are also developing and highlights that this -- that not only is imaging technology critical for diagnosing and staging patients, but will play a fundamental role in predicting and measuring disease control as well.

Moving to the last slide. To wrap up, this slide summarizes the year ahead. It is a big year with many inflection points across the entire business. I will not go line by line, but we have a lot to talk about in 2026, with the next 3 major catalysts being resubmission of Pixclara and of course, Zircaix and the release of the Part 1 global data. We are looking forward to delivering these important milestones to patients and shareholders as the year progresses.

With that, I will pause and hand it over for questions.

[Operator Instructions] Our first question comes from Laura Sutcliffe with Citi.

At the risk of potentially making myself a bit unpopular, I think we'd like to understand a bit more about when we might see some data for 591, the safety data. And perhaps given that you said you will disclose at the same time that you go to the FDA, whether the next steps are things that you need to do at Telix or whether you're waiting for the FDA to do something on their end to be able to get to that point?

Laura, thanks for your question. It's not a bad question or an unpopular question at all. So we have had an independent data safety review board that has under the clinical charter of the study has reviewed the data and progressed to randomization ex-U.S. However, in order for us to send the information to the FDA and disclose the information publicly, we need just to complete the clinical case report forms and formally close out and quality control and validate the data because that's obviously what the FDA wants to see. As soon as we have that data -- and I haven't seen it, I'm not privy to it. But as soon as it's available, we will simultaneously disclose it and submit it to the FDA. So we're not waiting on anything from the FDA. It's all on the company side, and you will not have long to wait.

Our next question comes from Tara Bancroft with TD Cowen.

This is Nick on for Tara. Congrats on the progress and the strong guidance for 2026. We were hoping that you can dive in a little more on what you've seen in the early innings of the 2-product strategy for Illuccix and Gozellix and how you anticipate that will evolve this year to reach the 25% growth in the precision medicine revenue?

Yes. Thanks very much for the question. Kevin, do you want to pick this one up for your wheelhouse?

Sure. Yes. Thank you for the question. So the 2-product strategy is -- enables us to really manage the economic needs of HOPPS accounts and the way that they perceive and their preference for a reimbursed product over really a non-reimbursed product.

As you know, MUC or Main Unit Cost has really kind of changed the environment and the reimbursement environment there as well as the way that the pricing happens in the HOPPS accounts. So being able to have a 2-product company enables us to manage that particular customer type and the self-standing -- or we call them IDTF group -- in a different way as we manage the preference they have for a reimbursement price or one that might be a little more price sensitive.

So and then, of course, we have a longer view of the precision medicine business and PSMA specifically, as we think through what over time can happen and what will happen with CMS as they continue to evolve and change reimbursement. So that enables us to kind of manage the ASP, if you will, as the CMS may or look more towards the ASP reimbursement model. So it gives us options in the future without locking down a singular product on that.

Our next question comes from Shane Storey with Canaccord Genuity.

Kevin, I'm going to stick with you, if that's okay. Question on Pixclara. Just maybe some descriptive piece, I guess, around the customer channel there. It's quite different from your PSMA urology presence. Is that potentially a first work example for how the Varian relationship might evolve? Just some thoughts on that, please.

Kevin, are you there?

Yes. So I'll take that first then, Chris. So Varian is -- we're really excited about the possibilities in that, a lot focused, of course, on PSMA and Illuccix, Gozellix. And so as we think about that from a commercial perspective, we have a -- what we call a Ninja team.

As you know, there's not as many sites as there are that do PSMA prostate scanning as there are that are going to do neuro scanning. So we have a smaller team that's focused on the referral, the neurologist. And the idea behind that is we already have the relationship at the NucMed level. So we're able to drive those patients into the scanner, if you will. And then we have a team that already has the relationships at the other end of that where they're reading it. So the idea is it's a referral and then into the existing relationship we have at the nuclear medicine side. And of course, if that is not an Illuccix or Gozellix site, it gives us good access into those sites, and it's a real competitive advantage to be able to offer these more orphan drug type technologies because of that.

Does that answer your question, Shane? Okay. Chris, anything to add?

All right. No, that's good.

Our next question comes from David Stanton with Jefferies.

I might be following a dead horse here, but I just want to make it clear and help you to make it clear. You'll be reinvesting earnings to get close to 0 NPAT for F '26, F '27 and F '28. Is that what the market should be thinking going forward, please? I ask because it's a question I get asked the most.

Yes, that's fine. No horse is flogged, David. Happy you asked the question. So we're not giving guidance beyond 2026, but it's a reasonable expectation that in 2026 and 2027 that we will be investing -- other than for risk management and for appropriate balance sheet management purposes, we'll be investing the majority of our earnings back into the company, okay? So that's in a number of different areas. That's in R&D. That's also in growing and developing our commercial team. And of course, we continue to also invest in infrastructure and capital works to support the business.

So it's not all just R&D, but a profit objective for this year and next year is not the name of the game.

Our next question comes from David...

Do you have a further comment, David, that you'd like to ask? All right. Well, we'll move on. This is a very challenging conferencing service, and I apologize to those that are participating.

It's a follow-on from Dr. Stanton's question. Just from Darren, there was a clear comment there that I think that the investment in growth will consider the commercial performance. I think that was interesting from our perspective. Just as we look at the sales guidance for '26 and the R&D guidance for '26, should we think that if the commercial performance is at the upper and lower end of those ranges, the R&D will follow?

As an extension of that, within the R&D spend, is the earlier stage clinical trials, are they the ones that would potentially be put on hold for a little bit to the extent that the commercial performance doesn't meet expectations?

I can start, Darren, and then maybe if you want to add anything. I mean -- so yes, we've focused -- we've chosen in this presentation to highlight the clinical studies that are the real priorities for the company. So that's the 5 studies, including the BiPASS study. We are obviously going to be investing in other clinical studies this year. And to the extent that we need to make adjustments -- it will be outside of that sort of ring-fenced 5 studies, the 4 therapeutic studies and the BiPASS study.

We clearly expect that 2026 is going to be a strong year. We don't expect to have any difficulties in financing our R&D pipeline. But as you have noted, and as Darren, I think, made it very clear, generally, we take the view that our R&D investment is discretionary, and we can make adjustments as required.

Darren, do you want to add anything? Okay. I'll take that as a no.

Our next question comes from Craig Wong-Pan with RBC.

Just a question on the 25% growth in Precision Medicine. I was wondering how much growth was coming from markets outside of the U.S.

Sure. I'll answer that one and then maybe, Darren, if you want to chime in on anything that I've missed.

Right now, because we only achieved our European reimbursements towards the back end of last year, it's a very small proportion of the revenue is currently ex-U.S. The majority of it is -- 95% of it is U.S.-based. We obviously expect that mix to change over the course of this year and also as we add in other markets, such as Japan, which has a high-value PET -- advanced PET procedure code that's quite internationally competitive. But for the moment, for the most part, the majority of our revenue is U.S.-based.

Our next question is coming from Andy Hsieh with William Blair.

Chris, I want to ask you about the recent collaboration with Atley and Stanford, focusing on astatine-211. So in your pipeline, you have 3 alpha emitters: Actinium-225, you have lead generator that's in progress, and then now astatine having a California supply chain. So I'm curious about your view on this isotope, another short half-life. Just wondering about how it fits into your product portfolio.

Yes. It's a bit of sort of outside of the major sort of activity area. But essentially, we do see value in alpha emitters. The majority of our late-stage programs, as you know, are beta-emitting isotopes. We think that they're going to be a workhorse for the foreseeable future, but we can see ALPHIX coming over the horizon.

As you know, most of our clinical stage programs are with actinium. It's probably from a supply chain perspective, the lowest hanging fruit. We have one program, TLX102, which is with astatine that's in early clinical translation. We think that for applications where a targeting agent needs to cross the blood-brain barrier that radiohalogens are a better perhaps a more practical pathway than a radio metal with a chelator. So we are exploring astatine mostly in the CNS setting.

Then we do, as you know, have a lead generator that we've developed. It's a very novel and very compelling generator design that we think can be rolled out for large-scale lead production. We currently today do not have any clinical programs using Lead-212, but we have a number of preclinical programs that we expect to take into patients by the end of this year that are not currently disclosed, and they have the potential to use Lead-212.

We are exploring several different isotopes. But I think as a company, we've elected to put a proportion -- not a large proportion, but a modest proportion of our R&D expenditure into understanding the future landscape of alpha because we think it has some potential. I hope that answers your question.

Our next question comes from David Dai with UBS.

Just on the gross margin for the business, it seems like it's remaining stable at 53%. But then the RLS business, the gross margin has been quite poor. So just thinking about the gross margin for RLS business moving forward, what are some of the key drivers of gross margin expansion for the RLS business that you can provide?

Well, I'll just make a comment, and then I'll invite Darren to chime in. So the RLS business -- so just to be clear, when we report the RLS segment, we report the RLS segment purely in terms of third-party products. So these are not Telix products. These are, for the most part, fairly generic nuclear medicine products. And RLS' operating cost is largely covered by delivering those third-party products.

So a useful way to think about it is as a subsidized -- third-party subsidized manufacturing infrastructure. When we report the products that go through the RLS network that are Telix products, they are captured in the segmental reporting for precision medicine. So I just really want to make that very clear.

So when you say the gross margins for RLS are not very good, it's got nothing to do with Telix's product portfolio. RLS margins -- because these are generic sort of fairly commoditized nuclear medicine products, they have a much, much lower margin.

We provided an average margin last year, which I think frees a lot of people out because all of a sudden, we went from mid-60s margins down to mid-50s margins or low 50s margins. That was an average effect across all of the products in the group, including the RLS products. Does that make sense?

Yes, that makes sense. Yes.

So yes, so don't be sidetracked by RLS. The most important thing is that when we put our products through RLS, we -- that gross margin number, which we report faithfully for the Precision Medicine business as sort of mid-60%. That's our -- that above-the-line cost is our distributor margin, which clearly is different when we run a product through our own pharmacy network.

Now it's critically important for us to maintain key distribution partnerships in key markets. So we obviously, do pay that above-the-line cost. But when we produce a product that goes through our nuclear pharmacy network, the gross margin is rather different. So you should expect to see, as we have a larger share of our product volume going through our in-house pharmacy network that, that gross margin number has the potential to improve and trend towards 70%.

Our next question comes from Andrew Paine with CLSA.

Maybe one for Kevin, but you mentioned winning in the PSMA is about executing at scale, and we've seen that in the growth and the challenges you've overcome in that market so far. You spent a bit of time talking about this, but how clear is it that moat -- how clear is that moat there for you given the potential competition on the horizon? And also, can you just dig into the changes in camera technology and how you see that as supportive to the sensitivity of PSMA imaging, which may not be fully appreciated?

Well, I think Kevin has done a great job of running through what the competitive barriers to entry, and there are multiple. I mean it's not just product, it's also clinical, it's also manufacturing and supply chain. So I'm not sure what competitor you're talking about that's coming immediately on the horizon. But nonetheless, we see those as, I mean, pretty well enumerated sort of barriers to entry for competition.

On the topic of camera technology, generally speaking, we've seen a step change in sensitivity on PET cameras over the last 3 to 5 years because of the demand for PET imaging, not just in prostate cancer, but across a whole lot of indications, including neuro-oncology, neurodegeneration, cardiovascular disease. We're seeing a lot of camera installation going in and the next generation of scanners are in order of magnitude more sensitive. And so that just means that we have to keep abreast of it.

We need to make sure that we're running clinical trials and clinical studies that demonstrate the improved utility. We are clearly detecting disease early and earlier. I mean, we have our most recent studies that were done in China, for example, with absolutely state-of-the-art scanners because they're brand-new scanners. We're seeing PSA levels down to fractions of a nanogram per ml. And so the camera technology is part of the complementary story to Tracer development that should not be forgotten about. I think I'll pause there in terms of that particular topic. There isn't too much more else to say. Is there another question?

Our next question comes from Melissa Benson with Barrenjoey.

So Kevin mentioned you had a full alignment on the agreed deliverables with the FDA for the...

Melissa, I'm sorry, I can't hear you. Now I can hear you. Go on.

I'm sorry. So I think Kevin was mentioning there was alignment on the agreed deliverables with FDA, [ per the K ]. So I was just wondering if there's anything you can share regarding what those agreed deliverables are, but specifically, if there's any new clinical data required or if it's more preclinical analytical data only?

Yes. Most of the CMC remediation topics are around laboratory documentation, manufacturing documentation and process documentation. We do have a deliverable to the FDA around comparability between the research grade material that we used in the Phase III trial and the commercial scale-up material. But we have that data set well in hand, and it's not a material time delay to the resubmission.

Our next question comes from Steve Wheen with Jarden.

It's Steve here. So my question was just a bit of an extension of some of the others. But I guess for Kevin, I'm just trying to understand the European market with regards to Illuccix and Gozellix, I guess. Just they've been approved for some time. The launch in the U.S., obviously was incredibly rapid. And just trying to understand what's holding it back or slowing it to not really be much of a feature for your growth in the next 12 months?

Kevin, I can start and then maybe you can finish. I mean, it's not that it's not a feature. It's just that the European market has a very different reimbursement landscape. The U.S. has a much more immediacy between product approval and reimbursement, whereas in Europe, sometimes there can be as long as 9 or 12 months delay between product approval and reimbursement. And there's simply no material product sales until you have reimbursement. It's also not a class reimbursement. It's an individual product reimbursement in most countries.

So until you have reimbursement, you simply don't have material sales. So for the -- what you would classify as the traditional EU 5 countries, we have only just received reimbursement in some of them.

Kevin, I don't know if you want to add anything there?

Yes, there's very little other color to add in my prepared remarks, which was really 2025, the international team under that direction was really focused on gaining market access through reimbursement. And now we in that EU 5, the plans now are to execute those market launches. And so you'll see that as we continue to grow in 2026 as we execute against that launch. But Chris is right, in each country is different, each product is different. So it takes a bit to get that approved in the system and then begin the launch. So we're in the midst of that right now.

Can I just ask an unrelated question just with regards to your R&D the expensing of Zircaix through the R&D line, is there a shelf life for that particular inventory just with regards to just noticed your comment that there is the potential once it's approved by the FDA that, that could then come back and be backed out of the P&L?

Yes, that's right. That's our expectation. And the shelf life goes far beyond the launch time of the product.

Our next question is a follow-up from Shane Storey with Canaccord Genuity.

Sorry for extending the time, everyone. My question was going to come off the back of Melissa's question actually on Zircaix and except everything you've just said there. But just as far as how we should think about FDA's review phase once the resubmitted BLA is accepted, we've been sort of assuming 6 months. I just unsure how the breakthrough status and priority review might influence that, if at all?

Yes. We don't know yet for Zircaix. For Pixclara, we have a reasonable idea that it's going to be a rapid review also because it's a single a single issue CRL. We could imagine for the Zircaix review because there is a number of issues that it may take longer, but we haven't received guidance yet from the FDA on this topic.

We will be engaging with the agency shortly on this topic as we are preparing to resubmit, but we won't know that information for a little bit when it comes to Zircaix. No worries. But I do note that it has a breakthrough designation. And I actually want to compliment the agency. They've been highly engaged, very helpful, very proactive. They gave us a lot of extra time around the Type A meeting that they really didn't need to do.

So we feel like it's a pretty good collaboration, and we're working with the agency towards the drug approval and nothing less than that.

Okay. I think I have a feeling that we're wrapping it up there. I don't know if there's any more questions coming through.

We do have a final question, a follow-up from David Stanton with Jefferies.

Saving the best for last. Chris, just I note that you've talked to a Part 2 interim analysis in calendar '26. I wonder if you could sort of give us any kind of timeline as to when that might be? Is it third quarter? Is it fourth quarter? What should we be thinking there?

Yes. Obviously, I get increasingly reluctant to estimate timelines on clinical trials because [Technical Difficulty] by like to the day or to the week rather than to the quarter. But right now, the Part 2 study is recruiting really nicely. We're seeing good site expansion and getting plenty of patients consented into the study. That interim analysis is based on about 80 or 90 events, I don't know the exact number, sometime -- somewhere around that. And we would expect that, that should lead based on the current recruitment trajectory for some time in Q4 of this year for that futility analysis to read out. So that's the reason why we have it sitting there in the calendar for this year.

Well, I think that was the last question. I just want to apologize profusely to all the attendees for the audio challenges we've had today. It's a new conference provider. I'm not sure we'll be using it again in the future. But I just wanted to thank you for your questions and for your attention.

Obviously, if there are follow-up questions, we'll be happy to receive them directly and follow up in due course. Thank you for your time today.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Okay. Good morning. Thanks for joining us here at the JPMorgan Healthcare Conference. My name is Chris Cooper. I cover Australian health care here at JPMorgan. For this session, we're very fortunate to be joined by Christian Behrenbruch, the CEO of Telix. Chris will speak for about 20 minutes or so, and we should have some time for Q&A at the end.

Well, thanks very much, Chris, and to the JPMorgan team for the opportunity to present. Just the customary disclaimers and forward-looking statements. So for those of you who don't know, and we're an increasingly well-known company in the radiopharma space. I know there's a lot of folks that are starting to take interest in the company and its commercial trajectory. We're a fairly vertically integrated radiopharma company specializing in oncology. We are solely focused on radiopharmaceuticals. We have a very much a precision medicine-oriented approach in the way in which we think about radiopharma.

A lot of new companies have emerged in recent years that are focused really just on the therapeutic aspects of radiopharmaceuticals. But if you think about what you get when you develop a radiopharmaceutical, you get a signal with every dose that you put into a patient. And that signal is extremely valuable in terms of understanding the efficacy and the targeting the delivery of your payload. So for every target that we develop as a company, we develop both an imaging agent and a therapeutic.

And this has actually served the company well from a commercial strategy perspective because we've been able to monetize that precision medicine business early in the company's life. So we are a commercial stage company. We've built a very capable commercial team. In fact, I think it's one of the great assets of the company. And certainly, from a commercial execution perspective, the last 12 months have been very successful for the company. I'm going to go into a bit of detail on our therapeutics pipeline. That's going to be more so the focus of this presentation, a little bit on our new capabilities around basic R&D.

When we founded the company almost a decade ago, we didn't really have the appetite to do discovery or new asset development internally. But we now see that there's an opportunity for us in some key areas, and I'm going to give you a bit of insight into that as well.

And then last of all, one of the things that differentiates Telix very much from other companies is the commitment and the investment that we've made. We've invested about $0.5 billion in the last 2 years on manufacturing, supply chain, distribution capabilities. We own a nuclear pharmacy network in the United States, which we think is very important to future distribution of therapeutic radiopharmaceuticals. And that vertical integration really sets us apart from competing organizations. So it's a very full story.

Our lead commercial product is in the prostate cancer space. Actually, we have 2 products, Illuccix and Gozellix. Gozellix is a life cycle management product for Illuccix. It's been a very successful product launch. We are now -- and 2025 was an extremely busy year for the company. We expanded into 17 other countries outside of the United States, including Europe and the U.K. and also, we have an approval in Brazil.

We are -- we filed an NDA now in China, and we have a Phase III study, active, a bridging study in Japan, which will complete this year as well. So really, our goal as a company, and again, it's a little bit different than some of our peers is to really be globally active. We think that, that's important. And again, the precision medicine paves the way for a therapeutic presence in these countries.

As we look more and more clinical practice guidelines, patient selection and patient stratification through imaging is how we deploy radioligand therapy. And so having that footprint in these other countries is not just about generating some early and important revenue streams for the company, but they're also about establishing that physician presence and that customer relationship.

Gozellix was a great success for us last year. So we got a new drug approval back in April of last year. We got pass-through for this product, which became effective 1st of October. So our last -- this past quarter was our product launch quarter. We had a really nice quarter. We'll be putting out our financials next week around the middle of the week, and you'll be able to see what the impact of that is.

But again, this is -- it was a life cycle management with some really nice differentiation in terms of how we deploy the product, how we are able to reach patients that are perhaps further away from major metropolitan areas but also much larger capacity production really into the hands of those academic centers using our cyclotron technologies capabilities, and I'll maybe talk a bit more about that later on.

Financially, this is a snapshot of the company's growth over the last 5 years since we became a commercial stage company. I really do think that the commercial execution is something that we've done extremely well. Our guidance for the full financial year is in the USD 800 million to USD 820 million range. We expect to see this growth trajectory to continue over the next -- really over the next 2 to 3 years. It's not just about our prostate cancer imaging franchise. It's really about how we have layered in multiple products that are coming online very soon that are targeted at really building that deeper relationship with specific referral physicians that we have a strong level of traction with, particularly in urologic oncology, and I'll talk a little bit more about that.

So we also -- through our radiopharmacy business, we have a certain amount of third-party revenue. We've actually continued to grow those volume really nicely in that part of the business over the last 12 months. So it's been a successful acquisition, although quite demanding on the organization. We went from about 350 people at the start of last year to almost 1,200 people at the end of the year. So we introduced a lot of capability but we also organizationally matured a lot last year. And I would say that with some of the setbacks that we had last year, which are reflected in our market cap, we really went back. We reengineered the bench strength in our development teams. I think we really augmented our capabilities.

And I feel that 2025 is a bedrock year that we can really build on in a very promising way in 2026. So in terms of growing the commercial near-term revenue-generating part of the business, there are sort of 3 parts to the strategy. Pixclara and Zircaix, NDA and BLA resubmissions are proceeding as we expect them to. Pixclara will be submitted very shortly. Zircaix is well on its way. We've got one more FDA meeting coming up, and then that will follow Pixclara. We've generally had a very high degree of engagement with the agency. So I feel like those resubmissions are in good hands. And we do expect to launch those products in 2026, obviously, subject to regulatory approvals in the United States.

We do have plans, of course, to expand other geographies as well as we did with Illuccix. The 2025 for Illuccix was really about getting those marketing authorizations and getting reimbursement moving outside of the United States. We expect to see the financial contribution of that in 2026 or at least start to happen. And as I said, we do have a plan for follow-on registration for Pixclara and Zircaix as well outside of the U.S. That's very much in play right now.

The other thing that we're working on is really expanding the indication in our existing prostate cancer franchise. So we -- prior to Christmas, we launched the BiPASS biopsy study, which I'll talk a little bit more in a second. This is really a game-changing indication expansion for prostate cancer that we think will significantly increase the total addressable market for Illuccix and Gozellix. And again, it's part of our longer-term growth strategy as a company.

The PSMA market itself has a lot of headroom. We see today that it's about a $3 billion TAM. We're a significant player in this. We have now doubled down in terms of our presence in this market segment with Gozellix. We see opportunities just through practice guidelines and continued clinical adoption to expand the market. We see BiPASS as a potential part of that. And then we have a long-term life cycle management commitment.

So we have several other follow-on products. I think it's now accepted in the industry that some -- like other parts of pharma, that regular life cycle management of these diagnostic imaging products are going to be important for maintaining commercial leadership. We have a very clear game plan for how we're going to do that, including picking up some capability in the fluorinated PSMA space. We have a Phase III study that will launch this year based on a very novel approach to flexibly radiolabeling PSMA11 with either gallium or F-18. There's a physician choice there. We're happy to serve that choice in a flexible and differentiated way.

I did mention the BiPASS biopsy study. So this is really about going upstream from the current label space we have in prostate cancer imaging. The majority of patients are either pre-prostatectomy high-risk patients where you're looking for extra pelvic metastases or patients that have reoccurred following a definitive intervention and have a rising PSA. We believe that biopsy is something that can be optimized. We're not looking to eliminate biopsy. What we're looking to do is to make sure that when a patient gets biopsy that they are the right patient for a biopsy. There's more than 1 million biopsies that are performed in the U.S. every year, really only about 20% or 30% of those are actually beneficial to a patient.

So if we can triage that, that's very powerful. It's got a clear pharmacoeconomic benefit in terms of patient impact and diagnostic impact. But what it also does is it positions us very much at the front of the queue. We're going to be there at the beginning of that patient journey, and it puts us in a position to repeatedly serve that patient over their prostate cancer journey over the course of their life. And I think that's not just a clinical advantage, that's a commercial advantage as well.

So this is a Phase III trial. It took us about a year to get it over the line with the FDA. These kind of very early-stage intervention-driven studies are extremely clinically challenging to get launched, a high degree of regulator buy-in to get a label forming study all over the line. We've now done that. It's actively recruiting internationally and in the United States. So I'm really excited and recruiting very fast. This is going to be a very quick study for us to get done.

Just maybe a little bit of comment and build on my earlier comments about scaling globally, really over the last 3, 4 years, we've built a pretty impressive international footprint in terms of our ability to deliver product. This is not just for diagnostic products. This is for therapeutic products. So this includes GMP manufacturing capabilities in the United States and Europe, and we're increasingly building capabilities in other parts of the world as well.

We just opened our first production center in Japan which is a commercially important market for these products late last year. And we have a couple of key partnership relationships as well in Latin America, where we do do manufacturing in a joint venture and also in China, where we have a regional strategic partner. So very active global footprint, and part of the investment that we made in buying radiopharmacy infrastructure was really to acquire that step change in scale function for the company.

We delivered 150,000 Illuccix doses and Gozellix doses last year in the United States, either through our own pharmacy network or with key partners, long-term partners, like Cardinal Health. In totality, the group delivered about 2.9 million doses to patients last year across all of our operating segments. This is really about building a foundation for long-term volume growth and delivery to our patients. So I think the commercial execution and the manufacturing and supply chain execution for the company has been very strong and is getting stronger every single day.

In terms of the investment strategy, so it's useful to think of the company really in terms of kind of 3 epochs. 2025 was a transitional year for us where we really started that large-scale reinvestment phase for the company, which is the sort of middle period. We had our initial commercialization. Our first product approvals, now it's really about diversifying that revenue stream to multiproduct and regional expansion. But the goal between now and the end of 2027 is not an earnings-oriented goal. The goal is to really take the revenue that we generate from our commercial business and maximally reinvested into pipeline and infrastructure.

We're very blessed. I mean, we're butting up to $1 billion in revenue. We expect to significantly exceed that over the next couple of years. It gives us enormous earnings capacity in a nondilutive way to reinvest in the business. And we're doing that extremely assertively. So we're trying to set expectations with investors and analysts. This isn't an EPS story. Even though we are classified as a health care company, a lot of people see us as a health care company. We're really a self-funded biotech company that's doubling down and tripling down on our pipeline and our supply chain capability.

So the next 2 years are going to be really exciting in terms of building that infrastructure, building out that pipeline, and we have 3 therapeutic programs that are in Phase III pivotal late-stage trials this year that starts to build a ton of value creation for shareholders as we get new data points come out.

Once we get into 2028, that's where we expect to see our investment needs outstripped by earnings. And then I think maybe we'll look more like a regular health care company at that point in time. But right now, it's -- think of us as a self-funded biotech company. And I think that's a -- I think it's a very powerful position to be in given the market dynamics that we experience.

I did mention in my opening comments as well, a little bit about our interest in being a little bit more of an in-house innovator. This was something, speaking as the founder CEO of the company. I was never really that keen to do. I felt that there was lots of great innovation being done in academia and small companies. We can be a channel partner and a go-to-market partner for that. But what we're seeing now is the emergence of all kinds of exciting new isotopes. And if you look at the products that -- I like to think of them as first-generation radiopharmaceutical products that are out there that are either very unoptimized small molecules or they're somewhat unoptimized macro molecules.

And actually, as we see things like lead-212 and actinium and astatine come forward, there's a real desire to match the pharmacology of those targeting agents with half-life of those isotopes to build products that have better efficacy, better patient tolerability. And so we've decided that alongside in-house isotope research and cyclotron technology development capabilities that we are also going to develop a biologic centric innovation capability to look at some of these formats that are in the middle of the PK spectrum where there are hours to day, blood half-life where they match very, very well on to some of these next generation of radionuclides that are coming down the pathway.

And we've got 2 really exciting programs, 1 in DLL3 and 1 in [ avß6 ] integrin binding domain, which are getting ready to go into the clinic so by the end of this year, they should be ready to go into person human studies with alpha-emitters extensively

Okay. So just as a wrap up before I go into a couple of snapshots. I'm not going to go exhaustively through our pipeline, but just to spend 5 minutes or so going through some key examples. This is our late-stage therapeutic -- or clinical stage therapeutic pipeline. So this does not include a number of assets that we are developing preclinically. So everything that you see on this list is being administered into patients today or has an IND approval to go ahead. So it's a pretty substantial pipeline of assets. Notably, our TLX591 prostate cancer therapy is in Phase III. We've completed a run-in study, which we'll read out very, very shortly, and we are already recruiting ex U.S. part 2 of that study, so the randomized portion of that study.

We also have a go ahead for putting our Carbonic anhydrase IX program into a Phase III study as well as our [ IDIN ] 131-based glioblastoma agent, which has shown some promising efficacy. And I'll go into a little bit more detail on second. I think just as a general comment about our pipeline, 1 of the things that you'll notice is that we are not a platform technology based on a single radionuclide. That's not how cancer works. We don't think that's how radiopharmaceuticals will be developed, we think that it's really important to choose the right isotope for the right application, the right -- it has to be aligned with the biological problem that you're trying to solve.

And so that's 1 of the reasons why we have invested and built such a strong in-house capability on the basic radioisotope and isotope sciences part of the business to be able to facilitate that diversity of decisions around our isotopes.

Okay. So very quickly, just a couple of key snapshots. I'm not going to go exhaustively through the whole pipeline. As I mentioned, our 591 asset, which is an antibody-directed PSMA therapy or radio ADC, as we like to call it, we have completed a run-in study, which was something that we agreed with the FDA as part of our new manufacturing package. And we have Part 2, which is the randomized segment of that study is already recruiting in a bunch of countries outside the United States, Australia, Canada, U.K., Turkey, Singapore as a whole raft of 7 or 8 countries that are already recruiting.

We are shortly going to be disclosing the Part 1 of that study, although I note that data safety review has already taken place of Part 1 to enable Part 2 to move ahead. So we see this as a fairly straightforward process from a disclosure and an FDA engagement perspective, and that will happen in the very near term. We've seen historically really good data with this asset. It's highly differentiated, we inject a much smaller amount of radiation into the patient. We have a very condensed dosing schedule. That's 2 shots, 14 days apart. We have a very differentiated clinical utilization in terms of -- we don't need specialist infrastructure. We don't need radioactive toilets. There's a lot of things about this asset that make it very nice to administer.

And we get really positive feedback from the key opinion leaders that use it. So I'm excited to see a real push this year on completing that randomized Part 2 and hopefully continue to get this sort of data that we've seen historically, which is very, very encouraging from product differentiation perspective.

Our follow-on program in alpha, TLX592. We did a study with a proxy to Actinium, what we have seen in other assets, for example, with the JNJ KLK2 data is that assets that have a long circulation timing of blood tend to have -- and where you have highly perfused organs, like, for example, the lungs, you tend to see adverse events with alphas. We wanted to make sure going into our first actinium program that we understood the biology and the pharmacophore that we're using very well.

And so we did an imaging study first, a nontherapeutic study to really look at biodistribution and to feel confident that we had something that was the right pharmacology to take into patients. It was a very, very slow because it's an imaging study. It doesn't confirm much patient benefit, but very enlightening. It enabled us to set mass dose, it enabled us to design our first-in-human study with Actinium that has now received clearance to start clinical trials, and we're in the process of recruiting first patients into that study.

So I'm really looking forward to seeing that story evolve, it's our first true alpha program and very, very differentiated approach for targeting PSMA with an alpha-emitter. We are looking holistically at our therapeutic landscape in prostate cancer. We are interested in earlier stage disease. We look at that through the lens of the alpha program. We look at that through the lens of our collaboration, for example, with Varian and looking at how you do image-guided SBRT in early-stage patients. I think there's a real role there for the combination of external beam radiation and endo radiotherapy together, is that something that we're really looking at.

If you look at the prostate global trial, our Phase III trial, it's a mixture of first-line and second-line castrate resistance. So it's in that sort of middle of the treatment journey.

And then TLX090 is really at that end-stage journey. We see a prescriber appetite for radiopharmaceuticals in advanced patients. The art of palliation in nuclear medicine has been somewhat lost because of successive product cannibalization. So there's an opportunity to go back in there and really reestablish nuclear medicine-based palliation but with a next-generation product that has a lot better economics and a lot better patient safety profile. This is a really exciting asset, and it has huge patient impact. So a lot of patients -- a lot of prostate cancer patients that reach the end of their hormone therapy and their PARPs and their radioligand therapy. They don't have other treatment options. They go into palliation with a lot of pain. This is a really important opportunity to serve the patient going into that transition to palliation.

So we're getting our -- is basically a bridging study to a traditional samarium-based agent. It will give us a good understanding of how we stack up against historical agents in this area. And again, that program is getting really nice momentum with key opinion leaders that are involved in the study.

I mentioned in the beginning that 1 of our strategies is to really double down and that's with a particular referral physician. That's not just on the diagnostic and imaging side, but also on the therapy side. So we do have nice Phase I and Phase II data in clear cell renal cell carcinoma. We have the LUTEON trial now, which is up and running, it's a Phase II/III trial. It's really about a fast run in dose finalization into a Phase III trial. That's a key execution focus for us this year with the new TLX focus on real clinical execution and timely clinical execution. So we expect to really get a good data momentum there in this program this year.

We've seen nice examples of targeting. We've seen some really interesting patient examples where this asset has made an impact on patients. And so we've got a lot of expectations at this program, it will yield good outcomes for the company over the next couple of years.

And then just very quickly, outside of uro-oncology, our IPAX BrIGHT Phase III trial has started a pivotal trial. This is, again, an adaptive dose optimization leading into a primary label registrational study, it builds on what we've learned in the IPAX-2 study. So we really have a clear understanding of the dose range that this thing works well at, very good understanding of the patient safety profile. We've seen excellent evidence of any tumor effect in the studies that have been performed to date, some of which has been published recently in peer review environment. So it's really, again, a very exciting opportunity for the company that will generate quite a bit of momentum this year in terms of late-stage development.

And then finally, just 1 other call out, as I'm running out of time. One last call out is really our FAP program. Part of what we did last year was not just invest in our supply chain but also we augmented our pipeline in some key areas that we think are important for the future. FAP is clearly an interesting target. We think we have the absolute best pharmacophore in this space. We've got data in several hundred patients with lutetium and actinium and natrium. So we have a data set that we can really design late-stage trials around right now.

We're at the stage where we're getting the CMC package together so that we have a very clear run at late-stage studies with this asset. It is a theranostic pair. So we are developing the imaging agent as well. So really great opportunity and very much a pan-cancer indication. I think one of the challenges that we'll have over the next couple of years is both FAP and CAIX have applicability in a very wide range of cancers where we've seen clinical utility in a fairly wide range of cancers. We're going to have to be disciplined about how we prioritize some of those clinical indications. And that's some of the decision making that we're going to have to make over the next 12 months, particularly for this assay. It's a lot of different directions that this could go.

But however you rack and stack in 1 of the things that I think I want to get across to you today is just the opportunity that we have in the business. So not just on the precision medicine side of things. I mean we're butting up against $1 billion of revenue. We see a clear pathway to surpass that. So there's a large addressable market there for our products that we can continue to take but really also that future frontier of that therapeutics business. And when you look at across all the different disease area franchise that we work in, it's a very substantial opportunity for the company.

So without going into individual, and I might just leave this slide up as we go into Q&A but this is what we have to look forward to in 2026, I particularly want to call out the near-term readout on Part 1 for TLX591s, ProstACT Global and also the resubmission of Pixclara and Zircaix is proceeding as we expect but so many other milestones to be hit this year, both on the therapeutic side and the precision medi side.

But I -- and it's not just the slide, the way it's written, but it's really in terms of how we think of the key catalysts for this year, it starts to reflect Telix moving much more with that therapeutic focus in mind. That's the prioritization of our investment. It's where we think a lot of the news flow will come out of this year. So I think it's a very exciting year ahead and really builds on the bedrock that we created in 2025 for the company. So I'll pause there. And Chris, over to you.

Thanks, Chris. Feel free to raise your hand if you have any questions in the room. Perhaps I'll start. So perhaps at the top left of the slide there, Chris, the prostate therapeutic, I'll take imminent as weeks more likely than months?

Yes, exactly.

Okay. And maybe then in terms of the Part 2 sort of randomized enrollment, how quickly does that get up to speed? And I know you sort of still think this is going to be launching in the relatively near term?

Well, we've got -- it already is launched. So we've got approval for Part 2 and it's recruiting in 7 or 8 countries. I mean...

In the U.S., sorry.

Oh, in the U.S. yes, so that will be subject to what the FDA says but we've had no difficulties with non-U.S. regulators in terms of moving the study ahead. We view this as a discussion that has to take place and will hopefully result in U.S. patients being added to the study in fairly short order. But we've had no challenges in moving the study ahead with other sophisticated regulators. So I think it's really just about hitting that milestone.

Yes. Got it. Okay. Zircaix, so you mentioned the positive Type A meeting you had shortly before the end of the year. Now you had to address some CMC deficiencies, which were raised in the CRL. Were there any other observations that had to be addressed as well? Are you following up separately on that issue? And maybe just an update on the timing of the resubmission.

Yes. So the whole span of topics that came through from the CRL are really all around manufacturing and comparability between our clinical and our commercial scale material. When we run clinical trials with radiopharma, we aren't typically using large commercial scale practices because you're dealing with large amounts of radioactivity. Radiopharma is still very much a small batch production or a small-ish batch production continuous type of environment just because you have a decaying product. So we had a bit of extra work, and it's the first time that anyone's put a PET biologic in front of the FDA, and it was our first time and their first time, and I think we learned a little bit together.

There were some things that we were surprised at that we've had to go back and fix but they're not significantly adding to time lines or anything else like that. The -- we have an upcoming meeting with the FDA to look at the clinical comparability data that we have proposed or the clinical comparability strategy that we proposed when we filed the BLA that was deemed not to be necessary by the FDA that analytical comparability would be sufficient. But upon review of the package, they determine that they wanted to see clinical comparability. And so that's where we landed. Fortunately, we did a clinical comparability study, and we have an open study protocol that we anticipated, perhaps European regulators wanting.

So we're in pretty good shape in terms of that package. So once the FDA tells us that they're happy or otherwise, we're in a good position to move ahead with that refiling.

Thank you. Any questions from the room at all? Yes.

Thank you for the presentation. As we think about the next 5 to 10 years in terms of radiopharmaceuticals, what do you see as the biggest challenges for that market to really scale up both on the therapeutic side but also on the infrastructure, supply chain, et cetera.

Well, I think it is exactly that. I think it's the infrastructure and supply chain but I mean that is somewhat an investment-driven outcome. I mean, I think we see a lot of companies that are out with very novel radionuclide even things like actinium where there really isn't a commercial supply chain available. I'd say that lutetium has an established supply chain but it's vulnerable, and vulnerable supply -- I mean, even when you take something like technetium that we use 40 million times a year around the world, it's still a vulnerable supply chain. So -- these are definitely challenging. I think that execution lines, clinical execution wise, the biggest issue is the lack of clinical infrastructure to support this.

When I -- on the rare occasion that I lose sleep at night about this industry. It's a lack of text, it's the lack of practitioners. It's how do we get radiation oncology up to speed on these therapies, how do we make it easier for medical oncologists to integrate radioactive therapies into standard of care? How do we run clinical trials where we actually prioritize the integration of radioligand therapy with standard of care rather than the sort of traditional head-to-head approach that nuclear medicine favors.

So yes, how do we -- I guess the fundamental problem when we have to solve is how do we make this class of drugs available to a more general prescriber base? And that's a really tough challenge to solve. There's a lot of opportunities as well there for different types of organizations that will do things in a different way. Anybody else have a question or comment. Still got a few minutes left. So well, maybe you'll have to throw one at me.

Pixclara, Chris, if you don't mind. So you got the NDA resubmission there on the top of your slide. I believe you said I read it down, very shortly, will be the time line...

Well, we wanted to get it done before Christmas, but everything moves at the speed of cold molasses before Christmas. So it's very, very close to getting done. We're just kind of dotting the Is and crossing the Ts on that package. So yes.

But to clarify your expectation, both Pixclara and Zircaix you still expect to be commercial opportunities within the calendar year.

We do. Yes. And Pixclara, we have -- we believe a very clear agreement with the FDA on how to move forward. We have the data that we need to satisfy the more the data analysis that they need to be satisfied to move ahead. Unlike the -- it would be very tempting to -- when a company of our size, and we submitted 3 drugs last year, we got 1 over the line. We had 2 setbacks. It would be very tempting to ascribe a kind of systematic issue there, but there isn't, they're just completely different.

Pixclara was a single CRL topic around data analysis and what the FDA -- and by the way, at this stage of labeling. So we're not talking about mid-cycle review, we're talking about at the stage of labeling, right, where we had a disconnect on how the clinical data manifests itself in the submission.

That single topic issue has been we believe, result in our resubmission. We had no CMC issues. We had no manufacturing-related issues. That package is very straightforward from a regulatory perspective, from a CMC perspective. It's the exact opposite with Zircaix. Zircaix has a gold standard confirmatory Phase III, knocked all 14 primary and secondary end points out of the park. The issue is not clinical. The issue is really around manufacturing. It's a super complicated asset.

I dare say, we probably expect to see -- although I don't know that the agency has such an appetite for these days but we'll expect to see revised guidance industry come out of the experience that we had with the FDA because I think the first time that somebody really put a full package around a biologic-based radiopharmaceutical in front of them. And when you have a reviewer that's looking at your product as though it's a cytotoxic ADC, you're going to have some disconnects in terms of kind of understanding.

So I think it's -- we certainly feel like we came out of the process with our 2 setbacks last year, a stronger company. We understand what we're going to have to do differently in the future. We have a much more paranoid lens around how radiopharma is different and not different relative to other sort of biologics. And I think that's a competitive advantage for us to really understand where those issues are with the agency. So the challenge you have when you're submitting drug approvals, is that's the end of the road, and that's where the success happens or it doesn't.

Before I let you go, I do want to ask you 1 on Alpha. But before I get to that, we still have a couple of minutes. So just additional opportunities, maybe taking a step back on your existing commercial product. So you mentioned late last year, you had some good Phase III data from the study you'd run in China, with Illuccix. You said today that's now been filed. Maybe just contextualize that opportunity for us? And also Part B of the same question, the BiPASS process. I mean moving upstream, you talked about the challenges involved. How near term and how realistic are those opportunities?

I think they're very realistic. And we see more and more clinical interest in using imaging at the front end of the decision-making process. And -- but no 1 has really collected the data and made the clinical case yet for doing -- so that's why the buy. There have been small academic studies that have done that have shown some promise. We've learned from those studies, and we've built on them. I think our clinical team does a great job of monitoring the state of the art.

The BiPASS study is a really well-designed study that's going to be a label generating study because we've agreed with the agency that it's a label generating study. And I think that it enables us to really move upstream from where we are today and impact patients much earlier in the journey. The TAM associated with that is massive. If we can reduce the number of biopsies down to 200,000, 300,000 biopsies a year, we can more or less double the market opportunity for prostate cancer imaging but it's done in such a way that it's really additive to health care.

I mean if you look at the cost, both in terms of the economics of clinical service provision and the morbidity and impact on the patient that moving upstream is really impactful. It's a no-brainer from an economics perspective. So I think that's a very bright spot for the company in terms of driving value. I think that when you look at Telix as a company, commercial execution is something that we do really well. That should give you confidence that once we have, for example, Zircaix approved, we'll go back into that same referral physician that we've built a very deep relationship with it's going to be a rapid product adoption. I mean the -- my greatest personal disappointment last year was not getting Zircaix [ over liked ] because prescribers are waiting for it. We actually kept our expanded access programs open for Zircaix and Pixclara, just continued to show our commitment to patients. We did that a pretty significant cost company.

So we're keeping that enthusiasm alive, but really want to see those 2 products out of the market. Regarding China and Japan. China is a strategic opportunity that's really about paving the way for therapy. That's the key interest that we have in China as well as our partner interest. Japan is rather different. Japan is probably the second largest homogenous market for nuclear medicine products. It's got an advanced PET procedure code that's reimbursed at a decent level, not too far behind in the U.S. We see about 110,000, 120,000 scan market opportunity in Japan at a good price point, that's well and truly worth prosecuting -- it's probably the best opportunity that we have in Asia.

I promised a question on Alpha, if you don't mind, Chris. I'm going to rush you though. So maybe just 45 seconds on what you think with alpha-emitting therapies.

I think it's got great promise. It's just that we probably don't develop them yet in the way that we should. And I think that there's a long way to go on the supply chain before they're viable, but we and others, of course, are working on those.

Great. Thank you very much for your time. I appreciate it.

Great. Well, thank you, everyone, for joining our fireside chat with Telix. My name is David Dai. I'm one of the biotech analysts here at UBS. [Operator Instructions]

In the meantime, I'd love to introduce Kevin Richardson here, the CEO of Precision Medicine of Telix. It's a great pleasure to have you, Kevin.

Yes. Great to be here. Thanks for inviting us.

Excellent. Great. So Kevin, starting just can you provide a quick high-level overview of Telix, including both your diagnostics and also therapeutic platforms?

Sure. Yes, excited to. As you know, we're really one of the few pure-play radiopharmaceutical companies that really focus on 2 platforms that work really well together, the diagnostic platform, which we've initially launched Illuccix and now Gozellix into and, of course, have several others in the diagnostic space. We platform that technology with a corresponding or pair -- a therapeutic pair on the therapeutic side with our 591 therapy, 101 and 250 therapy. And then one of the unique differences around Telix and the rest of our colleagues out there is really around our TMF solutions as well, which really brings together our ability to supply -- we call it our strategy is from the isotope to scanner or isotope to injection room so that we can supply that all the way through the supply chain system.

We've done -- we've demonstrated that really around some of our most recent acquisitions around ITG, some real brain power and property down in Houston as well as Optimal Tracers in California; Seneffe in Brussels, Belgium. And then one of our latest ones is RLS that really brings together really the power of really regional manufacturing all the way through last-mile delivery to our customer base. So really making sure that we own all parts of that is important to the overall strategy of Telix that we've been laying out over the last couple of years. And then you've been able to kind of see that as we've made these acquisitions to really manage that strategy to really be a one-stop shop from isotope all the way to the injection room.

What about your therapeutic business there? Can you tell a little bit more about that?

Sure. The therapeutic business is really anchored right now around our 591 therapy and our antibody approach. As you know, we've finished our Part 1. We're waiting to move into Part 2. We haven't given really an update on when we're going to give that news yet. But in -- outside the U.S., we've moved into recruiting Part 2. So really excited around our 591 therapy. And then the 250 therapy around clear cell renal cell carcinoma and 101 is really moving forward well, and we have updates on that as of the last quarterly results.

So it's a big part of the way that we look at the market is that we are not a diagnostic company. We are a therapeutic company that is really leading the way with our diagnostic business. There's a couple of ways that that's really important is that the diagnostic business is really building key relationships with payers around the world. It's building key relationships with regulatory bodies around the world. And most importantly, it's building relationships that we believe we'll be able to capitalize on in the customer base.

So we're in thousands of accounts around the U.S., and it's really important that we build that nuclear med, that urology and ultimately, that medical oncology relationship so that when we develop and launch and go to market and start to commercialize the therapeutic, we have that relationship in hand. And we'll have multiple diagnostics along the way with that. So we'll have great payer relationships as we go into that process as we -- even now with Gozellix, we're diving deeper into some of the commercial payers as we continue to build this database relationship with payers.

Got it. That's really helpful overview. So let's focus on the prostate cancer diagnostic business, which is the precision medicine and your lead program, the commercial program is Illuccix. And over -- in the last quarter sales, we saw sort of like flat $155 million versus $154 million in the second quarter, but we did see volume growth grew about 3% quarter-over-quarter. Can you just maybe share us -- share with us some of the dynamics you're seeing? And what are you seeing in terms of the ramp and adoption of Illuccix despite TPT pass-through expiration?

Sure. So we were really extremely pleased with Q3 2025. As you know, Illuccix lost pass-through in the start of the third quarter. So it was a pretty even playing field for a little bit. I'd say even in the status of now, quite uneven when you know that by that time, Gozellix had been approved, HCPCS code had been established, and then we were just waiting on a transitional pass-through approval from CMS. So we were quite pleased with Q3 results, understanding all those dynamics at play. And we're quite pragmatic about our approach to commercialization. So as things evolve in the strategy, like we had planned for this event, we had planned for transitional pass-through, but the tactical execution of that kind of has to wait until those milestones are realized.

So as we think about Illuccix kind of managing through Q3 and our sales and marketing team's ability to not only hold on to that business but grow it on a unit basis was really important. So really managing a simply put strategy of going deep into accounts that we have already established with Illuccix. So either getting more patients into those accounts that use us mostly exclusively as well as going deep into the market share split accounts where they might use two different PSMA agents up to and including more of a wide strategy, how do we bring on new scanners that are coming in and/or competitive accounts.

So managing that in a very dynamic marketplace takes a real dogmatic approach and disciplined approach to the way we commercialize. And so I would kind of relate that to the modular approach that our customer service or customer-facing team really approaches. We center everything around that relationship at the Territory Manager level. And then we surround that territory manager with subject matter experts to help facilitate the conversion or the deep strategy from a market development team that really focuses on going deep into accounts and really working with the local referrers to drive more patients into that, educating referrers on the power of PSMA Illuccix.

And believe it or not, there's still a lot of value in that, while PSMA has experienced a massive growth streak over the past 3 years, we still get urologists that refer for bone scans that we have to reeducate. I personally have experienced that with friends around from California to Phoenix to New Jersey, where they are looking for a place to get a PSMA scan because the urologists didn't refer that. So we have work to do in that, and that's that last little 10%, 20% of the penetration of the TAM that we're looking for is the way it's defined today. And then when you really think about the market development going deep, then we've got the -- once we get an account converted, they need to make sure that the scanners are set up right.

So we have a medical imaging specialist that comes in and makes sure the scanner is ready for a gallium scan and the customers know how to read and the differences between the two. We believe that Gallium has higher inter-reader agreement, better clinical accuracy. And to do that, we want to make sure the scanner set up for that promise to be fulfilled. And then if -- once you switch to a new product, it's a little bit different of a process. So we want to make sure that our reimbursement specialists are there, our field market access people to make sure that the paperwork is done correctly and everything is smooth with the reimbursement.

And then finally, if you really want to understand at a deeper level around the clinical science of inter-reader agreement and indeterminate bone lesions and how to really differentiate the two products in that conversion, then a big part of that is our medical team, our medical affairs, medical science liaisons. They're subject matter experts specifically on the difference between gallium and F-18, of course. And they play a big part of being able to help peer-to-peer differentiate the two products.

So it's a real customer-centric customer-facing approach that we call it, it's a modular approach that requires a disciplined approach from the TAM and then to manage all that value in the Telix future pipeline as we educate customers on that to manage that value so that price really isn't the reason that they choose Telix or not. It's the value proposition that Telix brings as a company and as an individual function that's solving some of their problems.

Got it. Got it. It's exciting to hear that not just price, but also many different factors at play, right, that really helps drive growth of Illuccix in many different markets. Now excitingly, with respect to the new drug that just recently got approved, Gozellix, right? And those TPT pass-through. And what we saw in the third quarter was that you actually increased the guidance, right, from $770 million to $800 million to $820 million, right, top line side of things. So this means that you're seeing some numbers from Gozellix launch perspective. So just help us understand, Kevin, what are some of the things you're seeing on the momentum of this Gozellix launch so far heading into the fourth quarter, especially after the TPT approval.

Yes. Sure. Well, we started the Gozellix story 3 years ago. And so there's a lot of things that have changed in the past 3 years in terms of reimbursement and the market and why we wanted to bring Gozellix in. So Gozellix is a true innovative product. We brought it in as a part of life cycle management, really focused on being able to reach not only urban and suburban areas, but more rural areas. So the focus on Gozellix development and the true innovation was around the stability of shelf life. How long can we keep the isotope on the molecule and get it to where we want it to go so that you don't have indeterminate bone lesions, you don't have separations. And so it was a big part of the strategy.

But part of what that enabled us 3 years ago as we started was to understand then if something came off transitional pass-through, it went straight into a bundled package, right? So we knew that we needed to truly innovate in order to ensure a HCPCS code. And so it wasn't really about a matter of expanding production capacity or anything like that on a cyclotron. That's more about -- it's not about the efficacies reached and the economies reached and increasing the capacity size. It's about how far we can go with the product to really reach the full potential of the TAM.

So we started that 3 years ago. And as we edge towards that, CMS changed a bit, right? They came out with MAC pricing. And so we were able to manage then our strategy and tactics based on what the scenario would be at launch if it were under MAC pricing and assuming that we did or didn't get reimbursement pass-through. So once we got a HCPCS code, well, then transitional pass-through was just a little bit closer. So we were able to tighten up our tactical plan on how we were going to execute that. And so all of that was a part of a very disciplined approach that started 3 years ago as we honed in on what would be October 1, 2025.

Now with all the splashiness going on at one end of the market, if you will, around pricing and kind of the F-18 battles, we tried to keep our eyes on the prize, if you will, which was maintain a dogmatic approach to pricing and a dogmatic approach to the execution of both our deep and wide strategy, where we were going to go get more patients, where we were going to take share and where we're going to open up completely new accounts. And that was an important part of that as we got closer.

So now we got HCPCS sometime in early September. We were notified about CMS in late September, really a week before. So in the world today in hospitals, as you know, there's just some issues around pricing committees and things like that. So we're incredibly excited about the progress we're making. We're excited about our Q3 results. So once we saw our Q3 results in the midst of all that splashiness, we were able to raise guidance and what we thought was appropriate for our progression and our progressive move from Illuccix and Illuccix split accounts to what would look like to be more Gozellix-only accounts kind of moving forward.

Remember, HOPS accounts are a real target for that and -- because of their CMS reimbursement, but they too have different payers inside of a single HOPS. It's not just CMS. So really managing that mix has been an important part of that progressive planning process. The more data that CMS gives us that's more accurate and actual, then we can quit speculating and start driving through the scenario plan that we built for that. And that's really where we are right now today.

So we're in the middle of that tactical execution, and we feel very comfortable with the progress we've made and excited enough about that progress to raise guidance. And then, of course, we haven't given guidance for 2026 yet. But as we see progress in, you'll see that in the first quarter, and we'll be happy, and we've been pretty accurate with our guidance so far. So happy to talk more about that in the first quarter.

Absolutely. Looking forward to that. Just -- anything you can share on the -- after TPT was approved October 1 so far, it's November, anything you can share around how the launch for Gozellix looks like so far? Any kind of physician feedback you're hearing from physicians on clinical and logistics aspects of Gozellix?

Yes, sure. No, like I said, it's progressing according to plan, and we feel comfortable with that. Again, there are pricing and new product review committees that we are in big accounts, which these are HOPS accounts that we have to kind of manage through. But the feedback of the first cases that we've done are great, fantastic deliverability of the product through our radiopharm partners and our own radiopharm RLS has been a significant improvement in terms of just their ability to manage multiple doses and manage the operations inside.

We are continuing to work on what we call our distant pet strategy. Those accounts are a lot -- a little more slower to come to market because of their sensitivity to reimbursement. They're smaller hospitals or more rural. So we're working through those issues as we start reaching further and start reaching the promise of Gozellix outside. So the promise of Gozellix in urban and suburban areas is flexibility, reliability and delivery, more timeliness of dosing and you're not as worried about -- you can get a dose there earlier in more metropolitan areas because you can deliver more gallium quickly. And then in the more rural areas, we can just go further, and we'll continue to start driving into that.

So I think from a progression standpoint, there's been a lot of work done previously, and now we're just tactically executing that through our sales and customer-focusing team. So very happy.

Got it. Got it. And you mentioned about that 10% to 15% of potential market that Gozellix could potentially enter. How has that been so far?

Well, I think it's progressing as well. Like I said, that's more of a price -- it's not a price-sensitive market. It's a reimbursement-sensitive market because they are so small that this is a big expenditure as a percentage of what they do. So we're working through those details now on their pricing committees, and they were waiting for transitional pass-through. So that's progressing.

As we look into Q1 and beyond, we will give guidance based on PSMA and not really the split between Gozellix and Illuccix, but we are very positive about how the progress of the uptake has been and the physician feedback has been great in terms of the deliverability and really the image itself has been very well accepted and adopted.

Got it. Great. And then moving on, you have this Phase III trial called BiPASS, which is going to -- going after patients with prostate cancer diagnosis. Can you talk a little more about this trial? And how do you think you're able to use this trial to expand the market logistics for that?

Sure. Yes, we were excited about BiPASS. And me as a man, I am very excited about BiPASS because of what the alternative really is, right? -- that the alternative right now is a pretty invasive procedure with a probe that is anchored in the anus and then a template biopsy is delivered 12 to 40x. So it's quite invasive for what that looks like. And I would say that PSMA can improve on the sensitivity and specificity of that as well as the adoption. There's 800,000 to 1 million biopsies a year in the U.S. and about 20% of men say no. They say no because of how invasive the biopsy is and some of the side effects of that biopsy.

So the number of biopsy itself in PI-RADS 1 through 4 is that kind of adoptable market piece that we're looking at around that 800,000. So if you look at an existing TAM that's mostly BCR at this point of about 600,000 plus then you can see it more than doubles that available market to us and really changes where PSMA sits in the patient journey. So instead of taking it from a staging or a biochemical reoccurrence after definitive therapy, it puts you prior to definitive therapy. So we start looking at gallium scans in terms of serial play, right? You get it at the diagnosis, you get it after the definitive therapy for maybe a response to the therapy and what that may look like kind of along the way can give us multiple times that they'll want to use a gallium scan.

So we see it as an amazing patient benefit and more than doubling of the market in a step change with a positive trial. And then we see that we can continue the BiPASS trial and really move into the other section of PI-RADS 5 and really kind of paint that whole picture with the PSMA scan. So the way we position it is that it gives the patient the one and done or none and done just based on how positive or negative they are on the scan. So either one biopsy just will be more precision. It would be right where the tumor is, and you don't have to do a template to figure out where it is because you know right where it is up to they get a clean PSMA scan with high predictive value. So they're good to go.

And as you know, there's a lot of anxiety around getting that PI-RADS scan and really understanding where you're going to get a Gleason score because those two together give you really a risk stratification of metastatic disease, how aggressive is this and/or is it metastatic. And so the ability with BiPASS upfront to alleviate some of that and give them clinical decision-making power early in the process is going to be really important.

Got it. That's really helpful. And so on that front, anything you can say in terms of data expectations or when should we be expecting completion of the trial? When do we actually think we actually see any data coming out of it?

Sure. No, it's an interesting question, and we're all kind of curious about that, but we haven't disclosed anything on that yet. We have disclosed that we've done our first patients in Australia. We're finalizing everything with the FDA now. We've got sites registered and lined up. They're just about to start recruiting, and we'll announce that as soon as we get that first patient in the U.S. Remember, the follow-up on a diagnostic trial is not like it is on a therapeutic trial. So we're seeing pretty quick recruitment in Australia. I mean if you -- imagine, if you will, you've got a patient, it's really an intent to treat -- it's an intent to biopsy trial. Meaning that if you see clinical indication in a patient that you want to biopsy of them, then they qualify for BiPASS biopsy.

It's typically a rising or a high PSA and a PI-RADS 1 through 4, and then they would be indicated for a biopsy. So they're simply just adding on a PSMA scan, which will give them more information. So we see it as a pretty fast recruiting trial. I mean, still to be seen, but we're seeing good uptick in the trial in Australia right now as we kicked it off. So we -- hopefully, we'll be able to give some more guidance in Q1 once we get the U.S. space going as well.

Got it. That's helpful. Great. And moving on to your other diagnostic programs, Pixclara and Zircaix, maybe focus on Zircaix, so far. Now we've recently seen that the program is actually recently being included in a number of guidelines, including SNMMI-I, EANM, ACNM. So could you talk about the importance of the inclusion of Zircaix in those guidelines?

Yes. I think that is a really important step in the society backing the product. That comes from 3 years of confidence in Telix and our PSMA agent and our ability really working with those physicians on PSMA to understand the value of that scan that translates easily over to a ZIRCON study that came out that has really high sensitivity specificity as well. So that confidence is really a platform confidence now in that PSMA PET drug where they want to see this enacted. It also comes from an expanded access program that we did in many sites around the U.S. as we came off the trial, we went to expanded access. So there were a lot of patients that benefited from that trial that really adds to the value of what the society wants to do with that.

Remember, it's that same scan anxiety comment that I said before. You typically get a kidney lesion identified on some kind of other scan that you came in for. And they said, here's what's going on with why we scanned you. However, we see something in the kidney that we were going to need to investigate and/or the horrible words of watch and wait, right, that we're just going to have to measure the significance of this lesion by the size over time. Is it growing fast or not? And as you know, ccRCC, clear cell renal cell carcinoma, is one of the most aggressive forms, right? So waiting 6 months or a year between scans may not be the best time line for that patient.

So being able to see those smaller lesions and get them identified quickly so you can get the appropriate treatment as fast as reasonable is a more appropriate treatment algorithm for that patient. So that's why Society of Nuclear Medicine and the same for the European society put that in the guidelines as a proposal that they really see the value and what that's going to do for their patients.

Now that also leads the way to another important guideline, which is the NCCN guidelines, which will happen as soon as we get the product approval. We feel pretty confident that the NCCN is favorable. The other societies are favorable, and that's an important step as we get to reimbursement and how the insurance companies will reimburse is based off that NCCN guideline. But the confidence of the nuclear medicine societies that have really been the ones working with this product is really important in terms of getting to that next step. So it would seem as though we have their full backing on moving forward with that product, which we know we have because we talked to them in alliance.

That's great. Yes, on that front, anything you can update us on in terms of the submission progress so far? Any kind of remediation process with the third-party manufacturing facility? Anything you can share on that?

Sure. Yes. Well, I mean, it's still working towards that Type A meeting and submission dates for that. So we'll let you know as soon as we get that and move forward with that. As far as what we're doing on the CRL, we know that we have a clinically acceptable and safe product. The ZIRCON study demonstrated that. But like all true innovators, we're going for a BLA with radiopharmaceuticals, which is kind of a first-in-class and so we had -- we were working through that educational process on both sides to get the manufacturing where and how we want it for the scale-up and production of Zircaix when we go to launch that around the U.S.

So more to come on that as soon as we make that public and move forward with that. But the team is working tirelessly for that Type A meeting, which means that we can then submit post that. So really excited about it.

Got it. And then for Pixclara resubmission, you've guided to resubmission by the end of the year. What are some of the key gating steps for you to resubmit the application again?

Well, we had the Type A meeting. So the biggest step was really getting in step with the FDA and what they wanted to see. This is a 505(b)(2), which means that it's using the existing data, and we've come to an agreement with the FDA on what other data they want to see or what data and how they want to see the data. So we are just working towards that, and we're holding tight to our submission in 2025. So again, once we make that, then we'll -- they have 60 days or so to respond. And then we'll -- that's when we'll be able to announce when we get that back from them of when the next PDUFA date might be, given that they accept the file.

Got it. That's helpful. Any changes in terms of the FDA interactions given all the changes that's going on with the FDA?

Well, I mean, I think that's a question for really all of us in the industry today is how that's managing. So Telix won't be held to any other standard than anyone else. They won't get less interaction than anyone else. So it will be an industry issue moving forward. But we continue to have great conversations with them. We continue to have the appropriate level of interaction with them. And so far, we're pleased with the progress we're making on both those fronts and don't feel as though that there's -- we've been negatively affected more than anyone else in the industry by just what's going on in general with the FDA and then what's happened in the last 38 days, I guess it is, right? Hopefully, there's some news today that may break that, but...

I hope for that. And the last question on Zircaix. How confident are you that you won't need a clinical trial for the resubmission for that?

Well, we're comfortable with where the FDA communicated with us what we needed to do and what we needed to demonstrate in terms of getting it to a commercial stage product. Again, the clinical trial of ZIRCON was a well-constructed trial and had great results. And so it's not that it's not an approvable drug. We've just got to manage it through that process. And again, innovating is difficult sometimes and being a BLA radiopharmaceutical first-in-class is always just leading the way and coming to an understanding across some of those issues that may be a little muddled in some areas. But we're pretty clear on our direction. The team has clear direction and good communication with the FDA, and we just continue to work those things out as we move forward.

The commercialization of Zircaix is really kind of exciting because our TLX250, when it crosses over and gets approved into Zircaix, it would be inside the same commercial strategy, right? So it's still a urology call point. It's still a urology referral into a nuclear medicine like reading room. And so we're prepared as a commercial team to take the synergies of that and bring it to bear in the marketplace. So like I said, the same thing that holds between diagnostic and therapeutic advantages of having a diagnostic team. It also has the same advantages of having a previous diagnostic, right? We have great relationships with payers, great relationships with regulatory bodies and great relationships with customers. So we have a landing place for a product that we have an existing sales force that's out there each and every day calling on them.

So we're really comfortable with the go-to-market plan. We've done a lot of unbranded like education around clear cell renal cell carcinoma in the urology marketplace and the way that they're managing it today. So we're excited and look forward to the day that we do get that approval and kind of enable that selling organization that put it bluntly, has done a fantastic job in the PSMA market and be able to utilize that same approach, that modular customer-facing approach to be able to use it with two products. I mean, it can only make them stronger, right? It can only make us more valuable in the marketplace in terms of our customer interaction and just a much simpler sell as you start thinking about the urologist and how they are referring into these diseases that were diagnosed one way 2 years ago, you see the same thing that's going to -- we believe will happen inside of ccRCC.

Got it. Great. Excellent. So we've got about 3 minutes left. I love just to kind of switch gears and talk a little bit more about the therapeutic business, especially focusing on TLX591, especially with the ProstACT global trial Part 1 data readout, what can you say about like what's the top line data expectation, we should be watch for safety, dosimetry? What sort of safety of this dosimetry data we should be looking for here?

Sure. Well, I think that as we've disclosed that we're through recruiting for Part 1, and we've moved on to Part 2 basically outside the U.S. Inside the U.S., we're waiting for the data readout, which we haven't disclosed yet when that's going to be. It's still percolating, if you will. So we're incredibly motivated to kind of move through that, as you can expect. And I think that with any therapeutic trial, you're just wanting to make sure that you're at the acceptable levels of toxicities and you're showing probable efficacy in terms of what we're looking for. So it's just a Part 1 to really move into Part 2. And we think it's a great way to really demonstrate the value of the product in a way of moving into that really Phase III clinical trial.

Yes. Well, I guess the question is what level of safety that will get you confident to move into a Phase II -- Part 2 study?

Yes. We really haven't disclosed the levels that we're looking for yet. So we'll have more to come on that.

Got you. Makes sense. Okay. Great. And then just lastly, any kind of near-term milestones you want to highlight over the next 6 to 12 months that we should watch for?

Well, I think -- well, for the therapeutic business, it's exactly what we're talking about, right? So we've got to initiate Part 2, give the readout and then move to that interim data readout of Part 2. So that's a big therapeutic milestone. I think from a -- it will be a big milestone. We'll be talking about our 2025 results in Q1. That will be a good indication of the success that we're seeing in Gozellix and that continued move when you see our guidance for that, that will be a big milestone in terms of our ability to execute in that PSMA market, given all the dynamics in that market.

And then really, the launch of BiPASS is the game-changing kind of step change in terms of launching it and then the recruitment period and then ultimately, what that looks like in terms of getting to that positive, whether that's -- when we can really give that expected date will be a big time over the next 1 to 3 years will be a big change. And we think that, that really moves the game, like I said, from this really battle between serial scanning of patients and puts us right upfront in the priority position and really establishes ourselves as the market leader, we think, in prostate imaging.

Okay. Great. Well, with that, we're out of time. Thank you, Kevin, for joining us. It's a great pleasure to have a fireside chat with you.

Yes. Thank you. Thank you for your time. Thank you for the invite.

Thank you so much. Yes. Thank you, everyone.