Replimune Group, Inc. Aktie

All right. Let's go ahead and get started. Welcome everyone to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, [ Joyce Zhou ], Priyanka Grover and [ Rati Pinhe ]. Our next presenting company is Replimune, and presenting on behalf of the company, we have CEO, Sush Patel.

Thank you, Anupam. I'll just refer you all to our...

Sush if the slides don't work, do you want to just make this a fireside, where you and I can just have a chat.

Happy to do that.

All right. Safe harbor statement.

I'm playing catch up now. All right. I'll refer you to our forward-looking statements. So it's been a -- 2025 was a tumultuous year for Replimune, but as Anupam and his team at JPMorgan have sort of tagged us as the turnaround story. And I'm excited to share the resilience we've shown and why we're actually now poised to deliver on the promise of oncolytic immunotherapy for patients. So near term, we're looking forward to our approval, and we're already ready to execute on our commercial launch plans. That involves working very closely with the oncology and interventional radiology stakeholders. We've done a lot of work on now and ready to go. And we're also worked to simplify the logistics for our modalities so that we can enable next-day delivery and also stability at room temperature for our asset.

Now one of the things that we're really confident on is this is something that can be used broadly for a treatment of many cancers. And one aspect of that is when you look at the first-generation drugs such as T-VEC, these were predominantly used for the injection of small superficial lesions. What we've been able to do now is show through deep injections, including viscera, lung and liver, that we can get to a lot more patients. And we've been able to do this reproducibly and that we've now done more than 1,000 deep injections, which I think is really important as we think about the potential of this modality longer term. We've also treated more than 1,000 patients, and we have many HCPs that have a lot of experience with RP1, including in the U.S. We've seen durable responses, systemic responses, which are again very important. We're now moving forward with randomized trials and also moving beyond skin cancers to other more prevalent tumor types.

So as we think about Replimune's mission, we really were founded with the intent to develop more potent and systemically active immuno-oncology drugs. And this really starts with our first 2 assets, RP1 and RP2, which encode a number of proteins and transgenes to really drive a more potent and systemic activation of the immune system. So one thing we have is GALV, which is a fusogenic protein, that drives immunogenic cell death, both our assets RPQ and RP2 have that.

We also have GM-CSF in the constructs. And then RP2 was really designed to drive even more potent activity in more immune insensitive tumors, and that includes CTLA-4. Now one of the things we want to do beyond the assets themselves is really our approach to injecting, how we inject, where we inject. Now what we have seen is when you just inject superficial lesions, we are able to see uninjected responses, including in the viscera, lung and liver, which is great. However, we've always believed that when you have a patient that has both skin and deeper injections, it will actually maximize outcomes if we're able to inject both of those locations or if they've only got deep lesions. And what you -- what I'll show you shortly is that this hypothesis is actually now translating into clinical benefit for patients.

So I'm going to start with our pivotal data set in anti-PD-1 failed melanoma, and that's from the IGNYTE trial. I think one of the important things really to provide context of the data is to understand that from the outset, we selected a very rigid and rigorous criteria for PD-1 failure. Because what we want to know is that this is a combination regimen, and we want to make sure that further PD-1 therapy in these patients really would not be expected to do anything probably in the 5% range. And so we use this criteria where essentially we ensured that there was sufficient prior exposure to PD-1-based treatments. That means at least 8 weeks, although 95% of patients had at least 12 weeks of treatment.

The last treatment before coming on to the IGNYTE trial was a PD-1-based regimen and that these patients progressed while on that regimen and had confirmed progression. So this is one of the most rigid criterias for any trial to ensure that these patients have definitely failed their treatment. So now I just want to give you an exert to some of the data we presented at an oral presentation, a late-breaking oral presentation at the SITC meeting this year. And it sort of just further highlights the benefit we're providing to very tough to treat patients. These were particularly difficult subgroups from that trial.

For example, if you look at the primary resistant population, we see that we get about 32% response -- sorry, 34% response rate, which is actually very similar to the overall patient population. Primary resistant patients are patients who actually blown through their prior treatment in less than 6 months, difficult to treat. And it's great that we can actually see a very similar benefit for those patients as we see for the overall population. We also see benefit in patients who have failed both CTLA-4 and PD-1 as well as later-stage patients with a very consistent benefit. So again, these are really important things as we think about how we position this regimen and the unmet need in this population.

So one of the important questions you always get when you're doing a single-arm trial, particularly with the combination is well, what is RP1 contributing? And I mentioned one of the ways we got to that was this very strict criteria so that we know that further PD-1-based treatments really wouldn't do very much, as I said, about 5%. So when you see about a 34% response rate, we know that the RP1 is really contributing. However, we've also done some additional analysis, and this is what I'm sharing on the next couple of slides.

This is looking at patients as their own control. And so if you look at the 11.5% response rate, this is looking at the response rate patients had before coming on to the IGNYTE trial. And then if you look at the 29.8% response rate, that's what they experienced after receiving RP1 and nivo after they definitively failed their prior treatment. So in oncology, it's very rare that you actually have an earlier line treatment and then in later line treatment, you actually see the response rate increasing.

If you look at another subgroup here, primary resistance, as I mentioned earlier, these are particularly hard-to-treat patients. Those patients had a 0% prior response rate, and we got them into a 28% response rate on the IGNYTE study. So again, this is just another way to try and explain and show the contribution of RP1 to these patients. Secondary resistant patients, yes, they had about a 30% response rate. Even that's lower than what you might traditionally expect from frontline immunotherapy, you get about a 40% response rate. But after definitive progression, then we managed to get another 1/3 or so of those patients back into response. So again, this is very meaningful for treaters, and it's why physicians tell us that this is something that they really want for their patients given how difficult these patients are to treat.

Now responses are important, but the other thing you want to know is are these responses durable? And so this is another analysis we've done looking at time to progression prior treatment, which is the red line on these graphs and then after the patients have received RP1 plus nivolumab on the IGNYTE trial. The slide on the left is looking at all patients. And you can see that we start to raise that tail -- we start to raise that curve and see a tail, which is what you want to see with immunotherapy. And then on the right, you see that really for responders, this is quite a striking difference from the benefit they receive versus their prior treatment. So again, very important to show that what RP1 is contributing.

So now at our Type A meeting and subsequent communications, we have got a confirmation from the FDA that this is an acceptable trial design for registrational purposes. And just so you know that one of the questions we had is, well, you have a limited dealer's choice, why do you allow PD-1 monotherapy on that trial? Well, actually, that was -- it is an NCCN approved option, although in reality, it's very rarely used. And what we were able to share with the agency is even though it's an option, nearly all the patients in this trial, which has now enrolled about 60 patients are actually getting Opdualag in the control arm.

So they felt comfortable with that. So this should be fine moving forward. The study is going really well. It's enrolling. And as I mentioned, we have over 60 patients enrolled now. That's predominantly in the U.S., but we've now recently started enrolling patients in Europe and have expansion plans for the U.K. and Australia in the very near term. We plan an interim overall survival analysis from this study in the second half of 2027.

So that's just sort of now transitioning on to preparing for the commercial launch in melanoma. Now we have a significant patient opportunity ahead of us here. There's about 10,000 addressable patients, about 80% of these patients will have something they can inject and be eligible for RP1 treatment. Now as I mentioned, the IGNYTE trial really showed a broad benefit across different patient subtypes and will really be an option for all patients when they fail on their PD-1 containing regimen regardless of the line of setting they came from. So for example, if they had adjuvant failed, they could be used -- could be treated in frontline with RP1 plus nivolumab or frontline patients whether they received Opdualag, ipi/nivo or monotherapy PD-1. So really, I think, a very practical regimen that can be used broadly. And also the safety profile we see is very tolerable. So again, it's something that I think is going to be practical and broadly used in the treatment of these patients.

Now for us to sort of maximize that opportunity and treat as many patients as possible, it will be important that we could do image-guided injections. It's about 80% of patients will have sort of deeper lesions, and that's going to involve interventional radiology. We've done a lot of work with that stakeholder group, a lot of research. And I think the great news is they're excited to do this, and they really think about this as sort of reverse biopsy. So we're actually injecting something versus something they do quite routinely in terms of taking something out of a tumor, and they're very excited to do this.

Now they're also really impressed with the systemic non-injected responses we see with RP1 plus nivolumab. They predominantly work on local treatments, so they don't see that and they find that quite compelling. So this is something that we've also gotten quite excited about. Now many of these interventional radiologists are, however, involved in the treatment of HCC and liver metastases, and they use procedures such as embolisms, TACE, TARE which tend to be a lot more complex than what we're asking them to do in terms of image-guided injections of RP1 plus nivolumab. So again, this is something they feel very comfortable being able to do with some basic education. And so they're also excited about taking this modality and adding it to their treatment armamentarium beyond the existing sort of local treatments they have today.

Now as we think about the patient opportunity ahead of us, it's roughly split 50% in the hospital, 50% in the community as we think about the melanoma patient population. And our initial launch focus is going to be on about 150 accounts. Now these are accounts that account for about 25% of the overall patient volume, but there are also accounts predominantly hospitals that have integrated IR within the facility. So if we're asking them to do these deep injections, it's something that they can do from a logistical perspective in a more straightforward way. We've also seen that these accounts tend to be in larger academic centers, but we've also had a lot of experience for these patients within our clinical trial.

We've seen experience in top academic sites, but we've also seen that we can then take that 150 or so sites into a broader population in the community. And actually, what we've shown through our expanded access and compassionate use program is that those requests have not just been coming from the hospital and academic sites, they've also been coming from some of the community sites. So now we have experience with, for example, Kaiser on our EAP program and some large oncology community sites such as Minnesota Oncology, Baptist and Memorial in Florida. So again, the idea that we can initially start in a targeted approach with these integrated predominantly hospital academic sites, but broaden this out to something the community can use and actually treat the patients where they are.

We have also got commercial supply for RP1 ready today, and we have an end-to-end manufacturing facility in Framingham, Massachusetts, where we produce drug product, drug substance, we do the fill-finish. We do the packaging and labeling and actually are ready to then send the product to our 3PL so that we can enable next-day delivery for patients.

So now if we think about beyond melanoma, we've actually also generated quite a lot of data in other skin cancers beyond PD-1 failed melanoma, got a nice body of evidence. We also have monotherapy RP1 activity in these patients and actually have an opportunity to treat these patients in a very unique way actually. So in terms of monotherapy, we often see that these immunocompromised patients really aren't able to receive checkpoint inhibition for various reasons. Shortly, I'll share some data with you that we have on solid organ transplant patients who unfortunately often develop non-melanoma skin cancers. I'll also share some data with you in early disease because this is an obvious area where we want to take the modality to see if we can cure patients. We've got some data in low-risk patients in CSCC, but an interesting area that we can pursue in the future is looking at high-risk patients for sort of cancer prevention approaches.

So just now moving into some of the data from our experience. This is looking at RP1 monotherapy in locally advanced CSCC patients who have received solid organ transplant. Now today, the management of these patients is quite challenging. Physicians will use checkpoint inhibition in these patients, but predominantly for renal transplant patients because if they do see organ rejection, they have the fallback of dialysis. There really isn't great options for other types of organ transplant liver, heart, lung. And one of the objectives of the ARTACUS study is to broaden out the types of organ transplant failure patients we have. So what we see with the RP1 monotherapy is we see about a 34% response rate and a nice disease control rate in these patients and that response is very durable.

But we've also seen that we don't see any allograft rejection, whether it's renal, heart, lung or liver. So this is an option now that can broaden kind of the options for these patients who are desperately in need and really don't have other great options. So that's something we're very -- certainly very excited about. One of the things that's important for these patients is that you also want to make sure you don't sort of modify their steroid kind of regimens, or immunosuppressive regimens, and that was one another benefit that we saw in this study that we did not need to do that. But the other thing we saw is that the monotherapy was very well tolerated and actually seeing a similar kind of side effect profile than we see in non-immunocompromised outside the fact that we don't see any of these organ rejections.

Now this is another setting that's very interesting as we think about future potential for RP1 as monotherapy. This is looking at low-risk resectable CSCC patients. Now these patients are predominantly managed by dermatologists today. They are patients who get a lot of lesions. They had a lot of mos surgeries. They just keep getting cut as new lesions pop up. Now what happens is they often reach a point of sort of surgical fatigue or there may be areas where lesions pop up in regions that are just very hard to actually do further surgery. So this data is from an investigator-sponsored study we did and the investigator enrolled 10 patients. What we saw was a 100% response rate and 83% complete response rate or [ PAT ] CR rate.

Again, this means that these patients could then not have to go through surgery. This is actually something that's a great option for these patients. And one of the nice things that we know with dermatology is they're very used to injecting things. And because you don't have to use this in combination with checkpoints, this is also a benefit for that stakeholder group because they don't typically infuse or have infusion capability in their practices.

So now as we think about expanding RP1 beyond skin cancers, it's going to be important, as I mentioned, to be able to do these deep injections. As I mentioned, we've done more than 1,000 of these. One of those deep lesions that's very common or a couple of these lesions are common at sites of the liver and lung metastases. And unfortunately, these patients have a very poor prognostic outcome. And what we've shown is that we're able to do that. We've actually done more than 800 lung and liver injections now and that we see a nice benefit. In fact, we're taking that experience and we're already using it in our registrational trial in uveal melanoma because uveal patients nearly all metastasize to the liver, and we're seeing that we can do that. We're also seeing that we can inject primary tumors in HCC and BTC, and we've also got a cohort that we've initiated in that setting.

So as I mentioned, it's not only important to show the feasibility of these deep injections, but what's the outcome and benefit. So this is looking at some -- excuse me, this is looking at some data from the IGNYTE trial. And if I sort of guide you to the left-hand side, this is looking at a table where we look at the response rate for patients who only had superficial lesions, we see about a 30% response rate consistent with what I shared with you from the IGNYTE data earlier. But as I mentioned, one of the things we always want to know is if I inject both superficial and deep lesions or only deep lesion, lung and liver, how does that result in terms of outcomes? And what's encouraging is that we see at least a similar response rate and actually numerically higher for those deeper lesions, which is one of the things we've always wanted to see because these patients tend to do worse. And so it's great that we can actually numerically improve the outcomes.

Now the other important aspect here is that can you do this safely? And if you look at the safety profile of superficial versus deep lesion injections, we say they're actually quite similar. For liver, we actually see a very low rate of bleeds because we're using a very thin needle. And so that's something actually the IRs also tell us is actually very attractive. And even for lung injections, yes, we see pneumothorax at a similar rate that you would see for lung biopsies, but these are self-resolving and it doesn't actually prevent patients getting the full amount of treatment for RP1.

So not only are liver and lung metastases a big problem, they're very common across a number of different tumor types. And if I just sort of refer you to the uveal, as I mentioned, these have a lot of liver metastases. More than 70% of these patients have liver metastases. This was an obvious area for us to investigate. Now uveal is actually a very tough to treat disease. It's not like cutaneous melanoma. It tends to be immuno-oncology insensitive. So checkpoint inhibition doesn't work very well in this patient. So we made the decision to actually use RP2 because we wanted to drive more potent activation in these patients. And so this is some Phase I data that we have in uveal melanoma, where, again, we get about 1/3 of patients into response, whether you use monotherapy RP2 or RP2 in combination with nivolumab. And we also see a disease control rate of around 60%.

These patients, as I mentioned, had repeat liver injections, and we showed that we could do that safely and reproducibly with a very limited bleed rate. This data led us to actually then move forward with a registrational trial in uveal melanoma, which is called REVEAL. This is a checkpoint naive population. So while we're predominantly expecting second-line patients who have either failed tebentafusp or the IDEAYA combination in HLA negative, we actually see that we're actually getting quite a lot of frontline patients, which is actually encouraging. We have more than 50 patients already enrolled in this randomized trial, which is, I think, great news. And again, patients do need options.

We expect to have some preliminary data for about 90 patients as we think about Phase II to Phase III transition in early 2027. However, the primary endpoint of this trial is overall survival, but we have an opportunity to also look at PFS because it's a seamless Phase II/III design where you can show PFS and then get full approval on overall survival. The more time-based endpoints of PFS and formal OS will take a little bit more time in the '28, '29 period. But again, we're well on our way to taking the next asset forward in a registrational trial.

Another area, as I mentioned, moving from liver to primary injection of liver and other tumors is looking at cohorts in HCC and biliary tract carcinoma. Now the HCC cohort is used in combination with atezo-bev. And we've now recently also asked based on sort of some of the investigator feedback, they'd like to add a monotherapy cohort. So we've done that. We should have data from these 10 or so patients either at the end of this year or early next year. So that will be our first data set in primary liver. And now in Q4, we also enrolled the first few patients in the biliary tract carcinoma. So again, we're kind of sort of executing on that vision that we have, which is shown here is moving from a Wave 1 sort of focuses on skin cancers, and we've done that extensively to moving to that Wave 2 primary liver metastases -- primary liver cancer and liver metastases with the data I shared in uveal, HCC, et cetera.

And really now, the team is actually gearing up for, okay, where can we go next? So there, the idea is looking at liver, liver metastases and also some other settings that are actually tough to treat, including PD-1 failed renal cell, GI cancers and sarcoma subtypes. So that's sort of what's coming next as we think about where we can take the pipeline more broadly. So to conclude, I hope I've shown to you why we're poised to deliver on the promise of oncolytic immunotherapy pending and pending near-term approval, we're ready to launch. We're ready today, and we have commercial supply available.

We're also very much excited about expanding the benefit for RP1 through a number of trials that we have ongoing, the 7 or so trials I mentioned, moving beyond skin cancers through deep liver and lung injections to other indications outside of skin and addressing really a difficult-to-treat patient population with a high prevalence. And then in summary, we have a cash of around $270 million. That allows about a year runway for us, but that does also allow us to fully fund our commercial launch. So thank you for your attention.

Thanks, Sush. I'll ask the first couple of questions. But to the extent there are any questions in the audience, feel free to raise your hand, and I will -- I can call on you. So with the PDUFA coming here on April 10, this is a Class II resubmission. Just remind us of the time lines and cadence of meetings with the agency with a Class II resubmission.

Emily, do you want to take that one because you've been on...

Sure, I'm happy to. A Class II resubmission doesn't have a predictable cadence of interactions with the agency, but we are very happy that they've been collaborating with us with regular information request that we've been able to respond to on time or ahead of time and hope that we are working together towards our PDUFA.

Yes. And like along those lines, right, like I know you're not going to give us a ton of details here, but have the nature of your communications been addressable quickly with the known data that you have? Has there been any surprises in the nature of their requests, that type of thing?

Yes. No surprises, predominantly follow-up from the Type A meeting, as you would expect, and we've been able to respond to them in a timely manner because there was data we had on hand that we could provide at times data that was in our prior BLA that we were able to point to and clarify.

Okay. And I just want to kind of confirm that your review team kind of at the oncology division, CBER, that's not seen meaningful turnover in terms of team leads and things of that nature?

It's hard to know because as I stated, we don't have interactions and meetings where you can see everyone around the table. We do believe there are some new faces based on the follow-up questions from our prior BLA, but we know our project manager has remained the same.

Yes. Just so we know in the Type A meeting, we did have some new attendees, new people, including OCE representatives at that meeting, and we believe they're probably now also involved in the ongoing review and information requests that we're getting.

Questions from the audience? So our understanding is that before the CRL, you guys were in label negotiations based on the questions that you've received, could the label be more similar or different relative to what your prior expectations were?

Well, just as I shared with you, we really demonstrated a broad benefit for patients across different subtypes. So we would expect the label to reflect the population we studied. And again, therefore, we would expect to have an equally broad label as we get to that point in the resubmission.

And then how is enrollment going in IGNYTE-3? And how has the regulatory process here impacted your kind of confirmatory enrollment here in the U.S.?

Okay, I'll let Kostas take that.

I can take that. So like Sush said, we have over 60 patients now in IGNYTE-3. There's continuous excitement and support by the PIs as we move forward. The study is expanding to Europe. We had our first patients coming in late last year, and we're expanding to the U.K. and Australia sometime soon. The CRL was a big surprise and disappointment to all of us to the scientific community also but we got overwhelming support by our PIs. After the CRL, you would expect to see a dip on the recruitment.

To the contrary, what we saw is that the trajectory continue at the same pace, maybe even better than that. So that shows that the scientific community is supporting and believes in that treatment. In addition to that, what we saw was an increase in the compassionate use requests, which is also another signal that the scientific community believes in this treatment, but also the fact that there is great need for additional treatments in this patient population in advanced melanoma.

Questions from the audience? Just to be clear, has the FDA provided any guidance on the specific number of patients needed in IGNYTE for an approval? Because I remember previously, there was no requirement.

No. They've been very consistent in saying the trial need to be underway. We have been providing regular updates on enrollment. And look, we're very committed to actually getting this trial done. As you saw from Kostas, it's going well. We've always provided a very robust assessment and projections to the agency. And so we have had not any further communication or questions on that front.

Any final questions from the audience? I have a couple more, but -- then I guess from a physician perception standpoint, has the physician perception changed at all for RP1 with this kind of prolonged regulatory process.

Again, I'll let maybe Chris and Kostas take that.

Yes, I'll take it. So what we hear from the physicians is that there is a great need for additional treatments in this patient population. That hasn't changed. What also happens out there is that after patients fail ipi/nivo, they have very limited options to be treated. TILs have been approved recently, but they come with some challenges in geographic access and also some tolerability access. We present the data at SITC on the biomarkers that is still more confidence in the mechanism of action and how the platform works that show that not only we recondition the tumor microenvironment, but we also resensitize the tumor to the treatment of PD-1 by increasing CD8 for the lymphocyte infiltration as well as PD-L1 expression. I think all of those things show that the sentiment that we get from the medical affairs side, I should say, is that there is a lot of support. There's a lot of interest. And sometimes there is a lot of anxiety from the PIs and the KOLs, when this system is going to become available for their patients.

We've also seen a big increase in compassionate use requests. So again, I think just indicating that patients that need access and physicians really want to give their patients access.

We've got a question in the portal, which is, can you ask management, if any change -- if there's going to be any change in who the patient population will be with this resubmission versus the first time around?

So during the Type A, we obviously discussed the different patient populations. The FDA did not indicate that there will be a narrowing or they want to see a subgroup. Obviously, we'll have to have those conversations so we continue the review. But at this point, as I mentioned, the study population was broad, and we saw consistent benefit across subgroups. So we should -- I would expect the label to reflect that.

Okay. Last chance. Any questions from the audience? All right. Thank you, Sush and team.

Thank you.

Thank you so much.

Good morning, everyone. I'm Sushil Patel, CEO of Replimune, and welcome to our Investor Event today.

Firstly, I'd just like to refer you to our forward-looking statements. We've got a packed agenda today, and the first part of our event will focus near term on RP1 plus nivolumab in anti-PD1-failed melanoma. And if FDA approved, how this treatment regimen fits into the treatment landscape and what will be required for RP1 adoption through a moderated panel with top experts in the field.

The next part of the event, we'll discuss additional data with RP1 in skin cancer. We'll have one of our experts and study investigators share their experiences in several disease settings, including in the earlier-stage setting. This will include new data in the neoadjuvant CSCC setting. Finally, we'll discuss where the extensive RP1 data generated and the science is leading us and the potential of the RPx platform to unlock novel ways and approaches to treat cancer across many more cancers and patients in the future.

So today I'm joined by several of the management team. I'd like to start with Chris Sarchi, our Chief Commercial Officer; Emily Hill, our CFO; Kostas Xynos, our Chief Medical Officer; and Nina Aragam, our SVP of Portfolio Strategy. We also have an esteemed group of experts with us covering various treatment disciplines, including oncology, interventional radiology, pharmacy and dermatology and these individuals really practice across various health care settings covering leading academic centers, community hospitals and private practice.

We will formally introduce each of our KOLs as the day unfolds. We're excited that RP1 plus nivolumab has been granted breakthrough designation by the FDA, which highlights the benefit of the regimen, provides over existing treatments and really shows there remains a significant unmet need for patients where new and more effective options are very much needed.

We are well positioned to deliver on the potential of oncolytic immunotherapy, starting with RP1 in anti-PD1-failed melanoma, including from a regulatory, CMC and clinical perspective, with multiple data sets, which we believe are compelling and we will discuss today. If FDA approved, there is a significant RP1 opportunity with approximately 10,000 addressable anti-PD1-failed melanoma patients in the U.S.

Our commercial team is in place, and Chris will talk you through the launch preparation and our targeted approach to gain adoption over time, which includes having approximately 150 sites injection-ready on day 1. Now Replimune made an early strategic decision to produce our own products here in the U.S., and we have a deep experience in the manufacture of viral products. And this is a process that we've optimized over many years and have an attractive cost of goods and off-the-shelf product, which can be ordered and delivered to patients the next day.

Our mission was to develop the next-generation oncolytic immunotherapy that was intended to generate potent systemic activity, and this has included combining our assets in concert with anti-PD1 as opposed to monotherapy, which many of the first-generation approaches took. Now with the IGNYTE data in anti-PD1-failed melanoma, we have reached a critical point in that journey which you'll hear about shortly, where the data shows robust systemic responses in noninjected lesions, including those in the viscera.

In addition, RP1 plus nivolumab comes with an acceptable safety profile in a setting where existing options can result in significant toxicity for patients. IGNYTE data has demonstrated only injecting superficial lesions can result in systemic activity. However, if deep visceral lesions are also present, the data also suggests the benefit of injecting multiple anatomical sites.

And the hypothesis around this is perhaps [ we're affecting ] the tumor micro environment and/or different resistance mechanisms within different tumors. Seeing this activity in liver and lung metastases certainly addresses an important clinical need as we know patients with visceral disease tend to have worst outcomes. Now these deep lesion injections unlock the potential for the interventional immuno-oncology as a new treatment paradigm, which involves a collaboration of oncology and interventional radiology. This expands the potential for the RPx platform to benefit more patients across tumors.

Now it's my privilege to introduce Nikhil Khushalani, who is the Vice Chair of the Department of Cutaneous Oncology at the Moffitt Cancer Center, and he's going to provide some context on the existing treatment landscape in the advanced setting and the opportunity if RP1 is approved to provide patients additional benefit. Nikhil.

Thank you, Sushil, for that kind introduction. Good morning, everyone. Certainly a pleasure to be here. My name is Nikhil Khushalani. I'm a cutaneous medical oncologist at the Moffitt Cancer Center in Tampa, Florida. My practice is exclusively skin cancers, across the spectrum of melanoma, cutaneous squamous cell carcinoma, basal cell, Merkel cell, and you name it, too.

No discussion in melanoma in my mind can be complete without actually showing the seminal slide from the publication CheckMate 067. Many of you may already be familiar with this data, but I'll just summarize this in a few lines. This was a pivotal trial of almost 1,000 patients that were randomized to 1 of 3 arms. Recall that these were therapy-naive advanced melanoma patients. And at that time, when the trial was conceived, ipilimumab or the anti-CTLA-4 agent was considered the standard of care.

The experimental arms here were the nivolumab-containing arms, either as monotherapy shown in the green curve here, or in combination nivolumab plus ipilimumab in the red curve. And the intent of this trial was to demonstrate superiority of the nivolumab-containing arms relative to ipilimumab. The trial clearly demonstrated that this was a positive study, and these are the final results that were published earlier this year and presented over multiple years.

But this essentially looks at 10-year overall survivorship, something that we could not discern for those of us who have been doing this a long time, we rarely had any form of 10-year survivors from advanced melanoma with a few exceptions of patients who were treated with high-dose IL-2. But despite this, what you can see at 43% overall survivorship, it still tells us there's a lot of work to be done. We have a high unmet need. More than 50% of patients treated with frontline anti-PD-1-based therapy develop either primary or acquired resistance to treatment. And therefore, there is a lot of interest in second-line treatments and beyond.

This was one of the earlier forays in a multicenter study. These were patients who had previous anti-PD-1 refractory disease as their immediate prior line of therapy. And these patients received low-dose ipilimumab in combination with pembrolizumab, really trying to answer the question whether the addition or introduction of ipilimumab in this combination restored some element of efficacy. The response rate in the 70-patient multi-institutional trial was 29% with a modest progression-free survival and certainly in the overall survivorship that harbored approximately 2 years.

This was taken a little bit further with the Southwest Oncology Group, again, multi-institutional trial within a cooperative group setting that randomized patients who had previously seen anti-PD1 therapy and had progressed to receiving either ipilimumab alone asking the question, can you simply salvage these patients with one drug or did they actually require a combination of ipilimumab plus nivolumab. These were randomized 3:1 to the combination versus ipi alone and demonstrated an improvement in progression-free survival for the combination with a higher response rate of 28%, which essentially mirrored what we had seen in the previous smaller study.

Again, recall that these were patients who were treated essentially prior to the era of combination checkpoint inhibition with either anti-CTLA-4 plus anti-PD1 or anti-PD1 plus anti-LAG3, which is nivolumab plus relatlimab that we currently have. So for those patients in that latter category, Lifileucel was approved in 2024 February. Many of you are very familiar with this data. This was a trial that we, at Moffitt, were very heavily involved with. And my colleague, Dr. Amod Sarnaik from Moffitt was the lead investigator on this study. The initial report was on Cohort 2 within that trial of 66 patients. These were cryopreserved TIL. And as you can see, the response rate, approximately 1/3 of our patients had objective responses, and the median overall survivorship was approximately 17 months.

So again, favorable outcomes. This was updated at ASCO just earlier this month and 5-year survivorship of 19% and 1/3 of patients had ongoing responses at 5 years. What this tells us is that these responses in 1/3 of patients are durable. But what it also tells us is about 65% to 67% of our patients unfortunately lose their sensitivity and certainly require additional treatment as well. All of you, again, are very familiar that qualification for TIL therapy is an intensive process, requires very coordinated workflow between medical oncology, surgical oncology, the cell therapy facility and in many centers, either the transplant units or the immune cellular therapy units.

These are patients that are carefully selected, have to have adequate cardiopulmonary reserve. They have to be able to tolerate lymphodepleting therapy and high-dose Interleukin-2. So again, a niche population. But clearly, if you identify the right patient, this is a very appropriate option for them. This is also demonstrated in a European trial of TIL versus ipilimumab. So what I do here is summarize the immune therapy options for refractory disease, typically for BRAF non-mutated patients. For those who have BRAF V600 mutant disease with advanced melanoma, we can certainly use BRAF and MEK inhibitors that have excellent efficacy, but finite duration of response.

So I sort of highlight these as 3 buckets. You have patients who progress on anti-PD1 therapy, either primary or acquired resistance, you could consider anti-PD1 plus a combination, so either anti-CTLA-4 or anti-LAG3. I showed you the data with the anti-CTLA-4 combinations. If you use anti-LAG3 in that combination, the response rate is a very modest 12%.

So again, not a great robust response that you would like to see in that setting. Certainly, Lifileucel is an option for patients with anti-PD1 plus anti-CTLA-4, or anti-LAG3 again, I highlight what your potential second-line options are with the associated response rates. I think we're still a little unclear. A lot of more patients are treated now with anti-PD1, anti-LAG3 or nivo-rela combination in the frontline setting. We still haven't clearly identified what the appropriate second-line treatment for those patients is. In a small retrospective letter to the New England Journal, 11% response rate was identified within anti-CTLA-4 either as monotherapy or in combination, again, telling us essentially that there's a lot more work to be done.

So this summarizes in bullet form, the significant unmet need for patients with advanced melanoma that progress on frontline anti-PD1 therapy. There are limited treatment options. Some of these are good. They can certainly work, but they help a minority of patients. Combination therapy is reasonable. Certainly, combination of anti-PD1, anti-CTLA-4, such as nivo plus ipilimumab has higher toxicity, greater than grade 3 toxicity in over 50% of our patients and 1/3 of those patients have to discontinue treatment secondary to toxicity.

Pivoting to the IGNYTE study. This was a trial that examined intralesional RP1 in combination with nivolumab with the primary endpoint being safety and efficacy and additional endpoints of overall response rate as well as survivorship on these trials. I think the key takeaway from here is the strict and stringent definition of what constituted anti-PD1 resistance or refractory disease. This is very commensurate with the society of immunotherapy in cancer guidelines. Patients had to be on an anti-PD1 for at least 8 weeks and had to have confirmed progression while on treatment.

I think it's also important to recognize that patients who were receiving anti-PD1 in the adjuvant setting, which is actually quite a substantial number of our patients who receive this had to be receiving treatment and progressed to be eligible for this trial. Again, that constitutes a fair number of patients that we clinically treat in the real world population. And this slide highlights the response data across these various subgroups that I would argue is actually truly a real-world population.

What I showed you earlier was some single agent PD1 progressors, but realistically, at least in the United States, a good number of our patients get combination immunotherapy in the frontline setting. So we saw impressive overall response rates of approximately 34%. But importantly, in 2 categories, the anti-PD1 anti-CTLA-4 failed patients, a very good response rate of 28% and those patients who had primary resistance to anti-PD1, again, similar efficacy and those patients who had received adjuvant anti-PD1 therapy. Again, a very good efficacy as measured by response rate.

So this was not a particular subgroup of patients or a selected subgroup of patients that responded. These were responses that were seen with this combination across the board. These responses tend to be durable. The median duration of response to this combination in this cohort of 140 patients was 33 months. And the overall survivorship, I would argue, as a clinical oncologist is actually quite impressive at 54%, 3-year overall survivorship certainly needs additional confirmation in larger studies, which is the current trial that is ongoing.

What's important in this is to demonstrate that responses were seen in visceral lesions as well as deep injected as well as non-injected lesions. What you see on the right-hand side, the blue bars represent the tumors or the lesions in each patient that were injected, whereas the red bars represent the ones that were not injected. So there's clearly a response even seen in the non-injected lesions. What you have on the left-hand side is a numerical representation of deep visceral lesions that were not injected. And those responses were seen in over 70% of patients and close to 100% some degree of response.

It may not have met criteria of objective response, but almost some degree of tumor volume reduction in the uninjected lesions. This, to me, as again, a clinical oncologist implies 1 of 2 things. Number one, this could be an abscopal effect from the drug that's injected. In other words, eliciting a systemic response distant from the injection. But more likely in this setting, it is likely a representation of restoration of sensitivity to anti-PD1 therapy. Again, for us, I would argue, is one of the holy grails where we really would like to try to have reversal of T cell exhaustion for our patients.

This spider plot on the left and right side, respectively, highlights the injected and non-injected lesions in terms of kinetics of response and response over time. You can clearly see for responders. This improves. But even in the tumors that are uninjected, you could see a very similar kinetic of response, again, suggesting distant efficacy as well in combination with nivolumab.

At the same time, I would bring your attention to non-responders that means patients perceived not to truly benefit. These are patients with best overall response of either progressive disease or stable disease. They had a similar kinetic of response, again, in both the injected as well as the uninjected regions, even though their overall response may have been either stable disease or progressive disease. So this phenomenon is not uniquely restricted only to those with an objective response, it can actually be seen even in patients with disease progression.

There was a numerically higher response rate with the deep visceral injections versus the superficial injections, though I would admit that these numbers are small. The superficial obviously constituted from a practical and workflow perspective a higher percentage of patients, but those where deep lesions were injected demonstrating feasibility of these deep injections.

And as Dr. Sheth from Interventional Radiology will show you shortly, that this is very doable and certainly very feasible. There was numerically a higher response rate that was seen when the deeper lesions were injected relative to only injection of the superficial lesions. Importantly, this combination has a very favorable safety profile. Most of the toxicity is grade 1 or grade 2 at worst, essentially fatigue, fever and chills for these patients that tends to last for the first 24 to maybe 36 hours and resolves. Really no additional intervention is required.

There were 5 instances of grade 3 toxicities, almost all likely related to nivolumab, and there were no Grade 5 events. So there is essentially no increase in cumulative dose-limiting toxicity with this combination. I think, again, as clinical investigators, we like to try and understand what truly occurs not only in the peripheral blood, but also in the tumor microenvironment. And these were correlated biopsies from tumor tissue taken at baseline and again at Day 43, both from responders as well as nonresponders. This is a heat map, as you can see. Essentially, the blue lines represent a low gamma interferon signature and the red lines and eventually becoming red boxes represents a high gamma interferon signature. And from a clinical standpoint, a high gamma interferon signature typically portends a better response to anti-PD1 therapy or immune checkpoint inhibitor therapy.

And you can clearly see between the responders in sort of the second and then the far right, there is a significant increase by Day 43 in terms of the gamma interferon signature. And similarly, you can actually see an increase in that gamma interferon signature even in nonresponders, but certainly not to the same degree or extent that you see within responders. So this suggests that within the tumor microenvironment, a more inflamed signature can be obtained and potentially RP1 contributing to that efficacy.

Similarly, this is in blood, looking at T cell clonality. These are T cell receptor sequencing done from peripheral blood mononuclear cells, and this is specifically highlighting 3 patients, which is that the combination can increase T cell clonality, both in terms of number as well as generation of new clones, which is clearly highlighted on the far right, the blue dots or blue squares that you see represent T cell clones and the ones closer to the Y-axis represent clones that are new. So this suggests that a greater repertoire of T cell clonality occurs, potentially due to greater expression of neoantigens from the RP1 in combination with nivolumab.

So in summary, what I hope that I have been able to show you over this -- the last few minutes, is that this combination of intralesional RP1 plus intravenous nivolumab in patients who are refractory to anti-PD1 therapy offers an impressive response rate of approximately 33% with an impressive duration of response. This response was consistent across a real-world population. These are patients who are truly refractory to frontline therapy.

Importantly, the combination was tolerated very well, without any significant additive or synergistic toxicity. There's feasibility of both superficial as well as deep visceral or deep-seated lesion injection. And certainly, there is both pharmacodynamic evidence of response, both within the peripheral blood as well as the tumor level, suggesting an inflamed microenvironment.

So with that, I will hand this over to my interventional radiology colleague from MD Anderson, Dr. Rahul Sheth, who is an associate professor at that esteemed institution. He has a lot of experience with intralesional therapy. Rahul?

Thank you for your attention. Good morning, everyone. My name is Rahul Sheth. I'm an interventional radiologist from MD Anderson. If the interventional radiology is not speciality [indiscernible] placement of needles and catheters throughout the body. So in that way, you can think of us as the FedEx of medicine. We'll get your drug wherever it needs to go. So like Dr. Khushalani said, I'm going to focus on the visceral delivery of RP1.

He kind of gave a good explanation for the why behind it, which is that we see better overall responses when you combine the superficial with the deep injections. And so what I'd like to cover is the how. So how do we do these procedures? Also, what is the patient's experience like for these procedures? And then we'll finish on kind of a peak behind the curtain of the coordination of care that goes into these procedures. So I'd like to start with this chart, which Dr. Khushalani showed earlier, but I think it's worth spending a little bit more time on because the data, to be honest, are nothing short of remarkable.

What we see here is each cluster of bars refers to a single patient and then the blue lines refer to the lesion that was injected showing the best response. And then the red bars are other lesions, these nontarget lesions that were not injected and again showing their best overall response. So what's impressive here is how much red you see in this [ plot ] below 0. Patients had responses, not just in the injected lesions, but in multiple lesions that were not injected.

In fact, and you see Patient Example 2, some patients had better responses in the nontarget lesions compared to the ones that were injected. So this really underlines an activation -- or reactivation of an adaptive immune response against the tumor. So from my perspective, having done thousands of these injections of intratumoral immunotherapies into visceral lesions across dozens of trials at MD Anderson, this is frankly something we haven't seen before. And that is why it's extremely exciting for us to have an agent that really has this profound effect on visceral lesions.

And so just to highlight a little bit about the anatomy here. So these are depictions of the visceral sites that were non-injected that showed responses. And if you look at the big picture here, virtually every lesion in this chart showed some degree of response. So the lesions that had any sort of reduction were about 96%. And then when you look at the ones that had a complete response overall, it was about 36%. So a 36% complete response rate in lesions throughout the body that weren't even injected with this agent, I think, is very impressive. And again, something we just hadn't seen before, which really underlines our excitement for this.

Of course, when you're talking about doing visceral injections a very common and important question to answer is the safety of this. Is it safe to put a needle in through the skin into a patient's lung or liver and inject RP1 into these areas? And so when you look at this chart, it divides the patients into essentially 3 buckets. One is the patients who only the superficial lesions injected. One is a combination of both the deep and superficial and then the 22 patients who've had only visceral lesions injected. And the bottom line is the toxicity is very comparable across all 3 buckets and very manageable. So no patient really had side effects related to the placement of a needle. And this is consistent with what we've seen across our trials at MD Anderson, which is that the actual intervention for delivery of these intratumoral immunotherapies is extraordinarily safe.

There are toxicities related to the actual immunotherapy, as you'd expect and so you get these IR AEs that are all low-grade and manageable. But the actual intervention itself is not something that should dissuade an oncologist from referring a patient or certainly a patient from getting this procedure. From a perspective relative to biopsies, these are all very, very low-risk procedures. And then Dr. Khushalani, like I said, talked about the why, but I think seeing it in graphical form is really quite impressive.

So this is an example of a patient who got about a 3-cm lesion in segment 7 of the liver, circled in blue. You can see a baseline. It's a sizable lesion. The patient began to receive RP1 injections into this lesion. And over the course of 2 years, you can see that spot essentially completely involute. And so this is a terrific response. When we think about the local therapies that we could offer in interventional radiology to this lesion, there's really nothing that is on our shelf today that can do something like this.

When you look across the board for patients who had liver injections, the overall response rate was 25%. The clinical benefit rate was about 50%. And importantly, nobody had a bleed and nobody had elevation of the liver enzymes to suggest any sort of degree of hepatic toxicity. And then diving into lung. So lung is probably the organ where people have maybe the greatest degree of concern about because of the risk for pneumothorax.

The clinical benefit again is, I think, quite impressive. So here's a patient who had right-sided lung lesion that was injected, circled in blue on the top row. You can see by 20 months, it's gone, completely gone. But more importantly, all those spots in red were non-injected lesions. And you can see, again, over the same time course, those lesions also completely regressed. So again, underlining this systemic immune response is being reactivated by the delivery of RP1.

The objective response rate here was actually even more impressive, 57% with a 71% CBR for lung injections. And then when you look at the toxicity here, the most common side effects you would have with any lung intervention is going to be pneumothorax, which in this case was about 6% -- 5.8%. To put it in perspective for biopsies, we do about 10,000 lung biopsies a year at MD Anderson, so we're very familiar with what the toxicity for this is. And 6% is far lower than our expected toxicity rate for pneumothorax for lung biopsy.

So lung biopsies are the bread and butter for interventional radiology. This is what we do all day every day, now we're talking about a procedure such as RP1 delivery, which is even safer than kind of our lowest tier complexity procedure. So just again to bring home the point that this is a safe procedure.

So let's talk about what this is like for a patient. So I'll just walk you through kind of the 3 most common scenarios that we use image guidance for. So the first is going to be a superficial lesion. In this case, we're showing a metastatic lymph node. This is an ultrasound image of that. And you can see with the arrow pointing the needle within there. So for these procedures, these are very quick procedures. These are even things that some surgical oncologist at their own institution do within their clinics.

These patients do get sedation for this, so they'll come, they'll get IV fentanyl and Versed just to take the edge off. The procedure itself maybe takes about 10 or 15 minutes, but add on another 15 or 20 minutes just with preparatory work and the imaging that's required for this. They'll get x-rays afterwards, they'll go to a recovery area. They're watched for about 3 hours. They get x-rays a couple of times during that just to make sure no pneumothorax does pop up. If one does, often we just watch it and it resolves on its own. If it does seem to be growing, we'll place a chest tube, which is entirely managed as an outpatient. It just gets removed. They don't need to stay in the hospital. So this is entirely an outpatient procedure.

And then for liver, you can use either ultrasound or CT, really operators choice, which is the best of modality to visualize it. Again, in this case, they're getting sedation. So a combination of fentanyl and Versed. The procedures last maybe about 10 or 15 minutes. They're likewise watched for 3 hours afterwards. That's really just because we copy paste our operating procedure for biopsies. But as you can see from the safety profile, this is safer than a biopsy because the needles used are actually smaller. We're not taking chunks of tissue out, so there's less bleeding associated with this. So you can certainly imagine a future where we're watching them for a shorter period of time because of the benefits from a safety standpoint.

And to end, I'd just like to talk a bit about the coordination of care that goes behind this. I mean, certainly, there are some moving parts. We're working closely with our oncology colleagues as well as pharmacy to get the medications ready and available for the patients. And so this is our very low tech solution -- low tech, but effective, I would say. So the best time for us to be involved for the management of these patients is actually at the beginning.

So once the medical oncologist sees a patient who they think would benefit from these procedures, they reach out to us. We review the imaging together. We identify the lesions that we think would benefit from injection. And then we start a spreadsheet, which is literally an Excel file that we have on our share point. We copy paste a screen shot of the lesion. So it's there in that Excel file, which can be accessed by any of the physicians in our department. We put their information there.

And then we plan out their cycles. I mean, so from the very beginning, we know what their schedule is going to look like over their 8 cycles every 2 weeks. This is extremely helpful for us to schedule them so that we know they're on our books going out to the end of their treatment cycles. It's also very helpful for our colleagues when they're doing these procedures because I may have reviewed this imaging. I know what the plan is, but my colleague who might be doing the procedure hasn't reviewed this before. So you have an image right there in front of you, you know exactly what the plan is on the day of without really any extra effort.

So this is a very simple but effective solution for us to maintain the communication as well as coordinate the scheduling so that these patients can get treated in an effective manner. So I'd like to now hand it over to Chris Sarchi, who's the Chief Commercial Officer, who's going to talk about the plans for commercial success.

Well, good morning, and thank you again for joining us for today's Investor Day. And so now that Dr. Sheth and Dr. Khushalani have shared with you some of the clinical data that's driven some of the early excitement behind the potential for RP1, what I'd like to do is focusing on some of the research and insights we've been gathering to develop a really comprehensive understanding of the market dynamics. I'll share with you how we've applied this to our launch strategy, including how we're planning to show up on day 1, and how we've taken some of these elements and incorporated into the commercial model build-out.

And as Sush said a few minutes ago, our commercial model is in place. Our teams are fully hired, trained and launch-ready. We have about 60 customer-facing team members in place today, half of them focused on demand generation, the other half focused on pull-through to help us support a positive first experience for providers and patients. And we think this approach is meaningful given the fact that despite recent advances in the treatment of advanced melanoma, a significant unmet need still remains.

We know that there are about 13,000 patients a year here in the U.S. who progress on a PD1 containing regimen. Of those patients, we believe about 80% or 10,000 of those patients will become candidates for RP1 and nivolumab once approved, including about 2,000 patients that will be progressing in the adjuvant setting. And so based on a lot of the research we've done as well as real-world data that we've analyzed, we know that when patients tend to progress in this setting, 20% of them will progress and present with superficial lesions only, another 20% will present with superficial and deep lesions and the remaining 60% will present with deep lesions only.

Now this is important as it underscores the relevance of injection guidance and technology in the treatment process here. But importantly, it underscores the importance of the multidisciplinary treatment team and the collaboration that needs to be in place in order to maximize treatment outcomes. And we're going to spend a lot of time today talking more about this. Now beyond that, we know that patients tend to be identified evenly across hospitals and nonhospital settings.

And while the environments are slightly different, the one common thread is that for the vast majority, nearly all medical oncologists here in the U.S., the IR component is currently part of that referral process. They work together with biopsies. They have a relationship and that's currently in place today. Now as we started thinking about our build-out rather than focus solely on this sort of quantitative data, we wanted to take a qualitative look into that as well, get a deeper understanding of the insights behind the treatment process, what are the unmet needs that exist and how can we best satisfy those unmet needs with the introduction of nivolumab and RP1.

So our teams have done a lot of work with regards to research and insight gathering. We've had over 30 third-party programs and medical advisory boards, some commercial advisory boards as well. But one I want to bring to your attention that occurred just a couple of months ago in Dallas, and this was led by our medical team. They brought together over 30 practitioners. We had medical oncologists, interventional radiologists, advanced practice providers, pharmacists, surgical oncologists who spent 2 days together, and the goal of that session was to define what great looks like when it comes to establishing an operational protocol for intratumoral injections within their practices.

Now the output of this work will be available as a white paper around the time of our approval. Beyond that, there'll be a pending publication that will occur in the months to follow. Now in addition to this research, we conducted over 60 blinded market research interviews with interventional radiologists. And as you can imagine, a tremendous amount of insight was gathered during that process. But I want to highlight just a couple of those findings for you here today. First of all, as we started to look more into the treatment path that exists today and how this is going -- the workflow is going to be established, we identified a couple of unmet needs that we actually incorporated into some innovative roles that we've applied into our commercial model build-out, and I'll share some of those with you in just a couple of minutes.

Now we had hoped that the interventional radiology community would embrace the opportunity to actively take part in the treatment process. I think what surprised us was the genuine level of excitement and interest to play an active role in the treatment of melanoma with these patients by the IR community. So that was really exciting for all of us and still is today. We're going to continue to focus in on that area going forward.

Finally, this opportunity allowed us to really clarify and further reinforce the understanding of the referral pattern that exists today between medical oncologists and interventional radiologists. But what we did learn was there's an additional opportunity for us to continue to strengthen those relationships, particularly when it comes to cross-functional collaboration across the multidisciplinary treatment teams. And so with that said, we took a step back and thought more about our non-branded campaign that we're planning to roll out prior to approval.

Now some companies tend to approach this from an unmet need perspective. For example, the unmet need that still remains within treatment of advanced melanoma or we could have focused in on the mechanism of action behind intratumoral therapies. Rather, we decided to double down on the importance of multidisciplinary treatment opportunities here and the result was this non-branded campaign that we've highlighted as the oncolytic frontier.

And for those of you who aren't with us here in person today may not have the slides available, what I'm showing is a depiction of 2 divers each with a different tool in hand, if they're focusing in on the same target. This is overlaid on an ultrasound background, and we believe it really underscores the importance of cross-functional collaboration that has to exist within this market to be successful.

Now the results and reaction has been very positive, generating a lot of great discussions so far. But I think some of the quotes you see here on the right best capture what our real goal of this process is. And as you hear from Dr. Su Chandra and Dr. Riad Salem out of Northwestern, advanced cancer management used to primarily be under medical oncology. Now it's truly multidisciplinary. And the novelty of this treatment isn't just a procedure, it's the process and the collaboration that ultimately benefits patients.

Now this is our true goal for this collaborative work that we're doing between medical oncologists and interventional radiologists. And we're really excited with the uptake we've seen with this campaign so far. So as we rolled this out, we finalized the commercial build-out across our organization, right? And at that time, we started thinking about how we were going to target key accounts at the time of approval.

Now it started with an understanding of the landscape. We know that it's a relatively concentrated market. We know that there are 3 states across the country, Texas, Florida and California. They tend to treat about 25% of the patient treatments in the U.S. But we needed to go deeper than that to really establish a viable target list. And so we started there, and as you can imagine, much [Technical Difficulty] came from those key geographies, but we needed to go [Technical Difficulty] List of targets that have these qualities [Technical Difficulty] the highest potential treatment sites in the country based on claims data -- historic claims data. We then identified those that had the most well integrated interventional radiology ideally within their own institution.

And the third component we overlaid here was those that had prior intratumoral experience -- injection experience, primarily the RPx platform through clinical trial involvement or through use of prior T-VEC. And so this constituted what we called our early adoption list, right?

And this will become our priority upon approval and to see how we're going to operationalize this at the time of launch, we'll spend the first 2 months really ensuring that there's a positive [Technical Difficulty] We're not taking a one-and-done approach. We want to ensure there's the health of account that's been established. And by a healthy account, what I'm referring to is an account that has fully embraced the injection process. They understand the treatment path that they want to put in place within the institution and logistics have become seamless within the group.

We're going to take a little more time to ensure those foundations are set and then we're going to build from there. Now based on the definition I shared with you around early adopters, it's easy to understand. This will be heavily weighted in the hospital side, 80-20 during those first couple of months. Once we've secured that foundation, we're going to roll in another 200 accounts taking our target list to about 350 accounts. This represents just over half of the patient treatments in the U.S.

And as you can see, as we're now shifting slightly into the community, that balance goes from 80-20 to roughly 60-40. Once again, we're going to secure our foundation over the next 6 to 9 months within this setting. And then we're going to roll in the final 850 targeted accounts to take us to a total count of about 1,200 accounts representing just over 80% of the patients here in the U.S.

Now 2 important points that I want to relate to you. First of all, the commercial build-out that we have in place today was built with capabilities in mind to allow us to evolve over time. So the structure I've shared with you today will be the same structure that evolves and takes on these additional accounts over the first year plus of our time line, accounting for over 80% of the patient treatments in the U.S.

The second point I wanted to relate and it's really an internal passion of ours as a team to make sure that we need to leave no patient behind. For the accounts that manage the remaining 20% of patients here, we're not going to be able to call on them in person, through in-person promotions. However, like I said, our commitment is to make sure no patient gets left behind.

So we've hired a small group of very experienced inside salespeople. They're going to be leveraging claims data for patients that begin on the PD1 treatment for advanced melanoma and target those accounts with outbound calls. Once they've identified an account that has a patient who is a potential candidate for RP1, they'll connect them with the appropriate resources internally, ultimately to help ensure that they evolve into the treatment flow with RP1. Again, another commitment to make sure that no patient gets left behind.

And we talk about this treatment flow, it really begins once the patient has progressed on the PD1 containing regimen and the medical oncologist has made the decision to institute RP1 plus nivolumab. Once that happens, because 60% to 80% of these patients will benefit from interventional radiology, we're going to be helping to continue to coordinate a cross-functional collaboration where a treatment plan is established, including the scheduling of up to all 8 doses of RP1 really at the start.

RP1 and nivolumab will be administered every 2 weeks. And this next step is really important. Going back to the patients that progressed on a PD1 and you saw this from Dr. Khushalani's presentation earlier. Unfortunately, roughly half the patients that begin in the PD1 containing regimen early on will progress within 6 months. Now for those of us who've had family members, friends or loved ones diagnosed with cancer, you know that when a provider tells you that the treatment is no longer working, and we need to find another option, a renewed sense of urgency sets in for that patient, right?

It's a sense of urgency to help regain control of this disease. So I'm really proud of what the team done has done to help us accomplish that. We're implementing a drop-ship distribution model that will allow a next-day delivery for RP1 once the decision has been made to treat that patient with RP1/nivolumab combination. RP1 injections will be delivered on an outpatient basis and nivolumab will be continued for up to 2 years afterwards.

And this is important for a couple of reasons, and I'll come back to this in a few minutes, but particularly related to patient treatment continuity and practice economics. So we'll come back to that in a few minutes. But we anticipate there's going to be 2 key areas that we really need to focus on within this treatment algorithm. First of all, we need to ensure there's a sense of confidence in injection process. The other is that we're working to help elevate the level of coordination and communication between medical oncologists and interventional radiologists when it comes to this treatment setting.

And so in helping to do that, we've leveraged a lot of the insights we've gathered from physicians and practitioners over the last year and developed what we believe are 2 innovative roles to accomplish those goals. The first is built on a traditional role of a nurse educator. However, here, our nurses are already on board. They've gone through HIPAA certification and training, and they'll be available on the day of injection to stand side-by-side with practitioners to help ensure there's a high level of confidence in the injection process.

There are also going to be other tools and resources available to them, artificial skin flaps with tumors on the surface to help train other staff within the office if they want to do that ahead of the patient arrival. These patients will be treated for superficial lesions, primarily in the exam room -- in the patient exam room in the office. And the primary focus for these nurses will be the medical oncology team. Now you've also heard us, I think, in recent weeks, talk about our interventional radiology oncology coordinators, or our IROC. This is the team dedicated towards the interventional radiology community.

We've hired 10 of these specialists with a deep level of experience in interventional radiology. On average, they have about 18 years in this space, half of them come from the IR suite itself, having experience as either technicians or nurses. The remainder comes from a deep-seated experience in medical device sales where they spent a lot of time in the IR suites, most of their career has been spent in scrubs and they've developed really valuable relationships built on trust with this community that's going to be really, really important, with the introduction of RP1 and nivolumab.

And so one of their primary responsibilities also will be to be present upon some of those first injections to instill a greater sense of confidence in the injection process. In addition to that, they're going to play a role when it comes to helping elevate awareness around reimbursement, in particular, the procedural codes that will be in place for the interventional radiology community. Finally, they're going to play an active role in helping to coordinate the communication between medical oncologists and interventional radiologists.

And so they're going to have several different tools available. Dr. Sheth showed you one of the tools they use at MD Anderson, which actually was one of the models we looked at about a year ago. And so once the team sits down and examines the patient scans, they'll then look at these order sets that will be provided. They'll identify which lesions they want to inject. And they'll monitor that and record that in a treatment tracker, very similar to the ones that Dr. Sheth shared from MD Anderson. These tools will be available upon approval. And shortly after that will be available for digital uploading as appropriate within the institution.

So we think this is going to play an important role in helping to elevate again that level of communication and coordination across these 2 functional areas. Now earlier, I talked about establishing the health of an account and why that was so important. I want to take you through what a day in the life would look like as we start to do that. So once we receive an order, for an initial loading dose of RP1, our sales representative is alerted.

From there, the communication cascade begins, where they reach out to their medical oncologists, the team that's there, they reach out to pharmacy as well as the reimbursement and access department, ensuring everything is in order. There's nothing left still to be addressed before that patient treatment begins. What then happens and really delving deeper into the health of the account is these 2 next steps. As I've already mentioned, we'll have teams available for day of injection guidance to help to support that confidence.

But importantly, as I said earlier, this isn't a one-and-done approach for us.

On the very next day, we'll have our team back into that clinic, back into that institution, assessing how that procedure went. Did it work well? Were there gaps that were identified? Is there additional training that needs to take place? And if so, are there additional injectors we need to pull into the process to make sure they're well trained?

Once that's established, we're going to continue to go back in there and ensure that we've helped to elevate the health of the account, which again, goes back to the importance of a highly targeted launch approach for both short-term and long-term success. Now one of the things that's so unique about this launch versus every other launch I've done is that the reimbursement landscape today actually supports the treatment path that I've been describing with you today.

So what typically happens when an oncology product enters the market in the U.S. as you see a site of care shift from the community into the hospitals until a permanent J-code is established to help support further reimbursement, right, that typically takes 6 to 9 months. Now if you think about the patient descriptions that I've shared with you today, for 60% to 80% of the patients who are progressing on a PD1-containing regimen, that's the exact setting we want them to shift into because that's where the IRs are.

So the reimbursement model shifts those patients to the hospitals where the IRs are already present. Once they're there, procedural codes are in place today that are very meaningful for the IR community. In addition to that, because RP1 is administered in an outpatient basis, the vast majority of these accounts are going to benefit from 340B outpatient pricing, which is again economically meaningful for the institutions.

I want to go back for a second and talk about the story I shared a minute ago for all of us in the room and all of us online, who've had family members, friends or loved ones who've been diagnosed with cancer. We know that, that relationship between providers and patients becomes personal, right? The vast majority of patients don't want to give up this relationship. The introduction of RP1 plus nivolumab will allow providers to maintain that patient continuity with that patient because they can immediately begin to administer nivolumab in their office.

Reimbursement already established and they continue with that for up to 2 years. So not only do they maintain the important patient relationship that's critical for both their patients and providers, but they've established a new revenue in their practice that will continue for up to 2 years with nivolumab along with any superficial injections, they choose to administer in the practice with RP1 along the way.

So we really believe that the reimbursement landscape today not only helps to minimize barriers to access, but will help support the treatment pattern that we're looking to instill with the introduction of RP1 and nivolumab. Now while this is happening, we have a team of national account directors who are out meeting with some of the largest national and regional payers across the country today. They're walking through our preapproved information exchange deck, our PIE deck, where they're talking about the level of unmet need in this segment with the market as well as some of the introductory data that was uncovered with our IGNYTE clinical trial.

The purpose of this is to help streamline the coverage policies shortly after approval to support the use of RP1. And so you'll hear more about that in the coming months. Finally, when we think about what comes next from a patient perspective, I'm really excited to share with you today that on a day of approval, we're going to be launching our patient support program called ReplimuneConnect Plus. And while this is going to have many of the core services and features that your traditional patient support programs have to help support patient access, all of our patients will also have access to what we're calling a concierge level of support.

Now this will include nurses on staff who can help answer questions patients may have regarding the treatment they're experiencing. We'll have case workers to help with coordination of scheduling and reminders of appointments, particularly important if you're having multiple providers helping with the treatment process. And something that oftentimes is overlooked that I'm really pleased we've incorporated into our patient support program here is caregiver support.

We know the important role caregivers play in the treatment of these patients and caregivers will have the ability to take part in this program as well, including emotional support that will be offered through our case workers as needed. And so what we've shared with you today are a lot of the different elements of the strategy we have in place and the reason why we believe a highly targeted early adoption to RP1 and nivolumab, not only it's going to help with our franchise success, but will help deliver the promise to providers as well as patients for long-term growth and opportunities.

And so you've heard me talk a lot today about RP1 and nivolumab. And I'm excited to close out by sharing with you for the first time in a public forum that once approved, will be transitioning from RP1 to our branded name of TUDRIQEV. And for us, when we think about this brand name internally, this embodies a tumor-directed, intelligently enhanced virus that upon approval, promises to offer a new option and a new sense of hope for patients with advanced melanoma who progressed on a PD1-containing regimen. So with that, I really thank you for your time today. I hope this was helpful. I'm going to turn it over to Emily Hill, our Chief Financial Officer.

Okay. I'd like to invite our KOLs up for a panel. I volunteered to do this because I have the pleasure as the head of IR leading -- interacting with a lot of you in the audience and on the webcast and hearing a lot of your questions about how a potential launch of RP1 would go, what its place would be in the clinical landscape and how coordination would transpire between the oncologists and the interventional radiologists.

So we have an array of expertise joining us today. I'll be facilitating some of the questions. And then we also have team members with microphones in the audience to take your questions as well.

All right. So with me today or we'll have -- starting over on the left, we have Dr. Sheth. He is an interventional radiologist and the associate professor in the Department of Interventional Radiology at MD Anderson, and we have the Bhavesh Shah, who is a pharmacist and the Chief Pharmacy Officer in the Hematology Oncology Center at Boston Medical Center. We have Dr. Kim Margolin, medical oncologist who's the Medical Director at Borstein

Family Foundation, the Melanoma Program at Saint John's Cancer Institute. We have Dr. Nikhil Khushalani, medical oncologist and the Vice Chair in the Department of Cutaneous Oncology at Moffitt Cancer Center. And joining us shortly will be Dr. Sherrif Ibrahim, who's a dermatologist and the owner of the Rochester Dermatologic

Surgery and an associate professor at the University of Rochester.

So I will take this opportunity to start with some questions.

Maybe starting with you, Dr. Khushalani, you presented a slide on the existing landscape and some of the data around those therapies. I'd love to hear your perspective on how RP1, if approved, would fit into that landscape?

As I showed earlier, Emily, there's definitely an area where RP1 plus nivolumab can fit into this refractory setting of anti-PD1 refractory disease. The vast majority of our patients, barring any contraindications receive anti-PD1-based therapy where the monotherapy or combination therapy. To me, the data clearly shows that intralesional therapy, which we do very commonly at our site at the Moffitt Cancer Center, both in the clinic, we have a dedicated space where we can inject superficial lesions and then we work very well in collaboration with intervention radiology, where we can utilize their expertise and continuous systemic therapy as well. So that way, the deeper injections can be injected. I think utilizing this in that setting of anti-PD1 refractory disease is very appropriate. And the advantage is that we can inject both superficial as well as deep lesions because we have the expertise to do that.

And Moffitt is a large hospital, obviously. Can you talk a little bit about who does those superficial injections and what your experience has been and what you expect it to be like coordinating with interventional radiologists?

So at our site, for example, if this is a standard of care therapy, it typically will be done in our clinic. Within the Cutaneous Clinic, we have a procedure room. We would do it there. We have already trained several of our surgical oncology advanced practice professionals, so nurse practitioners as well as physician assistants have already been trained with intralesional injections. On protocol, we have a dedicated advanced practice professional, a nurse practitioner who administers the superficial injections. So again, all of that is in clinic in the outpatient setting. Our surgical oncologists led by Dr. Zager and team are also very intimately involved. So this truly becomes a multidisciplinary discussion in terms of which lesions to inject, how much to inject and all of that is determined a priority upfront.

For those tumors that require deeper injections, we collaborate very well with interventional radiology at our center because we have sort of the mother ship, and we also have additional satellites. A lot of the deeper injections have to be done at the mother ship, whereas the more superficial -- should I say, the more superficial deep lesions, for example, image-guided nodal injections can be done at the center or the site that I'm at. But essentially, it's a coordinated effort between MD, APP and IR.

Dr. Margolin, if you don't mind, I'd like to switch to you. It's obviously a different hospital setting, a smaller community hospital. And if you could talk about your experience with injections of therapies and who else on your practice, you would rely on for injections?

In my hospital, I think that I would echo what Nikhil has told you with the exception that we don't have as many different sites, and we don't have mid-level -- so-called mid-levels, advanced practice providers who are likely going to learn. I know that when we were doing plenty of T-VEC and when I had an APP with me before she was moved to another site, she had been doing superficial injections just as Nikhil described. We have a very good relationship with our IR individuals, and they're just making a mental note when I get back to go over some of those elegant slides that Dr. Sheth showed in order to get them ready for the launch little bit later in the summer.

So I think things will work similarly. It will probably just need to start at an earlier step in the operational pathway than what you just heard from Nikhil.

Okay. Thanks. Dr. Sheth, I'd like to hear an interventional radiologist's perspective, and you've had a lot of experience, particularly with RP1. You talked a bit about the comparison to lung biopsies. Can you talk in general about the patient's experience, the logistics of the procedure. And how these injections work. How do you prioritize a lesion?

Yes. Thanks, Emily. So I'll start with the end of your question first because I think that's from an operational standpoint, kind of where all of this begins. So the conversation really begins when an oncologist identifies a patient who would be a good candidate for this. And that's where the dialogue, I think, really kicks off because we review the imaging. We're looking for lesions that we think are safe to inject, which really is a very low bar. There's very few lesions that we see on scans that we feel like we can't get a needle into safely.

So then we're starting to think about lesions that we think would have the most clinical benefit. So that's a priority. So whether it's a lesion that we think if it grew, it starts to impinge on some structure that might cause some clinical harm, then that's a reason to select that lesion. Certainly, lesions that look like they'd be the most responsive to it based on their vascularity and viability or other priorities and also based on the biology.

So as we saw injecting these visceral lesions across multiple anatomic sites might stimulate a more sort of profound and promiscuous immune response that would attack multiple epitopes. And so sort of distributing the injectate across multiple sites is another sort of philosophy that we apply here.

So once we've decided that, then like I showed you in my very bread-and-butter Excel chart, we sort of map out the patient's plan for the next 8 cycles. And so that way, we can get them on our schedule. There's no last minute sort of scrambling to find a spot for them because they're due for their injection, et cetera, and we can really chart everything out ahead of time.

Once we do that, then it's really just sort of just following the dotted line because the patient's experience is more straightforward, to be honest, than our biopsies, which I said we do all day, every day. These are smaller needles. There's no cutting needle involved. It's just a high-gauge needle that delivers the drug. And so the anticipated toxicity as we've seen from our experience is much lower than we would expect with the biopsy. And so in that regard, it's a much more straightforward experience for them.

And then from a workload standpoint, I would add, similar to what they've done in the Melanoma Clinic, we've also trained our APPs to do these injections. And so it's not just the physicians who are doing this. So as we have scaled this up, our [ RPAs ] and NPEs are doing these with CT and ultrasound guidance, which really kind of unburdens the faculty by quite a bit.

Okay. Thanks. Dr. Ibrahim, you've also had extensive experience with RP1. I know you'll talk later a little bit about your experience in some of the data, including ARTACUS as a monotherapy. But I'd love to hear a dermatologist perspective, on the injections, on the injection techniques and particularly with the ARTACUS patients on the repeat injection experience of your patients.

So my exposure to skin cancer patients is very different than everyone else on the panel. If you think about it probably less than 5% of skin cancer patients make it to these guys and 95% plus are treated really under dermatology and maybe related specialties as well. So my experience with injection of RP1 has been exclusively as monotherapy done within the dermatology office. I have a private practice. So we are very accustomed to using this both in the ARTACUS setting and then in a smaller investigator-initiated trial that I'll speak on in depth after this panel.

We find it easy to incorporate in our workflow. As dermatologists, we are used to injections and other procedures, perhaps more than any other specialty. And so I think with a drug like T-VEC, there was a sort of mystique or aura around it that we never had access to that. And there were so many patients, particularly, again, as monotherapy that we felt would benefit from a drug as such. And RP1 is really going to, I think, sort of shatter those boundaries.

And again, we've incorporated it very easily within the flow of our day, both in the ARTACUS trial in immune-compromised solid organ transplant patients and as well in sporadic small squamous cell carcinomas, which I'll speak on more shortly.

Okay. I appreciate your perspective. Lastly, Bhavesh, I would love to hear since you sort of across all of these groups, your thoughts on the logistics of RP1. Obviously, as cold chain handling, being an injection, how do you view the challenges of those logistics? Are there any limitations to those logistics? And how does they influence the practice in the hospital?

Yes, definitely, I can speak to that. So obviously, we already closely work with interventional radiology and a lot of these administrations. So for example, at HCC, we do a lot of TARE and TACE that pharmacy is actually part of that. And then, of course, if you're doing cell gene therapy and IMLYGIC, you also have an infrastructure to do this. So I think most organizations are sophisticated enough to actually handle the storage and the handling and then it's just basically coordinating with interventional radiology for the procedure. So I don't see any issues. I think this is nothing new that we're actually going to be managing.

Okay. I'll take a moment. Are there any questions from the audience?

Peter Lawson from Barclays. I guess I have to ask the question across the panel that how many patients you treat in the relapsed/refractory setting and kind of how many would potentially be candidates for RP1?

I'll take the first stab at that because a lot of these patients are identified through the medical oncology clinic in the refractory setting. Now again, it's a biased opinion because Moffitt is a large cancer center. We have a large catchment of patients that are initially treated in the frontline setting in the community and then get referred to us for consideration of clinical trials.

I would say at our center, and I'm sort of trying to think immediately off the top of my head with regards to numbers, we probably see upwards of 300 to 400 refractory patients that are referred to us on an annual basis with advanced melanoma. I would say at minimum, at least 50% of them should be candidates, if not more, for consideration of RP1 plus nivolumab.

I suspect many of them will be eligible for injections. I'll have to sort of do some additional calculations to try and identify that. The bigger group that I think may be potentials include those who are refractory to adjuvant therapy. Now recall that adjuvant therapy with anti-PD-1 monotherapy is what the current standard of care is. So those patients theoretically could get one of the combination immunotherapy regimens.

A lot of us will use ipi plus nivo as our go-to regimen, particularly if that patient is still resectable. So for example, you have patients with positive central nodes getting adjuvant anti-PD-1 that's by far our most common group of Stage III patients and they relapse in that regional nodal basin. So those patients then often will get ipi/nivo again in a quasi neoadjuvant setting to go back to surgery because they're still potentially curable with a surgical intent.

The other group that I mentioned earlier is truly the more advanced metastatic unresectable population, and we would coordinate with interventional radiology. Dr. Margolin, your thoughts?

Yes. I agree with Nikhil, and I think that one of the unresolved questions as yet will be, and I would love to sort of direct sort of part B of this to Dr. Sheth is a question of how much visceral disease is too much. Although I agree with Nikhil, many patients, and I think we saw in some of Chris' slides how people -- how and where people relapse. But there are many different ways to relapse. There's one that Nikhil just described, where you have nodal disease draining the primary site, which is a phenomenon that occurs, maybe a little bit more now that we're doing less lymph node dissections following a positive sentinel node but that doesn't mean it's the [ kiss of death ].

It just means we have to be more creative such as was described. But on the other hand, there are patients who not necessarily right after adjuvant therapy, but maybe 1 or 2 steps down the way will come back with widespread metastatic disease. And the question I have is how much visceral tumor is too much for this therapy. How many can you inject both?

We've talked about starting with injecting superficial disease, if it exists and then deciding whether the patient needs visceral injections or if a patient has nothing but visceral disease, liver mets, lung mets, in particular, at what point you say, "oh, that's too much, we cannot help that patient with this strategy. " So maybe you can answer that.

It's a good question. I guess I would answer it in kind of 2 different perspectives. One is from a safety standpoint. So is it possible to inject? I think the short answer there is yes. I mean, in general, I'd say the patients that end up on an IR's table are going to be the ones with advanced refractory disease kind of across the cancer spectrum.

So these are not patients that are new to us. This is kind of the only side of cancer that we see, to be honest. So from a safety standpoint, I think it's very doable. Well, the fact that we get 10 cc is also great because it's more volume that we can distribute across multiple sites. So that's another advantage. From an efficacy perspective, that's a harder question to answer, of course.

I mean as we all know, greater tumor burden means harder response on immunotherapy kind of across the board. So I think that's still yet to be determined if it's too much from efficacy standpoint, but certainly from a feasibility standpoint, I think even high burden disease is doable.

Li Watsek from Cantor. I've got two questions. First is, I guess, how do you decide whether you will inject lesions yourself versus referring to your IR colleagues, especially for patients with mixed lesions. I wonder if you can give us a rough estimate in terms of percentage of patients?

And the second question is in terms of number of cycles you will give. I know in a trial, you can give up to 8 cycles. How do you envision the number of subcycles you will give in the real world? Would you treat patients until progression? Or would you treat beyond progression?

I think both great questions. I'll take the first stab at it. For the first part of your question is if I have a patient now who has, say, for example, both superficial as well as deep lesions that theoretically could be injected, what would I prefer injecting? I would say from a practical and workflow standpoint, I would anticipate that those patients would be treated primarily in the clinic with injection of the superficial lesions unless I felt that the burden of disease in the visceral organs was noticeably higher.

And I think that's where the art of medicine comes in. Is it that burden of disease in the visceral organs was noticeably higher where I felt, these are patients that need IR immediately. What is reassuring to me at least in the data, and I showed, I believe, one slide on that, is that many patients whose deeper lesions were not injected had a response in those deeper lesions as well, presumably from the superficial injections. So I think the important aspect here is not only is there a local treatment effect, but there's definitely a systemic effect, whether that is due to reenergizing of response to anti-PD-1 therapy, which is what I believe the mechanism is rather than a true abscopal effect, which is hard to discern given that this is a combination trial.

So I think I would practically, for most patients start with superficial or nodal injections that we could conceivably do in the clinic. And then at the first restaging, which is usually at the 8- to 12-week mark, if I clearly see benefit in the superficial lesions but not the deeper lesions, then incorporate IR injections at that time. The good part would be at that time, if you actually see responses in the deeper lesions as well, you don't need IR's help at that point.

I'm just going to follow that with a brief remark and then I think we'll ask Dr. Sheth to express something that he told us about yesterday regarding who does what. I didn't mention earlier that in between the medical oncologist and the IR individual is often a surgical oncologist. We didn't go into that very much. But oftentimes, if it's a lesion that's just a little trickier than what the medical oncologist feels comfortable with and/or requires ultrasound that I think, at least in our center, the surgeons are more comfortable with, I'm not an ultrasonographer, that's when we turn to the surgical oncologists, and we have -- I have a multidisciplinary clinic as I'm sure is the case at many of the larger institutions, but Dr. Sheth talked to us yesterday about injecting visceral and superficial at the same time.

Yes. So I would say there's a couple of scenarios that could play out. One is if a patient has both superficial and deep lesions. And in the same cycle, it makes sense to treat both at the same time. Then in that case, actually, one thing that came out of that Dallas event that Chris mentioned was that we asked that question to IRs. Would there be hesitation amongst IRs to inject the cutaneous lesions, which don't need image guidance in the same setting as the deeper lesions when you're doing image-guided injections. And kind of universally, there was no concern about that. I mean that's clearly the right thing for the patients, not making them shuffle back and forth between different clinics on the same day to get different injections from different people. So that's, I think, from a workflow standpoint, very, very appropriate, and it was not sort of a concern amongst IRs.

And the other kind of option or possibility is if they have, again, both superficial and deep lesions. It may be that you alternate. So it may be that if you have 10 cc and they have enough volume in cycle 1 and cycle 3 and cycle 5, you inject the superficial in clinic -- in Melanoma Clinic and then on 2, 4 and 6 you inject -- you come to IR. And so you're sort of alternating back and forth. So I think there are several different ways that it can play out. But I think it was very nice of the flexibility that we have for those patients.

I think part two of your question was would we continue this indefinitely. I would certainly go by the label. And the label would likely be mirroring what's on the clinical trial, which is up to 8 doses and then a break from the intralesional therapy with continuation of the nivolumab. And if after an additional 12 weeks of nivolumab, there is demonstrable progression or the clinical investigator treating physician felt that the patient would benefit from additional intralesional therapy, I believe we would have the leeway at that time to reintroduce that drug.

Interestingly, we -- in our setting, we only do superficial injections. And within the -- particularly ARTACUS clinical trial, we now have patients that have been on drug for a year. And so they are getting treatment every other week. And none of the patients have progressed to visceral lesions. So there may be definitely a distant effect that is happening.

Roger Song from Jefferies. So two questions -- 2-part question. One is, it seems you all have the experience treating intratumoral injection with RP1 or T-VEC. And then just do we have a rough consensus understanding which lesion and how much volume to treat for each cycle. So just among the expert like you guys, and then the another question is, what's the learning curve for physicians or surgeon IR do not have the prior experience to get to the point closer to your level, say, I feel comfortable to using RP1 to treat my first patient.

So I can start with that. I'll start with your second question first actually. Because there is no learning curve. I would say every IR who comes out of training from any program has the ability to do these deliveries. Like I said, it's simpler than a biopsy and the biopsy is kind of our bread and butter. You can't graduate from an IR residency if you're not being comfortable doing a biopsy. And so likewise, you can't graduate from IR residency without the skills needed to do an injection like this. So that would certainly be something that anybody in any hospital setting or community setting should be able to do quite straightforwardly.

The volume question is an interesting question. So what's the right volume to do this. So going back to the IGNYTE trial, what was I think, honestly, very impressive is how straightforward the volume calculation was for those patients. We've done many, many intratumoral trials with a variety of complexity built into the way we calculate the volume. Some of it as it was with IGNYTE, which is a single axial measurement, you get a size of lesion and you have a very simple table that tells you the volume to inject. That's as simple as it gets.

It got a lot more complicated on other protocols where you're measuring actual volumes in 3 dimensions and percentage of this and that. What's great is that it works. So in the IGNYTE trial, it works with the simplest way to do this. And so [indiscernible]. So I think that makes it very easy for us when we're calculating these volumes for these patients when it becomes clinically available.

And going back to part 1 of your question was how would this be distinguished from the approved agent T-VEC right now. We actually use a fair bit of T-VEC at our center. We've had investigators who participated in the original registrational OPTiM trial, Jonathan Zager, and then the rest of our surgical oncologists.

And right now, on an average, we treat anywhere between 5 to 7 or 8 patients per week with T-VEC injections. But this is a niche population. These are patients with visible disease, superficial disease, almost exclusively what we refer to as in-transit unresectable disease with a small burden of nodal metastatic disease. We do not use T-VEC for patients that have distant visceral disease because as the data has shown, it does not really work in those patients at all.

But we've seen some good responses and up to 6 months of T-VEC, and we've actually published a fair bit on that as well. The differentiating feature here is the ability to continue systemic therapy and potentially elicit a distant response even in uninjected lesions as well.

Allison Bratzel at Paper Sandler. A couple of follow-ups for Dr. Sheth. First, could you just talk to what makes an uninjectable lesion uninjectable. What proportion of visceral lesions do you think can be injected? And then going back to the volume question, you mentioned it's beneficial. You can inject up to 10 mL per administration. I think that's a higher volume than T-VEC. I mean could you talk more on for your average patient with visceral lesions, what's the expected total volume per patient? How would that differ for a patient with superficial lesions only?

Yes, sure. So uninjectable lesions, I think, are going to be a rarity and that's just based on our experience for the past 10 years or so. There's very few places that we don't feel safe putting a needle into. And so I think that's going to be very, very uncommon for us. Certainly non-injected lesions would have responses, which is great, but not being able to inject a spot is, I think, going to be extremely rare. So unusual circumstances, maybe the tumor is eroding into some blood vessel or, I don't know, is very, very central in the lung and you'd have to cross a bunch of blood vessels to get there, something like that, but these are very rare scenarios.

In terms of the volume, yes, so you have 10 cc that's different than T-VEC where you have 4 cc. So from a -- usually, the visceral lesions are larger, and so it's nice to have the ability to inject the appropriate volume for the lesions and certainly, if you're trying to inject more than one to be able to spread it out across all of those lesions. For the cutaneous ones, I think I'll punt it down the line here because I think they would have a lot more experience in terms of how you dose those lesions.

Well, it's primarily, again, based on size for the superficial lesions as well as nodal metastatic disease looking at the longest dimension of that lesion. And it's not unusual for us to utilize almost the entire 10 mL for those lesions as well.

It's a total size of volume of tumor additive and distributed amongst that up to 10 mLs. We've done that routinely in dermatology as well.

Albert Agustinus from Leerink. I was just wondering about your experience for cleanup and inactivation after the administration of RP1 and your experience in patient education at home care compared to T-VEC. And I guess like my second question is that will your approach be different for patients where you see a systemic response versus none?

Yes. So for the first part in terms of the biosafety, we don't anticipate it being any different. I mean, just a sterile dressing, they have -- the company has a very nice biosafety data in terms of swab tests and things like that, about the presence of virus on the dressings. And it's extremely low. We've never had any conversions or anything like that. We don't need to do any deep cleans besides our regular sort of turnover for one patient to the next. And so the bio -- safety biohandling side of it is no more complicated than T-VEC and something that is very, very streamlined for us.

In terms of the second part of the question, I think that's probably better answered by the medical oncologists in terms of response to systemic therapy. Is that right? That was kind of your question.

I'm not sure I understood the question exactly. Would you mind repeating it?

Is there any difference to your approach, if you see patients that respond systemically versus the ones that are not?

The approach to what exactly?

To the treatment about like volumes injected and I guess, like the cycles and everything.

Well, I mean I think that when -- maybe I'll let Nikhil go on. But basing it somewhat on T-VEC and on the RP1 experience, the lesions are injected until they're gone. I think in the case of T-VEC, sometimes we would inject at the site occasionally. But if you -- given the fact that RP1 is available to inject more different types of lesions and obviously, these visceral ones, you have plenty of opportunities in many patients and many more patients available to treat a lot of different lesions, sometimes in a rotating fashion as Rahul also described. I don't know if you want to more eloquently...

I think practically, this would be a dynamic process. So let's hypothetically state that a patient presents with 3 liver lesions to start with between 3 and 5 centimeters each. So Dr. Sheth, the IR at Moffitt would theoretically have the ability to inject 1 or 2 or all 3 lesions. But every 2 weeks, when they come back in, they will get an ultrasound. And that will, in a dynamic fashion, tell us whether that lesion is responding or not.

So let's say that 3-centimeter lesion now became 1 centimeter. So then Dr. Sheth or team will need to determine, #1, is it still safe enough to inject? And if it is safe enough to inject, we certainly won't inject 5 mL, we would now inject 1 mL into that. So it would be a dynamic process. I don't anticipate for the first 2 or 3, maybe even 4 cycles of treatment that the volume would appreciably decrease or change.

We could theoretically continue with 10 mL if we have adequate amount of lesions to inject. But actually a decrease in the number of lesions is a good problem to have. It tells me the patient is responding.

Yes, those are my favorite phone calls to make. When I call the oncologist and say, hey, listen, there's nothing left for me to inject.

My name is Priyanka and I'm from JPMorgan. So across a variety of practices in the panel, just generally speaking, what portion of lesions are considered superficial in your practice versus deep lesions?

That's a great question. I think when you look at superficial lesions, we're primarily talking about in-transit disease, which would probably be maybe 20% of our practice or regional nodal metastatic disease, if you incorporate that as well, if that is unresectable disease, I would say somewhere between 20% to 30% of our practice.

Metastatic melanoma unfortunately, is primarily a systemic disease, with the vast majority of patients who go on to developing metastatic disease having disease in the lung, liver, bone and brain. Certainly, we're not injecting the brain, we're not injecting the bone and we're not injecting fluid cavities essentially ascites or malignant plural effusions, but virtually everything else that is safely injectable, I would say, 70% to 75% of our patients would have visceral lesions.

I'll make another comment about that, which is just sort of popped into my head. It's customary to sort of not take the approach to medical oncology of saving the best for last. I think, however, in the case of in-transit disease only, with minimal prior therapy, let's say, just prior adjuvant PD1 antibody, it wouldn't be such a bad idea to consider RP1 plus nivo as their next therapy, very low toxicity, very high activity, very easily administered and easily received and avoidance of some of the systemic toxicities that you get with more aggressive forms of systemic therapy. I don't know if you...

No, I would agree completely. I think the -- to me, any patient that currently, for example, in our practice is receiving T-VEC, theoretically could be a candidate for RP1 plus nivo with selected exceptions, those exceptions being if T-VEC is being used in a setting where immunotherapy theoretically is contraindicated or if a patient has prior immunotherapy and developed significant dose-limiting toxicity that precludes the continuation of immunotherapy, then certainly monotherapy with an intralesional agent would be very reasonable. But I think most of those patients would be candidates for RP1 nivo.

Except that right now, monotherapy is not going to be approved.

Correct. What I meant was those patients could get T-VEC. They could continue with T-VEC because that's what we would be using for those patients.

Conor McKay here from Evan Seigerman's team at BMO. I just had a question maybe on supply chain. I'm curious, what has your experience been with Replimune's next-day delivery and maybe some of the KOLs in the panel who work in kind of higher use settings, hospitals with significant IR capabilities. Would you consider ever carrying your own sort of hospital inventory for use? Or is the sort of next day delivery sufficient for what your needs are?

Yes, we actually -- it depends on the volume of patients that we have. If we're doing 6 to 8 patients a week, then we definitely would have inventory on hand. But if it's like 1 patient a month, then it's probably on-time delivery. But it's like depending on the volume and then the -- essentially, some organizations have the storage within their clinic. So it's much more easier to do that. Some have actually off-site, so they might have to coordinate. But the on-time works actually pretty well. When we started initially with IMLYGIC, it was on time that we're using. And then we gradually kind of like started to carry more inventory as we need more patients.

Can I ask you a question. Regarding that, what about insurance authorization? And how does that affect the next-day delivery issue?

Yes. So I mean, obviously, the authorizations obtained before the delivery is coordinated. So these are all planned pretty much a week in advance, at least we require an authorization to have at least 7 days in advance. Yes.

No, I agree. That was exactly the point I was going to make because all of our patients for any line of therapy require appropriate prior authorization. At our center, it takes anywhere from, I would say, 5 -- 3 to 5 working days to up to 2 weeks or 14 working days depending on insurance to get that authorization. So it's rarely an emergency. It's not that a patient for intralesional therapy needs to be started on treatment the very next day.

I think it's very reassuring as a practitioner for me to tell our patients that as soon as I get the authorization, I could -- our pharmacy will reach out and we'll have the product on site the next business day or within 48 hours. But again, at high-volume centers, it wouldn't surprise me if they're stored on-site itself. But again, we make a business case for that within our P&T Committee.

This is [indiscernible] from Leerink Partners. Can you talk about your experience with reimbursement with the buy-and-bill model, especially under different scenarios of potential drug pricing?

Sure. So obviously, every single organization, this payer mix is going to be Medicare and commercial. I think Medicare, I think everybody knows what the fee schedule is for Medicare. And then commercial is going to be an ASP plus whatever percentage you have negotiated with that commercial payer. So -- and then, of course, your 340B, then it's actually much better from a financial perspective from reimbursement. So yes...

Bhavesh, could you just add to that a little bit about when we're talking about practice economics, your thoughts on an initial temporary J-code, how does that work? And how does that impact any of the experiences in the hospital?

Yes, it's interesting. I think there's a myth out there that if you have unclassified code that organizations will not use the product. And I always tell manufacturers, if I don't want to add their drug to formulary that it's because of the J-code, you don't have unclassified. It's actually a joke. It gets paid. Actually, you actually get paid sometimes even more if it's unclassified because a lot of payers don't have great workflows in the background to actually set a fee schedule so we can actually have a higher reimbursement if it's unclassified.

There's a little bit of workaround that you have to have compared to a permanent J-code. But essentially, there's been plenty of oncology drugs that have been on the market with unclassified J-code. So it's not something that we can't build workflows around and get reimbursed.

What about you, Dr. Sheth? Are there challenges to the procedure codes that you use? And are there procedure codes in place that you will use with RP1?

Yes. So there are procedure codes in place that we use today for T-VEC for image-guided delivery of T-VEC. And so on Day 1 of RP1 availability, we'll have a code that we can use for that. Certainly, long term, there are efforts through our medical societies to get dedicated codes for this that are organ-specific and sort of more commensurate with the planning and the work that goes behind the scenes for this.

So there will be a long-term plan for that, but we're certainly ready to go from Day 1 for that. And I would say, philosophically, of course, this is a relevant question kind of across the management of the patient. So whether or not the IR code is a major revenue generator for the IR department, most importantly, it's something that offers a therapy for the melanoma patients. So from the medical oncology side, which are usually the ones who are driving our reimbursement committees, they see the value in this.

I think since we're talking about reimbursement, can I just throw in something else. I think the other challenge that we look at this is that you have an alternative, which is a cell therapy, right? And the issue with that is that it's inpatient requires ICU stay. And then when we budget for cell therapy, it's like 1:1. So you don't have 340B value. You actually are taking its value, you have a lot of competing priorities with other cell therapies, bispecifics, gene therapy, clinical trials. So we're basically trying to push things more outpatient, and there is definitely a higher -- better reimbursement from a financial perspective. So...

Since you brought up cell therapy, we hear from this audience sometimes that there are concerns about whether an unmet need still exists with the introduction of TILs. I'd love to hear your thoughts on your experience with TILs, the remaining unmet need if there is one and how you would prioritize a patient for potentially RP1 versus TILs?

Sure. So we are a high-volume TIL site, if you may call it that. I would say -- I would make the argument that Moffitt is in the top 5 in the country in terms of volume that -- of TIL patients, we were part of their registrational trial as well. But again, part of it is dedicated workflow where we in the cutaneous clinic identify the patient that may be considered a TIL candidate, refer the patient to our TIL expert or designate cutaneous oncologist who takes care of these patients and then eventually does all the workup for those patients and then gets them to the inpatient setting.

And along that route or along that journey, there's definitely a significant attrition rate because not all patients who are referred to us for consideration of cell therapy are eventually candidates for cell therapy for some of the reasons that I mentioned earlier. So this is tough treatment. At the same time, it is very good treatment. So we just have to identify our patients carefully. Current clinical trials and active research into TIL is trying to understand how can we fortify these TIL.

Can we make them better? Can they really be engineered from T cell engineering perspective to hone in even more specifically on tumor-associated antigens. So that certainly is going to continue to be an active area of research. To me, if a patient is a potential candidate for intralesional therapy with RP1 plus nivolumab and also a concurrent candidate with TIL, I think it would behoove me to say that it's reasonable to consider them for intralesional therapy first.

And if they did not respond or did not benefit from that treatment, then potentially take them on to TIL. Again, a lot of that, I think, comes down, Emily, to the art of medicine to really seeing these patients, having that experience to identify that. But again, we are a biased population because we see so much of TIL that is referred to us. There are many institutions out there where they won't even consider TIL for their patients because they don't have the means to do it. Kim, anything else?

Yes. Just talking about the concept of bridging because TIL cell therapies take several weeks to get ready. And of course, the patient usually needs another few weeks to get ready. So it's often recommended that patients be treated on a bridging therapy. I think it's a term that comes from lymphoma and leukemia where there are many different choices, and it's often possible to keep a patient stable or put them back into remission on a therapy that they can get in between their standard therapy and their transplant.

In this case, the transplant is the TIL therapy. I think, therefore, that a way of almost dichotomously defining patients as being TIL candidates and having access to TIL therapy versus those who don't either need it or don't have access or aren't eligible would define whether RP1 nivolumab strategy is used as a bridge where if the -- with the intent to do TIL so that the TIL harvest is done and then you do the -- this as bridging therapy.

If the patient does very well, you keep the patient on this therapy and keep the TIL cell product frozen. If the patient doesn't do well, you have the TIL as the backup versus patients who are not going to get TIL cells at all for whom the RP1 plus nivo strategy is the definitive strategy. We don't have that many other good therapies for bridging in melanoma that wouldn't have already been used by the time a patient is a candidate for TIL cells.

Okay. Do we have any follow-up questions from the audience?

I think I just might add something to this because there might be challenges with insurance to actually have coverage for both drugs for bridging, so I think that would be probably impossible to get approved maybe.

Yes, you may be right about that. But I certainly hear from many TIL, maybe, again, Nikhil can speak to that, but the concept that it's the TIL team who are recommending bridging if possible. So...

Yes. I mean at our center, it's unlikely the only time that we would consider truly bridging therapy is if we have a patient with BRAF mutant metastatic melanoma, where we know that even after intervening therapy, you can stabilize or elicit a response in about 20% to 25% of patients. But eventually, that response also dies out. So they need to get back on to immunotherapy or some form of cellular therapy.

Those are the only patients that we would consider putting them back on your choice of BRAF/MEK inhibitor combination. But I certainly would not give them chemotherapy, for example, as bridge because I personally think that actually burns the further bridge because you're going to give them lymphodepletion at a later time point as well. I think in my mind, we're sort of -- and I tell our fellows is we're treating ourselves rather than the patient where we are trying to convince ourselves that, that bridging therapy really works when it probably does not.

I think, Bhavesh, you may be right in terms of complicating the TIL payment package, which is already very complicated because if you start -- if you harvest TIL and you make them and you get them to the pre-rep frozen part, then the insurers might have a....

And then you have to pay for it.

And then you have to pay part of it. Yes.

Maybe a last question for Dr. Khushalani because you mentioned BRAF. If approved, obviously, label dependent. Are there any subgroups based on RP1 data that you wouldn't consider, including BRAF patients or adjuvant relapsed patients?

That I would not consider for intralesional.

Any subgroups you would exclude based on data?

Not really. I mean I don't think there's any group here from the real-world data that I showed that would be considered not appropriate candidates for this. I think the only -- again, this is because of the experience that we have and the volume of patients we see, there are patients who have remarkably rapid disease progression. And no matter what you do for them, their disease unfortunately keeps growing by leaps and bounds. They may not necessarily be appropriate candidates, but I would make the argument they may not be appropriate candidates for any therapy. It's hard to really say that. I don't think there's any class of patients that I would not necessarily utilize this.

Yes. I think there are some problem groups actually. There are going to be patients who had a threatening immune-related adverse event while on PD-1 blockade and for whom you really do have to decide if you risk that again in combination with the RP1. There's patients with acral melanoma who are known to be far less sensitive -- whose disease is far less sensitive to any form of immunotherapy than those with bread-and-butter cutaneous disease.

And then not to mention, of course, mucosal melanoma, where we could talk about whether you've treated any of those patients. There seems to be -- we'll be hearing about some promising data with uveal melanoma metastatic. So maybe we can make some headway with mucosal melanoma in visceral sites, which is where it usually goes and rapidly and hematogenously. So that will depend heavily on the IR folks.

Okay. You'll have another opportunity to ask these guys questions at the end of the day. So with that, I'll invite up our Chief Medical Officer, Kostas. Thank you. Thanks, guys.

Good morning, everyone. My name is Kostas Xynos. I'm the Chief Medical Officer at Replimune. Thank you very much for attending today's event. Before I start my presentation, I just would like to make a comment on what was mentioned before about patients with acral melanoma. We did have patients included in our clinical trial with acral melanoma and actually, the response rate in these patients was much higher than what we saw in the general population with cutaneous melanoma.

So I will start with an overview of our platform's pipeline, and you're familiar with the RP1 development in the skin with IGNYTE in the advanced melanoma space in combination with nivolumab. This is a study that supports our BLA. ARTACUS is a study in patients with solid organ transplants that develop skin cancer, and RP1 is used as monotherapy. And finally, IGNYTE-3, which is our confirmatory study in a population similar to what we have with IGNYTE that is recruiting now in combination with nivolumab.

RP2, which we believe is a more potent molecule in addition to GM-CSF and glycoprotein. It carries a CTLA-4 payload aiming to avoid the systemic adverse events of EP without compromising efficacy. It is our second molecule. It's the one that leads the expansion of the platform beyond skin cancers in tumors with real treatment gaps and mainly lung and liver involvement.

RP2 is assessed in a signal-finding basket trial in multiple solid tumors, including among others, sarcoma, mesothelioma as well as adrenal cancer in second-line hepatocellular carcinoma, in combination with atezo/bev and in metastatic uveal melanoma in a registration potential trial in combination with nivolumab. All trials are open and aiming to generate signals to address treatment needs in patients where treatment options are limited.

So in the next 15 minutes, I'm going to walk you through our key learnings and look at how we plan to expand our skin franchise beyond melanoma. We have to date injected safely more than 700 patients across the platform, injecting not only superficial lesions but also deep structures like lymph nodes as well as lesions in deep organs like the lung, the liver as well as the adrenal.

The IGNYTE trial that enrolled the real-world melanoma population has shown durable systemic responses across all subgroups, including patients with challenging disease and poor prognosis, such as patients who have low expression of PD-1, patients who have primary resistant disease. These are patients who [ flowed ] through their treatment within the first 6 months and also patients in the adjuvant space.

The waterfall plot on the right, which Dr. Khushalani very eloquently described before, shows that responses are not driven by the injected lesions only as both injected and non-injected lesions respond with similar kinetics depth and durability. Recently, we presented also data from our lesion analysis that shows that injecting both deep and superficial lesions results in an enhanced response. The combination of RP1 plus nivo has shown favorable safety profile with generally on-target and transient adverse events, grade 1 and 2, low incidence of 3 and 4s and no grade 5 events.

Importantly, the biomarker analysis of the IGNYTE patients have shown that treatment with RP1 not only expand the existing T cell clones, but also generates new ones while increasing PD-L1 expression, indicating an enhanced antitumor immunity. All of these learnings have led us to the IGNITE-3, which is our confirmatory study. This is a trial design for the study. This trial will provide further data on PD-1 failed melanoma setting to support our accelerated approval with IGNYTE and will serve as the basis of our global patient access.

This slide summarizes the design of the study. This is a one-to-one globally randomized trial of approximately 110 sites of RP1 plus nivolumab versus physician choice. Physician choice will include chemotherapy or includes chemotherapy, I should say, of [indiscernible] or retreatment with monotherapy in 400 melanoma patients will progress on anti-PD-1 plus CTLA-4 treatment.

The [ regional ] IGNYTE-3 focuses on the post anti-PD1 and CTLA-4 failures. It is because this is a patient population with a great unmet need as when these patients progress, treatment options for this population are very limited. The primary endpoint of the trial is overall survival. An interim analysis is planned and estimated in the second half of 2027.

The study is well underway in the United States with close to 50 sites open, and we have a plan to expand ex U.S. in the second half of this year in approximately another 50 sites in the U.K., in the. EU and in Australia. The study is expected to complete enrollment in the second half of 2028. In addition to that, I would like to highlight that we have a very active Compassionate Use Program -- Global Compassionate Use Program with more than 50 patients included, and we also have an Expanded Access Program in the U.S. with more than 10 sites open.

IGNYTE had multiple cohorts outside of advanced melanoma. These additional cohorts included patients with non-melanoma skin cancer. Non-melanoma skin cancer is the most frequently diagnosed skin cancer in Caucasians with almost 5,000 patients post PD-1 treatment. While non-melanoma skin cancer can occur anywhere in the body, it is mostly found in sun-exposed areas like the head, the face, the neck and the arms with most lesions being injectable.

Even though in frontline patients who have treatment options with systemic therapy or checkpoint inhibitors once they progress, there is no approved treatment for this patient population. Frequently physicians will resort to chemotherapy. Outside of non-melanoma skin cancer, we're also looking into soft tissue sarcomas, mainly in angiosarcoma, a population in need for additional treatment options.

We continue to generate data as part of the trial in all cohorts, and we have seen early signals in patients with BCC, MCC and angiosarcoma, meaning basal cell carcinoma, Merkel cell carcinoma and angiosarcoma, aiming to address the need for treatments in this patient population as it is reflected by the physician [ cohorts ] that you see on the right-hand side, highlighting the challenges of treatment with chemotherapy as well as the need for new drugs in this space.

So recognizing the need for new therapies, this table gives you an overview of the data we have generated today in patients with non-melanoma skin cancer treated with RP1 plus nivo that are naive or have progressed on PD-1 treatment which is the treatment of choice by many physicians in most of these indications.

In some of the cohorts, indeed, the numbers are small, but the signal is very clear. We see significant and over 12-month durable responses translating into strong signals in PD-1 naive as well as in PD-1 failed, MCC BCC and angiosarcoma ranging from 30% to 100% as well as in locally advanced PD-1 failed CSCC, cutaneous squamous cell carcinoma patients similar to what we saw with CERPASS. CERPASS was a study that did not meet the primary endpoint. However, we did subsequent analysis.

We looked at the different subpopulations, the locally advanced population -- we saw in the locally advanced population numerical increase in responses. However, most importantly, we saw a double of the CR rate in this population. So locally advanced population is a target population for us. And [ MCC ] patients that have failed PD-1 treatment are in great need for treatment options, and these are the cohorts that we pay the most attention to.

These cohorts continue to recruit patients, and our plan is to publish our data and have a discussion with the agency once the data matures on a path forward for these populations. This is a comprehensive map view of how our skin cancer franchise looks like today. indications are listed on the Y axis and disease settings on the X axis. In green, we see that the tumors that we have ongoing trials in and with blue areas that we have identified as opportunities.

In PD-1 refractory populations, we have generated data and early signals to provide a robust foundation to expand beyond cutaneous squamous cell -- beyond cutaneous melanoma into major skin cancer areas, including Merkel cell carcinoma, basal cell carcinoma and angiosarcoma as well as locally advanced cutaneous squamous cell carcinoma.

In the PD-1 naive population and the early treatment population outside of angiosarcoma and neoadjuvant CSCC, which you're going to hear a little bit more from our next speaker, I would like to highlight a little bit the ARTACUS trial. This is a very unique trial. It's a trial that addresses a real unmet need in patients that develop skin cancer after they have received an organ transplantation.

This is a population in great need of treatment because these patients, once they develop skin cancer, due to the immunosuppression that they receive in order to keep the transplanted organ, they have no other treatment options because checkpoint -- because of the effect that the checkpoint inhibitors have on the immune system. The trial is actively recruiting in the U.S. And we're very excited today to have with us Dr. Sherrif Ibrahim, who is an investigator in ARTACUS and he's going to share some very exciting data from the study as well as from an investigator initiated study that he led at his institution in patients with cutaneous squamous cell carcinoma treated with RP1 monotherapy in the new adjuvant setting.

Dr. Ibrahim.

Thank you, Kostas, and thank you, everyone, for having me speak to you today. My name is Sherrif Ibrahim. I'm a dermatologist. I practice in Upstate New York, Rochester, New York and have a practice that's really dedicated to the management and treatment of skin cancer only. We do several ongoing clinical trials for both diagnostics and therapeutics in the skin cancer space.

What I'm going to talk to you about today is a big shift in everything that we've heard predominantly with the exception of the last few slides. We've heard about melanoma. We've heard about RP1 in the setting of combination therapy with other systemic immunotherapeutics. And we've also heard about delivery of these treatments at large cancer centers. And so as dermatologists, we are really gatekeepers for all things skin cancer and related to skin cancer.

We are the first people to diagnose these and treat upwards of 95, if not more percent of these skin cancers. And so my interaction with Replimune first began as an investigator on the ARTACUS trial, which I'll get into a little bit later. But during this experience, I have approached the company, and I said, what if we use RP1 as a monotherapy for an injection for a very early-stage squamous cell carcinoma.

So again, a shift from melanoma to non-melanoma skin cancer, where we know that there is a huge unmet need. And so we were approved to do the first investigator-initiated trial through Replimune. We have completed the trial, and I'll take you through that today. So it was treatment of very resectable cutaneous squamous cell carcinomas. So these are new spontaneous UV-driven tumors, measuring anywhere from 1 to 3 centimeters. So on the complete opposite end of the spectrum as far as severity of some of the cancers we've heard about today.

I do practice in a private practice setting. I was at the University of Rochester in the academic setting for about 15 years and then about 6 years ago, made the transition largely so that we can drive more innovation and research without maybe some of the overriding administrative burden of the university. So when we look at the unmet need for non-melanoma skin cancer, there is absolute dire need.

So if you're fair skinned in America, 1 in 3 people will get either squamous cell cancer or basal cell cancer and combine the incidence of these cancers is more than every other human malignancy combined. And so largely, the treatment of these are either surgical in the form commonly of something called Mohs surgery, which we perform about 3,000 cases in our office every year alone as well as destructive things like curettage or electrodessication things of such nature.

There are no currently approved or effective injectable or intralesional therapies, sometimes people will use methotrexate or 5-fluorouracil, but these are really largely ineffective and used for various reasons when nothing else is possible.

Surgery is very invasive. And we've heard previously today that most of these cancers appear on the head and neck. 85% of them are neck and up, other higher risk areas or more complicated surgical areas such as the distal lower extremities and the hands. They really set the patients back. Even a small lesion on an eyelid or the rim of the nose or the ear is very complicated, maybe not so much for the removal, but certainly for the reconstruction of these tumors, it's very involved.

And so there are currently no FDA treatments for -- nonsurgical treatment, particularly of squamous cell carcinoma. So we also know that cutaneous squamous cell carcinoma because of the UV-mediated etiology contains a very high mutational burden of any -- really higher than any human malignancy. And as such, it is believed that this should respond well to immunomodulatory therapeutics.

We see this with systemic administration of PD-1 inhibitors for locally advanced disease. And because RP1 injection, of course, has been shown to mount a very highly active immune response, we figured that this would be a nice application for this drug. So the study objective this was a Phase Ib single-center open-label study, looking at the efficacy and safety of RP1 for the treatment of surgically resectable cutaneous squamous cell carcinomas, not as neoadjuvant therapy, but as definitive treatment of these tumors.

And so our primary objective and endpoint was looking at a pathologic complete response. So after the patients underwent a series of 6 injections, the lesions were then excised or the area of the lesions were excised for complete histologic characterization. We are following these patients for 2 years to ensure that there is a significant duration of response and no delayed the disease-related events.

Here's the study design. So the patients were screened. They all had biopsy to confirm histologically confirmed cutaneous squamous cell carcinomas. They underwent 6 injections of RP1 in the office every other week and then went on to surgical excision of the treated lesions. And again, they are being followed now for 2 years. Currently, all patients have completed surgical excision and all of them are in the follow-up period of the study.

We enrolled 12 subjects, 3 of the subjects had multiple tumors. So there were 15 tumors in total, a fairly even split between men and women. And this is the demographic that we see for all sun-related skin cancers. They typically tend to be Caucasian male in their 70s, a nice distribution of tumors, 6 on the head and neck, 7 on the extremities and 2 on the torso.

From a safety perspective, this was extremely well tolerated. Essentially, we saw no adverse events. Most patients receive 1 to 2 mL injected for each cycle of treatment. We had one grade 1 event. Patients would say it seems a little bit red around the area and this one patient said it was red and sore. There were no serious adverse events, no progression of disease, everything was tolerated very well.

I know we had questions about safety and room turnover. We are a small private practice. We are not a hospital. So these patients were seen in the flow of the day. We have a minus 80 freezer. We don't have a pharmacist. So I am the pharmacist. We take the drug out of the freezer, pull it up, just alcohol rub, inject the lesion, wipe the rim down with the CaviWipes and we're on to the next patient.

So we did extensive swabbing that was all sent to Replimune and studied extensively. There were 0 events of any kind of infection with herpes virus. Jumping to the efficacy here, we see that out of the 12 patients, 10 out of 12 of them had a complete histologic response, meaning no evidence of the tumor once the area had been excised after the 6 cycles of injection and the remaining 2 patients that had some residual disease had a significant partial response.

So in total, there were 100% of the subjects that had an overall objective response rate as determined by histologic confirmation. So again, these are not the [ wow ] tumors that we've been looking at earlier throughout the morning, but this is how 98% of skin cancer patients present. So it's our job to prevent them from progressing onward to either a locally advanced or metastatic state. These are very easily addressable.

And at the end of the day, it's about providing our patients with options. Many of these patients have multiple tumors. So there's very rare that we see a skin cancer patient, treat them surgically and never see them back again. We see them over and over and over again, once a patient has one skin cancer, it's a 50-50 chance they'll get a second. Once they have two, it's almost a 100% chance that they'll have a third.

I would also like to point out really the beautiful cosmetic outcome that we see, particularly of the one on the right there where you see the patients scalp, lower leg on the left where that patient had 2 lesions that completely resolved, but also left essentially no mark on the surface of the skin. So we are seeing this as a very viable nonsurgical alternative in a setting where no such alternative that is effective currently exists.

So in conclusion, we had a 100% overall response rate in this pilot trial. The treatments were tolerated exceptionally well, with essentially no adverse events that we had seen. No patients progressed while on treatment. And it was from a company perspective, the first successfully executed investigator-initiated trial. And now we are in talks to potentially roll this out into a larger multicenter trial.

Maybe we kind of take a question or two on that? Or do you want me to continue? Okay. Great. So my initial involvement with Replimune was in the setting as a principal investigator, one of the sites on the ARTACUS trial. We heard previously from Kostas' presentation that the solid organ transplant population is truly unique when it comes to the skin cancer.

And if you look at all deaths in transplant patients, 24% of deaths in organ transplant recipients are due to squamous cell carcinoma. So these are patients that essentially have undergone the pinnacle of medical care and receiving organ transplantations and they die from skin cancer. They get more cancers. Their cancers are more likely to metastasize and less likely to respond to treatment. So these are patients that cannot undergo systemic immunotherapy because they are iatrogenically immunosuppressed.

So if you give them immunotherapy, they will reject their organ. And in the setting of say a kidney recipient -- organ recipient, they have the option of going back on dialysis, but if it's a heart, lung, liver transplant patient that means death if they get on immunotherapy. And interestingly, if you talk to a kidney transplant patient and give them the option, they say they would rather die than go back on dialysis. So really for those patients immunotherapy is not an option.

So these are our most devastating patients because we just don't have any treatments available for them. And so the ARTACUS trial looks at [ serial ] every other week cycle of RP1. Many of our patients are now getting to the 1-year mark. And so for them, these are not only the sort of most severe cancers that have not responded to surgery, radiation and combinations of that as well as chemotherapy, but also have no other treatment options.

So initially, the trial looked to enroll just kidney and liver transplant patients. But over the course of the study, and I'm on the safety committee for the trial, we've seen 0 incidents of organ rejection or organ failure in any way. And as such, the trial was expanded to include organ recipients, such as heart and lung as well. And so these are patients now with cutaneous squamous cell carcinoma, receiving RP1 as monotherapy up to every other week for up to 52 doses.

So we can see there was no cases of RP1 related allograft rejection, and that is such an important component of the study to really report. Again, none of these patients have other treatment options. We see that the vast majority of patients were renal transplants that probably mirrors the percentage of total organ transplant patients out there. It was well tolerated in these patients. So we can see a 23% response rate there and overall response rate of 35% in these patients. And this is durable at 24 months, we see that these numbers are substantiated.

I think looking at the clinical images really is quite impactful. We can see a liver transplant patient on the left and a cardiac transplant patient on the right. It also poses or demonstrates the difficulties and challenges in managing these patients. These patients don't just have one skin cancer, you can see on the patient on the right there, essentially, sometimes their entire face can be covered in skin cancer.

And what we see is clearance of these large areas where you can see at baseline, I don't know if there's a pointer, but you can see the target lesion here, but how clear his skin looks at 30 weeks and certainly the same is for the liver transplant patient at about 1 year of treatment.

This is one of our patients from our study center who was initially enrolled for the lesion on the back of the scalp there, which was advanced squamous cell carcinoma, probably amenable to surgery, but these patients get surgical fatigue over time, meaning they have so many squamous cell carcinomas that they come to the office every x number of months, whatever frequency that they can tolerate and we basically pick the worst 1 or 2 and treat them.

This is a gentleman that said, I've had it. I don't want any additional surgery. He was in his late 80s and he had a complete response to the lesion that you can see there just within 5 cycles. Interestingly, he had, as expected, new lesions appear, and this is now on the frontal scalp here. This is not disease progression because these patients get so many tumors, this is a new primary squamous cell carcinoma. And for this patient, he was essentially reenrolled with a new tumor on the ARTACUS trial, and that responded as well.

And this is a gentleman that I got to know very well over 20 years, and it -- since passed away from other causes unrelated to his skin cancer. But for him, the RP1 injections as part of the ARTACUS trial was absolutely life-changing. And this is done in the dermatology office. This also speaks to the fact both of these studies that we no longer have to refer these patients out to surgical oncology or medical oncology for treatment.

This is a treatment that we very much see being incorporated into the outpatient dermatology clinic. As a surgical dermatologist, I also have to rely on referrals from my medical dermatology colleagues. This also puts that in the hands of essentially every dermatologist out there and again, provides these patients with treatment options that currently don't exist. So thank you.

I know this is the last section between us and lunch, but I was told that you speak too fast. My [ Greek side ] gets in front of me, so I'll try to slow down. Sorry for the delay for lunch. For the next 15 minutes, we would like to focus on the evolution of the platform outside of skin focusing on tumors that have liver and lung involvement. Metastasis to both lung and the liver generally indicate a more advanced disease with worse prognosis and the lower life expectancy.

The median life expectancy for patients with metastatic cancer is often less than 6 months. The lungs represent the predominant metastatic target organ across the diverse malignancies due to the unique microenvironmental niche, the vulnerability stems from their distinctive anatomical and physiological features, a very thin blood air barrier, which is very advantageous for respiratory exchange.

However, it creates a structural fragility that facilitates [indiscernible] tumor infiltration. The liver due to its unique dual blood supply is also susceptible to metastasis because microphages have been observed to work as [indiscernible] CD8 T cells, and they can trigger apoptosis or they can force an immune desert. It is this unique immune environments in the lung and the liver that make immunotherapy less effective in treating metastases in these organs compared to other metastatic sites.

It is, therefore, very important to see how treatments behave in patients with lung or liver metastases. We know from our data that RP1-based treatment results in durable responses with similar kinetics in injected and uninjected lesions. And here, you can see 2 examples of patients with other participated now trials. On the left, you can see a uveal melanoma patient with multiple liver metastases. And on the right, you can see a melanoma patient with multiple lung metastasis.

Both of these patients have failed ipi/nivo and they were treated with RP1 and RP2, respectively. With red, you can see the injected lesions. And with yellow, you can see the non-injected ones. And you can see when we compare the lesion size at baseline and subsequent time points, we can see a reduction in size, not only in the injected lesions, but also in the non-injected lesions.

Given the challenging environment of the lung and the liver responses such as these are very important for patient treatment and they support our expansion to target cancers with liver and lung involvement. This is a slide that explains our confidence to move to liver and lung cancer.

Biomarker analysis from our IGNYTE patients looking at interferon gamma-related gene signature, like Nikhil presented suggest that [ RP1 ] can alter the tumor microenvironment, and it can convert immunologically silent tumors into inflamed ones giving a better chance of clinical benefit with treatment with checkpoint inhibitors.

The T cell receptor sequencing of the peripheral blood also shows that RP1 plus nivo not only expands the existing CD8 T cell clones, but also generates new ones indicating an induction of enhanced systemic antitumor immunity. So similar to what we saw in the scans before, deep lesion injections provide a systemic and durable response in both injected and uninjected lesions. Interestingly, patients that receive liver and lung injections had a 40% response rate.

In addition to that data shows that when both deep and superficial lesions are injected, as you can see on the table on the right-hand side, responses increase by close to 25% from 29.6% to 42.9% as by injecting both, we're able to get an augmented local and systemic effect. This is very important as metastasis to the lung and the liver are associated with worse prognosis and that are the main drivers of mortality.

So deep injections were done without compromising safety as only minor and transient adverse events were reported and most importantly, in our trial, patients received almost all scheduled injections to the lung and liver with 8 and 6.5 injections, respectively. One cancer that frequently metastasizes to the liver is uveal melanoma, which is the most common intraocular cancer in adults affecting almost 1,000 patients per year.

The most common side of occurrence for uveal melanoma is the choroid and the initial treatment includes radiation and surgery. The majority of the patients with uveal melanoma will develop distal metastases with a poor prognosis. The median survival of uveal melanoma in patients with liver involvement is less than 5 months with a 1-year survival of 10% to 15%. Once the tumor metastasizes, the patients have limited approved options. Tebentafusp was approved in 2022, but it is restricted to patients that carry the HLA allele. These are the HLA positive patients. The HLA allele is found in 35% of African-Americans and about 40% to 50% of Caucasians.

The other approved option for metastatic uveal melanoma is liver-directed therapies like the Hepzato Kit, which is hepatic arterial infusion melphalan. This is a very laborious and lengthy treatment. Outside of the approved treatments, checkpoint inhibitors are also used by physicians to treat metastatic uveal melanoma. As such, more than half of the patients diagnosed with metastatic uveal melanoma are not expressing HLA, the HLA haploid-type, they have very limited approved treatment options.

These patients are then candidates for local regional therapies, liver-directed therapies alone or in combination with systemic therapies as well as checkpoint inhibitors with limited benefit or they are directed into clinical trials. In our Phase Ib study, we have treated uveal melanoma patients with RP2 monotherapy as well as in combination with nivolumab independently of the HLA status. Most of the patients were injected in the liver. We had a few patients injected in lymph nodes, and there was one patient that was superficially injected.

The safety does not differ from what we are seeing across the platform with patients tolerating the treatment well with mostly grade 1 and grade 2 flu like adverse events. And as you can see from the table in this metastatic uveal melanoma patients that were heavily pretreated with a median of 3 previous lines of treatment, responses in both RP2 monotherapy and combination arms are close to 30% with a disease control rate close to 60% in the combination cohort and a strong duration of response close to a year.

When we break it down based on HLA status, in the lower part of the table, you can see that similar responses were observed independent of HLA status in both HLA positive and HLA negative population. This is a very promising data set, especially in the combination arm and that led to the design of our Phase III trial in uveal melanoma. Based on the data then from the Phase I study, we have initiated an adaptive design Phase II/III global study in patients with metastatic uveal melanoma. This is a very important trial addressing a high unmet need and has been received with great excitement by the clinician and the scientific community as it allows both HLA-positive and HLA-negative patients as well as patients in frontline to participate in the study.

The scheme of the study shows 200 patients with metastatic uveal melanoma that a checkpoint naive have received one or less than one prior line of treatment. These patients are randomized 1:1 to receive either RP2 plus nivo or ipi/nivo. The first patient entered the study about 6 months ago in December of 2024, and the trial is actively recruiting in the U.S. with more than 15 sites open, and we're expanding ex U.S. in the second half of the year going to E.U., U.K. and Australia.

The trial has a dual primary end point of progression-free survival and overall survival with a plan go -- no-go decision at the 90-patient mark, which is estimated to happen around the first half of 2027 and a PFS interim analysis planned for 2028 that can be the basis for accelerated approval. Expanding our liver-focused approach, we have also initiated the trial in hepatocellular carcinoma. Hepatocellular carcinoma is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide.

In the United States, the incidence of the disease has tripled in the past decades with a 5-year survival ranging from 3% to 30% depending on the disease stage. The prevailing treatment in the frontline is atezolizumab in combination bevacizumab with an ORR of less than 30%, and there are around 3,500 patients that fail atezo/bev every year and are usually treated with tyrosine kinase inhibitors like lenvatinib, cabozatinib or sorafenib or immunotherapy with limited success.

The single arm trial of atezo/bev in patients that have progressed on atezo/bev is the study design. This trial is actively recruiting with 11 sites with a planned expansion to South Korea and preliminary data are expected in the first half of 2026. We're also planning to add a new cohort with biliary cancer patients. Biliary tract cancer or cholangiocarcinoma is most widely known is highly lethal with a median survival of less than a year.

Chemotherapy with gemcitabine and cisplatin in combination with durvalumab is a treatment of choice in the advanced setting and when patients progress in this triple combination, they have limited treatment options, either to be challenged with chemotherapy or mFOLFOX or targeted therapy with limited success or they are directed again into clinical trials. Given the high unmet need, we are planning to expand our trial. We plan to expand our liver basket to include patients with cholangiocarcinoma in the near future with the first patient expected to enroll in the study in the second half of the year.

So now I would like to take this opportunity to introduce Nina Aragam to share more about the future opportunities of the RPx platform.

Thank you, Kostas. So as you've heard today, we're extremely excited about the potential of the RPx platform and our future possibilities. The data we've generated to date is providing the basis for future expansion into skin, liver and lung cancers.

Data in the PD1-failed melanoma setting, our lead indication is the basis for the future expansion in skin cancers, including non-melanoma skin cancers with PD1-failed patients as well as early disease settings, as Dr. Ibrahim shared earlier today. Data from IGNYTE also demonstrated RPx' dual mechanism of action, igniting a systemic immune response while also being able to direct the tumor burden in -- the high tumor burden in patients with liver and lung disease, through direct injection.

Through this, we've initiated our liver program, and it is well underway with a pivotal study in uveal melanoma in a Phase II study in anti-PD-1 failed HCC and a biliary tract cancer cohort to follow. Our activity from the IGNYTE study also showed that we have a clinical signal in lung lesions, and RPx could address the high unmet need in PD-1-failed non-small cell lung cancer and mesothelioma regardless of PDL1 expression.

In addition, we believe RPx could also address cancers with high rates of liver and lung metastases such as head and neck cancer or renal cell carcinoma. These opportunities reflect our latest thinking on our planned expansion and clinical development plan. In addition to the proposed indications, we believe the RPx profile has the potential to reach more patients as a novel approach to cancer care. Patients with a variety of cancer who are unable to receive or tolerate immune therapy may find RPx as a safe and tolerable option as demonstrated in the ARTACUS trial.

Patients who are faced with surgical resection of tumors may result in deformities or organ loss may find RPx as an option to preserve their quality of life as seen in the neoadjuvant data shared today. Patients with rare cancers who have no approved treatment options may find RPx as a treatment option as seen in our Phase I studies as well as compassionate use programs.

And finally, Replimune is committed to exploring ways to ensure more patients can be treated with intratumoral therapies, and we will continue to evaluate and explore new methods and tools. As we've shared today, we are ready. We are ready for the potential approval of TUDRIQEV in anti-PD-1-failed melanoma and we look forward to the opportunity of bringing TUDRIQEV to melanoma patients who need it most.

We continue to focus on the enrollment of the IGNYTE-3 confirmatory trial to support our potential accelerated approval as well as global patient access. In addition, we will continue with our data generation efforts across skin and liver cancers as well as expand into our lung cancer program.

We are excited to lead the way with oncolytic immunotherapy treatment and look forward to sharing updates on our progress in the coming weeks and months. And now I'll hand it to Emily to take us into the Q&A session.

Okay. We're going to try to squeeze the management team and the KOLs on to stage for a quick final Q&A before we have lunch. So just give us a minute to assemble. Okay. I guess we're going to start with Peter.

Peter Lawson from Barclays. Emily, maybe a question for you initially. Just as we think about the launch and what kind of metrics will you share on the launch beyond revenue and kind of just help with modeling and kind of thinking about the underlying metrics?

Yes. Thanks for the question, Peter. Of course, we will look to share pertinent KPIs so that you guys can track the success of the launch. As you saw today, we've started with providing some information on injection-ready sites. We'll plan to continue to update that when we get to a place of an approval announcement and then on our quarterly calls, we'll also start to provide patient numbers once we've reported revenue.

We'll hold off on providing any revenue guidance until at least 4 quarters of launch underway, but at our quarterly update calls, we will continue to update patient numbers.

Li Watsek from Cantor. Two questions from me. I wonder if you can talk a little bit about your companion strategy and the timing of publication for RP1 program in other skin cancers. And the second question is on the new adjuvancy SCC data. I found that quite compelling, although it's a small patient number.

I guess, I wonder what proportion of patients do you think would be most suitable for RP1 treatment? And then what would be the subsequent treatment for patients achieve [ PR ], for instance, would you follow up with surgery? Would you wait and see? Would you consider retreatment?

I will take the first one. As far as the publication is concerned, we have submitted to a major journal. We're expecting a response from the journal. As far as the companion listing is concerned, I think once the approval comes, hopefully, then NCCN is going to list us immediately. Are you referring to additional companion listing? We're going to publish all of our data or most of our data, as we said before, in the non-melanoma skin cancer. However, we do not have control of what NCCN is going to enlist in their listing. The data is strong enough. However, the committee will have to make a decision whether they want to put in the NCCN or not.

I would just add, we have a significant number of our ARTACUS patients. So that probably would be something we do next year.

Yes. Yes. I can answer both parts. Same with ARTACUS, I know we are actively ready for publication with that with my own trial. The paper is written, we're ready to submit that. It's hard to say how many people will -- everyone is essentially a good candidate. It's again, whether or not the patient chooses to have that treatment. Others may choose to have a one-step definitive surgery for the patients that are PRs, the hope is that they would then have a smaller surgery and then maybe avoid more complicated reconstruction such as big flaps and grafts and other things that would negatively impact their lives, their appearance, their functionality and so forth.

Again, it's just about having options. Currently, there are no intralesional options available for the treatment of non-melanoma skin cancer. So the hope that this would be first in class.

I think one of the other questions to ask is what is the intent of therapy in that particular setting? What patient population are you actually targeting? For example, we do consider neoadjuvant anti-PD-1 immunotherapy for selected patients with resectable cutaneous squamous cell carcinoma. This was based on the multicenter trial of cemiplimab, which had a high pathologic complete response rate.

That was a multicenter trial, and there's currently an ongoing [ NRG-014 ] study that is basically asking the question, preoperative versus postoperative anti-PD-1 immunotherapy for resectable, high-risk cutaneous squamous cell carcinoma. The data from [indiscernible], which was presented and published at ASCO and the New England Journal simultaneous publication clearly identifies a group of very high-risk patients with CSCC that would potentially qualify for postoperative cemiplimab as well. Where this potentially fits in, I think one could consider a clinical study combining RP1 with an anti-PD-1 agent in a patient population that clearly has resectable, but high risk for relapsed disease, and those are patients that I think would be ideally suited for neoadjuvant therapy.

Anything else from the audience?

Okay. Well, if we don't have any last questions, we'll adjourn for lunch. Please try to get us your questions either for those of you in person during lunch or in the coming week. The company plans to go into a quiet period starting next Monday, June 30, and we look forward to talking to you soon. Thank you for being here or listening online.