Molecular Partners AG - ADR Aktie

Good day, and welcome to the Molecular Partners call and webcast. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Seth Lewis, Head of Investor Relations and Strategy. Please go ahead.

Thank you and welcome to today's call. My name is Seth Lewis, Head of Investor Relations and Strategy. And this morning, we're following up on the data presented this weekend at the Theranostics World Conference in South Africa for MP0712, our DLL3 targeting radiotherapeutic. This data reflects clinical imaging and dosimetry data that was conducted as part of a named patient access program under the legal framework for compassionate care in South Africa, also referred to as Section 21 of the Medicines and Related Substances Act.

This was done under the supervision of Dr. Mike Sathekge, Professor and Head of Nuclear Medicine at University of Pretoria and Steve Biko Academic Hospital and President and CEO of Nuclear Medicine Research Infrastructure, or NuMeRI.

We will start today's call with several prepared slides and then open up for a question-and-answer session. I'm pleased to be reminded that management will be making certain forward-looking statements throughout the call.

We're joined today by Patrick Amstutz, CEO; Michael Stumpp, Executive Vice President of Projects; Philippe Legenne, Chief Medical Officer; and Prof. Ken Herrmann. Ken currently acts as Chair of the Department of Nuclear Medicine at University of Essen in Germany; Chair of EANM Oncology and Theranostics Committee and serves as section editor of the Journal of Nuclear Medicine and serves as the Chairman of the Scientific Advisory Board here at Molecular Partners.

At this time, I will turn the call over to Patrick Amstutz. Please go ahead.

Thanks, Seth, for the kind intro. And from my end, a special thanks to Ken for joining this call and giving a medical perspective on our data. I also do want to thank Mike Sathekge for his work. He's not on our slide. He cannot be with us today as he has his conference still ongoing and many commitments but I also want to thank and congratulate [indiscernible] from his team because with the work and some of the data presented today, she and her team won the poster prize in South Africa.

We decided to do this conference call as the conference is not readily and easily available for everyone. So we are using this call to make sure that our shareholders but also other interested parties can look at the data, share data and that we can discuss it after we have presented a few slides to come. I'm going to the next slide, #4.

And this is a short recap what we're talking about. We're talking about radiotherapy. And in radiotherapy, we, Molecular Partners, are working on a vector. We also engineer half-life and our partners, Orano Med, bring the isotope. It's a true collaboration, a 50-50 collaboration and we carry out research and development together. Most importantly, Orano Med is a leading company in the lead space. So we, at Molecular Partners invest on the vector side. and on the product side, while we can rely on Orano Med for everything to do with lead.

And moving on to Slide #5. As we sometimes get the questions, why are you going with radio into small cell lung cancer and DLL3 and I think that the answer is that at this point in time, yes, DLL3 is a validated target with T cell engagers and there are antibody drug conjugates. At the same time, we do see a clear need for radiotherapy given that neither T cell engagers or ADCs will cure cancer in these patients. The T cell engagers have a good profile, but they do maybe lack the broad response rate of an ADC. The come with side effects, as we know, as we also develop T cell engagers and at the same time, they have a very good response duration.

Antibody drug conjugates are at the same time, have a higher response rate. This can work well in many patients at the same moment due to the chemoresistance that the response duration is often limited. Given those two good options, we think there is the need for an additional one that works on DLL3 and I will come to the targets and the specific trick that we need to apply there and has less, let's call it, resistance and at the same time works well in this disease, given that small cell lung cancer is known to be radio sensitive. So we believe all 3 options will be used, can be used in concert and possibly even in combination.

So let's just quickly go into the next slide and explaining a specific trick we use for targeting DLL3. And one point we had to understand and we were a bit anxious in the beginning was how can we target DLL3 with this very low copy number. And as experts on the call, you will all know that the other target that is most known as PSMA is characterized by high copy numbers. So we're talking more than 100x more copies per cell. And this is what we have to tackle. And the trick was to add half-life to our targeting agent, the DARPin targeting DLL3 as via internalization and falling up and replenishment, the apparent copy number of DLL3 is much higher.

So one cycle only, so full internalization takes less than 30 minutes. So within 24 hours, we actually see almost the same number of copies of DLL3 as you would see on a PSMA high copy number cell line or tumor. So given this trick, it was possible to reach in preclinical models, very high tumor accumulation in test animals. And today, we can then also show you that this is true for humans, and that will be part of this webcast.

Here, I will take the opportunity to move to the next slide, #7. And I see here that we have the imaging part. So we do first imaging with Lead-203 that can be followed by treatment with Lead-212. The 203 imaging we have now done and we will present the patient data in South Africa.

And here, I would hand over to Michael to lead us through the data. Thanks, Michael.

Thanks, Patrick. Also welcome from my side. I'm together here with my colleague, Philippe, in South Africa, and we attended over the last 4 days, really a fantastic conference in a very nice country, great guests, great friends and of course, also meeting Mike and the whole team, so really happy to be on the call and report back.

So as Patrick said, we are in the process of summarizing the data for you all. So please feel free to ask questions. We should have time. So what we wanted to do first and this goes back almost a year is to assess how patients in South Africa under Special 21 regulation show what our drug is doing. And as you all know, the Phase I is ongoing as we speak in the U.S. So what you can see on Slide 7 is both the imaging but then also later treatment part, and we will today focus on the imaging side.

Let's move to Slide 8. This is a slide you likely have seen before. This is a patient who is characterized by metastatic small cell lung cancer, so likely the best surrogate or the best picture for patients, we will recruit also in the United States. Allow me to start quickly on the right side of the picture, you have both the colorful overlay of the SPECT and the CT as well as the gray part, which is the maximum intensity projection. What you see highlighted by the blue arrows are the 4 liver metastases and they were actually unknown at the time of diagnosis, so the patient could be upstaged and probably then treated with slightly more precision.

The primary lesion is indicated by the red arrow, that's part of the metastasis of the lung. As all other patients, we dose with 185 megabequerel of 203 Lead to be able to do the imaging. You see a time course at 4 hours, you see most of all the heart that's part of the design. You see some of the larger blood vessels that then gradually disappear over the first 24 hours. And the lesions appear more and more. Of note and I think this is what sort of was most gratifying, neither the liver nor the kidneys are lighting up strongly, especially if you focus over time, you will also see this in the next slide. And then we have more patients, they basically all give us same insight on the healthy organ side.

With this, I would move to Slide 9. What is shown in Slide 9 is now a time resolved summary of all the time points from that patient. On top in the dash line, you see the tumor lesions, blue highlight liver lesion, or metastasis. They are characterized by a higher specific uptake of activities given the percent per program. So it's like a concentration. The tumor -- the primary tumor is shown in red dash line and watch all the healthy organ. They basically all start a washout around about 24 hours and that's where the tumors then also get more and more visible in the protein, as Patrick just said before, the DARPin is accumulating probably driven by internalization and retention.

So in summary, we have continued uptake during the imaging period. We have higher uptake in the liver metastasis and we have washout from healthy organs, all nicely visible here. And that's why we are there to say it's a good profile.

Let's go to Phase I. Moving on to Slide 10. This is now just the multiple intensity projections of 2 more patients. So the patients who just looked at together is the one on the very left. Now the red arrow is again shown here. The second patient in the middle is the small cell lung cancer patient without metastasis. So the 3 arrows indicate all the primary tumor, which was not so easy to resolve because it's close to the area where the heart is. And the third one is actually a bladder cancer, metastatic urothelial cancer patient and the 2 arrows highlights the 2 metastasis that were found in the basically lower pelvic.

What you also see bottom left is then the SUVs, and this is important because it gives you a feeling of the contrast or the intensity of the lesion over the background organ typically in SPECT you go with SUVmean this is a technical reason, so you're averaging the whole area. You could also calculate an SUVmax the numbers I've given. So the numbers are very, very high, but SUVmean is in a range where we absolutely want it to be. Round about, say, 8 to 10 is probably the therapeutically relevant range.

If you look on the top right, you have both the mediastinal lesions and the metastatic lesion, even over the whole time course, every patient was imaged at multiple time points. And then the whole image analysis quantification was undertaken by our collaborators at Rapid. They're really state-of-the-art provider for doing this relatively complicated mathematics. And of course, guided also by the team in South Africa.

All the lesions go up, as we said, so they quickly go up and then they keep going up, but what is especially important they quickly go up within the first 24 hours. So we have progressive uptake, reaching probably about 80% in the first 24 hours. There is strong tumor retention. We basically don't see decline in most lesions and that's exactly what we're now going to look at again in the Phase I. We also will do imaging and then we will, of course, start the treatment.

Most likely all of the U.S. patients will be heavily treated in therefore metastatic.

Good. Moving on to Slide 11. Where are we? On the healthy organs That's, I think, the main value of dosimetry we can quantify of all the patients, the healthy organs. We picked 2 of them, the kidney and the red marrow, because those are that what we knew from anyone, the most likely potentially dose limiting organs. If you watch the 2 graphs on the left, I think what is really noteworthy, all the curves give us the same message. They go up for the first maybe 24 hours and then start to go down with a very nice close clustering.

So there is no difficulty to read this. Same for the red marrow. Of course, there are some differences, but the message is the same. They go up quickly and then they go down. When you take note of all this information and transform, they seem to absorb doses, you can arrive with the following graphs on the right. So we have given for the initial clinical Phase I dose, one time 75 megabecquerel, the absorbed dose is in gray or Lead-212 for both the kidney and the red marrow, this is well within the EBRT limits. EBRT limits were, of course, established for external beams. We probably are not correctly sort of reflecting this with alpha emitters but it's a good guidance and FDA also agreed with us that this is the appropriate starting dose.

Once you dose repeatedly, of course, these numbers will go up, but we are confident that the red marrow as we know will recover and we can continue to dose potentially also exceeding the EBRT limit. To focus on the right-most graph, this is for the highest starting dose. We are intending to give 200 megabecquerel, kidneys are still well below the 23% grade limit the wet mirror is within the range, but we are also approaching the 2 grades. So therefore, we will watch very carefully the hematological recovery.

Good, brings me to the Phase I design. This is also slide you may have seen before. So we will dose escalate in small cell lung cancer patients simply because they have a well-known and high uniform DLL3 expression so we can quickly accrue and dose escalate from 75 to 100, 150 and potentially 200 megabecquerel, all details are given before we then open the urothelial cancer patients we have indicated in green and that should lead us to a recommended Phase II dose more or less in 1 year from now, which should allow then Philippe's team to do a Phase II dose expansion.

Good. Ken, take us away, so next slide, Slide 13.

So thank you very much. So my name is Ken Herrmann based in Essen Germany. And looking at the first in human biodistribution is obviously very important, yes, very important step. This was a moment where you want to decide more or less is it worthwhile moving forward into the clinic or not. And the over the headline of my slide already takes away everything, all boxes are checked. And I will explain you why I think like that.

So first of all, human biodistribution is very favorable. We see very little background uptake. We see a little bit uptick in physiological organs like, for example, in the kidney and the liver. I'm going to discuss a bit more about it how this evolves over time. But overall, nice crisp uptake in the tumor. Don't forget these are SPECT images. These are not PET images. They're by definition a little bit more less crisp than, for example, PET images, but overall I think looks very exciting.

And second thing is the tumor uptick that we see is also visible. It's very late imaging time points, depending on the patient and on the scan shown, you can see it goes up to 120, 168 hours. So really 5 to 7 days of residual strong tumor uptick. This is really nice because this already means if we will get a significant good dose into the tumor, which is also important is when we look at the normal organs, it's actually the other way around, they seem to wash out. They seem to wash out over time, which means that when you look at the area under the curve, this separation between the dose in the normal organs and the dose in the tumor is the separation is getting bigger over time.

So this is absolutely favorable. Then Mike already quickly talked about the the normal organ doses. And I think it's very important to mention the limits energy from EBRT. We are now actually extrapolating from imaging into therapy. Nevertheless, if you take all these into account, it's absolutely safe to start with the starting dose and we have a very high likelihood that we won't see any significant toxicity even with the highest starting activity.

And then again, we, of course, have to monitor, especially when we talk about the bone marrow, it's very easy to monitor. The real response of the healthy organ because there we can very easily monitor, for example, the thrombocytes. So, in the end, I think all boxes are checked to really now go into the, I think, really exciting part to go now into therapy and perform the trial. But long story short is I think the data package, the things we have seen from the great group Mike Sathekge in South Africa is have to be encouraging to move with the therapeutic product into humans as soon as possible. Thank you.

Thanks, Ken and I appreciate that you'll stick around and join us during Q&A as well. I'll turn to the next slide now and hand back to Patrick.

Yes. Thanks, Seth, and thanks, Ken. And I do want to point out, before I come to the conclusion that this is very unique to radio and theranostic approaches, that you can get data as we just looked at before you actually go into a Phase I, before you have the big investments you know where you're starting from. And I think that is unique to this field and is one big excitement here, but also good for investors as we can before we choose to invest into a full Phase I/II we know where we are, and we can stop early, a very important thing and ability that this field allows and we can capitalize on Molecular Partners.

So maybe I'll just conclude and, call it, simple terms. First, we see a nice tumor uptake and also that was a question. We see fast rapid tumor uptake, which is important for lead as lead will be active in the first 48 hours. We see a good biodistribution in healthy organ, so low. And as Ken pointed out, the bone marrow is the part we need to monitor most. And the good thing is we can monitor bone marrow well. And that's why we are allowed by FDA to go to the EBRT limit at the 200 megabecquerel dose and then see how far we get. Hopefully, several doses in reasonable time, reasonable would be dosing every 4 to 6 weeks.

And I think, as we said, we can start at a reasonably high starting dose. And maybe Ken can also share a bit in the Q&A how he sees small cell lung cancer, as we do expect that this tumor to be rather radio-sensitive and something where we could expect initial activity in the first 2 doses already.

Brings me to the outlook. The Phase I/II is open. We are ready for screening. I think first patients are identified and should enter screening literally in the coming weeks. We will update on safety in H1. As you heard, the blood parameter is an easy one to screen for. So we will give an update and hope to have activity as of Q2, 3, 4. So second half of the year, want to show on activity. Response rates will obviously have to wait until we have dosed a meaningful number of patients on the right level, and that will likely be more very late in '26, early '27.

Before I come to the outlook and conclusions of the full pipeline, I do want to draw your attention for an opportunity that we learned about in this program. I mean we were optimizing obviously for the lead window. I'm on Slide 15 and -- but as also Ken and Michael pointed out, the tumor retention is remarkable. We see very good tumor uptake and retention over many, many days, almost no dropping versus the clearance in the healthy organs over time.

And this allows us to see also an actinium profile in such an approach. And given that we are a vector play, meaning we don't own and build lead or actinium facilities and distribution lines, we are agnostic. And so in future projects, we can actually go forward test both in parallel and then with possibly even clinical data decide which isotope is the more favorable one for a specific DARPin and keep in mind, it's always a multitude of factors. It's the target internalization, biodistribution. It is the disease and it is the vector and the half-life, and we can tune all of this to come up with the ideal candidate.

That brings me to the pipeline. So just to recap, this year is all about 0712. So we will is what we are driving. We're driving forward for patients, but also for shareholder value. 726 our ovarian will be progressing towards first in human. And then the other, and we have 4 boxes here, which depict 4 internal activities. And it's a bit semantic. So don't take us on the word. But you see some you choose the isotope upfront.

Others, we keep open and choose later. This is more semantic at this point in time, but what should change is that midyear, we do want to nominate 1 or 2 of these programs for future development and share the target and the plan. So a very exciting year ahead, focus on 712 and more to come.

With that, I turn to maybe the most important slide, the acknowledgment. I do want to thank our entire team at Molecular Partners. Many, many hands have helped to get this molecule where it is. very exciting moment. I want to thank our helpers and team, I call them our team at Orano Med because without them, this would have not been possible.

I also include Julien Torgue who has left Orano Med, but he will definitely always earn an acknowledgment on this slide. Then the NuMeRI team, Mike, his team for the very strong support, and I heard from my team that, that collaboration is going well, and we want to build on it also in the future. I do thank Ken for joining us here and stepping in and also then taking questions.

And my last thanks goes obviously to the patients and their families, especially in this trial, it was not always easy to be part of and so a big thanks to everyone who made this possible.

With that, I thank you all for your attention and we open for questions.

[Operator Instructions] Our first question comes from Jonathan Chang with Leerink Partners.

This is Albert Augustinos on for Jonathan Chang. Congratulations on the data. My question is regarding the future safety data. I don't know if I missed this but since red marrow and kidney are potential dosing organs, are there any adverse events that you are monitoring in the Phase I study based on these organs that we should pay attention to for your next update?

Michael or Philippe, I think the question is how we are monitoring the organs of interest, I wouldn't even yet say concern. I do think, obviously, blood and bone marrow is #1. We were often getting a question what is the dosimetry. Now we can share it. It is not so high. but it's still something we need to monitor. So maybe, Philippe, just a quick word from your side how we are monitoring the safety, especially on the red marrow.

So red marrow is one of the, if I could say, static organs that we monitor in clinical trials. We will also increase the blood draw to make sure that lymphocyte ANC and white blood cells stay as they should be. We expect when we dose in fact, it's a sign that the drug is doing something that's so important we would see a drop. We anticipate that it will recover within 2 weeks, 3 weeks and that patient can be redosed.

So there's no specific concerns about this, and it's one of the most monitorable, if I may say, organs that there is -- so this is not from an investigator standpoint, this is not the most complicated one to monitor. And let's also remember that in the world of small cell lung cancer and other neuroendocrine, the treaters are used to work with drugs that reduce bone marrow, so -- and I used to see them recover. So this is not something which is not unexpected and something that we are creating a big of anxiety for the moment. Does that address the question?

Our next question comes from Charles Zhu with LifeSci Capital.

Congratulations on this update. First, I'll start off with the comment. I really appreciate in context of your biodistribution data that you mentioned with the openness of looking at Actinium 225. I am curious, though, with respect to the lead MP0712. And can you comment on the additional -- on the radioactivity delivered window that you would expect to see. I'm looking at, for example, on Slide 9, at 24 hours, the tumors seem to have through 24 hours like only somewhat higher uptake relative to some of the healthy tissues. And I called out 24 hours specifically because that's what lead is 80% of its activity. So kind of wanted to get your sense there.

Yes. Michael, or should I take it? I think it's a very fair question, and I'll hand over to Michael and then maybe do some remarks afterwards.

Yes. Thanks, Charles. Excellent question. Absolutely. And that's why we also want to show the data and be fully transparent, but is not easy to learn from those imageries how the tissue will react to the famous radiosensitivity. I personally believe that tumor cells, small cell lung cancer not dividing rapidly with that area under the curve in the first 24 or even 48 hours they will probably be quite difficult to survive because you know the alpha decay produce double strand DNA break, whereas healthy organs were not dividing rapidly are probably fine. So I think it's a good sign that eventually the tumor curves go after healthy values. Hopefully, for our future programs, we can even increase that window. Back to you, Patrick.

Yes. No. And I think, Charles, you make a good point and there's even an internal betting what isotopes would have been or is better. So I think the answer is we don't know. And we gave lead a very good chance given the high energy we can deposit. And if you look at the dosimetry and healthy organs, we can give a very good amount. So we will give a lethal amount to these tumors.

Having said that, if you would just take a very simple tumor to healthy organ equation, obviously, actinium looks favorable on that dimension, not meaning that, that will lead to a better outcome for patients. So the mathematics are clear that they would place on actinium. But if you like, the lead profile, that has a good chance to work on this one as does actinium. And maybe I'll hand over to Ken as he has sort of seem most and also knows both. And I don't think it's an either or here, it would be much more of an end.

I fully agree, it's important that for any program to stay nuclide-agnostic so -- and then be open. I really think here, it's very smart to start off with lead because of the short half life. However, if, for example, we see the potential therapeutic index is not significant enough because to the point Charles, you correctly alluded, it's always an option to switch to actinium. Right now, I wouldn't be surprised if we see pretty good responses based on lead and the first 2, 3 half lives.

But in the end, this is exactly why I said it's super important now not to spend much more time imaging, but really now going into the treatment and look for the real toxicity profile, which, again, kidney and bone marrow is absolutely standard. So it's nothing really outside of what we would expect. And then the second thing is, look, how do we see responses because we should not over-interpret too much dosimetry to be fully honest, yes?

Thanks, Ken. And maybe just one comment because not everybody has looked at the patient data. And as you know, at the 24 hours when we had 1 patient, we often got the question, how much is actually already on the tumor. I think given the data we showed today, most, so 80-ish percent has reached the tumor at 24 hours. So we do think we have a very good profile there.

Our next question comes from Chiara Montironi with Van Lanschot Kempen.

Congratulations with the update, and good questions, everyone. So I just wanted to follow up a bit more on the safety. Can you basically remind us how many doses will the patient undergo and which strategies can be implemented to monitor the hematological recovery to avoid bone marrow toxicity?

I think that goes to Philippe or Michael.

No, no, I'm happy to take that again. So we'll watch many organs by the way, but we watch first hematox risk. And again, there are weekly measurement. Patients will have blood draws every week will be followed every week during the course of the treatment. So we will be able to monitor what's the time to formula reduction, if any and what's the time to recovery. So that on that one, again, we are pretty on top of it's standard practice, so we should be able to do that.

Your first question was about how many cycles. And I understand is what we are planning for is 4 cycles. We could do based on risk -- on benefit risk, we would go to up to 6 but better than what we are targeting are for the moment. And again, what we also anticipate is that we want to see effect after the second at some point when we get into the higher dose of the most effective deals.

And if I may, another question, any take on the fact that the uptake is higher on the liver mets versus the primary tumor?

Happy to give a first stab, hand over to experts, maybe Ken. For us, we saw that and then we were a bit surprised. And then we went back to our experts and the experts and they confirm that they have seen exactly the same with other modalities in small cell lung cancer. So it seems that the metastasis take up more radio activity on such vectors. This has been described. There's publications. I'm sure Michael can point us to the right ones, but that actually the metastasis are better in uptake of this radio activity and vector.

Having said that, in the U.S., we expect actually much more metastasis and all patients will be of that profile. We will have very seldom a single tumor without metastases. Mike, word from you.

Thanks, Patrick. Happy also to hear them from Ken. So I think all of us have seen these amazing pictures from prostate cancer patients, you have hundreds or even more micro metastasis. We expect we only see lesions that have a certain size, probably around about a centimeter And you can easily imagine that they are sort of fresh or younger tissue, the primary tumor, somewhat older than even necrosis, then how about vascularization, how about the DLL3 compression.

All of that, of course, are unknown. And ideally for an alpha emitter, you kill within the vicinity of where the internal drug is. So probably that's the better profile, heavily metastasize patients, high density of radioactivity on the lesion. Ken, anything?

Yes, I think it's super important. This is SPECT, right? This is SPECT imaging. SPECT is much more specific, equals less sensitive than PET. You should not compare this 1:1 but what you have seen for prostate cancer. With in prostate cancer, you always see PET scans. Then you want to compare this you, need to compare this with a good old scan in the times of NET1. And to be honest, what we see here is really a hot uptake. It's really intense uptake, number one.

Number two is, I also suspect a significant size difference between in the lesion, the liver lesion. Again, what we see here is actually a maximum intensity projection most likely or maybe only whole body scan. So this is not very granular. So I think right now, the key message is we see intense uptake in both the primary tumor as well as in liver mets. And anyway, if the liver mets would be higher than the rest, I wouldn't be mind because these are usually the ones which kill the patient. But I wouldn't be surprised that this is predominantly just size volume relationship.

Our next question comes from Bill Maughan with Clear Street.

So early in the presentation, you mentioned other DLL3 targeting modalities. So given the updated data, where do you think is the most likely place either in sequence or combination that your product will slot into the treatment paradigm? And second question is on the dose escalation. Now with what you know about dosimetry, when do you expect to start seeing efficacy signals and where do you really expect for your prime therapeutic window to be?

Thanks. I will take the first one. And I think the first answer is, obviously, we are moving this program forward in the U.S. So this will be, call it, last line, second/third-line treatment. We will have patients that have seen other DLL3 agents, likely tarlatamab as the approved drug. Luckily, there's reports that it's not DLL3 loss that leads to resistance there. So we think we will have activity. And that line is sort of your fast to market given the remaining high medical need in that population.

So I think in that sense, I think we will for design test post tarlatamab. Now there's 2 points I want to make. First, as you heard, these are likely 4 cycles of treatment. And doctors like that because first cycle is 4 months and you're done, done. So this they can also put in between cycles or lines because it's more an intervention. So we have spoken to doctors. They very much like that, that maybe after a first line, they can use this before going somewhere else. That's 1 point.

And the other is one of my hopes is that this can then go in a combination, especially with IO being either a PD-1 and/or a T cell engager, that's where I think the biological logic is highest because with an alpha like lead you create a lot of inflammation, a lot of damage to the tumor and you create an inflammation, and it's a very hot tumor after that. where PD-1 and/or a T cell engager would profit from. So I really think first-line combo is ideal from the mode of action, while we will have to test last line for a fast to market and in between, you have the opportunity to go to other indications next to small cell lung cancer.

I guess I'll hand over the other question, too. Now we're not in the same room. So I'll leave that open who can take the second part.

I can start, and thanks, Bill, for both questions. Excellent question as, of course, what we all and the team are working on. In terms of when exactly to expect the tumor response, of course, we will do the experiment we will learn what I can sort of give to you is in my personal impression. So we have, of course, done a number of mouse experiments. These cell lines respond extremely well. We have discussed with the FDA. We are really happy with the 75 megabecquerel starting dose, so just based on allometric scaling, we are exactly there where the mice responded very well.

We are even above where mice start to respond. And then, of course, it depends on the sensitivity of this particular cell type in this patient. But we hear this also at the current conference from experts, small cell lung cancer is expected to be radiosensitive. So as we said before, we should see something, hopefully, in the second dose cohort, around about 100 megabecquerel per cycle. And then, of course, the jury is out, not every patient will respond. That's also clear as oncology is heterogeneous and hopefully within the very early days of say, early months of this year, we have the confidence then to continue.

Maybe Ken, I mean you had shared with us that you have seen radio in small cell lung cancer and what you saw was encouraging.

Sorry, yes, very limited data, but even patients with very low doses. And in this case, I really mean tumor doses, not the doses given to the patient. But actually both low activity given and low tumor dose still very good response. Underlining that I think we should not overemphasize the meaning of dosimetry. We really need to understand how something works in the clinic. And that's why it's so important now not to lose time.

Of course, the question of Bill is very smart. When do you want to see efficacies? It's something you would know this upfront, people probably a fast a couple of groups. But I think we need to start observing very closely patients early on. Like I said, I've seen this for 2 competitive programs that you see efficacy actually potentially earlier than you sometimes think.

Our next question comes from Michael Nedelcovych with TD Cowen.

I have a couple. My first question relates to the potential actinium-225 effort. It sounds like your plan is to wait for clinical data with the Lead-212 Radio/DARPin in the second half of the year before potentially initiating a new trial with actinium-225. So can you confirm if that's correct? And if so, are there any steps you could take between now and then to prepare for that eventuality such as, for example, securing supply of Actinium 225? So that's my first question.

My second question is on the dosimetry data it looks like you provided it for kidneys and bone marrow, but not tumor or metastasis. Do you have the dosimetry data for the lesions? And if so, how do they compare to the healthy organs? And then my last question, if you don't mind. Three is on the dose limits for kidneys based on EBRT. How confident are you in the field about those dose limits as applies to radioligand therapy are there regulatory requirements that will require you to remain below those limits? Or is it more a decision based on sponsor preference?

Thanks, very great questions, and I will dodge the first one a bit, but also give you some update. Obviously, we know of the Actinium type profiles in. So rest assured, we're thinking in all dimensions here. What we're discussing here is mostly, let's call it, strategic path forward also for other targets, how we think about this. We will definitely update on 712. And if there should be an actinium track there, rest assured that is something we can look into.

And we, at this point in time, are not giving any timelines for that. I do want to add one word on the Actinium supply. I mean we at Molecular Partners at this point in time, will not build actinium, so that would again be a partnership. Now luckily, for actinium, most large farmers that are interested in radio have actinium supply too. So that is one angle of it. And the other is that actinium for your Phase 0, Phase I is quite available these days.

While for commercial, it's different, but that's where any way a different partner would be. So at this point in time, we're not looking to build commercial actinium supply agreements or supply but we are looking into how one does run and I'll be general early clinical trials with actinium for molecules we are interested in. I'll hand over the question on the tumor to, I guess, Michael, he's closest to the data. And then maybe yourself or Philippe for the last question.

Yes. So thanks, Michael. Excellent question as always. So we have done, of course, dosimetry on all organs. So it's a really long list, and you're looking spleen and all the small organ, but it's just a long list. So there is nothing really to disclose. And on the tumor side, of course, this is also something we did. We are still looking for benchmarks, but apparently, the field has not really come to a consensus or published a lot also like the conference Philippe and I attended, there were not a lot of numbers.

But if you just look at what we have on Slide 9, the curves, you can appreciate that the tumors are above the other organs. So that's probably as much as I want to say today. I wouldn't be led too much by the number because it's dosimetry, but the numbers we have are very attractive.

Yes. I can confirm that. And again, when we discuss with all the experts working either on lead or actinium, currently it's difficult to get true dosimetry per tumor per patient. And that -- those numbers, those benchmarks are not really out there yet. So that's why it's a bit it's tricky to we fully answer your question on the tumor uptake. You had a question on the EBRT limit for kidney and in the discussion that we had with the FDA or whenever we ask any experts who are working in that field and maybe Ken will give his perspective on it. we usually start with the usual 24 gray EBRT limit as a theoretical base for discussion.

And then we are happy, in fact, that we are pretty much always staying below that one across all those which we're planning to administer. And then there is, if I could say, negotiation because there is negotiation based on benefit risk, obviously. And because we don't completely know how alpha treatment compares to EBRT. So FDA is watching, is discussing and -- but is also open, and this is the type of discussion we have had, so based on our dosimetry, we are comfortable in how we are starting.

And also, obviously, we are monitoring this closely. through urine and blood measurements, regular ones and also a specific biomarker, which we have included in the trial. So we think we are on the good side from that end.

So I think the question is absolutely valid. On the other side, I'm obviously a bit concerned that we over interpret or try to over interpret the model we have. When we perform first human imaging at different time points, we want to get an idea. We want to give an idea of the time of express, we want to see if the tumor takes retained. You want to see, are there any organs we really have to additionally worry about. For example, I would not spend too much time on the doses.

First of all, can we really believe in numbers, then it's Lead-203. Next thing is Lead-212 and the next question would be, if you want to see tumor dose, what tumor dose do you want to see? What is the tumor dose you want to see? To be honest, even for Pluvicto lutetium-177, which has been approved as a multibillion-dollar drug, I could not answer you. So that's why here, I think the biggest question is, does this compound check all the boxes required to go into a first human therapy. And this is for me a clear yes. And now we're willing to see how the clinical data is and we all hope that the clinical data will speak for itself. And I think this is the key.

And again, yes, we have to watch the kidney, very standard. Now let's go out collect data and hopefully cure a few patients.

Our next question comes from Joris Zimmermann with Octavian.

This is Joris Zimmermann not sure if you can hear me.

Yes, we hear you well. We hear you.

Perfect. So my main question has already been answered. And so I'll leave that one. Maybe just on the timelines. You mentioned that we have or can expect safety and first efficacy from the Phase I/IIa trial still this year. Can you also give an outlook already on how that would progress from then onwards?

We can try. And I think listening also to Ken and all the others in the call, I think this is where we just have -- we'll have to find out at what those levels will we see what? So everything can also come earlier as we just heard, where we are, let's say, and we are very deliberate to say we will see activities. So these are case study type activity because we will not have a response rate.

For a response rate, you need x patients at the right dose in the right setting. And I think that's when I would point towards the outlook, and that will be a year plus from now, but that means we are heading towards the Phase II. That means we will have a recommended Phase II dose ready. That means we are almost in a Phase II. So we are at a very different point. And I really want to take that, that sort of the outlook. If we reach that, we are in a very different stage as a company.

Then we are the leader. That's the ambition we have. We're the leader in the alpha targeted therapy approach for DLL3 in small cell lung cancer and that's our ambition that in a year plus from now, we are heading towards that to move this. Two, what Ken said, let's go out and cure some patients. So I think that's really how I would summarize that. So a year from now, heading towards recommended Phase II dose would be an ambitious and highly valuable moment for us.

I'm showing no further questions at this time. I'd like to turn the call back over to Patrick Amstutz, for closing remarks.

So thanks. I think that last question was a very nice closing remark. I mean we are at the brink of this new chapter for Molecular Partners. We are a year plus away to hopefully be the leader in the targeted alpha radio field for DLL3 small cell lung cancer. It's an exciting moment, and I will close to requote, Ken, let's go out there and cure a few patients, I like that. And we will keep you all posted while we are on that quest. Special thanks to all of you and to Ken for joining this call. Thanks.

Thank you for your participation. You may now disconnect. Good day.

Okay. Welcome, ladies and gentlemen, to the last day of the JPMorgan Healthcare Conference. My name is [indiscernible], and I'm very happy to introduce the team of Molecular Partners, who will be taking you through their presentation, mostly Patrick, but then we have Martin, Michael and Michael here as well. After the presentation, there's time for some Q&A. So feel free to save your questions for the end, and I'll leave it to the team. Patrick?

Thanks. Thanks for the kind introduction. And also thanks for hosting this conference. It's always a pleasure to start the year here and feel the pulse and I think last year, we were all hoping for a turnaround. And I think here, I see now much more confidence for that turnaround after a few difficult years in biotech, I think we can look forward to 2026.

And for us, it was also very fortunate as Aktis Oncology did an amazing job in their IPO and Aktis is a radiotherapy company, and we got a lot of positive feedback for that field and also many questions. So big congrats, but also thanks to Matt and his team for opening the IPO window again and reenergizing the interest in radiotherapy.

My talk today will be mostly on radio, and I will put in a few other thoughts for us, but it's really about radiotherapy and MP0712, our DLL-targeted DARPin. That's going to drive the value next year, and that's where I want the attention of the audience, but then also of our investors over the year to focus while we are doing additional things.

For -- that's the forward-looking -- I will be making forward-looking statements. So here my disclaimer. And for those who are -- hello -- for those who are new to the story, just a short intro to what we are doing and how we are doing that. We are a Swiss-based -- Swiss and U.S. listed company. We have USD 100-plus million or Swiss francs, and we invest that to bring DARPin candidates forward.

DARPins are designed ankyrin in repeat proteins and what the field likes to call them at this point in time, especially in radiotherapy is mini proteins. And compared to, let's say, peptides, the mini protein has one advantage that has a class behavior. So what we learned from the first program, we actually can apply to the next programs going forward.

How does a workflow look for Molecular Partners? We start with our libraries. We have different libraries for different applications. We select binders. That's that one arrow. But behind that, there's display technologies, computational designs, deep data mining, and it has really especially AI and deep data mining has revolutionized how we do this.

We find more binders, we find better solutions to build candidates. The candidates are always focused to solve a patient problem. So we start with usually a clinically validated problem. We are not looking for new targets. We're not looking for new biology. We take a defined problem and build, engineer a solution. So it's always understanding the problem, the biology, finding the solution in our space.

Ideally, this solution is unique to what we do, which gives us differentiation, value for patients, but then also value for shareholders. If I look at our pipeline, I see a lot. There's many arrows there. But if I look where the value creation will happen this year, it is rather simple. I mean the focus is on 712.

So I think that's what we will be doing, and that's where most of the data will be coming out. It has a knock-on effect on the whole radio franchise, and it is directly useful, as I talked about, the class behavior that we can design better and better solutions going forward. Before going into 712, I do want to distract you with 2 programs that I need to throw in here.

And I will start with MPO317, then do MPO533, then come to radio. 317, I think most of us, including myself, would have classified that as a dead program. We didn't see much activity for the Monty Python, maybe dead as a Blue Norwegian parrot, but it got awakened, and it got awakened by investigators. Investigators saw the data of the Phase I.

And let me quickly show you how that looked, and I draw your attention to these images. You see pretreatment and posttreatment. And you see 317 is, you see the cartoon below, it is a local agonist. It binds to FAP and then it activates upon binding CD40, which is on immune cells, dendritic cells, macrophages to stimulate the immune system.

So it can stimulate an environment that is immune suppressive to become active again. You see that on the cycle 2, day 8 picture, how actually we can now see we can measure 317 in the tumor and the activation of the immune cells. And this activation did not lead to single-agent activity, unfortunately, in the Phase I trial, but it did activate investigators that were also on the trial to think about how one would use it.

And so it was mostly a group around Christophe Borg in France, and big thanks to him in his center to come up with a trial to test 317. I'll draw your attention here to the chart, and that's a chart and it is really a dismal chart, if you want, in cholangiocarcinoma, where after 1 year with just chemo, you see 10% of patients are actually still alive and the curve then becomes flat.

If you add a PD-1 to it, in this case, durvalumab, you see you maybe add 10% to that and you get to 20-something percent at 12 months. And the idea here is that this is really an immunosuppressive environment and could one now by adding 317 change this and give the PD-1 a chance to work. That's what they want to try. It's going to be 11 centers in France.

They will recruit 75 patients, randomize them, 25 standard of care, 50, 317 plus standard of care, and we will expect first results '27 and beyond. So very nice trial, very grateful for these investigators to actually do this. We only have to provide the drug, and we have all the upside for us and our shareholders.

So this might be a bit the role model also for the next program, which is 533. 533, we just presented a poster at ASH. Let me just quickly introduce the molecule here. We see it's a multi-specific DARPin, the green, the orange and the yellow DARPin binds CD33, 70 and 123. And the blue DARPin here would be a T cell engager. So you bind the AML cell in orange, recruit the blue T cell to kill.

And you might ask, why do we need 3 of these? That goes back to the disease. We're targeting AML and AML is a heterogeneous disease, if you want. The cells have very different origins. It's very different to a B-cell malignancy where you can take a CD19, a CD20, Blincyto and you're done. Blincyto is great because you actually chase those last clones.

You can actually really almost cure the disease, and this is unheard of in AML. So what we need is a disease, not to -- we need a product, not to debulk. There are different therapies to debulk, but we need something to eradicate the last clones, and that's what this drug is designed for, multispecific to address the polyclonality or multiclonality of the disease, T-cell engager to give high potency and then kill these target cells.

The data, these are top 2 cohorts. We have cohort 8 and 9. And the first thing that comes out is it only works and that in the design in low disease burden patients. So it's for killing the last clones that are still there. It's not to debulk. If we recruit the patient, call it, too late, we have no chance. In the low disease burden patients, we see nice responses. And if we look closer, we also see that we target many of the clones, so it's a polyclonal response.

In this chart, you don't see the, let's say, worst mutation, which is a TP53, but we also have activity in those patients. Given the focus in radio, we will not be investing very much more into this program. We will finish the Phase I and then possibly, and there are a few attractive options, move this into an IIT following the logic and the route of 317.

Good. So distraction is over. Now we're coming to the core bit, the focus part of the talk, which is the radiotherapy part. What -- how does radiotherapy work? You have on the one side, and this can be different. Usually, these are cyclic peptides. In our case, it's a DARPin, a vector. The vector has a linker, a chelator and is then loaded with a radioisotope, and we are focused on alpha isotopes. What we bring is not the isotope or the linker. We partner for that.

In our case, I'll have that on the next slide with Orano Med. We are experts in the vector and the half-life engineering and especially half-life engineering is very important in this field in our view. So one word before going into that in more detail on the isotope. Here, we partner with the leader in lead. Lead is 212. That's a radioactive form of lead.

It decays in a beta than 2 alpha decays, very potent, very fast decay, really killing tumor cells fast and actively. We are not investing our money in the supply of that, building that. Orano Med is the world leader. We're grateful for that. We leave that to the partner. We work more on the DARPin side and on the product development side.

Not only a big thanks to Orano Med, also to our advisory team. We have Ken, James, Jason and Michael here. They have been very helpful for us. For us, it's a new field and that we don't have to reinvent the wheel. We are fortunate to be able to count on the support of this group and other groups. And I would like to point out that it is very a collaborative field to work in as we're all pioneering a new class of drugs. We are treating patients with very high medical need.

So it's nice to work in this field and support each other, and we see much more of a support than a competition behavior. So big thanks for that. Now a bit more specific from the general to the specific 712, which is our first candidate to enter the clinic in small cell lung cancer. 712 targets DLL3 and DLL3 is now a validated target as tarlatamab is approved, a T-cell engager by Amgen. It has a response rate of 40% and around 10-month duration of activity. There's more to follow.

At the same time, and we also have T-cell engagers in our pipeline, it also has rather a high level of side effects. The alternative there is ADCs. They have a higher response rate likely because you don't depend on the activity of the immune system on the fitness of your T cells. The problem there is that small cell lung cancer is a very chemo-resistant tumor. So ADCs are, let's say, chemo and steroids, it still will likely be resistance to that, and you will have a much shorter duration of action. And that's what we see in the first clinical trials.

And here, radiotherapy comes in. I hope we can have the activity of the T-cell engagers and the durability with the response rates of the antibodies and the side effect profile that might actually be better than both. So that's the promise of radiotherapy in small cell lung cancer. 18 months ago, we published these results that was at SNMMI.

And you see here what you do is dosimetry, your dose, your drug to a mouse, you look at all the organs and what you're looking for is a positive tumor to kidney and ratio. But usually, it's tumor to kidney because these proteins are excreted via the kidney. We saw nice activity. And at the same time, especially when Dani on the stage here, presents, he always gets the question.

So why do you get so much on the tumor? And why does he get the question? It's because DLL3 is a very low-density target. So a cell, a typical cell in a human that with this disease only has a few hundred counts on the cell surface compared to all hundred, thousands of HER2 that even can go to 1 million. How on earth can we get so much in?

And I want to draw your attention then also to the blood value because we have seen by engineering a longer half-life, that's how we could boost the uptake. We didn't totally know why, but we saw a correlation of when we added half-life, much more went into the tumor. And the team then looked at this and came up with a very good hypothesis that we believe, and it is the following. It builds on internalization.

What you see here is you spike the DARPin. It has a floor for in this case, so we can measure. And we see within less than 30 minutes, all of that DARPin is internalized into the cell, and you can make nice pictures. And here, the DARPin is in green. And you see the DARPin is not on the cell surface, it's internalized. This has not been described in this way, while it is logic because ADCs work and they need to be internalized.

Now the interesting part was that if we then added DARPin to the solution, this internalization kept on sucking in almost catalytic the DARPin into the cell. So we're loading the cell over time. And if we would have only just given one bolus, that's that orange line to the right, that's the maximum you can get if you don't half-life engineer.

But with half-life engineering, we can load the cell and reach much higher activity. That's the cartoon. That's how this now works. We bind, we internalize, we likely fall off and the DLL3 is replenished to the surface. Now the other interesting part is we can actually follow this also in humans. And while our Phase I is just opening now and the first patients are being screened as we speak, we were able to get some patient images upfront.

And so the beauty in radiotherapy is you have a theranostic pair, so you can do imaging and treatment. In the imaging part, that's the upper part of the cartoon, we use lead-203. So it has no therapeutic activity. We can image. We see where the drug goes. We see the tumor. And then in the second part, we take the same vector, replace 203 with 212 and treat.

You can do this in all sites, and we started this on a named patient access program in South Africa with Mike Sathekge. And what I will present to you on the next slide is sort of an appetizer or teaser to the data that he will be presenting end of the month at the TWC conference in South Africa. And I think that's where our investors will definitely look, and we will be present. And I think that's when all the data will be released.

And the image I will be showing you on the next slide is sort of an appetizer to that. The Phase I/II will be the same. You will be first imaging and then dosing. And as I said, we will be opening 8 sites. First site is open in the U.S. to move forward. So let's look at the patient that we dosed, and we chose one because we thought this is most relevant for the patient profiles we will see in the U.S. because this is actually something we found.

We found metastasis in the liver, which is very characteristic for these types of patients, while other patients did not show that characteristic. It's a smoker, small cell lung cancer, and we dosed. Let me quickly move through. So here. Let's see at the 4-hour time point to start at the beginning. What you see there is not the tumor, that's the heart, that's the blood pool.

As I told you, we have engineered the half-life of the drug to actually be a reservoir to load the tumor. And that's what you see at 4 hours. You might ask, is that not a safety risk. The good thing here is alpha particles decay and only kill neighboring cells. So a clean decay in the blood is likely safe. That's a calculated risk we take. And the one organ, if you want, we have to follow is the bone marrow to see how much hit do we hit the bone marrow.

The good thing is actually the blood values, they come back, they recover, and that is going to be the question on safety and the 4-hour time point. If we now jump to 116. So we sort of let the blood pool leave and see what is left. And there you see now the primary lesion, the lung lesion, and you see 4 or 5 metastases in the liver. And you see the precision of targeting. You see we are not stuck in the kidney. We leave very rapidly, and we have a very good tumor to organ or healthy organ distribution. So very promising data for us.

And so that's sort of the hint we're giving here. And the full data will be released in South Africa, TWC, where you will also get the exact values over time. So what are we doing next? We're starting the Phase I dose escalation. We do start with a 75 megabecquerel dose, which is very in line with what others have done, if at all, on the higher end.

And that's because we could do the dosimetry in South Africa and the mouse work showing that also this blood tox is very reversible and likely not dose limiting, going up to 200 in 4 dose cohorts. If that looks good and when that looks good, we go into a fast-to-market strategy. That's the second line or small cell lung cancer trial there. And we can go also first line ideally in combination that would then be with a PD-1 and branch beyond small cell lung cancer to find other indications as DLL3 is not only found in lung cancer.

The timing of this is a question we get. Our goal is to recruit a cohort per quarter. So we will see the up-dosing. We will have safety results. We will have likely, let's say, case study second half of the year of activity and be able to update the market as we move. In this, you see that is sort of the slide to keep in mind, a big year for us, first activity in a patient population that needs more durable treatment that is safe. So this is the slide to keep in mind.

We obviously didn't stop with that. We have other targets, and I just picked out this one. That's the second up MPO726. This targets mesothelin. Mesothelin has a different problem. It is cut from the cell membrane, and you have a big shed portion. What remains on the cell is just the membrane proximal epitope, very small. Now the team has selected DARPins that now binds to this specific part of the protein and does not get stuck or sponged away or inhibited by the shed mesothelin as shown in the graph.

And then again, you see we did some half-life engineering here, too, as this is also internalized, albeit a bit slower, and you also see a very nice tumor to healthy organ ratio. And that brings me to sort of the last slide of the almost outlook of what we're doing. And you see in the chart, we have 712, 726 on the top. We're working on 4 additional targets that we want to select 1 or 2 mid this year for development.

And the point here is we have chosen those that we can then start to do combinations of these in the next projects to do multispecific to address tumor heterogeneity. As I told you, these alpha does not travel far. And if you don't have a very good distribution of your target, you can profit a lot from targeting more than one target.

I'll sort of come to an end here just by highlighting how we think about this. We start with the patient need. We have the target, the disease in mind, the surface internalization, the off-target expression. We design the ideal vector, including half-life and then choose the right isotope. As you saw, we have 10 slots of lead. We don't have to always use lead. We are -- in principle, we are open to other isotopes as our, let's say, value we bring to the table is the biology and the vector, and that is then paired with the best solution on the isotope side.

And with that, we really think we're uniquely positioned to build the pipeline. And I think I will actually recap very simply here before I open for questions. Focus this year is all about 712, first-in-human results. I think first stop is January. So just 2 weeks from now, first time to look at the dosimetry data, safety first half of the year, Cohort 1 and 2, activity second half of the year and with that, a validation of the product, but also the platform.

We're well capitalized with USD 116 million at CHF 93 million in cash in Swiss francs. We have a great team to execute what we want to do. With that, I come to an end, and then I'll take some questions. But before that, I want to thank you all for coming here. For those on the webcast joining us, I do want to thank my team that was here with me the last few days at JPMorgan, having all those investor and partnering discussions, the team at home. I do want to thank also the Orano Med team that was also here promoting our cause and their cause.

I thank our advisers, especially the clinicians that come up with these great ideas and trial designs and support IITs, something that is really helping patients where we, as a company, cannot go. And obviously, all the patients and their families in our trials. With that, I come to an end, and I would be open for questions. We have a microphone in the back. I think that will be...

[indiscernible] Zain Ebrahim from JPMorgan. My first question is just on the DLL3 in terms of -- and you've provided hopefully the data cadence that we should see this year in terms of safety in the first half of this year. And you alluded to the fact that from the imaging data that we're seeing, it does look like it accumulates more broadly in the blood, but the alpha decay time might mean that it's only a signal in the bone marrow [ to ] really think about where you're not seeing a signal on hematological toxicity.

But just maybe providing a bit more detail on what gives you confidence that you might not see a high level of blood toxicity and putting into perspective with the safety profile a little bit more that you alluded to for IMDELTRA would be helpful would be the first question.

Yes, sure. And I will be also very happy to give this question then to Michael. But from the preclinical work and from the dose symmetry that will be released, we feel confident that we will have a safe dose. But I think Michael can speak to that question.

Yes. Microphone 3. Thanks a lot for your question. So as Patrick said, Dr. Mike Sathekge will present in detail on this on the TWC conference. And what you probably understand is from all these patients that have been dosed, you do a very precise dosimetry, take every image, characterize every organ, the volume, the radioactivity and then calculate the time activity curve from that the organ basically exposure.

And then you look at the external bone beam radiation limits and then you can derive basically a safety margin. It's not obvious from the pictures because they are adjusted to the contrast of the image. But if you look, for example, what Patrick said at the tumor to non-tumor and kidney is always a good one, the blackest spot is in the liver and not the kidney. So the kidney gets less. But of course, you need to take the integral over time. And for lead, a couple of days are relevant, but for other isotopes, even longer time courses drive this even to a better therapeutic index.

Makes sense. Very helpful. And just kind of contrasting versus IMDELTRA, where do you expect to see the safety benefit for you versus IMDELTRA potentially?

Safety benefit. Of course, we haven't exposed the patient yet with 212 lead, but since the radioactivity decays very quickly, I think the blood values recover extremely quickly. We have seen that in animals. And in a 4-week dosing interval, I guess the patients will have only minimal experience of side effect and then have a good time for most of the time in the cycle.

And hopefully, we can continue to dose them without any additional toxicity. So I'm very confident that there will be a good safety profile, especially at the lower dose levels.

Very helpful. And last question I had...

Maybe just to add, I mean, that we work also with T-cell engagers and with radio. And I think let's just talk about the class. I mean T-cell engagers have heavy cytokine release syndrome. The patient feels ill and does not feel well. On radiotherapy, the patient feels almost no side effects. So the side effects come much later. You can have kidney toxicities, but they come much later.

And so I think just from the patient experience, it's a big difference if you're in the T-cell world or the radio world, and that you can go back to prostate and compare that. So if that applies, which it should too long, I think that's where the safety benefit comes in, in the patient quality of life.

That's very clear. And then the last question was on the activity signal that we might see in the second half of this year. What should we look out for? Will we see response rate data? Could we see a little bit more than response rate?

Yes. So I think the response rate for a robust response rate, we need a robust number. And so we will not be able to give the response -- full response rate. What I was hinting to is case studies. We will see patients that respond. That's the aim. I think the duration hopefully will take longer than end of the year as patients still should be profiting.

And the rate, maybe end of the year, we will get a first hint of that. I think just we also will be careful on how we represent the data. If you go out too early, it is not doing the work just. So we'll be very thoughtful about how presenting that. I do think case studies is the way I see other companies presenting their data. And I think that's also what we will be doing.

I had one question. Can you give a bit more details on the Orano Med partnership? And how do you see that evolving going forward? And maybe comment on any potential other partnerships that.

Sure. So the Orano Med partnership, I'll just maybe go high level. Maybe Dani add 1 or 2 words there. So on the Orano Med partnership, we have -- when we go a few years back, we had to choose an isotope provider as we don't invest our money there. And we had the choice between in alpha, there was no choice. It was clear alpha, actinium or lead.

And Orano Med really rose to the prime partner as they have a quasi unlimited supply of lead because they have mined -- they're a daughter company of Orano, the French nuclear power company, and they have 22,000 barrels of thorium in France. So they can more or less supply the world. And what happened in the meantime is that they went into a phase or had a very nice Phase II data, partnered with Sanofi and Sanofi has also added around EUR 300 million, EUR 400 million to build that infrastructure. So now our partner not only has the capacity on the lead side, they also have the cash to make it work, and they want to do that for their front runner.

So by the time we get there, the infrastructure should be established while we are moving forward our asset. At the same time, they have really good research. So we are doing this together. It's a 50-50 partnership on DLL3. It's important for us that it gets the prime attention of Orano Med. And in the future, we -- on the chart, you saw we have up to 10 products worth of either 50-50 or MP-owned slots for lead.

Maybe Dani can talk a bit more about the process and how they do lead and why we think they are at this point, the leader. At the same time, there's other lead companies. And the question is how can we, as a field, democratize lead and actinium that many more patients get access to it.

So happy to quickly cover the question from a production process perspective. So Orano Med, as Patrick mentioned, is sitting on the stockpile of basically nuclear waste, which they are using as a source material to basically start to harvest and they call it milk, the Thorium-228, which is a starting material for building their generators and the generator is basically the system.

They allude on a daily basis, lead-212. They need to allude this because it's so powerful. Otherwise, it would destroy -- start to destroy the generator itself. So they have a process established where they can on a daily basis now in different sites and they're expanding these sites, allude therapeutic doses and big amounts of therapeutic doses now getting ready for the Sanofi for Phase III and then for the registration of compounds with lead-212.

And maybe just adding on the aspect, lead, we like it for the properties. We like it for the short decay and allowing the immune system 2 days after you inject it to come back into the tumor. And this is very different compared to other long-lived isotopes. And for us, the focus now going forward, we've learned a lot during the last 4 years is to really say, think about the patients, the disease biology, the vector we are able to generate and iterating all these aspects together to make the best possible compound, being it lead or being it going forward actinium.

And I think that really depends on, as I said, disease and vector profile we are able to generate in that setting. So we're getting way more agnostic in that sense and trying to not decide upfront, but trying to decide on the data we are generating during the program progression.

Okay. So can we expect an actinium partnership at some point as well or...

Yes, sure. So if we just quickly stick with the 712, so DLL3 is internalized in 30 minutes. Let's say that was 4 or 5 hours. That means your ramp-up is much slower. You'll need a few days maybe to ramp up and by then, lead is decade. In that case, you will need actinium if you stick to the alpha strategy. So what Dani was saying will follow the science. Ideally, you choose only in your clinical setting.

And if in the compassionate care setting, you can actually test both isotopes or actually don't have to test both. You do one imaging trial and then choose the isotope when you know what we're up for in the human setting. And I don't know of any other area where this is possible that you fine-tune your drug on clinical data. And I think we're not there yet. I mean at this point in time, we're working with lead.

But in the future, we would love to have that flexibility, which is also then a uniqueness of Molecular Partners because we're not lead or actinium. We're a vector play. We make the best vectors with the optimized half-life, ideally multi-specific, then paired with the best isotope. And if you think more strategically what has happened in PSMA world, first was lutetium, then actinium, then lead, we want to get away of that. You get one vector, you have different isotopes, and you're not afraid to be skewed by the next better one because you have access to all.

Yes. And no, that's very interesting. And any comments on the development path of the DLL3 program beyond lung cancer?

Yes, maybe. Michael?

Yes, of course, our team is working on this. Small cell lung cancer is the obvious entry point because we know there is a high and uniform DLL3 expression. So by far, most patients will be amenable for treatment. Beyond that, and it's also on the slides, there is the other neuroendocrine tumors, mostly outside the lung. There you need to look out for patients with DLL3 expression. But again, we have the imaging that will be easy.

And we haven't disclosed anything, but we are also working on interesting indications beyond these 2 because there will be a lot of potential treatment patients with DLL3 expression. So it seems to be a really, really good target. So I'm so glad we are in this decade where DLL3 is on the -- basically on the rise. And hopefully, we can also combine with other potent principle to maximize survival for these patients.

And maybe just to add there, there, the imaging agent will can even become pivotal because you can then select the best patients in an indication where not 80, 90 or even more patients have DLL3, but with imaging, you can actually pick out the best patients. And this see what you treat and treat what you see idea is then pivotal, if you want. Any other questions in the room? That seems not to be the case. Thanks.

Good day, and thank you for standing by. Welcome to the MP0712 update call.

[Operator Instructions]

Please be advised today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Patrick Amstutz, CEO. Please go ahead.

Thanks for opening the call and the kind introduction. My name is Patrick Amstutz, and a warm welcome from my side to this webcast. We are here today to share the first Radio-DARPin human image and talk about the lead program and talk about the study to come. It was roughly 2 years ago when we signed the collaboration agreement with our partner, Orano Med, who will also be named several times in this webcast that we come together and pioneer radiotherapy. And today, we are opening the clinical chapter of this story.

I'm joined by Dani Steiner, Head of Radio Strategy; I have Philippe Legenne with me, our Chief Medic; and Michael Stumpp he is the program lead. He will be mostly for the Q&A part of the webcast.

Just 2 hours ago, Dani presented this data at the TRP conference in Amsterdam, the story behind the molecule, the mode of action, and he will be recapping that with all of you, hear this firsthand. We will hear Philippe's perspective of the clinical relevance and also the study design and all of us can ask questions to the experts.

Before kicking off, I just want to share a few thoughts on why this is a special moment for myself, but also Molecular Partners and the Radiotherapy field. First of all, this is unique to this field that we have the opportunity before we actually start the Phase I to have meaningful clinical imaging data of humans to derisk, to understand and to really speed up the development, and that makes it also very cost effective for us to develop such drugs.

MP0712, especially with this mode of action that we will be discussing, capitalizes on the rapid internalization of DLL3, the target I will just come to, to improve the therapeutic index to then help patients, and that will be most the core of this talk. And this target DLL3 is on cancers, mostly lung cancer, where we have a high medical need, and we need very potent approaches to create the therapeutic effect like radiotherapy.

So let's kick off and move to the first slide, which is actually the disclaimer. So we will be making forward-looking statements, but also going to now the Slide #3, that is sort of the introduction. And I shared with you that it was only in January '24 that we started and signed the deal with Orano Med. And what you see here is really the combination of 2 cutting-edge technologies on the one side, the DARPin and on the other side, the isotope in this case, lead-212. And together, we create a new modality, and that's what we're talking about today. We have engineered the DARPin to be kidney cells and especially we have optimized the half-life for matching the disease and the target, and Dani will be talking about that. While Orano Med is the leader and the pioneer in targeted alpha therapy, and we like lead and alpha as it deposits high energy in short time.

And for us, and this is important, I will come to that, is in short time means high impact. We have a low probability of escape and resistance and a great potential to synergize with IO approaches. And so if I frame the problem we're trying to solve, and Dani will talk about, it's really we have a small cell lung cancer patient in front of us with a very fast-growing tumor, high chemo resistance and a low copy number target. So how did we go about to solve that conundrum to come up with a candidate that actually has the potential to help these patients. So Dani, over to you. How did we try that? And how did we succeed?

Thank you, Patrick. Very happy to present here from Amsterdam just being on the stage on sharing this data 2 hours ago. So if we move to Slide #4, and I'm now fully focusing on the first program coming out of the Orano Med collaboration, the DLL3 and MP0712 lead-based program. So what we see on Slide #4 is preclinical data showing on the left-hand side, nice tumor accumulation at the 4- and 24-hour time points, low kidney values and as per design, as Patrick mentioned before, elevated blood levels needed for the high tumor accumulation.

On the right-hand side, you see the molecule is very efficacious at these 2 different dose levels, leading to strong tumor regression and complete tumor control. The key question that was raised here now several times at the conference how did you manage for -- target with such low expression numbers, and that's illustrated on Slide #5. How did you manage to get such high tumor uptake, while only having a couple of hundred of receptors per cell.

To understand this better, one from a scientific curiosity perspective, but also to inform us on next programs that are in our pipeline and new programs to be nominated, we investigated this, which is depicted on the next Slide #6. So let me guide you through that data. On the left-hand side, you see a cell internalization assay where you're basically spiking DARPin. And what you can see the cell internalizes -- the cell expressing DLL3 internalizes this DARPin extremely rapidly. So within 20 minutes, you have more than 50% of the cell DARPin internalized.

Then, if you move to the middle graph, we track what is happening with the DARPin by immunofluorescence assays. And what you can see, the DARPin nicely co-localizes in the endosome, which is staying here in red by the EEA1 marker. You can't see in the lysosome because the detection of the DARPin is integrated in the lysosome that will not be able, but you can nicely see in the endosome. And then if you move to the right-hand side, and that's probably the most relevant part of that data, if you now do a similar assay, again cell binding, but you measure the total fluorescence taken up by the cell and you expose the cells continuously to DARPin. What we can see is the blue curve where you get a continuous increase in signal of fluorescence inside the cell, which is indicating that the cell can continuously pump in basically this label.

The curve would even look more steep by using a radiometal, which is residualizing and staying inside the cell. Here, we're looking at fluorescence-label data. So integrating this data and moving to the next slide, our hypothesis how this molecule, how the mechanism of achieving high tumor uptake despite the very low expression of DLL3 is twofold. So first, from a biology perspective, DLL3 internalizes extremely rapidly and at the same time, is extremely rapidly replenished, basically leading to a high apparent receptor density over time.

The second aspect, the DARPin that we generated is able to piggyback on that internalization to allow us to follow that rapid internalization. And at the same time, the half-life extension we introduced allows the continuous refeeding of DARPin, allowing to really continuously reload the tumor with that radioactivity. Finishing all the preclinical package, seeing good efficacy and favorable safety profile, we then decided to move into the clinics that's depicted on the Slide #8, where you say -- we see we took a 2-step approach. So the first step is using lead-203, which is an imaging isotope with the same characteristics as lead-212 and the imaging isotope is used to collect SPECT/CT images, which you basically can use for imaging the patient and for dosimetry calculation, which allows you to inform then the next step, which is the treatment with lead-212 labeled MP0712.

Phase I has been submitted -- the IND for the Phase I in the U.S. has been submitted and is under review and pending approval by the authorities, we hope to initiate the Phase I before end of this year. In parallel, we received a request from the team around Mike Sathekge, one of the key leading Nuclear Medical Person in -- at NuMeRI in South Africa to provide MP0712 for imaging and potentially treating patients with small cell lung cancer or other neuroendocrine tumors.

Then in South Africa, a series of patients have been imaged using lead-203 and Mike Sathekge and his team will be presenting dosimetry and imaging data of the full series of these patients at the Theranostics World Conference end of January in Cape Town. Based on support from Mike Sathekge, we got approval to use one of these patient cases out of the series and present to you the data from that patient already today.

So if you move to Slide #9, quickly going into details of the patient and guiding you through that. If you focus first on the patient characteristic displayed on the left-hand side, it's a 69-year-old smoker, small cell neuroendocrine carcinoma of the lung. At referral, that patient was Stage 3 with a primary tumor located in the upper part of the lung. Treatment history, radiotherapy and chemotherapy. So maybe quickly -- let me quickly pause here. So this profile of that patient with the stage and the pretreatment history is what we believe gets as close as we can get to patients we would potentially need in our Phase I study in the U.S.

That patient received 5.1 [ milligram ] of 203 -- lead-203 labeled MP0712. And based on the assessment of those images, that patient was restaged into Stage 4 with additional 4 liver mets detected by that imaging. So let me quickly guide you through the data. I want to start completely on the right-hand side on the colorful image. That's a planar coronal projection. That's how nuclear medics look at these images where you basically see the orange indicates -- the more orange or yellow, the color, the more radioactivity. And what you can nicely see the radioactivity fully located with the primary lesion, which is indicated with an orange arrow and the liver metastases indicated with the blue arrows.

If you move then to the left-hand side, the gray images. So here, the more radioactivity you have the darker area. So what you can nicely see, this is like 4 hours, 24 hours and 116 hours post injection, what you can nicely see as per design, we have a high blood pool at the early time point, which decreases over time. And very importantly, we have no uptake or very low uptake in any of the healthy organs such as kidney and liver. Now focus zooming in on this tumor, what you can nicely see at 24-hour post injection, you already nicely see the uptake in the primary lesion as well in the metastasis, which is still obscured by the high blood pool. And once the blood pool is down at 116 hours post injection, you see even higher intensity of the primary lesion and the metastatic lesions.

So zooming out and summarizing this, we see initial high blood pool followed by a specific uptake in the primary and the metastatic lesions over time and a limited accumulation in healthy organs in line with the mode of action of 712 and as well in line with the preclinical data. And with this, I'm happy to hand over to Philippe to guide us through the next stages, which are ahead of us with that program.

Thank you very much, Dani. So we are going to spend a minute on that image -- on those images, and I'd like to bring a little clinical facet to them. You already spoke about the blood pool at 4 hours, 24 hour and 116. But it is interesting to note that this is exactly, in fact, what we have predicted per our preclinical work. And we can see that at 24 hours when this blood pool starts to go bit down, then we -- the tumors emerge and we see them most visible at 116. So in fact, this is a very -- from a patient standpoint, it's a pretty interesting image. And when we were discussing this with the experts, Mike Sathekge first, this is a patient where the prediction of that blood pool evolution and the image evolution makes them think that it's a patient that could have been benefiting if treated. okay?

So that's one. Then I would also want to emphasize 2 points. One is about the overall value of the SPECT. You mentioned that, Dani, but I want to reemphasize that basically, the patient was presented as Stage 3, but the value of that SPECT helps requalify that patient as a Stage 4. This is important for the patient treatment. This is important for the clinical team to adjust treatments, okay? So that's -- and then the third point I want to emphasize which is important this time for the development and for us developing that product. Basically, it's really the value of those early images that help us inform and derisk to a good extent, the upcoming Phase I, which is now going to start very soon.

So I'm going to move to the next slide on Slide 10 and describe a bit the Phase I, which we are planning, which we are close to initiating. This is a Phase I/IIa study for small cell lung cancer and other neck neuroendocrine cancers. That study is a U.S. multicenter study and obviously, dose escalation around 712 monotherapy. On the bottom left screen, some important points. You can see on the blue part, that basically we have 4 dose escalation steps, so pre-compressed dose escalation starting at 75 mg, which is at effective dose already or close to effective dose.

And I really want to thank in a way, all the inputs from the Orano experience already on that and also the interaction that we are having with the FDA and also the good quality of the protection, which we had from our preclinical package. So nice, compressed design starting at effective level. Obviously, patients will all get an imaging first and then will be treated alongside 1 to 4 doses and the dose escalation.

First, we focus on the small cell lung cancer. And then the green boxes is that at some point, we will branch and open other neuroendocrine cancers in green when we are close to an effective dose on the blue part. So now if I move on the right part, there is still high unmet medical need in small cell lung cancer. That means that if we get the right benefit and risk, the right signal of activity and efficacy, which we hope and anticipate, we should be able to still take advantage of a path for accelerated review and approval through -- in second-line plus small cell lung cancer. So there is an avenue here. And if we drive quickly and right, we should be able to take that one.

Then below on the right, you can see that in complement to that, obviously, as soon as we get a confirmed signal, we want to branch and open evaluation of combination with immune checkpoints, which we believe that the mechanism of action of lead and alpha in a way is the optimal complement to immune checkpoint inhibition. And also, we want to open registration with other neuroendocrine cancers, which where there is a high unmet medical need too. So a compressed and let's say, accelerated path across those developments. So that was -- I'm going to move to the next slide, which is Slide 11. So one could think why DLL3, we have heard that, obviously, T-cell engagers are started to be approved, Tarlatamab and their ADCs. But in fact, when we speak to experts, there is high appetite for more modalities and specifically Radiopharma.

And why? Because all those 3 modalities first are potent and can act in low expressing tumor, low numbers. So that's -- they have that in common in a way. Then what we can also say is that in the T-cell engager, the Tarlatamab, yes, it's approved. Yes, it's helping patients. It's great. But it still is moderate response rate with a promising duration of response. We should not forget that there are side effects with T-cell engagers and not every patient can benefit from them and not every patient is a candidate from them.

And it's still -- it's going to move into first line likely. Then next to it, ADCs are promising antibody drug conjugate candidates and basically, they promise a fairly high response rate. But for every time that we've seen ADCs in development, there is -- the duration of response is up to 6 months. So -- and they likely would move in first line. So it really opens for this additional modality of Radiopharma, which we are part of. We would like to first enter in second line. And then we think that there is optimal mechanistical combination with immune checkpoints that could make us good candidates for maintenance in first line.

So that's -- there is space and there is value for this as long as we move quickly. So those would be the main points I wanted to deliver on that slide. And I think I can move to the next one, which in a way is a bit of a conclusion. We heard Patrick and Dani on the preclinical package and on the specificity of DLL3 internalization. But I really want to emphasize this point of images today, which are starting to deliver. And again, let's listen to what Mike Sathekge will present at the end of January. But this is really a very effective manner to inform and there is our Phase I and what we have seen so far is highly encouraging.

As also Dani mentioned, we have filed our IND. It's currently in review, and we are expecting an opening of the first sites before the end of the year and initial data to be generated in 2026. And I hope we will be discussing this with you in 2026 on the effect of those first cohorts. So that's more or less what I wanted to say. Let me thank -- I guess, first, I would like to thank our colleagues from Orano and who -- this is because of this partnership that we are there and so quickly. Then the NuMeRI team, which is really working hard on helping those patients and generating some information and precious data.

Patrick, maybe you want to complement that.

Sure. And first of all, thank you, Philippe, and thanks, Dani, for presenting today. Also my thanks goes specially to our partners and most and foremost, to Mike Sathekge, who had the trust to do this trial with us to the patients and their families that were in these trials. So we have dosed, I think, roughly 8 patients so far. So big thanks to all of them making that effort and being part of this trial. And I also want to thank really -- yes, you all for joining this call, for being with us, for joining the new chapter of radiotherapy with -- let me summarize my conclusion, let's say, in 3 dimensions.

I think first, we have MP0712, unique mode of action and really slated to become the leading alpha therapy in small cell lung cancer. With that, we open the opportunity to build a pipeline on similar targets. So we have a very good understanding how to now work with the low copy number internalizing targets and our technology. We have the capabilities on top of that to run this fast up to, as we now see, clinical data in a very fast, cost-effective way. And the next stop is really Phase I where we want to bring home that value in for the patients in the clinical trial opening in the U.S.

With that, thanks, and let's open for questions.

[Operator Instructions]

Our first question comes from Jonathan Chang with Leerink Partners.

First question, what is your latest thinking on where 0712 fits the evolving small cell lung cancer treatment landscape? And then second question, what are the key learnings from this presentation as you think about what other targets could be addressed by Radio-DARPin approach?

I can kick off and then maybe I think it's one for Philippe. So where do we think we will fit? So I think at this point in time, we -- as Philippe pointed out, I think in a second and maybe third line setting, sort of last line setting in this case, a fast-to-market strategy as there is still a very high unmet medical need. And when we speak to doctors, especially for T-cell engagers, the side effect profile can be inhibiting, but we expect that also our side effect profile should look superior to that, also allowing more an intervention than a full line.

But keep in mind, it's going to be 2, 3, 4, 5, 6 treatment cycles and you're done. So that's just one thing to think about. Then long term, ideally, as Philippe pointed out in a first-line combined with IO, this seems to be quasi-ideal. So we hope that, that's sort of also the most logical setting to run a trial showing the combination of alpha therapy with IO to gain really long-term control over these tumors. So that's where I personally hope this will go. So use the high medical need for a fast-to-market strategy combined with a first-line strategy in combination. And maybe Philippe will talk a bit about branching out into other indications than lung as I have read that DLL3 is the next HER2 where more and more indications are coming up.

Yes. Thank you, Patrick. So just to reemphasize what you said, there is high unmet medical need and no good standard of care in second/third line. That is -- small cell lung cancer has been a bit more up to very recently. There is a good glimmer of hope with the DLL3 coming in and Tarlatamab is helping the proportion of patients. However, it's only a proportion of patients. And it's both, in fact, either Tarlatamab or the potential ADCs in development will be moving in the first line.

We also know that there is like a preservation of the expression across lines for DLL3. So it's, in a way, it's inviting and there is that need will still be there in relapse. So we can start there. This is where we should start and there is -- where this is a quick path to approval. Then I think as Patrick was also mentioning, it's a lot about first line and maintenance. And we need to cure those patients or to keep them in a very long status in the maintenance part. And immune checkpoints are well established here. And in fact, likely all the biology points that radiation [indiscernible] immune checkpoint is a great duet. So this is likely where I would like to develop that drug just as we get enough of good signal in relapsed/refractory moving early in.

So that's still the small cell lung cancer part. Then if we look at the other neck and the more this area is now being researched and the more we find that the other 3 is relevant. So -- and there is not good standard of care, post first line in other neck. So those are the avenues where we can further develop those, and this is where we have a plan in our phase, in our expansion to start evaluating that signal.

Thanks, Philippe. Maybe I actually do love your second question, which is sort of posing towards pipeline build. So where does this leave us? And I think it actually the DLL3 understanding has really led to a renaissance of us looking at ADC targets. When the radiotherapy field started, everybody was saying, yes, yes, will be -- it's going to be like ADC. And it turns out that the short-lived peptides are very different than full antibodies because of the internalization that we actually presented to you today.

So we are in a position like to take the best of both worlds, so to take targets that are rather low copy number and internalizing fast as we did show and build a set of programs around those where we think simple peptides that are fast in, fast out are likely going to be missing part of the therapeutic window.

Next to that, we have targets that are just very difficult to reach with peptides like the [ mesofilling ] approach we're doing. And if you want in the third wave, we're also looking into bispecifics. Now I'm not in the room with Dani, but he is our Head of Radio Strategy. And I do want to give him the opportunity to talk about this because he's spending a lot of time on that. We literally have 3, 4 targets already in development lined up to be next. And that's really because we have built the capability to -- after we have a candidate, be able to test it with a compassionate care setting, as we have shown you now in a very fast way. But Dani, maybe you add a few words how you see the next wave, I think you call them waves of targets in our pipeline.

Thanks, Patrick. You summarized it really well. And I think for me, in the context of 712 and DLL3, the learnings we made how to piggyback on this rapid utilization, rapid replenishment of low-density target antigens has been extremely valuable in that sense. And for me, it almost becomes a strategic imperative to consider this for the future pipeline.

So that's why we've been starting and have already initiated activities looking at other ADC validated targets where we say the biology risk in that sense is low, but we can exactly try to duplicate what we've been seeing on DLL3. So that will be for us. I say this is wave #1, where I feel like we can execute very fast.

Our next question comes from Charles Zhu with LifeSci Capital.

This is Su on for Charles. How many grades of alpha particle radiation would you expect to have a therapeutically meaningful effect on tumors? And similarly, to what degree are you able to exceed the EBRT radiation dose limits on healthy tissues given the field's experience on renal dosimetry and updated radiopharmaceutical dosing guidance earlier this year?

No, that's a great question, and I will just quickly give the short answer, and then I possibly ask Michael or Dani to answer. And just to sort of -- I can now reference the advanced cell, very beautiful advanced cell data on PSMA. I think they started to see activity when they were dosing around, I think it was 100, 100 plus for even less [ mg ] . And that was in their second lowest dose or even lowest dose, lowest dose in stable disease on the prostate and second dose, it was already leading to very good responses.

Now we don't know how much tumor uptake there is at their dose and how -- and what their therapeutic index is because that is just not known. We just know how much they gave. And if we look at our dose, I think their lowest dose was 60, and we're starting at 75. So from that part on, we think we're really on par. Now how much they reach the tumor versus us, we don't know. And the second part is we also are comparing prostate cancer with a lung cancer. We also don't know. But I'll be happy -- and then the healthy organs, I mean, that is part of the equation, we will see.

I mean our hypothesis is strongly based on that the blood pool will be not toxic. We'll see a drop in blood cell count, but it will come back hopefully fast, that we can redose fast. That's what you see on the image, while the healthy organs look very, call it, healthy. I mean that's kind of the image we did show today. But maybe Michael or Dani, you're better on post to give the absolute numbers. I don't see if Dani wants to go first or Michael goes first.

No, absolutely. Thanks, Patrick, and I hope you can hear me. So it's very, very difficult to say and to be sure, but obviously, we designed the protocol together with all the experts believing that we reach this range as I say, also second, third dose. It's very important to have a safe dose delivered and hopefully, within the grades we are expecting to get, so the field has a huge range of numbers from, say, double digit, triple digit. So it's very, very difficult to say where we'll end up. But I'm very confident with the protocol we designed, we see what we need to see.

Dani?

Not much to add from my side. And I think one of the key questions will be for small cell lung cancer patients is like at which dose levels do they start to respond. And I think for healthy organs, we have a pretty good understanding in terms of EBRT limits. We can -- we know how much people are -- or other companies are going above these limits for their clinical trials. But tumor uptake and understanding at which level tumor uptake will be sufficient in terms of triggering the desired response. I think that's really something we will need to now explore in the Phase I trial, and we will be guided by the data.

Our next question comes from Mike Nedelcovych from TD Cowen.

I have 3, if you'll allow me. My first question is on the competitive landscape. Can you offer us key points of differentiation between your program and other DLL3 targeted radioligands in clinical development, such as the one from [ Addera ] or that from Novartis? And I know the clinical data for 0712 are limited at this point, mainly illustrative, but are there any early from the empirical data that suggests your program is indeed differentiated? That's my first question.

And then my second question is on your isotope of choice, lead-212. It seems like the most compelling image in terms of tumor to normal organ ratios is probably from 116 hours post injection. I think that several lead-212 half-lives later. So I'm just curious whether lead-212 is the right isotope to capture the DLL3 replenishment phenomenon that you described. And I'll stop there if there's time I can ask my third question.

No, thanks. All great questions. Let me quickly start with the differentiation. And let's start with the Mariana peptides. Mariana gets very nice tumor-to-kidney ratios. And I would say the best published data is 15% injected dose. So my guess is that is the max they will get versus our 60. And if you just do the math, a peptide that is not half-life engineered will just be able to load the cell once. So we think for these low copy number peptides, the half-life is not ideal. The idea of fast in, fast out is not the best way to go.

You might then dose several times that you could do or you have to half-life engineer the peptide. That is the peptide side. Then you have the [ Adhera ] data. And I think there, the differentiation is that [ Adhera ] as us, takes a longer half-life. We go with HSA binder, which we really hope and we see has a very clean blood distribution. The [ Adhera ] has an FT-type molecule, so it will bind to immune cells. And from the data that is published, you see a much more uptake in the liver. And keep in mind, we did show liver uptake. And this is because we have lesions in the liver. The livers of our non-lesion patients look very clean that I can say.

So from that point of view, I think we have a differentiation over the Mariana with half-life. And we have a differentiation of an FT-type approach by our HSA technology, which for us positions us at the, let's say, winning strategy in this approach. I'm not saying you cannot half-life engineer peptides, you can. But as of now, those are the 3 molecules in the clinic.

Then your other question is also super interesting. And I mean, we also looked at the images and said, yes, sure, this is -- why not test other isotopes. And in principle, there is nothing to hinder us from doing that. At the same time, don't underestimate the lead approach. As -- and Dani nicely pointed out that the uptake is also there. You just don't see it because the contrast is so strong. And in these images, you always go for a contrast. So if you would just take out the liver and cut off the blood pool, you do see uptake much earlier than what you think you see here. So -- and also Dani presented the fast uptake. We're talking 30 minutes. So within a few cycles, so within 10 hours, we see good uptake. It's just hidden behind the blood pool.

At the same time, you're also right, nothing speaks against the long list isotope like actinium that you could also use. What you would not likely want to use is lutetium because our blood pool would be too high and with the long pathway and the broad killing, you would have too much side effect. So you see a clean alpha strategy. You see a very good potential for lead and the upside, if you want, for other isotopes.

[Operator Instructions]

Our next question comes from [ Kiara Montorani ] with Bern [indiscernible] Kempen.

Congratulations with the update. So I was wondering if you could provide more color on what to expect from the first Phase I data next year, whether we are going to see some efficacy data points? And also, you have submitted the IND and will start Phase I year-end, pending regulatory clearance. I was wondering whether you foresee any risk there.

Can you repeat the risk question, we just acoustically couldn't hear the second part of your question. What type of risk do we foresee?

Yes. So you just submitted the IND and we start the Phase I year-end, pending the clearance from the regulatory FDA. So do you foresee any risk over here?

Yes. I think Michael speak to like what do we expect in, let's say, the first data set, but also how is, I guess, the question is and it reaches a bit after regulatory shutdown in the U.S. and our interaction with the authorities. I think, Michael, you are in almost a daily exchange. So I think you're best positioned to answer here.

Yes. Thanks, Kiara. And I indeed was in the U.S. last week at the conference. And obviously, logistics is a key challenge right now because not everyone is working. Many things have been piled up. So we are monitoring this very closely. Luckily, our supplies within the U.S., so we don't have to cross the border. Luckily, FDA is really doing a good job in turning around question. So nothing to look out from there. But should anything change, of course, this will have an effect. Also starting up sites, of course, everyone needs to be there, the usual routine. But we are very confident we have a very good collaboration and team size to say this should be possible by year-end. And again, we're very grateful to everyone involved who makes this such a smooth process. Philippe?

What I can add in terms of study dynamics, we are -- again, we learned a lot from our colleagues from [ Morano ] and there is a lot of interest on development in small cell lung cancer. So there is appetite. And what we have selected a team of investigators, it's a combination of, I would say, early starting sites, more on the private side, if I may say, and also academic side. So we have a good mix. And that's why we think that we should be able to have a good throughput. So that's that.

And I think you were also asking on when -- what type of data when. So again, every patient gets imaged. So we hope you know that when we start in January, ideally, we would be able to start seeing images fairly quickly and then patients quickly -- in small cell lung cancer, patients get quickly dosed. So I think that should develop fairly quickly in the first part of the year to get some early data.

Our next question is a follow-up question from Mike Nedelcovych with TD Cowen.

This question is on the regulatory path and supply chain. I'm curious if the trial enrollment and data cooperate and you can indeed pursue accelerated approval in the U.S., is it at least conceivable that you could have a registrational package in the next, call it, 18 months? And if so, do you think that the Orano Med supply chain will be sufficient at that time for a reasonable launch?

So I can start, thanks, Michael. So I have high confidence in Orano Med's supply chain ability. So I don't think 18 months is a problem. I'm not sure everything will go through smoothly. But of course, once we have data, we go again to the agency, some review, some learning. None of my programs has gone as fast as the COVID times. So if we had COVID times, I would say, yes, absolutely. Generally, I think it's more in the time frame of a year.

Okay. Well, I'm not showing any further questions at this time. I'd like to turn it back to Patrick for any further remarks.

No. Thanks again for this very good call for all the questions. We are excited to now be moving towards Phase I in the U.S. Obviously, shutdown is hopefully over, and we can progress fast. All questions are going in the right direction and next up will definitely be the Phase I.

Again, with the ambition to be the leading alpha therapy in small cell lung cancer and to branch out and build a pipeline building on this unique differentiation now with clinical imaging data showing the value of our platform. So a big day for us. Very pleased with the outcome and looking forward to generate value in lung cancer with 712 and building a pipeline beyond lung cancer. Thanks, and stay tuned, and we'll be in touch.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.