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spk04: Good day and welcome to the Molecular Partners fourth quarter and full year 2023 results conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on a touch-tone phone. To withdraw your question, please press star, then two. Please note this event is being recorded. I would now like to turn the conference over to Seth Lewis, Senior Vice President, Investor Relations. Please go ahead.
spk05: Thank you, Betsy. And welcome, everybody. Good morning and good afternoon to the 2023 full-year earnings call for Molecular Partners. My name is Seth Lewis, Senior Vice President of Investor Relations. I wanted to just go over a little bit of housekeeping before we began. Obviously, we are speaking today in reference to the press release, which was issued after the close of market yesterday, as well as the full year annual results, which are in the annual report, which can be found on our website, molecularpartners.com. And we'll be making reference and prepared remarks today to the presentation, which slides are also available under the investor section of our website, molecularpartners.com. If you are following along in the presentation, I will refer to you, we are going to make certain forward-looking statements today, and I would refer you to our latest filings and most recent filings with the SEC and with the SICs. For the sake of the replay today, we are recording this on March 15th, 2023. If you were on slide three, I just wanted to take you through the agenda briefly. We are joined today by multiple members of our management team, including Patrick Amstlich, our CEO, who will take you through both the highlights of 23 and the outlook for 2024. Robert Hendricks, our Senior Vice President of Finance, who will go over some of our financial numbers. Philippe Lejeune, who is our Acting Chief Medical Officer, who will touch on our MPO 533 program in AML MDS. Anne Goubier, our Senior Vice President of Research and Early Development, who will discuss the Switch DARPN technology as well as our C-Kit program. And Danny Steiner, our Senior Vice President of Research and Technology, who will touch on the Radio DARPN platform and the DLL3 program. With that, I will pass the call over to Patrick. Please go ahead.
spk10: Thank you, Seth, for the introduction and kicking off our full-year earnings call. and also a warm welcome from my side to all the audience on this call. And it is a special pleasure today to be here, not only with the usual suspects, Robert and Seth, who are usually joining these calls, but also to have Philip, Anne, and Donny on the call with me, as they are the ones who are really driving the progress of our programs, and they will be speaking about that progress here today, and that's a special pleasure. to see the team coming together and move molecular partners forward. I'm now moving to slide number four, and I will start with a short recap of what we do and how we do it. The DARPN is a novel therapeutic modality, a novel class that we have validated in more than 2,500 patients in seven clinical, with seven clinical compounds. And the DARPINs are different to other modalities, so not antibodies, not small molecules. They're at a size, maybe a tenth of an antibody, and they're really well applicable for multi-specifics. And our quest is to use the DARPIN difference to turn that into differentiated drugs. So what we do is we create unique DARPIN solutions to clinically validated problems that are of high medical needs. So true patient value means high medical needs. And we termed the early clinical readout that you can translate into similar agent activity as when we move a drug into development. We also will want to know if it works or not fast. And as we are working in many different fields, we love to work with partners that we don't have to reinvent the wheel. And that is why that main molecular partners and our strategy on partnering with those or collaborating with the world class partners is part of the strategy. I'm moving to slide number five. The 23 was an exceptionally productive year with progress on literally all of our programs. And those who are working in our field know that that's usually not the case. Often one has a setback in one or the other program. But this year, every single one was moving forward at speed and producing the results we were looking for. First and foremost is MPO533, our tetraspecific T-cell engager. A year ago, roughly, we dosed the first patient. At ASH, we reported good safety and efficacy of the first four cohorts, and today we are recruiting, or we have fully recruited those cohort six. On the Switch platform, we were able to nominate the first target, and we're working towards a candidate, and we'll talk to that. And we are absolutely excited, as the Switch concept is something that is very dark and unique. And you will see we will be able to target targets that are not easily accessible other ways. On the radiotherapy side, this is a whole field Molecular Partners is heavily investing in. There is two key breakthroughs after last year. One is the reduction in kidney retention or accumulation, and we were able to now increase tumor uptake by engineering the half-life. We were able to strike a collaboration with Oranomet, providing lead also for our lead asset DLL3. And we have progressed with Novartis on the targets and programs we're working with them. Those are two distinct targets that are exclusive to Novartis. 317, we have advanced through phase one. We have those several patients and could see a favorable and strong safety profile. And we have biological proof of concept showing activation of antigen-presenting cells and remodeling of the tumor microenvironment. And we end the year with 187 million, and this brings us well into 26, meaning we are capitalized to reach key value inflection points. Moving to slide number six, this is the pipeline chart and sort of is my agenda for the next, for the call. 317 I did speak about, that's the antigen presenting cell activator. This molecule has little single-agent activity. It is ideally combined with other IO drugs. That's why this is on the partnering track, and I will talk to that in the summary, but we will not cover it in the presentation itself. 533, Philip will talk about, and we'll talk about the switch start pin and explain that, and Donia will cover the radio piece. With that, Before we go there, I will hand over to Robert to share the financial overview.
spk07: Thank you, Patrick. With that, I'd like to run you briefly through the key figures of last year's financials and the guidance also for the year 24. My name is Robert Henrich, and I'm the VP SVP Finance at MP. The numbers I present here are stated in million Swiss francs, and I'm on page eight at the moment. Three numbers, it's a full slide, but three numbers in particular. First one would be the revenue. The revenue of $7 million this year is exclusively related to the agreement we have with Novartis on the radiolegan therapies, as indicated. Part of this number is a recharge of research FTE, and the other part is a recognition over time of the upfront of $20 million that we received under the December 21 agreement. Under that last element, we still have around $4 million to be recognized in 24. The revenue number in 22, as you may recall, largely related to the funds we received from Novartis in early 22, upon their exercise of the option under the Insobeb License Agreement. Second number I'd like to point out would be the operating expenses, total of 68. The guidance that we provided during last year was 65 to 70. and the expenses ended right in the middle there. For further breakdown, the R&D share of this number amounts to $49 million and the SG&A number to $19 million. You can see that the overall costs have been reasonably stable over recent years. It's fair to say that the reduction of just over $4.9 million last year related largely to a lower expense for the listing of the company in the U.S. as well as a natural attrition in headcounts. The third number, as already pointed out, would be the cash balance of 187 million. You can see that's down from the 249 end of last year, so an effective burn of 62 million. This amount will carry us well into 26, and we consider this continues to put us in a privileged position in the industry. Also like to add and remind here that the company remains without any debt. We feel that these three numbers tell the financial history of MP in 23 and the solid financial state of the company. If I then move on to slide nine on the guidance, we will guide on the operating expenses only, not on revenue or any other metric. We do guide for a total of 70 to 80 million, of which around 8 million are non-cash. For clarity, this guidance is, as always, subject to the progress and changes of our pipeline and excludes any potential payments related to partnerships. To summarize and conclude, what I think is most relevant to recall from this overview is the continued solid financial base entering into the year 24 that will allow us to continue to invest in our pipeline and to bring drugs to patients. Thank you for your attention. Happy to take any questions during Q&A later. And with that, I hand to Philippe, who will provide an update on NPO 533. Philippe?
spk02: Thank you very much, Robert. and good morning and afternoon to all. I am Philippe Lejeune, the Acting Chief Medical Officer at Molecular Partners. I'm happy to share an update on our MP0533 program in AML, including some learning from the dose escalation trial. Looking now at slide 11, I want to remind us that AML remains one of the most deadly cancers where despite initial frequent responses and reductions in blast, the persistence of leukemic stem cells drives the frequency and quick relapses. A major challenge for design of therapies in AML is that individual AML blast and leukemic stem cells lack a single clean target. However, the opportunity is that AML cells can be differentiated from healthy cells like hematopoietic stem cells by their co-expression of specific agents or specific targets like CD33, CD123, or CD70. Moving to slide 12, we have designed MP0533 DARPIN treatment as the first PETRA-specific T-cell engager binding to tumor antigens CD33 CD123 and CD70 on the ML cells and to CD3 on the effector T cells. MP533 is designed to induce T cell-mediated killing preferentially when two or three target antigens, CD33, CD123, or CD70, are co-expressed. Per such design, MP0533 is hypothesized to preserve healthy cells, hence opening a broader therapy window that has been seen for other T-cell engager therapies. MP0533 has the potential to kill all AML cells, the BLAST and the leukemic stem cells, despite heterogeneity translating into long-term disease control. Moving to slide 13, we can see that this scientific hypothesis of creating a therapeutic window is demonstrated on MOM13 cells, describing on the graph the low potency on single antigen-expressing cells versus 100 times more potency when antigens are co-expressed on the cells. This data, alongside with additional clinical experiments, Sorry, there is an ambulance just passing. Just one second, please. OK, so I was just saying that this data, alongside with additional clinical experiments, including AML patient samples, will be published in the next coming weeks. Focusing on slide 14 now, the CP101 dose escalation studies in patients with relapsed refractory EML and high-risk MDS is ongoing and has now recruited the first six dose levels across... Can you hear me?
spk10: Yes, we hear you.
spk02: We do hear you, yeah. There's a beep. There's a strange sound coming up. Okay, there's a beep. Okay, so I was just saying that, you know, the study, the phase one, has now recruited the first six dose levels, across nine sites and four countries. And the preliminary data was reported at ASH 2023 from the first four cohorts as Patrick mentioned earlier on. Moving to slide 15, this slide refers to the safety profile of this population of elderly, heavily pre-treated patients with comorbidities, but this has been manageable. The most frequent treatment-related adverse events reported are infusion-related reactions, and cytokine release syndrome with no DLTs reported to date. This is important to mention. Slide 16 reports evidence of clinical activity, which was presented at the last ASH, and you can see that in each cohort three, of dose level three and dose level four, the patient achieved ELN response of MLFS and CR. by 17, summarizes the near future and some upcoming changes to our study design. Indeed, we are planning to initiate soon the last seventh dose level upon the dose escalation committee review. We are also submitting an amendment allowing to increase the doses even higher as the safety profile has been so far manageable. And we want to evaluate how higher dose could impact target saturation and onset of response further. We also want to evaluate the impact of adding another dose at day 12, as you can see in the little square, to see if we can even increase the impact on the ML cells as early as possible. We look forward to sharing with you an update on the program at the end of H1 and more data later coming up in 2024. I'm now handing out to my colleague, Anne, who will update you on Project 580, which is aiming at a complementing need in the treatment cycle of AML patients. Thanks.
spk00: Thanks, Philippe. And good morning, or good afternoon, everyone. In the coming slide, I will show you how DARPins can further change the game for AML by significantly enhancing the therapeutic outcome of hematopoietic stem cell transfer. So, like we moved to slide 19, As you know, HSCD is potentially curative for ML patients, but a lot of patients relapse, and conditioning regimens are highly toxic, encompassing GVHD, organ failure, sterility, or secondary malignancies. So one can apply reduced intensity conditioning, but then the risk of relapse is higher. So our developing solution aims at delivering a safer and more potent conditioning regimen for HSCD, with the potential to transform treatment in AML and other conditions. So in order to understand how this works, let's skip slide 20 and go directly to slide 21. The key issue with cure and conditioning regimen is that they are not targeted, leading to bystander toxicity and ultimately lower potency. So our solution is to target CKITS, early expressed on hematopoietic stem cells and leukemic stem cells. The challenge here is that, as we know, blocking CKIT binding to its ligand is not enough for the hematopoietic stem cell depletion. You need to induce killing of the CKIT-positive cells. And for this, we are leveraging our CD16-engager proprietary platform, which holds the potential to be safer than a CD3-engager or ADC and to be more potent than an antibody by targeting the activating FC receptors and not the inhibitory receptors. Remains one challenge is that the macrophages are limited in their activity by the don't-it-me signal delivered by CD47. So the solution to that seems obvious, which is blocking CD47, but as you know, CD47 bloating therapy has been limited due to the high toxicity linked to the expression of CD47 on LC cells. So our solution is a conditional CD47 blocking, which will ensure that CD47 is blocked only on CKP-positive cells. And for this, we are leveraging our switch DARPIN technology, which makes sure that CD47-blocking DARPIN remain masked when CKP is not expressed. and that CD47 is blocked when cyclic is expressed. So I will not go into detail of the mechanism, and if you are curious about it, I invite you to go to our website. There is a very educational and very clear video that explains the depth of the mechanisms. But now let's move from the theory to real data. And in the coming two slides, I will show you that the switched harping is indeed safer and more potent. So slide 22 highlights the power of the switched harping for conditional blocking of CD47. So what you are looking at here is the percentage of free CD47 on cells. So what it means is that this line decreases when CD47 is blocked. So when you look at the light blue line, which is cyclic negative cells, you can immediately see that there is no CD47 blockade until very high concentrations. So this tells us that at physiological concentration, the molecule will be inactive and thus safe. The dark blue line illustrates the cyclic positive cells. And here you can see that silica-47 blockades start at very low concentration. So when you compare the light blue and the dark blue, there you see the depth of the therapeutic safety window, which is here more than three log in concentration between the CKIP-positive and CKIP-negative cells. So the conditional blocking of silica-47 ensure a high safety profile. Now, how about a thick acid? The slide 23 shows the therapeutic potential of our SeqIP switched DARPIN, and I would like you to focus first on the dark green bar, and this illustrates the phagocytosis induced by IgG1 antibody. So as expected, an anti-SeqIP IgG1 antibody does induce phagocytosis, but you can immediately see that this phagocytosis is limited in intensity, especially compared to the dark blue line, which represents the switched DARPIN. And this tells us that we can expect a much deeper hematopoietic stem cell and leukemic stem cell depletion in patients with the DARPin as compared to an IgG1 antibody. So, of course, you could combine this antibody with a CD47-blocking antibody like Magrolimab. But as discussed earlier, you will face a high safety hurdle. And on top of this, as you can see here, comparing the light green to the dark blue, you are not as potent as what we see with the DARPin, most likely linked to the fact that in the DARPin, both CD47 and CD6K targeting are in the same molecule, and then the same synapse, and both benefit from anti-CD16. So this data showed us that we have a molecule that is not only safer, but also more potent than anything you can obtain even with a combination. So next step is a cyanoefficacy study, and the beauty of this study is that it is perfectly translatable to the human setting, from the doping regimen to the safety and efficacy against HSC. We're expecting data from this study in the second half of this year, and planning to be in the clinic in 2025. And with this, I'm very pleased to hand over to Danny, who will introduce you to another groundbreaking aspect of DARPing technology, the radio DARPing.
spk08: Perfect. Thank you very much, Anne, and welcome everyone from my side for this call. So it's a pleasure to, on behalf of the team, give you an update on our radio DARPing therapy platform and respective pipeline assets. So as probably all of you know, the field of radiotherapeutics is experiencing a lot of excitement, push, driven all by strong clinical efficacy and good tolerability data that first compounds on the market or new emerging compounds deliver. What is limiting the expansion of this amazing promise to other cancer types is vectors that are matching targeted radiotherapeutics requirements. and allow a broad target space to be common. And that's exactly where we saw the benefit or the opportunity to come in this diagram. If you move to slide 25, so just for those of you who are not familiar with radiotherapeutics, the ideal properties of a radiotherapy product candidate are to deliver the radioisotope selectively to the tumor while sparing healthy tissue. And there's a special focus on kidneys and bone marrow, bone marrow being very tightly connected to blood levels, which are the most dose-frequent, dose-limiting organs. If you move to slide 27, 26, apologies. On the left-hand side, if you had a target in mind with a cavity where a low molecular weight compound vector with high affinity and specificity can be identified, this is perfect. This is the ideal targeting moiety. The problem is that there is very limited target where this exists, where this possibility holds up. So to open up the target space, the most proven class of a class are protein-protein binders where you can generate high affinity and specificity binding proteins that bind surfaces of a broad range of tumor targets. And to this class belong the monoclonal antibodies and antibody fragments and all other small proteins. The problem here is that all of these protein-protein binders have key limitations for the effective and safe use as radiotherapeutic vectors. For antibodies, the high or long systemic half-life, high life is leading to bone marrow toxicities, and the size is leading to a limited tumor penetration. And for the small proteins, they are limited by kidney accumulation and lower tumor uptake. So please remember those two elements, high kidney uptake and low tumor, high kidney accumulation and low tumor uptake. This is the dimensions where we felt looking into the molecular properties and biological mechanisms behind this, the team had the strong conviction that the DARPIN platform is ideally suited to exactly building on the unique properties of DARPINs to overcome these challenges. So if you move to slide 27, so this is just like showing you the engine that the team has built for building our radiotherapy therapeutics candidates. Starting from the left-hand side, the starting point is as for all our projects, building a diverse set of high-affinity diapins against a specific target of which, where you see, and that's always the lower graph, These diapins, they nicely accumulate in the tumor, but at the same time still have very high kidney levels. So in the next step, we address the first limitation, the kidney. So what we've been building is what we call stealth design, which I will show you more data, a bit of data on the next two slides, where we reduce the kidney level down to below 25%. As a next step, we are addressing the second limitation, so we're bringing up the tumor load by using our Half-Life toolbox specifically built for radiotherapy and therapeutics, increasing the tumor uptake while keeping the systemic exposure low. And if needed, as a last step, we're building, we're increasing affinity of the respective binders to ensure tumor retention. So the novel two aspects of the radiotherapy therapeutics engine are the two middle ones, step number two and step number three, and I'm going to show you a bit more of data to these two points. So if you move to slide 27. Please focus first on the upper right side cartoon where you see this is what we call a normal or parental diaping. What happens if that diaping gets excreted by the kidney? It gets into the primary urine. Here, as all other proteins as well, it's reabsorbed. You get a lot of radioactivity into the kidney, and this is called kidney damage. What we've been building on is the extremely robust architecture of the diopin scaffold, heavily reengineered the whole backbone, and we call this the stealth diopin. And this is now basically not recognized by these cells in the kidney anymore, and the diopin with its radioactivity is directly excreted into the urine. If you move to slide 29, I'm showing you some in vivo data supporting the strong kidney reducing effect of the stealth diet pin. So if you look at the left hand side first, this is the example of our front row runner program on DLL3. So we successfully engineered three out of three diet pins in three to four iterative engineering rounds, each of them taking three to four months, including all the production down to the in vivo testing. Now, if you move over to the right-hand side, you see after integrating all these learnings from the first program, we manage for new tumor antigens for three out of four diapins within a single round. We manage them to bring them down to low kidney levels. So what I wanted to take home from this is that we really established a robust, reliable engineering solution to bring kidney down to low levels. So moving over to the second challenge, I'm showing you how we addressed the key limitation of tumor uptake, and this is where we used systemic half-life extension to increase tumor uptake. Focusing on the left-hand side, so you always see two examples here on HER2 and DLL3. On the left-hand side, you have like the naked stealth diaping, which shows a tumor accumulation in the single-digit percent range, very low blood level or non-detectable blood level at these time points. And then if you go over to the right-hand side, we applied different half-life extension noieties leading to very low or low or medium and increasing systemic exposure. And this nicely drives the tumor uptake up to a 30% on the tumor. And please keep in mind, all of these molecules have much lower systemic exposure compared to an antibody. So quickly summarizing, quickly summarizing. So the stealth darpene for reduced kidney accumulation and the half-life extension for increasing tumor update is the basis of our radio darpene therapeutic engine and basically the basis to build our pipeline. In our pipeline, we have two targets with Novartis, then two targets with Oranumid, including DLR3, and quickly expanding on Oranumid, extremely happy with the collaboration that we've already started one and a half years ago, amazing team, great capabilities, great expertise, and also there is like very strong data emerging on LATCH212 as a radio client of choice in this specific case. And then we have additional targets which we are moving ourselves, which are not partnered at this current point in time. So we are looking very much forward to sharing more data at key upcoming conferences in the next month. Months to come. And I'm finishing here. Happy to answer questions. Then in the Q&A session, I'm handing over to Patrick for the outlook.
spk10: Thanks, Donny, for the exciting overview that we have on the radio space. And before opening for questions, let's just look at the outlook. It's a really exciting year that we have ahead. And I will start with the first and foremost, most exciting one, which is 533, our AML drop. We're excited to look into the first data with you of those course five, six, and a taste of seven still in the first half. Give obviously the protocol amendment a push that we get that through that we can then go to higher doses and share with you what we are developing in very close collaboration with our KOLs. A strategy that goes beyond relapsed refractory, but where else would one apply this molecule? And there is clear need in this indication, and we're starting to understand how we would also move forward beyond relapsed refractory. On the switch or CK side, it's clear we are striving fast toward candidate selection. We will talk about that still in the first half of this year. Then, as Anne has pointed out, it's all about the non-human primate study. We will report the data second half of this year, and I think this is maybe the most translatable data or value we ever had at Molecular Partners. So we are convinced that if we see strong data in non-human primates, the risk or the ability to translate that, the risk is low, the ability is high to translate that into patient value next year, meaning in 25 already. From Donny, we heard on the radio platform, it's all about the first candidates. We want the DLL3 also first half of this year that we can then move into IND-enabling studies and see the first in human data next year. We will add, as Donny said, the platform is ready. We're moving forward, add new targets and additional candidates. And in that side, it's also a mandate to us to broaden the collaborations, and move the ones we have forward. 317, I think we have recruited the last patients. We're still kind of in the trial, but we are expecting to close that, clean the data, open the data room for partnering, and advance those. And just to remind you on our cash position, we are well financed with 187 million in cash. That brings us into 26. capturing all those value inflection points that I pointed out. With this, I want to thank you that have been listening to the call. I want to thank the team here. I want to thank Seth, Robert, Philip, Donny, and Ann for presenting today. I want to thank the entire molecular partners team. It has been an exceptional year. It is hard work and also great team spirit to work here. is a pleasure and the hard work comes easily if you work in a great team. I do want to thank all our partners and especially our KOLs running the trials and the patients in those trials. And with that, I would end the presentation part and open the floor for questions.
spk04: We will now begin the question and answer session. To ask a question, you may press star then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then do. At this time, we will pause momentarily to assemble our roster. The first question today comes from Richard Vosser with JP Morgan. Please go ahead.
spk03: Hi, thanks for taking my questions. Two on MP0533, please. Just whether you could give us any additional colour, I suppose, the first question on, you know, what you're seeing and what has led to the, what is more important than leading to the further dose expansion, whether it's, you know, the safety profile is clearly very benign, which is great, but, you know, Is there a sense that efficacy needs higher doses? Just some context of that, if you can. Second question, maybe just sort of an idea of how much higher the doses are, if you can say about that. And thirdly, when should we think about that phase two enabling decision? Is that more in 25 or is that more in the second half of 24? just some color there would be helpful. Thanks very much.
spk10: No, thanks, Richard, for the fair and good question. So maybe just a bit color on the doses. And when we started the trial, and obviously Anne and Philip can then follow up on that, but the highest dose was calculated with knowing that we would only reach around 80% receptor occupancy in the bone marrow. You have to know in the blood is one thing, but then you have to penetrate into the bone marrow where you expect also the leukemic stem cells and others. And so we're just kind of looking at other T cell engagers that were held back by safety. We designed the trial and the top dose was 80% receptor occupancy. So the news that we can go to higher doses is definitely helpful because you want to go beyond that. you want to go to 90 or above, which gives you then hopefully an even more complete killing of these cancer cells, especially the leukemic stem cells. Now, if this is needed or not, it's too early to say. We're in dose range six. We continue to see activity of the drug, but to understand if the dose response is there and we get a better and deeper and prolonged killing of these cells, We cannot comment today, and we also said we would not piecemeal the data, so you'll have to be patient until we give that update, and that will be obviously where we will be looking. And keep in mind, it's also about this MRD, so minimal residual disease, so we will be following the clones, so the clonality of disease, and see if we can be killing the high-risk clones, as those are the ones which drive relapse fast. So it's more than just the response rates, it's really understanding what the drug is doing also in the bone marrow. Maybe I'll quickly pause there on that one. Maybe Anne, she's nodding her head, I think I covered well. So maybe I'll just. On top of that add, why Philip was pointing out that we want to dose escalate or kind of dose escalate in faster. So you know we have a step of dosing and we are adding an additional step in there to reach the higher dose faster. And that is something in the first patient you saw we had efficacy and we saw deepening over time. Now one point that has been pointed out by our KOLs, could you go in an earlier line setting to kill remaining cells after you have a complete response, but you are still MRD positive, so you still have some leukemic cells, leukemic stem cells, could we kill those fast? And obviously this could even be before transplant, and there you don't have three months where you want to wait, so you need to be fast. This is already implementing some feedback we're getting from the KOLs for an earlier line where this would ideally be in two, three weeks we have the full efficacy. And that's why we are excited to be able to look into that to a steeper dose escalation. And that also goes back to your first question. I mean, we see good safety. So that's one or the key driver that we can do that. So we think The molecule allows us to explore kind of where the realms are on safety, and we do see CRS. I can also tell you we do see T cell activation. So we have the biomarkers there. So all of that is hinting that the molecule is doing its job, and we need to find out how we can tune how we use it to get the best patient benefits.
spk05: Patrick, just one thought there, and then we can allow and move on to the next question, but also to one last piece of Richard's question as far as dosing. While we haven't disclosed dosing, I think it's fair to say, and we have said before, that where we are now in dosing, we are either at or above where others have gotten to when it comes to bispecific antibodies with T cell engagers, certainly. but I don't think there's additional comments there, but I wanted to just open it up.
spk10: I often miss the obvious ones, so thanks for pointing that one out. All good.
spk05: I just wanted to, I know there's others in the queue.
spk10: The last point of Richard was what will be gating, and I think there is definitely two things. One is what is gating to go on in relapsed refractory, And we have clear cutoff criteria there. And I was talking about the clonality and how we kill those clones. And that will be likely a gating mechanism. Do we move to earlier lines or not? We're working on that. This will be part of the update later this year that we really share the strategy. You now heard a bit in which directions we are thinking. And I can tell you it's a very good and close collaboration with the KOLs. Richard, I hope that was covering your points.
spk05: I think we got it. Operator, I think we have another question.
spk04: As a reminder, if you would like to ask a question, please press star then 1 to be joined into the question queue. In the interest of time, we ask that you limit yourself to one question and one follow-up. If you have additional questions, please re-enter the queue. Your next question comes from Mike Medelkovich with TD Cowen. Please go ahead.
spk06: Thanks for the questions. I have one on MP0533 and then one on the SWITCH DARPN platform. So for MP0533, when we get the updated interim data from the phase one trial in the first half of this year, what are you hoping to see? What level of efficacy in a given dose cohort would you consider a success? And on the expanded dose cohorts, is there a chance that we get those data by ASH at the end of this year, or is that more likely to be a 2025 event? And on the Switched ARPAN platform, can you describe the broader strategy for the platform? So the first targets would seem to be relatively de-risk, but perhaps a smaller indication. What are other good targets for this approach? In a blue sky scenario, what indications might you go after?
spk10: Hey, thanks for the question. I think I'll just hit the first one and then hand quickly over to Philippe. But I think I personally see two cutoffs. And if we, or where we will stand in the first half versus second half in the dose escalation, we will see. But we always communicated that for relapsed refractory settings, so the patients we see today, that's where we're aiming for a roughly 30% response rate with well beyond three months disease control. As I was pointing out, if you want to move to earlier setting, it's really about this MRD conversion. Can we also kill the difficult-to-kill clones? So those are the, in very short, the elements we're looking for. And maybe, Philip, kind of you're closer as you may comment on more, a bit more on safety, talking to these KOLs on a daily basis.
spk02: Yes. Thank you, Patrick, and thanks for the question. First of all, I just want to reiterate that what is really the position of strength is that the agent seems to be very well manageable and tolerated so far. So it shows CRS, it shows IRRs, but enough to make us confident that it's doing something, but little enough that we are still within safe boundaries. So that's the position of strength, and this is why we want to keep Optimizing it, we want to densify in the first cycle and we want to go higher to make sure that we give a chance to as many patients as possible to reply. Because again, we see activity, but we want to see a maximum of activity in most cohorts. In terms, I also want to say we are working on fairly large, those escalation cohorts, six to nine patients so far. So those can give us some good level of learning. And then the question is, when are we going to get the next important, relevant batch of data? And it still is a bit tricky to say because, in fact, we are hoping to go higher, as was said already. And it will depend, you know, at some point potentially it will hit the DLT so then we can expand immediately. Or at some point we will see that it's not worth going higher because in fact we have saturated, you know, all the targets and we have maxed out what we think is a reasonable goal for activation. But all of that, as you know, It takes a few months before we get the final translational data that can really guide us for that. So it depends a bit on what we are going to see in Core 7, potentially 8, 9, or even higher, to really understand when we can trigger the expansion and also the movement into the earlier line, which is a goal. Thanks.
spk05: Thanks, Philippe. The last question, I think, was for much more Anne on the switch and blue sky scenario. I think that's a wonderful question to ask somebody in early development, so I'm excited to hear Anne's thoughts.
spk00: Yes, thanks. As you rightly pointed out, SICKIT, DARPA, and switch is just a starting point. And, of course, there is a broad applicability for this platform. You can think of it from a target point of view because here on the SICKIT, it's just a first step. Now you can think that you apply this platform with Anne Gate. So you need two targets to be expressed to initiate your therapeutic activity. So from a target point of view, you can revive well-known targets that have been stopped or have been limited due to their expression on their systems. So, I mean, a good example is, for example, or this kind of target where they are beautiful, they are expressed on the large tumor cells, They are very highly expressed, but they are limited by the fact that they express on LC cells. So thanks to the switch, we can allow gating and make sure that we wouldn't do the killing on the out-cancer cells. The second thing you can do with this platform is allow different effector motility and make them safe. Like seeing just about CD3 engager, making sure that your T cells are engaged only when your targets are expressed. Or it can also allow using co-stimulations. If we think, for example, CD28, which carries very high toxicity risk. Now you think and you think that this will be activated only when a set of two targets are expressed. So you are opening a broad field of applications that honestly go even beyond that we can do only ourselves. So this is where also we will be looking for partner to completely exploit this switch platform.
spk09: Thanks Anne.
spk04: The next question comes from Kathleen Silverman with WeRank. Please go ahead.
spk01: Hi, team. Thanks for the question. I am on for Dana today. A bit of a tag on to Michael's question from TD Cowen. The scenarios for potential stock movement on the first half 24, 533 interim dose exploration data, if I break it into thinking at it as a layering and a floor, The layering being what's your conviction and potentially seeing like some other CD3 T cell engagers have seen a belt shaped response or some have called it a step up response. And do you think there's a reason to maybe think about seeing that at this does cohort five level? And then the last one, which I think you've pretty much nailed is the floor scenario, which was Michael's question. So in the relapsed refractory data, knowing that durability will be immature and you are targeting getting eventually in a larger trial over three months as a threshold in this current cut that we'll see in the first half, are you going to be sharing those directional signals like the MRD and the biomarkers of T cell engagement? Thanks so much.
spk10: Yeah, happy to go on the first. I do think our molecule looks different than the other T cell engagers. So we also, just on the safety side, we have really been able to dose to these doses that are above what competitors have been doing. So we also hope to have a bit of different response profile and to really be able to control disease. And as you rightfully pointed out, we will not be, obviously, it's just a matter of time, be sitting on data of several months follow-up. And you also pointed out that MRD level can be a good surrogate marker on the depth of effect that then directly links to duration. And yes, we will definitely want to update on what we have. But keep in mind, clonality of the disease, it always takes time. You have to follow it over time. So it will be a limited data set, but we want to share what we have and how that leads to the decision-making at molecular partners to then further invest in the molecule. And it will be an interim update. Thanks.
spk04: The next question comes from Flora Zinnerman with Octavian. Please go ahead.
spk09: Hi, I'm Flora Zinnerman from Octavian. Congratulations on all the progress, impressive, and thank you for taking the questions, one on the RDT platform and one on MP0317. On the RDT platform, you've announced two partnerships, but also you have two internal assets or targets. Can you shed a bit more details on your plans that you will follow up with the two internal targets and any potential partnering you see there. And then on MP0317, where do you stand there and when can we expect the next update, any potential partnerships announcement? Thank you so much.
spk10: Thank you. And I'll quickly take 3.17 and then hand over to Donny to talk about the radiodarpin and our internal targets and isotopes and everything. So 3.17, as I said, we are literally finalizing the trial. We are filling the data room with all the data, and that should be open, I guess, as of next month, allowing interested parties and partners to look at that. I do remind ourselves that at the moment the I-O combinations are not at the peak. We were joking that a few years ago this would be a multi-million or multi-hundred million dollar upfront. Those times are not now. So we are really looking for a partner that commits to the program, runs several combination trials, and we're not going to try to optimize the selling price, but more that a partner can run these combination trials. And it's always very difficult to comment on timing. With this, I would hand over to Donny to talk about kind of the internal undisclosed targets and our thoughts on sourcing of isotopes and other partnerships.
spk08: Yes, thanks for the question. So maybe I start zooming out quickly on the target. Our aim for peaking the target is, of course, driven first from the medical needs side, but also then there. We are zooming into targets where we feel like those are very difficult to address targets with certain, I say, biological or microbiology requirements that need to be met in terms of specificity, what part of the target do they address, location of target expression, so all elements playing into this, and we are very careful about nominating and picking those targets. So we have internal programs ongoing where we say like we love to move them to a point where we say we have like this, I think, almost like proof of mechanism, proof of that we can really match those profiles well. And then afterwards, we have We would love to keep that element of freedom to decide ourselves, are those targets which are ideally suited for a short half-life, short-range alpha meter like lead, we really like lead from its profile, or would we better go into an extension into other collaborations where we more build like on long-lived alpha emitters or even better emitters if indicated by the respective tumor indication by the respective tumor biology. So we keep it open for now, but we're definitely not only focused on lens. Thanks, Danny.
spk04: As a reminder, if you would like to ask a question, please press star then 1 to enter the question queue. This concludes our question and answer session. I would like to turn the conference back over to Patrick and Sus for any closing remarks.
spk10: Again, I would like to thank my team here for all the work and all the great Q&A and shedding some light on the questions. I would like to thank you for your attention, all the good questions that we got. I think it's clear we're heading into a very data-rich period with a lot of also strategic work on the background linking the data to decisions. We will be working internally and be closely communicating with all of you to share what we have and how that forms a decision and especially the investment potential that we see for the cash we have and are truly excited to be bringing forward differentiated DARPIN therapeutics for the patients that today have no good treatment options. And with that, I would like to end the call. Thanks again. Take care and speak soon.
spk04: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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