Molecular Partners AG

Good morning and welcome to the Molecular Partners fourth quarter and full year 2024 results call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing star then zero on your telephone keypad. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. 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 and Strategy. Please go ahead.

Thanks, Drew. And welcome, everybody, to the Molecular Partners year-end results in the 2024 highlights call. My name is Seth Lewis, and I'm joined today by members of our senior leadership team, including Patrick Anstrutz, Chief Executive Officer, Robert Hendricks, SVP of Finance, Philippe Lejeune, Chief Medical Officer, and Michael Stumpf, Executive Vice President of Projects and Head of the DLL3 Radio Program. The team will make some prepared remarks, and then we will open the call for your questions. If you haven't had a chance to see the press release issued yesterday after market close, you can find it on our website, www.molecularpartners.com, where you can also access a copy of today's presentation. Today's fault is being recorded and will be available for replay. Before we begin, I'd like to remind you that management will be making forward-looking statements about the future development of certain programs. These statements reflect the current estimates in Molecular Partners and are subject to change. For the most up-to-date information, please visit our website, www.molecularpartners.com. With that, I'll turn the call over to Patrick Amstutz. Patrick, please go ahead.

Thanks, Seth, for the intro and kicking off the call. And please, again, go to our website and grab the presentation. And we will be referring to a slide number that we're on. And the slide number that I will kick off with is slide number five. A warm welcome from my side. Great to have you all on this call. Before diving into the highlights 24, we did put on the 20 years molecular partners logo because it is our 20 years anniversary. And it coincides with being 10 years listed on the Swiss and then later on the U.S. Stock Exchange. And it has been 20 years of a quest to make drugs that matter for patients. And we have never gone away from that. And this has really brought us where we are. And if we look back, it has not been a straight line. It is hard work for specific results. And twice, we actually reached clinical pop with the wet AMD drug, Avicipor, and with the COVID drug, Ensovibet. And I think the call today is really to highlight where we are and how we're lining up our new programs to be in a position to have more of such readouts in the future. So let's look at the highlights 2024 and what we have done. It was a year of execution to get our programs closer to that clinical readout. Let me start with the radio dark pin franchise where we have CLL3 targeting 712, that is our lead compound, passing all IND-enabling studies and ready to go into the clinics, and Michael will be talking about that. We also selected a new target. And I mean, if we say selected a target, it also means that we have data. We not just took a target. And it is mesothelin, and we will touch on that too. And maybe most importantly, this third bullet point is the expansion of our Oranomet collaboration. And as you know, in the radio field, we bring the vector, but we still need access to an isotope. An isotope supply is challenging. And with this collaboration, we have secured 10 slots for products, real products, not just candidates, products for lead 212, one of the most promising isotopes out there. So I think that is one of the possibly most important things of last year that we have secured that access to isotope. On the key selling gauge side, it is 533, where a year ago we had mediocre or underwhelming results. And it was a year of understanding those, working with our investigators and putting that back on track. And Philip will talk about that, how we have tackled the target-mediated drug disposition problem and are very curious and hopeful to see what the future will bring. On the switch side, there was a bit of a change. A year ago, we were moving six to one. That was the NK engager and switch. We have, call it, upgraded that to the T-cell switch, and we will talk about that as we move. There's another program, RE17. It is less of strategic focus today, but still we finalized phase one. We had very good safety. We saw biological activity. And we will be moving this one forward in combination with the PD-1 in an investigator-initiated trial. We ourselves decided that we would not invest that much, but we still see a potential future for it, and there is support from the investigators to move it forward. And last but not least, we did a small financing round late last year to bring in our friends from HBM, a very strong, reputable Swiss investor, and the round was also backed by things like BBS and Suvretta, adding $20 million to our treasure chest, which makes us well-capitalized with the runway into 27, also well beyond those inflection points that I was pointing out before. So with that, let's move to the next slide. I'm now on slide number six. again which is this one yeah so with this one the pipeline isn't that number five now it's five so okay thanks for that so I'm slide number five let me quickly start with what is missing on this slide and what is less important the one line that is missing is the Novartis collaboration so you remember three years ago we entered into a collaboration with Novartis on two targets and we made DARPs against those two targets and moved them into research. Over the years, they did not progress that fast. The results were there, but I think both Novartis and molecular partners did not see the strategic interest in the target. This happens, and Maybe an explanation is all those research targets that we're moving, we never talk about before it is a candidate for exactly this reason, because often you don't move a target forward. In this case, because it was the Novartis collaboration, they were there, and Novartis, now after three years, that was the research term, decided not to move forward. We agree with that. We would also not move forward, so that line is missing. There was no technological setback. It was just not the right targets in the right time. They might come back, but as of now, this is not where we or Novartis would invest. The other one that we are not actively moving forward is 621, a nice molecule in HSCT, so stem cell transplant, we said that is not our focus interest. The success of 533 and also the success of the radio franchise is much more relevant and important. So that is one that we can sort of put on hold and opt for partnering. Now, where are we focusing? This is 533 and the radio franchise. And I will hand over to Philip later, our chief medic, to talk about 533 and AML and all the progress And Michael Stump will be walking you through the radio work on 7-12 and the latest from Mesothelin and our collaboration with Oranamed. So before we go there, I'll hand over to Robert to give us the overview of the financial situations. Over to you, Robert.

Thank you, Patrick. I hope you can all hear me well. Good morning, good afternoon to everyone on the call. I'd like to run you briefly through the key figures of last year. and the guidance for the year 25. My name is Robert Hendricks, and I'm the SVP of Finance here at MP. The numbers that I will present are stated in million Swiss francs. More detail can be found in the press release, as well as in the appendix to this presentation. Yesterday, we also published our full annual report in a 20F. Plenty of opportunity to dive into more detail. The entire presentation is also available on the website. Moving on to slide number seven on the key figures. There are a few numbers that I'd like to highlight here. First of all, the revenue number, five and seven. As Patrick has just mentioned, this is exclusively coming in both of these years from the Novartis collaboration. In 24, we recognized the last part of the upfront that we had received back in 22. And there is no more revenue to be coming from this collaboration. So that's on the revenue. Then the operating expenses at 66 million, well within the guidance that we gave, that was 65 to 70. Just a high-level breakdown without too much detail. Around 74% of these costs are R&D-related, so pushing the products through the pipeline there. The overall costs have been fairly stable over the years. The third number, just to highlight, if you look at the overview, is the net financial result. Clearly, we benefited. from high interest rates on our US dollar denominated deposits. This number is clearly volatile by design. And this year, I think we, as I said, benefited from the FX rate, the interest rates. And through the small raise we did in October, we gained another $20 million. So that added to the dollar pool that we have. With that, an intro also to the cash balance at the end of the year, ending with 149 million down from 187 at the end of last year, so resulting in a year-on-year cash investment of around 38, taking into account the receipts from the capital raise in October. The cash burn, therefore, for the year is around 54 million. This December 24 balance of $149 million will carry us well into 27, and we consider this continues to put us in a privileged position in the industry, and also like to remind here that the company has been and remains without debt. All these numbers combined on this page, we feel these numbers tell the financial story of MP in 24 and show the continued solid financial state of the company. Then moving on to the next slide, just a few words on the guidance for 25. We will not guide on revenue or any other metric. In terms of total operating expenses, we do guide for a total of 55 to 65 million, of which around 7 million are expected to be non-cash. And as always, this guidance is subject to the progress and changes in our pipeline and excludes any potential payments related to partnerships. So to summarize and conclude here, what is relevant to remember from these numbers, I would say, is the continued financial base, solid financial base entering into 25 that will allow us to continue to invest in our pipeline and to bring drugs to patients. Thank you for your attention. I will be happy to take any questions during the Q&A later. And with that, I'd like to hand over to Michael Stumpf, who will talk about our radio DARPA programs. Over to you, Nicky.

Thanks very much, Robert. Good morning, good afternoon, everyone. I hope you can also hear me well. I'm really very happy and proud about the progress and all the achievements the various teams have made in the year 2024. And let me first of all already acknowledge our collaboration partner, Ranomet. who is making all of this possible. I'll speak a bit more in detail later. And 2025 is really the year with the first clinical data from the radio darpins and lead. And that's why I'm so excited to be here. Things are moving forward and let's quickly So, moving on to slide 10, I'm pretty sure you have heard about the darpins before. So, the big blue picture there, that's where we put a lot of effort into understanding what's the ideal properties of a radiopharmaceutical. It involves some protein engineering, but it also certainly involves the linker, chelator, and of course, we also explored half-life extenders. Most importantly, however, for the patient's benefit is the alpha-emitting therapeutic isotopes, so that's the 212 version of lead, which has proven clinical efficacy, thanks to our collaborators from Oronamed. It gives release to a lot of high energy immediately within a very short time, and cells then undergo double-strand DNA damage. And because it has a relatively short half-life, it also seems to have an ideal waste management. And the safety profile is so far so good. Of course, we need to explore further inpatients. So all in all, we think that the DARPins are the ideal partner for lead. And that's what we are going to establish in the future. So moving on to slide 11, let's quickly have a closer look at why Oronamid is really one of the leaders in the targeted alpha therapy field. They are one of the pioneers. And I think the very, very big reason to mention here is they have the supply chain fully under control with virtually unlimited starting materials. You see a picture, these 22,000 drums of 2-3-2 thorium. That's where it starts with. So there is really unlimited supply. Runamet also recently validated their approach by an agreement with Sanofi, which is, of course, one of the pharmaceutical players in the field. And that included their lead asset, the Alphamedics program, which has shown very nice clinical data presented last year at ASCO. And, of course, there are a couple of technical advantages. That's how our teams chose to focus on that. Again, the short half-life, it makes it relatively easy for patient administration. They don't have to stay very long until they are so-called cleaned. The waste management is an asset. and a very high energy release from the alpha emitter with a clean decay chain. So lots of reasons to believe that this is the ideal isotope for us. We didn't stop there. This partnership was greatly expanded and that's what really changed late last year. In the beginning of the year, we announced it around JP Morgan. So it's a global partnership expansion more and above and beyond what we had before. We are now basically together the owner of 10 products that are composed of lead and protein moiety. And the first one has been designated, NPO712. I'll talk in more detail. That's our DLN3 program. And we also announced the name. program together with the one imagine a 55th cost chain split. Beyond that, we have two MPOE programs, number five and six here, where there is an opt-in and then we have another four MPOE programs. So we have a very rich supply chain, so to say, now for lead-based programs. Let's go one step closer on that slide 13, our first program that we are really very, very actively involved in development right now. This is the 712 program with a focus on DLL3 expressing tumors. Most patients initially we will be treating are small cell lung cancer patients. They have a very high unmet medical need, relatively low five-year overall survival. And most importantly, the target was validated last year by the approval of Amgen's Torlata map in DELTRA. So we believe there is room to get results above and beyond Torlata map, but it's also a proven pathway for approval. If you look again at the right picture, 712, that's a DARPIN that we added some albumin binding half-life extension to. So it's composed of three essential parts, the DARPIN binding TLL3, albumin binding moiety and the lead 212 radioisotope. Moving on to the preclinical results, just to be very brief here, and please feel free to ask questions. This was presented late last year. A very potent molecule, and the potency is very important because the target is actually expressed at a relatively low level. You see the brownish stain at the left, so there are different tumors, but The human small cell lung cancer tumors we have seen came with a relatively faint brown color, which means you need a molecule that's very, very potent. You see this A in the middle, that's the biodistribution. We get exceptionally high values at the tumor, thanks to the design of the molecule, and much above the kidney, so we also feel we have a good safety window. And very nice to see in this xenograph study on the right that we saw complete and durable regression in that very relevant model at a dose that is probably the right dose clinically. So with that, I think we can look at what the clinical program will be like. So there are many parts to the program. And as you can see, there is a green box. That's the phase zero component focused on imaging. And from the imaging, you can calculate then the doses for the various organs. therapeutic levels in the tumor lesion called dosimetry. Probably about 10 patients in the use should be enough. And we anticipate these studies to start in the second half of the year. The initial phase two, phase zero imaging will be complemented by a therapeutic part, phase one 2A study in patients, the first part, dose escalation with the main objective to establish the safety in the recommended phase 2 dose, thinking of about 15 to 20 patients. Of course, we need to get the buy-in from the FDA. And then a part 2 will be the dose expansion, where we hopefully can also go a bit beyond the small cell lung cancer patients, so including neuroendocrine carcinomas. And of course, looking then for responses and response rate, which will lead then, and we don't know exactly when, in the future to a registration study. And of course, there could be more than one registration study, depending on the integration and the line and maybe other factors. Moving on to now something completely different, our second program, just in a nutshell. I'm very excited about this one because it has a true DARPIN differentiation. We have found DARPINs that are very specific for the membrane proximal epitope, shown here in pink, and therefore not disturbed by a lot of very high levels of shed mesothelin that has hampered previous approaches. So that's the unique power of a DARPIN that can And again, it's a DALPIN with a half-life extension and net to 12. This will take some time to finish the preclinical development and the manufacturing, but hopefully we can also report on that progress during the year. Note that there will be a poster at AACR, which is, I believe, late April with more preclinical data. And just to conclude my part, there is one important biochemical distinction. You see here a graph in the middle on slide 17. where we have added shet mesothelin in high concentrations. And the distal darpin, which binds an epitope we don't like so much, so it's also then inhibited by shet mesothelin. Very different profile on the curve from the proximal darpin that's binding the membrane epitope. And that's totally maintained by ensures totally maintained binding throughout the whole activity race tested. And again, this will be shown at AACR 2025 in late April. So again, very excited what the teams are doing together with Oranomet, fantastic collaboration partner, and very excited to patient result from these programs. Thank you very much. And with that, I hand over to my good colleague, Philip, who is running the whole from the medical side, and will talk today about the 533 program. Thank you all.

Progress of our 533 DARP in. Can you hear me?

Yep, we can hear you now. You're good. Go.

Okay, so I restart. So, again, thanks, Michi, first. And I am very happy to share an update on the progress of our 533 DARPIN, which we are developing in AML. On slide 19, basically, let's remember, it's important to remember that AML is a very challenging disease. because of the heterogeneity of the cell population, as well as the difficulty to kill the leukemic stem cells, which tend to persist despite treatments, and they drive the recurrence. So, we have designed 533 as the first tetraspecific T-cell engager that recognizes DML blast and the LSCs, leukemic stem cells, through their co-expression of either CD33, CD123, or CD70. and kills them when they express at least two of the three TAAs simultaneously. By doing that, this multi-specific approach has the potential to open the therapeutic index and particularly kills the leukemic stem cells more effectively than a single targeting agent would do. Moving to slide 20. This slide describes the clinical journey that we have studied two years ago. When I reported last year, we were still in the blue left part of the schematic. We are now reporting on the orange middle one, and we will be initiating soon a new amendment corresponding to the green. In the initial dose escalation cohorts on the left, the blue, we were able to understand the manageable safety profile of the drug up to cohort seven, and obtained signals of efficacy, however too low and not durable enough. Then what we did is we identified with a group of international experts that we had in fact too much loss of exposure, likely due to the multi-target antigen sink. Let's remember we are targeting three antigens, two to three. And so at that time we initiated a first amendment to accelerate the step-up dosing and densify the regimen by adding an additional dose during the first 15 days at day 12. And I'll show you the results of that, and basically that we have now significantly increased the efficacy, and we are now very encouraged to further accelerate that step-up dosing and have a more frequent administration, particularly during the first cycle. This new amendment corresponds to the green schematic and has been submitted to regulators. Moving to slide 21, you can see on the left swimmer plot corresponding to the blue part of the dose escalation during which we saw some initial responses, however not enough and not durable enough as I already said. On the right part, You can see that the outcome after the initial amendment and the initial steeper step of dosing and one level of densification. And you can see that this now appears to be very promising with three CRs out of eight patients that were treated past day 12. Moving to the next slide, which is a waterfall. you know, that slide in a way that visual adds one level of granularity to the document to document the blast reduction on top of the full ELN criteria. And we can see here that the drug had effect with approximately half of the patients having reduction in blast, even during the dose escalation. However, the new amended cohort certainly has more. And also this helps understand that most of the patients that have blast reduction had a lower disease burden at baseline, as is frequently seen for effect for T-cell engagers. Moving to the next slide, slide 23, it's a key slide. Because when we discussed the blue curve representing cohort six with our experts, they were even surprised that we had even responders and blast reduction, because as you can see, there were only very few concentration peaks in the effective dose range on day eight, day 15, and day 20. So very little stimulation or effective stimulation to generate that blast reduction or initial responses. And this is, what is very interesting is that in the recent amendments, so corresponding to the orange curve, we see that in those orange curves, the concentration achieved effective ranges at the 8, 12, and 15 for significantly more time. And we hypothesized that this component supports the higher activity that we see in this new cohort. So based on those learnings, we have now built on this finding and are further densifying the dose and also introduce a B-cell depletion premedication to also reduce the proportion of patients who were developing ADAs at the end of the first cycle. So basically it's a two-pronged approach, more densification to generate deeper response, more responses, and a B-cell depletion to make sure that we have a maximum of patients that have long exposure beyond the first cycles. So slide 24, describe the further amendments. which is currently in review, and we anticipate to initiate it soon and communicate outcome of those new cohorts by the end of the year coming. Okay? So, I'd like to expand a bit on this now, meaning that the first experience regarding G-Cell Engager has driven us to develop further the platform, and we have initiated programs in solid tumors, where it is key to manage the on-target, off-tumor risk of toxicity. And you may know that there has been some good level of excitement recently on that topic with development from companies like Janux. So slide 26 is an example of how we are integrating the concept of masking the CD3 binders in absence of TAAs, as well as the concept of coactivation to mitigate the risk of T cell exhaustion. two scientific concepts integrated. And more precisely, you can see on the left schematic that this DARPIN has the CD3 masked in circulation. And on the right, that when engaged with a first TAA like here, mesothelin, and secondarily with a second TAA like EPCAM, this will free the CD3 binding to the T cell. And the CD2 co-activation does potentiate the immune mobilization. So this is a very sophisticated approach, highly relevant, we think, and again, some others are analogy, there's an analogy to what all of us are doing, but we think that we are doing it in a very sophisticated manner. And we'll share further detail of this interesting approach at the upcoming AACR. So on this, I want to thank you, and I will pass again the phone to Patrick.

Thanks, Philippe, for these very nice explanations and also showing us how we have worked through some challenging settings and findings to give especially 533 the best chance to succeed and help these patients. Let's have a look at what we can expect in T25. I will start on the radio side, and I think there, as Michael pointed out, we are really excited by the perspective to share the first clinical data of 712, the radio DLL3 programs. We do start with imaging as he explained that it's a phase zero approach, and then we can do dosimetry and have them clinical results in a fix in safety in 2026. Let me just take a minute here because in most instances, your phase zero imaging is maybe not that relevant. This is different here. We will have the understanding of how much of the drug will be in the tumor and how much will be on the healthy organs. And for those who are less familiar in the story, the one organ we're really zooming into and excited to then see results is the kidney. Because most of these approaches have high kidney absorption. So we'll be first and foremost looking for a tumor to kidney ratio. And should that be positive in the dosimetry, that is an exciting moment to move the program forward. So the imaging holds real value for molecular partners and the whole radiodarpin pipeline. Mesa will go forward, and we will update that at AACR, and we will definitely not stand still, but add additional programs that are some fully owned by us, others likely also moved forward by OranoMed. Moving to 533, as we just heard from Philippe, We are now at this moment where we can test maybe the optimized or even optimal dosing for this compound in a deadly disease. So that is a highly exciting moment for us. That's the reason we go to work, to test our drug in the setting where it helps patients. And we will be able to update with more data from Cohort 1, In H1, and for sure in H2, this new amendment that Philip was talking about will be in place and be delivering results, guiding us on response rate and especially also on duration of response. On the switch side, as I said, we are there moving forward. Hopefully, our first candidate can well be the mesothelin or maybe another one. We're still looking at a few. And we're also opening for partnering, be it 621 or also on the T cells, because we will not have the bandwidth to move all options that these new platforms give alone. Cash situation strong, almost boring for us, but I think boring in this market is a good thing as many biotechs are struggling for funding and we are in a position that we can execute our plans, move forward, bring value to patients that will then also move into value for shareholders. Now, before opening for questions, this is a moment to also thank you for dialing in. Thank the presenters that I had on the call. And they obviously just present the tip of the iceberg of the Molecular Partners team. And that team really makes all this work. All those hours, all those troubleshootings, all those coordination meetings, moving things forward, big thanks to everyone at Molecular Partners. highly and full of gratitude to be able to be part of that team. We don't do this alone. We do this with partners. I think the name Oranomed was said many times. Big thanks there. Also to Novartis. Without Novartis, we would not be in this call. We would have not moved forward in radiotherapy. And it is maybe more on a personal side that we're not continuing that one, but I'm sure there will be opportunities also with Novartis to move things forward in the future. The troubleshooting not only happens in our four walls. We are very closely with our investigators, KOLs, experts that know our drugs. Big thanks to them. And I do think the last and possibly most important thanks goes to the patients that are in our trial that are part of them and allow us actually to test these drugs early on to see if they actually do what we want them to do. With that, thanks for everyone diving in, especially also the analysts that cover us for these many years, us for those 10 years. Some of them have been doing it for 10 years. Big thanks for that. And looking forward to your questions.

We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you're 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 2. At this time, we will pause momentarily to assemble our roster. The first question comes from Jonathan Chang with Lyric Partners. Please go ahead.

Hi, guys. Thanks for taking my questions. First question on MP0712. Can you provide more color on where you are in the IND submission process and preparations for study initiation? And how should we be thinking about the initial clinical data by year end? And then second question, can you discuss why you think mesothelin is a good target for radiodarpins? Thank you.

Miki, are you on? Because I think that goes directly to your area of expertise.

Yes. Yes, I can start and then please continue. So, thanks, Jonathan, for the question. I'd love to sit down with you in more detail and go over, but just give you the top line. So, as I said, late last year, we started 25 with the GMP manufacturing that has moved forward really nicely. Of course, there are a lot of technical challenges to be overcome, including logistics. Q2, so next quarter, will be the submissions. Maybe there are several ones to the FDA. And that's where, hopefully, then in Q3, we can open the first part of the program, the imaging part. And in the latter part of the year, so I'm not exactly sure where we will be, we will then have the first therapeutic doses. If FDA agrees to our proposal to start close to therapeutic dose rates, we should see something maybe in the first two dose cohorts. And as you know, probably tumor shrinkage and then also the duration of it will probably take a bit of time. So early 26 will be then the clinical data from the therapeutic part, submission in Q2 anticipated. Your, I believe, third question, mesothelin, why is it a good target? Excellent question. Of course, we are hoping it will be a good target. There is certainly a high medical need in the ovarian cancer patients, and mesothelin expression is very high there. Whether it will be perfect for an alpha emitter in our molecule, we need to establish. It looks good preclinically, but whether it will then work, that depends truly on future data. There are a number of programs also using other modalities. But I hope with the alpha radiation of lead, we can tackle these two results. Maybe over to you, Patrick, anything to add from your side?

Yeah, no, and we often get the question on mesothelin because, let's say, in public, it's a bad target because others have failed on it and are not moving. I think what we do is we go back and we triangulate the data. And it's also a phrase we use internally. We like to work on clinically validated problems. And in this case, as you said, Michael, ovarian is immune more silent, so you don't have that much effect. You often have chemo resistance, and also not the highest response rate for ADCs. And meso was in principle a good target, but the shedding and the high level of free target made it a very difficult approach for radiotherapy because you don't want to be binding shed target being in the body everywhere and having an on target of tumor effect. So this is the hypothesis that ovarian will be radiosensitive when delivering an alpha via mesothelin. The target, very difficult for peptides to do, so we don't expect anyone from the peptide field to be able to crack that one. So it is DARP-unique and differentiated, and that's the thesis that we will have to prove. If it works, the good thing is I do think we are very differentiated versus other radio approaches.

Understood. Thanks for taking the questions.

Thanks, John.

The next question comes from Richard Vosser with JP Morgan. Please go ahead.

Hi, thanks for taking my questions. I wondered if you could just explore learnings taken from the Novartis programs before they were discontinued, what you could take there, and also whether there were any issues with the DARP in hitting the target, or was this, as you said, just the targets don't work or they've been de-emphasized? And then a second question just on, you mentioned the key for 7-12 is the kidney ratio to target ratio. So what could be, if you could help us with a good level on that ratio that we should be looking for when we see the data and you'll be looking for? Thanks very much.

Thanks, Richard. I'll start off with the Novartis one, and then I'll hand over to Michael. I think when we started this three years ago, and that was really our first steps into radio, and we learned a lot by sharing and learning what profile makes a good radiotherapeutic. So tumor to kidney, and Michael will come to that, half-life, and this is all also gauge to which isotope you need and you apply. And there Novartis is obviously lutetium and more recently actinium, while we are going towards lead for different reasons. The learnings, I mean, I can't be too detail-oriented here, but the one thing we all agree in this field is you have to test many candidates, meaning many different sequences to find the optimal tumor to kidney ratio. And you need to have the right models up and running, and different models will give you different insights. And it was very helpful to compare notes on the models, how to run the models, how to use the models. And at the same time, find what can you learn and what can you not learn from these models. And I think you have to understand this field is still in the early days. And for the DLL3 molecule, I think we were in iteration seven or eight. So that's the seventh generation that we had. With Novartis, just given the broad pipeline they have and the way they operate, we think never made it by level three. So it was maybe not that fast cycling. I do think, and I'm fair to say, I've said that on stage, that that was also learning for Novartis. And that was one reason they acquired Mariana, to have plot labs faster, to be able to cycle faster, to test more in shorter times. At the same time, the targets they picked, which were very reasonable three years ago, did not have the data or the excitement building. DLL3, when we started, was also not present. Then with Tarlata Mob and all the excitement, it validated itself. These targets are still as unknown, I would say, as they were three years ago, and nothing has built around them. So when you come to this moment, say, should we now invest another three, four cycles? Maybe it will yield, maybe not. On a target that today neither Novartis and us puts to the top of the list, we sort of together said, let's end it here, see how this goes on, and then rather re-engage when we actually have a candidate. I mean, this is a research phase. But the learning was really good. Collaboration was good. Scientifically speaking, I think both teams really liked that, and we'll see where it goes. I think I can also say that Novartis wants to see clinical data on lead. Now, we're talking about the isotope. They have obviously seen Oranomet, but for Novartis to add a third isotope to their war chest, that would need clinical data. That's at least what they're saying publicly. Maybe, Michi, could you be a bit, or could you take 712, tumor kidney? Yeah.

Yes, thanks, Richard. And also here, next time we'll meet, let's take the time and sit together and say, look at the piece of paper or the laptop screen. I think the challenge is, in animals, it's relatively perfect. So you can control everything. You can give a number. And preclinically, you've probably seen this before, we like to go above one, so ideally two to one, tumor to kidney. And then, of course, sometimes there's a question, which time point do you integrate over many time points? So animal model is relatively easy. In patients, we need to learn clinically whether there is exactly the same translation. In the end, it boils down to the therapeutic dose we can deliver. So ideally, we have, as Patrick said, more of the uptake in the tumors, but I'm pretty sure it depends on the tumor size, the blood perfusion, whereas the kidney will be probably relatively similar from patient to patient. So if we can deliver a therapeutically relevant dose to the tumors, and we're speaking in the order of 100 megabacquerels per dose, and the kidney stay below the safety limit that is at the moment accepted, so several grays, but it's exactly one of the questions we don't know for sure whether the kidneys for an alpha-imidoliglet have the same limit. So we will have to discuss. The FDA will propose our dose escalation rationale, and I'm pretty sure it will be similar to preclinical data, but I would not look for a specific number because tumors in patients are very different. So on average, I hope it's above the kidney value, but maybe in the end it's above the therapeutic link dose.

Excellent, thank you.

The next question comes from Mike Derakovich with TD Cowen. Please go ahead.

Hi, thanks so much for the questions. I have two. When it comes to DLL-3 and radiotherapy, do we know, you mentioned the kidneys, which I believe is nonspecific off tumor. uptake. Do we know, are there any on-target, off-tumor DLL3-expressing organs we should be concerned about when we see the first imaging or dosimetry data? That's my first question. And then my second question is on the Switch DARPEN platform. This is very unique and very promising. How do you think about partnering in terms of the scope and scale? Would you be pursuing a partner for an individual molecule or more kind of platform-wide? Thank you.

Maybe Philippe takes the first question on DLL3, and I'll be happy to talk a bit on the platform or candidate partnering.

Yes. So thanks, Mike. DLL3 is a clean target. That's why there is so much excitement about it, I would want to say. And, you know, experts are very excited, in fact, based on the recent accumulation of experiences. which has accumulated on the antibody, on the ADCs, or on the radiopharma approaches. So there is a body of experience which is still early but rapidly shaping. And I think what we know from the programs is that the pituitary gland is the only place, you know, which is has some level or a mini level of the left expression. All the rest is clean. And when we looked at the experience, for example, they did not have any specific, you know, safety profile. And of course, we checked on the pituitary gland and there hasn't been any, you know, adverse event that makes think that that would be an issue. But, of course, technically, if I could see, there is little expression there outside of the tumor. So, that would be the one that we'll watch. Although, again, we are not very worried, because if there hadn't been a problem, we would have seen it already. So, very clean target, and we are confident, obviously, and, you know, as we're preparing our protocol, obviously, what are the adverse events of special interest, and that this is short. for us, but also for the others.

And maybe just to add, because there is a big hype on DLL3. So I think on the target, people totally agree that that is, call it validated and a very good target to go after. And we just had dinner with a PI that is in many trials. And for me, what was reassuring to hear is that the different modalities, and we're talking T-cell engagers, ADCs, and radiotherapy, that he also said there is a need for all of them. None of them will cure as of now, and the sequence and how we can actually develop them was very exciting for him, and he actually sees a big place for the radiotherapy there, even a bit in an earlier line to help the others move forward. But thanks for the question. I'll take also the partnering one. And the question is great. I mean, some partners like to work on a candidate. These are either companies that have a specific need. Let's say you're, just take this as an example, you are in breast cancer, and then you want a breast cancer target and candidate for the pipeline. And ideally, then we have a candidate there. You sort of are the missing piece in the puzzle. As you don't know and kind of in which puzzle you fit well, that is sort of an opportunistic one. You obviously look, what do we have, which candidates do we have, and where would they fit? That is one part of the partnering versus the other. The big pharmas obviously take long shots. They see that they want to fill their pipeline over time, and often they say, okay, your targets are a nice showcase, but can you do these? And both discussions are valuable. Obviously, if you have to start from scratch, that's then 18 months, 30, yeah, two to four years of research and development, as we just saw with the Novartis collaboration. Usually they come with a good upfront, because there is high risk, so you have to also commit something there, versus a candidate that is ready to be in the clinics within the next 18 months, that is exciting. At the same time, that puzzle piece has to fit, and you don't know sometimes where it fits. So, both we're looking at. We're looking into both. Discussions are ongoing, and we will see how they develop from here. Thank you so much.

The next question comes from Chiara Monteroni with Kempen. Please go ahead.

Hello team, this is Chiara from Kempen. Thanks a lot for taking my question and congratulations with the update. On 7.12, I was wondering, the phase 0 and 1 will not run in parallel, right? So did I understood correctly that the phase 1 start is contingent upon good imaging data or am I wrong? Thank you.

Thanks a lot for the question. It's a really good one because we are proposing to the FDA that it should not depend on each other. We want to do them in parallel. We have the required animal data to argue for the parallel start. But in the end, of course, we will listen and have to live with what FDA decides. So stay a bit with us, ideally in parallel, but it's a regulatory question. And if that is, I think we'll probably keep them together just a few months apart because, you know, patients like to be treated and not just in it. So also for the patient, we keep them closely staggered.

Yes, of course. Thanks a lot. Really helpful.

Welcome. Thank you.

And the last question today will come from Joris Zimmermann with Octavian. Please go ahead.

Yeah. Hi, Patrick and Dean. Thanks for the presentation and for the opportunity to ask questions. I have a short one, I guess, just on the structure of your deal with Oranomet. If you could elaborate a little bit on how those different – programs are split between the two companies. I mean, you've nicely depicted that on slide 12, I guess, just to understand. So the later programs will be fully owned by you, and then there is two with opt-ins. But who will take the commercial lead for those? And then also for three and four, is it correct that this will be mainly led by Oranomid?

Yeah, I know. Thanks for the question. And this is a good opportunity to quickly explain how the deal works. And I'll do a short recap of how this all came about. So we started the collaboration on an MTA with Oronamed on the DLS redarpen. And so that was sort of call it the honeymoon. And we had made very good progress on it. And then we said, okay, let's move forward. At that point in time, we did a deal with actually three targets or three products. These were both 50-50. We got the first. The idea was they would take the second, and then the third, we would see how that develops. And I think we had underestimated the speed and productivity of what we were doing. And so what had happened is that we took the first, but then Mesothelin came about, and we had to approach them and say, Actually, we have a second, and then there was an imbalance, so we said, okay, then let's add a fourth that we get one and two, and they can have three and four in the 50-50, but commercial lead for one and two are with us. In the meantime, they were successful in their phase two and did a massive deal with Sanofi bringing in $400 million for late-stage development and commercial supply. So they have a clear mandate now to put that money to work, build the manufacturing sites, build the last mile, build the logistics. So Sanofi is not doing that. That will be with Oronomid. And it's sort of, I would say, it is clear where their focus is. And so we were like, okay, we have one and two, you have three and four, and your focus is late stage. Let's sit together because we cannot wait until you move to your programs. We want to do more. And then this win-win situation happened where we said, okay, let's add six. Molecular partners can move them forward and add early clinical phase zero-ish data Oranomet can opt in into two while four will remain with us. So I'm not going to go into all the details, but you see We are helping each other. They have time, focus, money to build the late stage. We are working a bit more on the early stage. And they also get then with the opt-in what they need to build their pipeline. So for me, it's a beautiful example of a win-win situation. And I do think on value, this has gone very much under the radar that we have 10 products worth of lead supply with the most advanced and credible uh partner you can have so big thanks to them indirectly also big thanks to sanofi for putting all that money to work and uh and we're ready one point also these are these are commercial products so if number eight would fail In phase three, even then we can go back and replace it. So these slots are up to commercial stage. So if you want, this is a 30, 40 target setting you can do. We don't have to. We can also do other isotopes. But I would say for lead, we have access to whatever we need.

Thanks very much. That makes a lot of sense. Maybe a very quick follow-up. You mentioned the high productivity. So how should we think of timelines and frequency of you and Oranomet disclosing the additional programs?

Yeah, that's a good question. You never communicate too much what you're doing in research because it is so, so risky. And if I would give you an update on our pipeline today in research and a year later, a lot has changed. That's why it's always that we're careful. But I think it's fair to say that My guess is we'll have two new targets that we will be talking about this year and also new column technologies that we're testing. So it's not that we are waiting in radio and sitting there, but we're also evolving our platform for a next generation as we go. So I think, in all fairness, roughly two targets per year is likely a productivity that is fair. Pending the results of 7-12, obviously we can ramp up more. Their clinical data will be key. If that looks as we hope for, then let's move forward and do more.

Thank you so much.

Thanks.

This concludes our question and answer session. I would like to turn the conference back over to Patrick Amstruth, CEO, for any closing remarks.

Thanks again. 20 years molecular partners, 20 years innovating and bringing drops forward. I'm also proud on the timing. This is almost with timing. We're right on the hour as we had planned. So also thanks, and thanks for all the great questions. We're off to an exciting year. We'll keep you updated as we collect the data. We'll also work closely with you to give you what you need to understand the data as we're doing that. And also I'll end with a big thanks to my team, treating physicians, and especially the patients. See you all soon. We're at many conferences going forward, so reach out and we'll be in contact.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.