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Good morning, and welcome to the Molecular Partners Fourth Quarter and Full Year 2024 Results Call. All participants will be in listen-only mode. [Operator Instructions] 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 and 2024 Highlights Call. My name is Seth Lewis, and I'm joined today by members of our senior leadership team, including Patrick Amstutz, Chief Executive Officer; Robert Hendriks, SVP of Finance; Philippe Legenne, Chief Medical Officer; and Michael Stumpp, 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 call 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 of 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 wrap the presentation, and we will be referring to a slide number that we are on and the slide number that I will kick off with is Slide #5. 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 [drug that matter] (ph) 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 top with the wet AMD drug, abicipar, and with the COVID drug ensovibep 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 us 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 DARPin franchise, where we have DLL3 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 the target, it also means that we have data. We now just took a target, and it is mesothelin, and we will touch on that, too. And maybe most importantly, the third bullet point is the expansion of our Orano Med collaboration. And as you know, in the radio field, we bring the vector, but we still need access to an isotope. And isotope supply is challenging. And with this collaboration, we have secured 10 slots of -- 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 T cell engager 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 Philippe will talk about that, how we have tackled 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 621. 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, 317. It is less of strategic focus today, but still, we've finalized the Phase I. We are very good safety, we saw biological activity. And we will be moving this one forward in combination with the PD-1 in 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, very strong repeatable Swiss investor and the round was also backed by exist things like BVF and [indiscernible], adding CHF20 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 #6, the pipeline?

It's Slide #5.

Okay. Thanks for that. So on Slide #5. 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 DARPin 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 and they 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 the 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 is 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, he said that is not our focus interest 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 up for partnering. Now where are we focusing? This is 533 and the radio franchise. And I will hand over to Philippe later, our Chief Medic, to talk about 533 in AML and all the progress and Michael Stumpp will be walking you through the radio work on 712 and the latest from mesothelin and our collaboration with Orano Med. So before we go there, I'll hand over to Robert to give us the overview of the financial situation. Over to you, Robert.

Thank you, Patrick. I hope you can all hear you 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 Hendriks, 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 the 20-F. So plenty opportunity to dive into more detail. The entire presentation is also available on the website. Moving now to Slide #7 on the key figures. There are a few numbers that I'd like to highlight here. First of all, the revenue number 5 and 7. 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 2022, and there is no more revenue to be coming from this collaboration. So that's on revenue, then the operating expenses at CHF66 million, well within the guidance that we gave, that was CHF65 million to CHF70 million. Just a high-level breakdown without too much detail around 40 -- 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 U.S. 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 rate we did in October, we gained another $20 million. So that added to the dollar pool that we have. With that, I'll enter also to the strategic cash balance at the end of the year, ending with CHF149 million, down from CHF187 million at the end of last year, so resulting in a year-on-year cash investment of around CHF38 million taken into account the receipts from the capital raise in October. The cash burn, therefore for the year is around CHF54 million. This December '24 balance of CHF149 million will carry us well into '27 and we consider this continues to put us in a privileged position in the industry. And also I'd 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 that financial story of MP in '24 and so 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 CHF 55 million to CHF 65 million, of which around CHF 7 million are expected to be noncash. 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 Stumpp, who will talk about our radio DARPin programs. Over to you Micky?

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, Orano Med, 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 DARPin and Lead. And that's why I'm so excited to be here. Things are moving forward. and that's quickly look back, but also then let's look a bit forward together. So moving on to Slide 10. I'm pretty sure you have heard about the DARPin before. So the big blue picture there, that's where we put a lot of effort into understanding what's the ideal properties of the radiopharmaceutical. It involves some protein engineering, but it also certainly involves the linker chelator. And of course, we also do 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 Orano Med gives release to a lot of high energy immediately within a very short time and sell the on-the-go 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 so far so good, of course, we need to explore further in patients. 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 Orano Med 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 material. You see a picture these 22,000 drums of [two Thorium] (ph). That's where it's down to it. So there is really unlimited supply. Orano Med 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 Alpha-Emitter program, which has shown very nice clinical data presented last year at ASCO. And of course, there are a couple of technical advantage, 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 waste management risk and asset and the very high energy release from the Alpha-Emitter, with a clean decay chain. So lots of reasons to believe that this is the idea of 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 JPMorgan. 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-loyalty. And the first one has been designated MP0712. I'll talk in more detail. That's our DLL3 program. And we also announced mesothelin our second DARPin program, together with Orano Med 50-50 cost share and split. Beyond that, we have two [MPO programs] (ph), number five and 6 here, where there is an opt-in and then we have another four MP program. So we have a very rich supply chain, so to say now for lead-based programs. So 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 the 712 program with a focus on DLL3 expressing tumors. Most patients initially, we will be treating our small cell lung cancer patients. They have a very high unmet medical need, relatively low 5-year overall survival. And mostly what the target was validated last year by the approval of Amgen's tarlatamab in [deltra] (ph), so we believe there is room to get results above and beyond tarlatamab, 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 tool. So it's composed of three essential parts, the DARPin binding [DLL3, albumin binding loyalty and the Lead-212 radio isotope. On to the preclinical results, just to be very brief here, and please feel free to ask questions. This was presented late last year. We have 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 are staying came with a relatively faint brown color, which means in the molecule that’s very, very potent, see this 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 xenograft 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 organ. And this together should build the confidence that we reach relevant therapeutic levels in the tumor lesion called dosimetry. Probably about 10 patients in the year, should be enough, and we anticipate these studies to start in the second half of the year. The initial Phase II Phase 0 imaging will be complemented by a therapeutic part Phase I/IIa study in patients, the first part dose escalation with the main objective to establish the safety and the recommended Phase II dose, thinking of about 15 to 20 patients. Of course, we need to get the buy-in from the FDA. And then the part two will be the dose expansion where we hopefully can also go a bit beyond the small cell lung cancer patients, so including neuroendocrine carcinoma and of course, looking then for response rate, which will lead them 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 DARPin 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 message in that has hampered previous approaches. So that's the unit power of DARPin that can discriminate very small differences. And again, it's the DARPin with a half-life extension and Lead-212. 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 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 Shed mesothelin in high concentrations and the distal DARPin, which binds an epitope don't like so much. So it's also been inhibited by Shed mesothelin, very different profile than the curve from the proximate that bind the membrane epitope, and that's totally maintained by ensures totally maintained binding throughout the whole activity raise tested. And again, this will be shown at AACR 2025 in late April. So again, very excited what the teams are doing together with Orano Med, fantastic collaboration partner. And very excited to look both back but especially forward throughout this year to have first patient results from these programs. Thank you very much. And with that, I hand over to my good colleague, Philippe who is running the whole from the medical side, and we'll talk today about the 533 program. Thank you all.

Can you hear me?

Yes. We can hear you now.

So again, thanks, Micky 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 TETRA specific T cell engager that recognizes AML blast and the LSC, leukemic stem cells through their co-expression of either CD33, CD123 or CD70 and cure them when they express at least two of the three TAA 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 simple targeting -- single targeting agent would do. Moving to Slide 20. So this slide describes the clinical journey that we have studied 2 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 blue we were able to understand the manageable safety profile of the drug up to cohort seven and obtain 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 sync. Let's remember, we are talking three antigens, two to three. And so at that time, we initiated the 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 step-up 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 waterfall, 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 [VLM] (ph) 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 8, 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 amendment, so corresponding to the orange curve, we see that there -- that in those orange curve, the concentration achieved effective ranges at the eight, 12 and 15 for significantly more time and we hypothesize that this component supports the higher activity that we see in this new cohort. So based on that learning -- on those learnings, we have now built on this lining 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 we -- 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 amendment, which is currently in review, and we anticipate to initiate it soon and communicate outcome of those new cohorts in -- by the end of the year coming. Okay. So I'd like to expand a bit on this now, meaning that the first experience regard T 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 of 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 Genix. 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 absorption. So it's scientific concepts integrated. And more precisely, you can see on the left, schematic that the DARPin has the CD3 mask in circulation. And on the right that when engaged with the first TAA-like here mesothelin and secularly with a second TAA like EpCAM, this will free the CD3 binding to the T cell. And the CD2 coactivation does potentially DNA mobilization. So this is a very sophisticated approach, highly relevant, we think. And again, some other analogy -- there's an analogy to what all of us doing, but we think that we are doing it in a very sophisticated manner. And I will share further detail on 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 333, the best chance to succeed and help these patients. Let's have a look at what we can expect in '25. I will start on the radio side. And I think there, as Michael pointed out, we are really excited by the perspective to share that the first clinical data of 712, the Radio DLL3 program. We do start with imaging, as he explained that it's a Phase 0 approach, and then we can do dosimetry and have them clinical results in efficacy and safety in 2026. Let me just take a minute here because in most instances, your Phase 0 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 to keep me 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 dose symmetry that is an exciting moment to move the program forward. So the imaging holds real value for molecular partners and the whole radio DARPin pipeline. [Mazo] (ph) will go forward, and we will update that at and we will definitely not stand still but add additional programs that are some folioed by us, others likely also moved forward by Orano Med. Moving to Slide 33, 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 Philippe 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 here moving forward, hopefully, a first candidate can well be the mesothelin or maybe another one. We are still looking at a few and we're also opening for partnering, be it 61 or also on the T cells because we will not have the bandwidth to move all options that these new platforms give a loan. 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 troubleshooting, 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 Orano Med 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 the personal side said 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. 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 dialing in, especially also the analysts that cover us for these many years. Also for those 10 years, some of them have been doing it for 10 years, big thanks for that and looking to your questions.

We will now begin the question-and-answer session. [Operator Instructions] The first question comes from Jonathan Chang with Leerink 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 discuss why you think mesothelin is a good target for radio DARPin? Thank you.

Micky are you on because I think that goes directly to your area of expertise.

Yes, I can start and then please continue. So thanks, Jonathan, for the question. I 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 the 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 later part of the year, so 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 made 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 on 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 and our molecule, we need to establish. It looks good preclinically. But whether it will then work that depends to the on future data, there are a number of programs also using other modalities. But I hope with the alpha radiation of that, we can tackle these to ourselves. Maybe over to you, Patrick, anything to add from your side?

Yes. No. And we often get the question on mesothelin because it let's say, in public, it's a bad target because others have failed on it and are not moving. I think as what we do is we go back and we triangulate the data and it's also in 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, so -- and also not the highest response rate for ADCs then Meso was in principally a good target for 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 radio-sensitive 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 DARPin 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 my questions.

Thanks. The next question comes from Richard Vosser with JPMorgan. Please go ahead.

Hi, thanks for taking my question. I wondered if 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 DARPin hitting the target? Or was this as you said, just the targets don't work or they've been deemphasized. And then a second question just on -- you mentioned the key for 712 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 a lot.

Thanks, Richard. I'll start off with the Novartis one, and then I'll hand over to Michael. And I think when -- and we started this three years ago, and that was really our first step into radio. And we learned a lot by sharing and learning what profile makes good radio therapeutic. 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 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 7 or 8. So that's the seventh generation that we have. With Novartis, just given the broad pipeline they have and the way they operate, we think never made it by on Level 3. 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 [Poplabs] (ph) faster to be able to cycle faster to test more in shorter time. At the same time, the targets they picked, which were very reasonable three years ago, did not like have the data or the excitement building, like DLL3, when we started was also not present. And then with Tarlatamab, 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. They should we invest in other 3, 4 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 reengage when we actually have a candidate. I mean this is a research phase. But the learning was really good. Collaboration is 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 Orano Med. But for Novartis to add a third isotope to their war chest that would need clinical data. That's at least what they are saying publicly. Maybe Micky, could you be a bit -- or could you take 712 tumor kidney?

Yes. Thanks, Richard. And also here next time we meet, let us take the time and sit together, say, look at the piece of paper the laptop screen. I think the challenge is in animal model is 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 2:1, tumor to kidney. And then, of course, sometimes there is a question which time point do we integrate over many time points. So animal models 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 profusion. 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 one hundred [indiscernible] per dose and the kidney stay below the safety line that is at the moment accepted, so several grades. But it's exactly one of the questions. We don't know for sure whether the kidneys for [Alzheimer to like] (ph) that have the same limit. So we will have the discussion with 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 two dosing patients are very different. So on average, I hope it's above the kidney value, but maybe in the end, it's about therapeutic window.

Excellent. Thank you.

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

I have two. When it comes to DLL3 in radiotherapy, do you know you mentioned the kidneys, which I believe is nonspecific off tumor uptake. Do we know -- are there any on-target off-tumor DLL-3 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 DARPin 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, take the first question on DLL3 and I'll be happy to talk a bit on the platform or candidate partnering.

Yes. So thanks, Mike. I reason is a clean target. That's why there is so much excitement about it. I would want to say. And experts are very excited, in fact, based on the recent accumulation of experience which has conveyed 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 for what we know from the programs is that we -- pituitary gland is the only place, which is -- has some level or many level of DLL3 expression. All the rest is clean. And when we looked at the tarlatamab experience, for example, they did not have any specific safety profile. And of course, we checked on the pituitary gland, and there hasn't been any adverse event that makes think that would be an issue. But of course, technically, if I could say there is a little expression there outside of the tumor. So that's really the one that will watch. Although, again we are not very worried because if there hadn't been a problem, we would have seen it already. So that's a very clear target, and we are confident. Obviously, and as we are 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 here 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 is was very excited 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, your -- 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 part 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 in 18 months, 30 yes. Two to 4 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 clinic within the next 18 months that is exciting. At the same time, it has that puzzle piece has to fit, and we don't know sometimes where it fits. So both we are looking at -- we're looking into both. Discussions are ongoing, and we will see how they develop from here.

Thanks.

The next question comes from [indiscernible] with Kempen. Please go ahead.

Hello team, this is Kiara from Kempen, thanks for taking my question and congratulations with the update. On 712, I was wondering, the Phase 0 and I will not run in parallel right. So did I understood correctly that the Phase I start is contingent upon good imaging data or am I wrong? Thank you.

Sorry. 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. So -- and if that is, I think we will probably keep them together just a few months apart because patients like to be treated and not just image so also for the patient, we keep them closely staggered.

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

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

Hi, Patrick and team and thanks for the presentation and for the opportunity to ask questions. I have a short one, I guess, on just on the structure of your deal with Orano Med. 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-in, 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 Orano Med?

Thanks for the question, and this is a good opportunity to quickly explain how the deal works. And I'll do a sort of recap of how this all came about. So we started the collaboration on NTA with Orano Med on the DLLS DARPin. And so that was sort of, call it, the honeymoon. And we have 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 have 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, we said, okay, then let's add a force 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 II and did a massive deal with Sanofi, bringing in CHF 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 site, build the last mile, built the logistics. So Sanofi is not doing that. That will be with Orano Med. And 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 you're focused at late stage, let's sit together because we cannot wait until we move your programs. We want to do more. And then where this win-win situation happened where we said, okay, let's add Molecular Partners can move them forward and add early clinical phase zero-ish data or Orano Med 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 high focused 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 products worth of lead supply with the most advanced and credible partner you can have. So big thanks to them. Indirectly, also big thanks to Sanofi for putting all that money to work. And we are ready. One point also, these are commercial products. So if #8 would fail in Phase III, 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 time lines and frequency of you and Orano Med disclosing the additional programs?

Yes, that’s a good question and that is like you never communicate too much what you’re doing in research because it is so risky. And if I will give you an update on our pipeline today in research and a year later, a lot has changed. That is 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, call them, technologies that we are testing. So it is 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 712, 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.

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

Yes. No, thanks again, 20 years molecular partners, 20 years innovating and bringing drugs forward. I'm also proud on the timing. This is almost switch 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 also work closely with you to give you the -- 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, and 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.

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. [Operator Instructions] After today’s presentation there will be an opportunity to ask questions. [Operator Instructions] 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.

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 Invest 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 Investors section of our website, molecularpartners.com. If you are following along on the presentation, we will refer you to -- 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 ESSEC. For the sake of the replay today, we are recording this on March 15, 2023. If you were on Slide 3, I just wanted to take you through the agenda briefly. We are joined today by multiple members of our management team, including Patrick Amstutz, our CEO, who will take you through both the highlights of 2023 and the outlook for 2024. Robert Hendriks, our Senior Vice President of Finance, who will go over some of our financial numbers. Philippe Legenne, who is our Acting Chief Medical Officer, who will touch on our MPO533 program in AML MDS. Anne Goubier, our Senior Vice President of Research and Early Development, who will discuss the Switch-DARPin technology, as well as our c-Kit program. And Daniel Steiner, our Senior Vice President of Research and Technology, who will touch on the Radio-DARPin and platform and the DLL3 program. With that, I will pass the call over to Patrick. Please go ahead.

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 Philippe, Anne, and Danny 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 4, and I will start with a short recap of what we do and how we do it. The DARPin is a novel therapeutic modality, a novel class that we have validated in more than 2,500 patients with seven clinical compounds. And the DARPin are different to other modalities, so not antibodies, not small molecules. There are the size, maybe a tenth of an antibody, and they're really well applicable for multi-specifics. And our quest is to use the DARPin indifference 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 will 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 the 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. 2023 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 tetra-specific T cell-engager. A year ago, roughly, we dosed the first patient. At ASH, we reported good safety and efficacy of the first 4 cohorts, and today we are recruiting, or we have fully recruited those cohort 6. 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 DARPin 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 of the 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 Orano Med, 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 1. 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 2026, meaning we are capitalized to reach key value inflection points. Moving to Slide number 6, 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, Philippe will talk about and will talk about the Switch-DARPin and explain that and Danny will cover the radio piece. With that before we go there I will hand over to Robert to share the financial overview.

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 2024. My name is Robert Hendriks and I'm the SVP Finance at MP. The numbers I present here are stated in million Swiss francs and I'm on Page 8 at the moment. Three numbers, it's a full slide, but three numbers in particular. First one would be the revenue. The revenue of CHF7 million this year is exclusively related to the agreement we have with Novartis on the RadioLigand 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 CHF4 million to be recognized in 2024. The revenue number in 2022 as you may recall largely related to the funds we received from the Novartis in early 2022, upon their exercise of the option under the Ensovibep license agreement. Second number I'd like to point out would be the operating expenses total of CHF68 million. The guidance that we provided during last year was CHF65 million to CHF70 million, and the expenses ended right in the middle there. For further breakdown, the R&D share of this number amounts to CHF49 million, and the SG&A number to CHF19 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 CHF4.9 million last year related largely to a lower expense for the listing of the company in the US as well as a natural attrition in headcount. The third number as already pointed out would be the cash balance of CHF187 million. You can see that's down from the CHF249 end of last year, so an effective burn of CHF62 million. This amount will carry us well into 2026 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 and 2023 and the solid financial state of the company. If I then move on to Slide 9 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 CHF70 million to CHF80 million of which around CHF8 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 2024 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 MPO533.

Thank you very much, Robert. And good morning and afternoon to all. I am Philippe Legenne, the Acting Chief Medical Officer at Molecular Partners. I'm happy to share an update on our MPO533 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 blasts, 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 end 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, but their co-expression of specific agents, of specific targets like CD33, CD123, or CD70. Moving to Slide 12, we have designed MPO533 DARPin treatment as the first tetra-specific T cell-engager binding to tumor antigens CD33, CD123, and CD70 on the AML cells, and to CD33 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. For such design, MPO533 is hypothesized to preserve healthy cells, hence opening a broader therapy window that has been seen for other T cell engager therapies. MP533 has the potential to cure 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 MOLM-13 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 preclinical experiments -- sorry, there is an ambulance just passing, just one second please. Okay, so I was just saying that this data alongside with additional true clinical experiments including AML patient samples will be published in the next coming weeks. Focusing on Slide 14 now, the [CP101] (ph) dose escalation study in patients with relapsed/refractory AML and high-risk MDS is ongoing and has now recruited the first six dose levels across -- Can you hear me?

Yes, we hear you.

We do hear you. Yes. [Multiple Speakers]

There's some very strange sound coming up. Okay, there's a beep. Okay, so I was just saying that, the study, the Phase 1, 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-patriotic 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 3 of those levels 3 and those level 4, the patient achieved ELN response of MLFS and CR. Slide 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, you can see the little square, to seek that if we can -- 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] (ph), which is aiming at complementary need in the treatment cycle of AML patients. Thanks.

Thanks, Philippe. And good morning or good afternoon, everyone. In the coming slide, I will show you how DARPin’s can further change the game for AML by significantly enhancing the therapeutic outcome of hematopoietic stem cell transfer. As we move to Slide 19, as you know, HSCT is potentially creative 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 DARPin solution aims at delivering a safer and more potent conditioning regimen for HSCT, 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 current conditioning regimens is that they are not targeted, leading to bystander toxicity and ultimately lower potency. So our solution is to target c-Kits, early expressed on hematopoietic stem cells and leukemic stem cells. The challenge here is that as we know, blocking c-Kit’s binding to each ligand is not enough for the hematopoietic stem cell depletion. You need to induce killing of the c-Kit-positive cells. And for this, we are leveraging our CD16-engager proprietary platform, which owns the potential to be safer than a CD3-engager or ADC, and to be more potent than an antibody by targeting the activating Fs 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 blocking therapy has been limited due to the high toxicity linked to the expression of CD47 on T cells. So our solution is a conditional CD47 blocking, which will ensure that CD47 is blocked only on c-Kit-positive cells. And for this, we are leveraging our Switch- DARPin technology, which makes sure that CD47 remain masked, CD47 blocking DARPin remain masked when c-Kit is not expressed, and that CD47 is blocked when c-Kit 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 the 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 Switch- DARPin is indeed safer and more potent. So slide 22 highlights the power of the Switch-DARPin for conditional blocking of CD47. What you are looking at here is the percentage of free CD47 on cells. What it means is that, this line decreases when CD47 is blocked. When you look at the light blue line, which is c-kit 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 c-Kit positive cells. And here you can see that CD47 blockage 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 logs in concentration between the c-Kit positive and c-Kit negative cells. So the conditional blocking of CD47 ensure a high safety profile. Now, how about a efficacy? The Slide 23 shows the therapeutic potential of our c-Kit switch target. 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-c-Kit 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 Switch- DARPin. And this tells us that we can expect a much deeper hematopoietic stem cell and leukemic stem cell depletion in patients with 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 test year there. 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 dark green, most likely linked to the fact that in the dark green, both CD47 and c-Kit targeting are in the same molecule, and then [indiscernible] and both benefit for anti-CD16. So this data showed us that we have a molecule that is not only safer, but also more potent than anything we can obtain even with a combination. So next step is [indiscernible] efficacy study. And the beauty of this study is that it is perfectly translatable to the human setting, from the building regime 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 DARPin technology, the Radio-DARPin.

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- DARPin therapy platform and respective pipeline assets. So as you probably all of you know, the field of radio therapeutics is experiencing a lot of excitement, push, driven all by strong clinical efficacy and good tolerability data that first compounds on the market or a new emerging compound 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 of the opportunity to come in this DARPin. If you move to Slide 25, so just for those of you who are not familiar with radiotherapy, 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-limiting organs. If you move to Slide 27 -- 26, apologies. So on the left-hand side, if you had a target in mind with a cavity where 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 are protein-protein binders where you can generate high-affinity and specific 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 a strong conviction that the DARPin platform is ideally suited to exactly building on the unique properties of DARPin 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 radio DARPin therapeutics candidate. Starting from the left-hand side, the starting point is, as for all our projects, building a diverse set of high affinity DARPin against a specific target of which, where you see, and that's always the lower graph, these DARPin, they're nicely accumulating 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 radio-DARPin therapeutics, increasing the tumor uptake by keeping the systemic exposure low. And if needed, as a last step, we are building -- we are increasing affinity of the respective binders to ensure tumor retention. So the novel two aspects of the radio-DARPin therapeutic engine are the two middle ones, step number two and step number three, and I'm going to show you a bit more of -- a bit 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-DARPin. What happens if that DARPin gets excreted by the kidney, it gets into the primary urine, fear, as all other proteins as well. It's reabsorbed. You get a lot of radioactivity into the kidney, and this is causing kidney damage. What we've been building on is the extremely robust architecture of the DARPin scaffold, heavily re-engineered the whole backbone and we call this the stealth DARPin. And this is now basically not recognized by these cells in the kidney anymore and the DARPin with its radioactivity is directly excluded 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-DARPin. 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 DARPins 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 managed for new tumor antigens for three out of four DARPins within a single round, we managed 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-DARPin, 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 [indiscernible] 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, so the stealth-DARPin for use, kidney accumulation and the half-life extension for increasing tumor uptake is the basis of our radio-DARPin therapeutic engine and basically the basis to build our pipeline. In our pipeline, we have two targets with Novartis, then two targets with Orano Med, including DLL3, and quickly expanding on Orano Med. 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 lead 212 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're looking very much forward 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 and handing over to Patrick for the outlook.

Thanks, Danny, 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 5.33, our AML drug. We're excited to look into the first data with you of those cohorts 5, 6, and a taste of 7 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 is clear, we are striving fast towards 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 2025 already. From Danny we heard on the radio platform, it's all about the first candidate 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 Danny said, the platform is ready. We're moving forward, add new targets and additional candidates. And then 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 where 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 CHF187 million in cash that brings us into 2026, 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, Philippe, Danniel and Anne 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.

We will now begin the question-and-answer session. [Operator Instructions] The first question today comes from Richard Vosser with JP Morgan. Please go ahead.

Hi, thanks for taking my questions. Two on MPO533, please. Whether you could give us any additional color, so it’s the first question, on what you're seeing and what has led to the -- what is more important than leading to the further dose expansion, whether -- the safety profile is clearly very benign, which is great, but is there a sense that efficacy needs higher doses? So 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 2 enabling decision? Is that more in 2025, or is that more in the second half of 2024? Just some color there would be helpful. Thanks very much.

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 the 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. [Multiple Speakers] So, and maybe I'll just on top of that add why and -- why Phillip 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. So 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 to 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 1 or the key driver that we can do that. So we think that molecules 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. We need to find out how we can tune how we use it to get the best patient benefit.

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 bi-specific antibodies with T cell engagers, certainly. But I don't know if there's additional comments there, but I wanted to just open to others.

No, I often miss the obvious ones. So thanks for pointing that one out. [Multiple Speakers] The last point of Richard was what will be gating. And I think there's 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. 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.

I think we got it. I think operator, I think we have another question.

[Operator Instructions] Your next question comes from Mike Nedelcovych with TD Cowen. Please go ahead.

Thanks for the questions. I have one on MPO533 and then one on the Switch-DARPin platform. So for MPO533, when we get the updated interim data from the Phase 1 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 Switch-DARPin 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?

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 the 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 Philippe, kind of you're closer as you make comment on more bit more on safety -- talking to these KOLs on a daily basis.

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 not enough to -- 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. So, because again, we see activity, but we want to see maximum activity in most cohorts. In terms of -- I also want to say we are working on fairly large, those [indiscernible] 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. At some point, potentially, it will hit the DLD, 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 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 cohort 7, potentially 8, 9, or even higher, but to really understand when we can trigger the expansion, and also the movement into the earlier line, which is a goal.

Thanks, Philippe.

And I think the last question I think was for -- much for 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 your thoughts.

Yes, Thanks. As you rightly pointed out, c-Kit DARPin Switch is just a starting point. Of course, there is a broad applicability for this platform. You can think of it from the target point of view, because here on the c-Kit, it's just a first step. Now, you can think that you apply this platform and gates. 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, [Epcom] (ph) or this kind of target where they are beautiful, they are expressed on a lot of tumor cells, they are very highly expressed, but they are limited by the fact that they are expressed on their system. So thanks to the Switch, we can allow gating and make sure that we will induce a killing of the cancer cells. The second thing you can do with this platform is allow different effects on mortality 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 us using cost simulations. If we think, for example, CD28, which targets very high toxicity risk, now using CD28 [indiscernible] and we 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 partners to completely exploit this Switch platform.

Thanks, Anne.

The next question comes from Kathleen Silverman with Leerink. Please go ahead.

Hi team, Thanks for the question. I am on for Daina today. A bit of a tag onto Michael's question from TD Cowan. The scenarios for potential stock movement on the first half 2024 533 interim dose escalation 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 dose cohort 5 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 the 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.

Yes, 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 direct the 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.

The next question comes from Joris Zimmermann with Octavian. Please go ahead.

Hi, Joris Zimmermann from Octavian. Congratulations on all the progress. Impressive. And thank you for taking the question. One on the RDT platform and one on MPO317. On the RDT platform, you've announced two partnerships, but also you have two internal assets or targets. Can you shed a bit more detail on your plans that you will follow up with the two internal targets and any potential partnering you see there? And then on MPO317, where do you stand there and when can we expect the next update, any potential partnerships announcement? Thank you so much.

Thank you. And I'll quickly take 317 and then hand over to Danny to talk about the radio-DARPin and our internal targets and isotopes and everything. So 317 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 IO-IO 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 will hand over to Danny to talk about kind of the internal -- undisclosed targets and our thoughts on sourcing of isotopes and other partnerships.

Thanks for the question. So maybe I start zooming out quickly on the targets. Our aim for picking 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 molecular biology and requirements that need to be met in terms of specificity, what part of the target do they address, location of target expression, so all the 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, I think almost like proof of mechanism, proof that we can really match those profiles well. And then afterwards, 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 be better to go into an extension into other collaborations that would be more built 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 length.

Thanks, Danny.

[Operator Instructions] This concludes our question-and-answer session. I would like to turn the conference back over to Patrick Amstutz for any closing remarks.

Well, 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 the 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.

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