Thanks for joining us. My name is Jonathan Chang. I am part of the Leerink Partners Equity Research team. It is my pleasure to host the management team of Molecular Partners. We have with us today CEO, Patrick Amstutz, and CMO, Philippe Legenne. Thank you guys for joining us. Thanks for having us here. Would you please briefly introduce the company? I can start. My name is Patrick Amstutz, thanks for having us here in Miami. It is a great pleasure. Molecular Partners is a biotech. We are Swiss originated, we are based in Zurich, Switzerland. We are around 120 plus coworkers. We have wet lab work, we are listed in Switzerland and in the U.S., with some coworkers in the U.S., especially around Boston. The work we are doing is in mini-proteins. We developed that at the University of Zurich. These mini-proteins are called DARPins, we profited from a very strong antibody background back in the days when we were doing this in the early 2000s. Great. Maybe tell us a bit more about what a DARPin is and how a DARPin's best applied? DARPin stands for Designed Ankyrin Repeat Protein, it's a repeat protein. You might not know, but the fact is that next to the Ig fold, repeat protein folds is the second-largest binding protein in nature. While antibodies were evolved to have many functions, they're also rather complex molecules, four proteins in 12 domains, repeat protein is a one domain, one function fold. It's rather ideal if you want to just have binding as a feature. DARPin in themselves are 10 to 18 kilodalton, depends on how many repeats they carry, and we can select to any given protein a high affinity binder. The real application comes in thinking not about the features, but the benefits the scaffold brings or the mini-protein brings, and we found two. On the one hand, it's the multi-specificity, we can add up to six of these binding specificities in one. On the other side, the differentiation comes in, call it stability and small size, and that's a field we're using for radiotherapy. Got it. How would a DARPin compare to other types of binding modalities? It's somewhere in between. If you take the small binders called peptides in the radio space, and you have the full antibodies on the other side, the DARPin will trend to be closer to a peptide than a full antibody. As the DARPin itself is just a binder, it is also going to be cleared via the kidney. There is some engineering one has to do for half-life, and I should say that we have now seven clinical DARPins. We have an extensive understanding of, A, how to engineer DARPins, but also how to half-life engineer for a specific half-life. In the clinical DARPins, we see anything from a few days to two weeks half-life. We can tune the half-life to the specific application we're going after. Got it. What are the priorities for the company? How would you characterize that? At this point in time, the key priority is radiotherapy, and the second kind of focus is T cell engagers. The split is roughly 80% activity in radio, and we can come to that on a more global level why, versus 20% in T cell engagers. I would say the productivity of the radio side is really attractive given that we can make a mono DARPin, we engineer it for low kidney, high tumor uptake, and can run that into the clinics, into a compassionate care setting, and with a low million-digit investment, have clinical data that then can guide the phase I and beyond. If you compare that to T cell engager, it's more a CHF 20 million investment to get to a full phase I to actually get clinical data that will guide your development. You're almost talking a 10x in investment to the first clinical readout. Just saying that, it's very clear that the return on investment on radio is exciting. That's why we are investing most there, and we still keep the T cell engagers because these can be extremely meaningful products. Understood. Maybe on the Radio-DARPin application, how are you thinking about the selection of radioisotopes? I think historically, you spent most of your time talking about lead, but more recently we're hearing about actinium. Yeah, that's a great point. We as a company, we are a vector play. We differentiate via the mini-proteins, the targets, the engineering, the biology, the patient approach. We're not investing money into isotope supply, manufacturing, supply chain. That we leave to our partners. As such, we are, you can say, it's maybe a rough word, isotope agnostic, which is not totally the case because we will fit the isotope to the application, so we're not agnostic, we're thoughtful on the isotope. In some cases, both isotopes can make sense. We can also move two, at least in the compassionate care setting. Given the low costs that we have there, we can move both and let even clinical data decide which isotope could be better. From that point of view, this makes sense. We have an agreement with Orano Med for lead, we just signed one with Eckert & Ziegler for actinium. I should point out that the Orano Med one spans into commercial supply, we don't see the need for that now for actinium. That is more an early-stage development agreement. Got it. You mentioned that your selection of radioisotope could be specific to the program, how are you thinking about sort of the pros and cons around the selection of one or the other? Yes. First of all, I think the big pro is that we have both. If you think about it, how the field evolved also with Lutathera, you started with beta, then these assets were developed, then alpha came along, actinium, and you can say maybe sometimes there is a challenge that the second generation eats the lunch of the first. Now after actinium, you actually see lead coming along. We'd want to not be in that trap to be in one or the other and be at risk. Let's do both at least alpha radiation. The difference is that the lead has an only 10-hour half-life, while actinium has a 10-day half-life. I like to compare that with the weather. You can think of the lead approach to be more a thunderstorm, where all the rain is just hailing down within 10 hours versus the same amount of rain coming over the 10 days. Depending on your target, your resident time in the tumor, and what your biodistribution tells you, one or the other isotope might clearly stand out, while in some cases, we simply don't know and would have to test both. Got it. Anything to add, Philippe? In regards to the choice of isotope, we, again, as Patrick said, we want to focus mainly on alpha, the part of the family of alphas. We are agnostic to both, so we want to develop for both, in fact. Depending on the indication, the target, we will adjust. We think we can inform both profiles even with the same target. Maybe you can update a bit on the compassionate care setting because we had to pioneer more for lead than for actinium. Yes. As Patrick was already saying a bit, we've been able to enable compassionate programs, which allow to de-risk very quickly the profile of the product. Some centers around the world, whether it's in South Africa, Germany, or other countries, have this specific regulation enabling early compassionate programs. It can be a win-win. It can inform the drug, it can serve some patients, and we are basically enabling that. Recently, we delivered our first program about DLL3, and that data was presented not so long ago, a month ago, in fact, in South Africa. This has been so full of learning and also de-risking for us the first step of the program of the development. We're now entering phase I, but we're entering phase I with a lot of learnings. Go ahead. I think you built that ability in South Africa for lead with- We certainly have. At MP, we have pioneered that, basically, we have really uncovered that opportunity. We are now considering doing more of that and supporting more of that for other profile. Again, we are also discussing beyond South Africa in some other centers. This is a very effective way of informing early program, de-risking them, and hopefully helping some patients. Great. Maybe we'll switch over to your DLL3 program. This is MP0712. Why is DLL3 a great target for your Radio-DARPin platform? Thanks for the question. DLL3 is one of the best targets you could think of. First of all, it's a validated target. They are T cell engagers, approved talquetamab, other T cell engagers. ADCs seem to have activity. Even CAR T are being developed. This is a very validated target. It's why it's also a very clean target, high expression in the tumor cells, and zero or little to zero expression outside of the tumors. That's the ideal type of target. I think what's also important when you consider clinical development, this is a target that seems to persist across the disease and across the treatment lines. Whether you are treatment agnostic first line, or whether you would be, for example, when we are going to enter, many patients would likely be treated with talquetamab, but we envision, and we know, in fact, that DLL3 expression still is there, so there is no reason to think that we wouldn't be effective there. Those are basically some characteristics which relate to the expression. I think there is more than that, which we think DARPin can have, and the profile that we have can be worthy of development and very specific, is that DLL3, as we've learned, is a very quick cycling receptor. For a product like ours, which has a half-life a little longer than a peptide, we think that we are staying close to the target when the receptor cycles, and therefore, it can replenish when we are there. It gives us, we think, a unique advantage in terms of our PK. Got it. Patrick, you want to add to that one? Yeah, maybe just to add some numbers. In our preclinical testing, the half-life engineering led to a 10x, so 10 times more DARPin/radioactivity in the tumor than if we just had a naked DARPin. Comparing apples to apples, if you want, the same binder 10 times more. We were first a bit surprised on that, but then we found this internalization mechanism, and I should point out that, DLL3 copy number is a few hundred per cell, so it's almost not there, versus 150,000 of PSMA, and we were surprised. How can we have so high uptake in tumors with so low copy number? We looked at cells. We did not find the DARPin on the cell surface. Literally no DARPin on the cell surface. Everything was internalized. I guess our surprise was, why do T-cell engagers work here? That ADCs can work was clear after that was a bit a question. They work well, I do think they will also be, in a way, limited by this rapid internalization, you'll have to also replenish and have a good half-life. What would you say are the key highlights from the imaging data you've shown so far with 0712? The key highlights was really nice tumor uptake. We see clean tumor uptake. We see that over a nice time range. We see rapid tumor uptake. We see very good clearance from the system. Given we have a bit longer half-life, we see that. We can measure the half-life. We see blood distribution, and then it clears mostly via the kidney. The key was that from the dosimetry data, we know we're in a, call it safe space for the kidney and for blood. Blood would then be, in this case, red marrow. That is the two organs we will look out for. At the same time, we see very nice tumor uptake. It supports all preclinical data, is actually a bit better than in the preclinical part, and all boxes ticked to go on. Maybe on the safety side, you have the expertise. Yes. First of all, for the several patients that were exposed in the compassionate program, we've seen absolute clean safety. It's imaging, so you would expect that, but it's better when you see it. That was our case. We could also, as Patrick was saying, see good uptake. The drug is going where it's supposed to go and not going where it's not supposed to go. That really is very reassuring. Then some patients were small cell lung cancer, not all of them. In fact, there were other neuroendocrine cancer patients. As you know, DLL3 is also expressed to a lower frequency in those, it was very nice to see that in neuroendocrine cancer of the bladder, for example. There was really good uptake in the mets. That was also very, let's say, encouraging. At the end of the day, I think the best summary of all of this is when we have the chair of our scientific advisory board, Ken Herrmann, he said, "Everything checks green." Good uptake. Now it's time to go phase I. That's what we are currently doing. Got it. How do you see 0712 positioned in the DLL3 competitive landscape and small cell lung cancer more broadly? Maybe I'll actually take the small cell lung cancer first, then hand over to Philippe. Philippe was just doing site visits, so he has first-hand impressions from treating physicians. First, I think one thing we did see also in the data is that we had a more robust uptake in metastasis than in the primary lesion. That's what we are expecting in this disease. I think this has been described not only for this disease, but metastasis are younger tumors, maybe better perfused, easier to access. This is a disease that defined via metastasis. I think that is also a smart choice, if you want, why DLL3 small cell lung cancer is good. I was in one investigator meeting. I think what I come out with is there is a competitive landscape, but there is much more need for drugs. I was going in there asking myself is, did tarlatamab close the door for competition or open the door? I come out clearly it is opening the door because these doctors now have hope. They see new modes of action. They see hope for these patients. Even with tarlatamab, it's nine-ish month survival that they give. That is not so much. Now they are so open to test new modalities. They really like the idea of radio because there could have been a skepticism, but I don't see that at all. There is more, I would say, a hype about it as radiation should work, because small cell lung cancer is a radio-sensitive tumor. Maybe for a bit more insights, I'll hand over to Philippe. Again, I come all excited and fresh and invigorated by the recent discussions I had with several experts as I visited their sites. I'm coming back just now from Cleveland, and before this, I was at Emory, for example. As Patrick was saying, the investigators who have been working with tarlatamab for now a year and a half, in the study and in commercial setting, they are very happy about having a new drug which does better than most recently. On the other hand, they start to see limitations, and they start to see that basically another modality is welcome. Of course, we'll have to start our studies in a post tarlatamab or some patients may not have gotten tarlatamab, but that would be more exception in the U.S. Because again, the DLL3 expression is conserved post tarlatamab, they really think that we should be effective there. This is where it will start, but then they also advise us to really envision very quickly to try to go earlier and to go into the, what I would call the consolidation maintenance setting, post chemo, just post chemo, and before the immunotherapy. Let's remember that the characteristic of a radiopharmaceutical like ours is it's a finite treatment. It's a four-month treatment, up to four cycle, maybe six or at least two. This is a short-duration treatment compared to an immunotherapy, which is up to progression. This is where they see that they would want to test the radiopharma at that place. How about versus a variety of ADCs in development, whether it's versus DLL3 or in small cell lung cancer more broadly? feedback from the experts who have been now playing with the different modalities and the different DLL3, B7-H3, TROP2, they have played with all of them. First of all, they really like DLL3 in small cell lung cancer, and also in some EP-NECs. This is for them is the reference. They would think that for an ADC, yes, they are seeing good effect. Let's remember this is phase I effect for the moment, so likely, that may stabilize. They also see a limitation in the duration. Also, let's remember, the current ADCs are using etoposide as a payload, basically topoisomerase, which is the current chemo. Everyone knows that there is a limitation. At some point, the resistance kicks in. There is no reason to think that the ADC would not face the same challenge. Good responses, quick responses, and quick renewal resistance. This is why they see that they very much welcome another modality like radio. Got it. Can you talk about your clinical development strategy for the program and what are the timelines associated with that? Sure. I can start with the simple things, then Philippe can go into details. We're planning 4 dose set levels. We start with 75 megabecquerel, one dose, which we, from all calculations, is a safe dose. We go to 105, 150, 200. They're always separated by four weeks and up to four cycles. In that, we have, I think, at least three patients before we can dose escalate. I'll hand over. What we heard from Ken Herrmann is that we should not be surprised to see activity even on low doses when he compares to other trials in small cell lung cancer with alpha. First of all, I want to say this is a very effective design, and we discussed that with the FDA, and we were very happy to see how the FDA was encouraging an effective design. We can start pretty high already, in a pretty much effective range as dose level 1. In fact, the DLT period is short, 28 days, that means that as soon as we pass that, of course, three patients in the first dose, we can initiate the other dose level whilst we continue the other cycle. It's a very effective design, and we learn through the inferior cohorts into fueling the dose escalation. That's the most effective design that you could think of. What we envisioned to have is, what we're planning to have is a more or less a cohort per quarter. That's what we are planning for, and we are starting now. In fact, we have started. That's where we are now. We have a group of investigators, top-notch investigators, a mix of private centers and academic centers who basically will bring the best in terms of speed, recruitment, and knowledge. That's our phase I dose escalation. As soon as we start seeing activity, we will expand for EP-NEC also. We will broaden to the other subpopulation. There is an expansion there. Likely that would be from end of H1 of next year, this is when we envision to have start to see the response rate, duration of response, and then being able to activate expansion. That's the main short-term development plan. What should investors be expecting in terms of data updates from the program, and when? First, by the end of this H1, we should be able to have a pass, a first de-risking moment. We want to make sure that the drug is as safe, that hematologic toxicity is not a problem, that we want to de-risk there. That's the first step. By the end of H2, we should have activity being described because we envision that we will be in dose level 3 likely at that moment, likely initiated dose level 4. We will have around the end of the year the first big moments of being able to start describing activity. In H1 next year, we will start to be able to describe response rate, duration of response, basically. They are the big 3 phases of our development. Understood. Let's switch over to your 2nd program, 0726, targeting mesothelin. Tell us about why mesothelin is a great target, and why you guys selected this as your 2nd target for the Radio-DARPin application. We chose meso because it is a very difficult target, and the one problem ADCs, CAR T, radio faces is mesothelin exists in 2 forms, bound to the cell, but then it's cleaved, shed, and in circulation, and there's a high level of circulating mesothelin. The epitope that remains on the cell is very small. We said, can we develop a binder, a DARPin, that only binds the membrane-bound form and not the shed form, meaning we will not be neutralized by all this shed mesothelin? This has not been achieved with any mini-protein so far, and no peptides. Only full antibodies were able to do this, and antibodies are not ideal for radio approaches. That's why we chose it. It's a high bar. On the other side, mesothelin in the indications, ovarian radiosensitivity, but also a bit of lack of T cell activity, so maybe a bit less competition from T cell engagers. We felt it's a good indication to go after, and we managed to get the DARPin, make that DARPin a Radio-DARPin. That was still the time when we did the engineering of the framework. Now we have full libraries that are already engineered, so we're cutting down the timelines there, and we feel that's good to go. We have biodistribution supporting imaging, and that's going to be the next stop, to do compassionate care imaging on that one. Understood. How should we be thinking about timelines for clinical development for the mesothelin program? For the mesothelin program first, it starts with a request. We got the request from the centers we've been working with for compassionate program to start evaluating there. We will enable that. We are starting to prepare for this, and likely in the Q3 of this year, we aim to enable the start of such programs in either South Africa or likely in Germany also. Got it. What is the latest status of 0533? This is outside of your Radio-DARPin efforts, and what are next steps for that program? MP0533 is our tetra-specific AML program. We are in the last cohort of the phase I. We see the profile. We see activity in a very difficult-to-treat patient population, and we're now evaluating the next steps for this program. Given our focus in more solid tumor with radio, likely we would invest in this program outside of our company, this could be a newco or a partnership, to give this the focus it needs, as we at Molecular Partners will be doing less of that. Might also be an investigator-initiated trial. We've done that with MP0317, our CD40 FAP. We're checking what is the best way to bring this forward, in what setting. Got it. Maybe just extending on that, how are you guys thinking about business development opportunities for the company? That's a very broad question. I think first of all, as you hear, we have likely more opportunities than we can fulfill ourselves or follow ourselves, we are principally open while we also need to focus on what we need to deliver. It's always a balance. We are getting requests in radio, but also on T-cell engagers for applications where larger companies are looking for support, and we evaluate those and see what we can do. We might add one, maybe max one, maybe two, for radio for targets that we are not pursuing or indications that we have precluded upfront. I also like the question because we have now done BD, we have several lead slots and actinium slots that we can fill, we're also looking for assets we can bring in that we don't always have to start from zero, but also can bring in assets that possibly even have early clinical data, especially for the lead profiles type settings that we have. We're very active on the BD side these days, always focusing on our key pipeline. The value creation happens mostly in MP0712 and MP0726. Understood. Just last question. Cash position, and runway. We will report data on the cash position. I think it's CHF 93 million end of the year. That is ever-rising amount in US dollars these days. The Swiss franc is so strong, a bit above $100 million. The cash runway will bring us into 2028. Everything we were discussing is well within the runway, and as you see, a lot of opportunities there that we can move forward with the cash that we have. Understood. Thank you guys very much for joining us today. Thank you. Pleasure.