Welcome back, everyone, to TD Cowen's second annual Radiopharmaceutical Innovation Summit. We're very pleased to welcome you to the Molecular Partners session. My name's Mike Nedelcovich, I'm an analyst with TD Cowen, and I'm very pleased to welcome Michael Stumpp, who is the EVP of Projects at Molecular Partners, Christian Lizak, who is the Senior Director of Radiotherapeutics, and Seth Lewis, who is the SVP of IR and Strategy. Gentlemen, thanks for taking the time.
Very welcome. Thanks, Michael.
Thank you.
So let's start with kind of a broad question to help orient folks who might not be so familiar with the Molecular Partners' story to your platform and pipeline. What is a DARPin, the modality that you all develop, and why is it well-suited for use as a radiotherapeutic?
Thanks a lot. So, welcome also from my side. We are a biotech company in Switzerland, and really happy to be part of the TD Cowen Radiopharmaceutical Summit. As you may have heard, we are actively, since a couple of years, developing DARPins in radiopharmaceutical applications. So the first question is a very good one: What is a DARPin? Molecular Partners has been around for about 20 years, so we're actually going to have our 20-year anniversary this year. And, back at university, before starting the company, we developed an exciting novel class of proteins, maybe call it mini protein nowadays, are made up of repeats.
So they have exactly the same structure that is juxtaposed next to each other in a structural way, or you can align them under each other, and they are derived from naturally occurring, in this case, ankyrin repeat proteins, so nature has evolved them for us. And we looked into nature at the time when the Human Genome Project was coming online, and realized these proteins are super abundant in the human genome, so roughly 1%. So each and every one of us has a lot of these repeat proteins, and we thought, "Hey, there must be a reason to that." So we, we looked it up. They're very ubiquitous.
They have a lot of different functions, but we could boil it down to a natural precursor, maybe a protein that has been around millions of years ago in evolution, and that's the one we then decided to build our company around. So it's a small protein, highly expressed, very soluble, brings a lot of protein engineering advantages, and we have mastered this now over the last, 2 decades, to the extent that we can really say this also fits very well. Funnily enough, we had some research in about 10, 15 years ago in radiopharmaceuticals, but the field wasn't ready at the time. There's a 2010 publication from Christian Zahnd, our first CEO. I'm also one of the authors. So we really actively looked into this and realized the small size is a very good starting point.
With the small size of a DARPin, it's about 15 kilodalton, we can penetrate tissues deeper, and this has basically helped us to the very day. We also make them now longer half-lives, even though in the beginning, we thought short half-life that comes natural to such a small protein is a benefit. But there is, of course, the kidney, which sometimes retains, especially the radiometals, so we have been heavily working on that. But I think all in all, small size, deep tissue penetration, and a great degree of engineering freedom has helped us a lot to venture into radiopharmaceuticals.
Great. Well, maybe, Christian, you can provide an overview of your radiopharma efforts to date and your various partnerships.
Sure. So I think as Mihi said, when we kind of revived our radio DARPin activities, I think it was pretty much with collaboration that we started with Novartis. That was at the end of 2021, so two and a half years ago. And at that time, we realized that we also need to invest in the platform, really what Mihi mentioned, to solve the kidney problem and also find ways to elevate tumor uptake. And so we have really, in the last two and a half years, invested a lot of activities in the platform, and I think with that accomplishment, we are now also in a position, besides the Novartis collaboration, to also start internal programs.
Yeah, maybe I can add just a thought on that as well. I know Christian says the kidney problem, which I think for everybody on this call and listening, understands the concept that as a protein, DARPins, along with any other protein therapeutic in the radio class, will preferentially go to and be excreted or retained, more problematic for radio, by the kidney. So it isn't something DARPin specific other than the fact that we're a protein, and we have spent time and presented on this subject, most recently, obviously, at SNMMI, which we'll talk about in a minute. But certainly the fact that we have engineered down the kidney uptake of those DARPins to preferentially now have a greater ratio of targeting the tumor versus being absorbed in the kidney, which really allows us to move into the clinic successfully, we believe.
Yeah. And maybe just to complement, we also have a collaboration with Novartis, since about 2 years on 2 undisclosed targets, so we have quite a nice portfolio together with Orano Med, our, other partner, and the proprietary effort. So it's a small pipeline within Molecular Partners, uniquely dedicated to radiopharmaceuticals.
Yeah, so you have the Novartis partnership, you have a partnership with Orano Med, which also serves as a supplier of the radioisotopes.
Yeah.
You have an internal pipeline as well. Am I correct in saying that of radiopharmaceuticals?
Yes, it's these three, these three parts, but obviously, we need partners for the know-how on the radiopharmaceuticals. And Orano Med is a 50/50 collaboration, so we have very active exchange since also more than a year. Very much like the collaboration, and they are one of the, the big names, I think, in the lead field.
Great. Well, let's hone in on your first clinical candidate, MP0712, for which, as Seth mentioned, you presented some exciting preclinical data, I guess it was just last week. So, can you take us through that molecule? What is the target? What is the radioconjugate? And your partnership with Orano Med, how does- how has that worked so far in pursuing this particular candidate?
Yes, absolutely. I'll start, and Christian actually was the presenter at SNMMI, so he knows the slides even better. It's a DLL3-targeted DARPin, so for small cell lung cancer and other indications, as we know now, that are DLL3 high. We were quite pleased that Amgen got the approval for their tarlatamab ahead of time, so it's now a validated target. It's an approved target for biologicals, and we believe the radiopharmaceutical approach can actually help patients even better in the future because of higher response rates. Of course, that's something we need to prove, but we are not the only company. A couple of our competitors are working on DLL3. However, I believe we are the only ones that use a DARPin approach, and the only ones that use lead-212, because Orano Med partnered with us, and that's an exclusive partnership.
So we started some time ago, focused, of course, on the DARPin generation. We always do that. We have a lot of expertise. You need the target, you generate high-affinity leads. We always have super high specificity, so I'm talking picomolar range, very exclusive specificity, and we can do this with a protein of about 10-15 kilodalton in size. And then the chelator is a bit special, so for lead, the best chelator is a DOTAM chelator. And then the 212-lead has recently had some very positive news at ASCO. I was there, very nice presentation, very long survival benefit, overall survival. So it seems to show, seems to indicate that with an alpha therapy, maybe even with lead-alpha therapy, can really help patients.
In that case, it was the SSTR2 space , but there is something about alpha therapy, and in particular, lead. You need to master, of course, the logistics. It's not easy. There's a fast half-life of about 10.6 hours, but Orano Med has set up this extremely well in the US with a central supply and are also expanding that into Europe in a second step. Maybe, Christian, more to add, so we have, of course, mouse data and so on.
Yeah. So I think for us, really, the key at SMMI was that we were able to present our lead candidate, MP0712, that we are now planning to bring to the clinic, hopefully next year. And I think besides that, it was also, for us, the first example where we could showcase what the DARPin or our radio DARPin platform is capable of doing. So DLL3 is a nice target. It is homogeneously expressed in more than 85% of small cell lung cancer patients, but at the same time, it's not very high in expression level, so it's also, if you wish, a bit of a challenging target. So it was also, for us, a good benchmark to see what we can achieve with our platform.
We were really very, very pleased to see that with the slight tweaking of half-life, we were able to get to tumor uptake values in the range of 30%-50%, even 60%. So that was the nice story that we could stitch together now based on various updates that we gave last year on platform, on kidney, and on half-life extension, and now to show for DLL3 the whole picture, how we evolve or how we develop that molecule.
Right. Can you elaborate a little bit on your efforts to optimize the tumor-to-kidney ratio? Because you had some nice results in the preclinical work.
Yeah. Let me try. So obviously, there are several parts you have to pay attention. So first of all, you wanna deliver as much as possible at the tumor, which means high affinity, so that you are binding for a long time once you're at the tumor, but also tissue penetration because you need to get to the tumor first. So trying to optimize the speed and the DARPin can go to the tumor, so specifically, we are talking about the on-rate. So ideally, from the engineering point, maximize the affinity, both on the on-rate and also on the off-rate, so a low off-rate. Then, of course, you don't wanna stay very long in the kidney, so ideally, if you end up in the kidney, go through quickly to the urine, and our engineers have approached this with so-called surface engineering.
So looking at the charge and other features of the protein so that they are not retained in the kidney. That's tricky because sometimes it comes at the price that something else goes wrong, so we had to optimize all of that. And thirdly, which is also not to be ignored, there are other organs. So if you end up, for example, in the bone marrow, that's no good news. So trying to optimize these three compartments, the tumor, the kidney, and the blood, and I can't disclose all of the amino acid changes we did. In the end, the combination of surface engineering to some extent, and the half-life. So how long do you wanna stay in the blood? Because you need to give the molecules a chance to enrich in the tumor.
It's not done in an hour, it takes several hours, but at that time, also to avoid the kidney. Now we believe that's why Christian could announce that MP0712, 712 has all the properties to have an ideal 60% in mice at the tumor-injected dose per gram, relatively low kidney, so we end above one range, precisely 2.4, and over time, that may even grow, and at acceptable blood levels. This is supported by the mouse studies we have done together with Orano Med, very safe molecules, very good efficacy. Now we are moving, as Christian said, into formal development. Hopefully, have soon, imaging and clinical results next year from the molecule.
Yeah. Maybe actually one comment on that, Mihi, to just elaborate. Obviously, one of the things that we're building here with the DARPins, and one of the benefits of working with DARPins, is that they are super stable. And not to speak ill of other classes, but one of the things that we know we can do here, and we've been building along with the DLL3 program, is the ability to do this again and again and again, and to take all those learnings to the best we can with kidney, with tumor uptake, with half-life, and to reapply that to the next program. Because as you said before, we are building a pipeline, both with Orano Med, we have the targets with Novartis, and then additional targets beyond that.
To make sure that we know or that our partners will know that the next time we endeavor on another program, that we're already at 60% of the learnings built into that naive DARPin, and the rest of it is just surfacing for that target or getting a little bit more specific to kidney, to half-life, to the biology of that disease. That's the ability that we're building into this throughout the value chain to make sure that we're not starting at day one for the next target, as you might have to with other therapeutics. So I think that's a massive difference that we're building into our platform on top of DLL3 being the first program.
Got it.
Yes, and the stability, Seth, I think that's also something we are quite often talking about for manufacturing. We are using a heat step because our proteins are completely undisturbed after such a heat step. And for radiopharmaceuticals, sometimes you also need to apply very harsh conditions when the nucleotide has to go into the chelator, you force it with heat and other tricks.
Got it. That's an important point. Speaking of the nuclide, you touched on this a little bit, but what are some of the pros and cons of lead-212, at least as your initial radioisotope that you're pursuing for DLL3?
Yes, I think here now a slide would be definitely useful, so I'll try my best to explain in words, and Christian, please help. So one thing is it's having a very clean decay chain. So as you know, all these radioactive isotopes, metals are decaying over time. And what happens to lead, it decays, and it emits an alpha particle, and this alpha particle has a very high energy, so like the other alpha emitters, and then leads to double-strand breaks in the vicinity. It doesn't go very far, but in the vicinity. And then other radiopharmaceuticals may decay to more problematic radio metals that then suddenly emit, say, beta emission, and that's not what we want. We want to have a very clean decay chain to minimize unwanted toxicities. And after a half-life of, say s o 10.6 hours is the half-life, but then after 2, 3 half-lives, the patient actually can go home without any other safety measurement.
So I think that's a dual benefit of an alpha emitter and a fast decay. The problem it comes at the same time is the logistics. You need to basically, that's what colleagues at Orano Med do, start the production at midnight, be ready for the shipment so that patients in hospitals can be dosed in the morning. And they have thought long and hard about it. It's a central supply chain next to a logistics hub, so they can fly these probes to any hospital. I think they reach more than 90% the hospitals in the US from one central supply, building more.
And then, of course, patients have to be infused or dosed rather quickly on that morning. So I think those are the, the top-line differences. So very high energy decay, very clean decay chain, comes at a price with logistics, and our partner has impressed us again and again. Open a new facility, can deliver hundreds of doses per week, so I think it's a great place to be in.
Yeah, I all credit, actually, to Christian, as one of the first people in our company that recognized these deficiencies in supply that were going to occur throughout the development of all this burgeoning radiopharmaceutical. You know, I don't want to call it a land grab per se, but as people were picking isotopes and supply and trying to isolate where they could get assured resources and purity and quality, you know, Christian, as one of the early developers on our side, was very quick to recognize the group at Orano Med as one of the worldwide leaders and one of the most important people we could be working with. So Christian, would love, you know, if you'd want to.
Yeah, maybe to add on this, I think what really makes Orano Med so special in this field, that they have a mother company that basically owns huge stocks of the source material. This is thorium-232 in huge amounts, and it kind of makes the supply of lead-212 kind of infinite. And I think it's a very reliable approach, it's scalable, and it's a chemical extraction process, so it's also a very safe approach. And I think that brings huge advantage in terms of securing isotope supply. And maybe the other advantage, I think Mihi already highlighted, this is really the decay chain, because one of the challenges in alpha decay is that you have this very strong energy, and when the particle is released, you have this recoil.
So basically, the radioisotope will be completely detached no matter what kind of nice chelator you have. And if you have some alpha-emitting daughter nuclides, as you have, for example, in the case of actinium, they might have an uncontrolled distribution in the body and then can cause some damage. With lead, you don't have that, you have one single alpha decay, and so you're much safer from that perspective, which also, I think, gives us the advantage that we can maybe play around a bit more with the half-life extension, whereas maybe this is more critical for other particles, actinium, but also beta particles, for example.
Thanks, Christian. Just to emphasize, the supply is in France, right? It's in a location which is easy to access. They can distribute from there. They have the thorium in a good location.
Yeah, I guess there's supply, and then there's supply, and then, but and maybe this is a question for Seth, but, can you remind us the terms of the agreement with Orano Med? What—how many targets are covered by that agreement, and, what does exclusivity look like? What is Orano Med's freedom to operate on their side relative to partnering?
Yeah, totally. And I think, I mean, this encapsulates everything because even the data that Michael was referring to at ASCO that was presented, that is Orano Med's 212 Pb, in collaboration with RadioMedix, that's in phase two right now, hitting all of its endpoints, has breakthrough designation with the agency. So it's an understood, and they are a clinical company with other assets out there. So it's great to know that they are already well-established on that critical path with regulatory, and that they have supply, and that a, you know, agency knows how to deal with them, which is great. To the extent with us, we were always clear that for our first target that we were going to the clinics with, we were not an isotope company.
We wanted to make sure that we were working with a company that had clinical ambitions of their own, and that was well-established on the clinical side. So Orano Med was hitting all of these points, especially with the, you know, interesting alpha generation that you would see from lead, but also the fact that their supply is as intact as it could possibly be for anyone. But we announced that deal in January of this past year, starting with DLL3. And then there's room for two additional programs within that collaboration. If things go well, God bless us, we'll do a million of them. But for now, starting with those DLL3, they're all 50/50 joint collaborations. Commercial will swap based on target, so at the moment, DLL3 is ours.
We're gonna pursue that as far as the lead party and the commercial owner of that program, but 50/50 invest, 50/50 split. And then they have the right to pick the next program, and then, therefore, if we keep going, then we'll talk about the third one. But you know, been a great collaboration, so it wasn't just on a chance that we took this announcement in December or January of this past year. As Michael said, for the past 2+ years, we've been working in collaboration in the back with Orano Med on a million different things as far as experiments and animal, and optimizing, and figuring out the right targets, the right half-life. And it's been a really great collaboration that led to this, so very successful so far. Very happy, very happy.
Great. Well, maybe one more question on seven twelve, and then we can talk a bit about the broader pipeline. So you mentioned first in human, anticipated in 2025. Would we—should we anticipate seeing imaging data first, potentially? And, is there a chance that we see efficacy data in patients later that year, or is that too much to hope for?
Mm-hmm. We are also very hopeful that it goes well, but, you know, we haven't made the GMP manufacturing. Also, we haven't talked to the agency, to the FDA yet. So hopefully, everything will go smooth, and we can announce next year, first in human. Whether we can disclose imaging data earlier, of course, I would love to, but it also depends on a number of logistics step. But the teams are working really very diligently and hard on that, and then we have to be patient and wait until the patients come, and everything comes together. It's the first time for us, right, to make a radioactive DARPIn enter a first-in-human situation. As you know, of course, you need to also do a tox study in animals. So, let's hope for the best. Let's hope for both images and efficacy data next year.
Then out of our hands, but I have full confidence in the team to get as close as possible to that.
Exactly. I think one of the pieces of that, there's twofold. So when the phase 1 is to begin, that will comprise both imaging and dose escalation. So that's in on the critical path for 25, no matter what. Ultimately, where we wanna be, you know, on top of that is, are there other ways that we could explore, potentially, doing imaging work ahead of that study? That's not the FDA, you know, program that must go on, and that's in 25. You know, that's the plan of the team. As to Michael's point, full faith in the team, we are all focused on that. If there are options to explore something earlier than that, we're not guiding toward that. We're not saying, "Aha, we have this," or anything. If it's possible, we'll explore it.
But in the meantime, all eyes on getting into the clinics in 2025 with imaging and dose escalation and having data as quickly thereafter. Because obviously, it's a very patient-permissive, very real-time setting that we're able to draw information from.
Got it. This question may be premature as well but, you know, after kind of a long drought, we now have some novel treatments for small cell lung cancer. Is there potential shift in the treatment landscape? How do you consider that when you think about clinical trial design for a radiopharmaceutical?
Great question. U.S. has the approval now for tarlatamab. Hopefully, our patients can profit from that very soon. And I guess based on past experience, what will happen then, some patients will progress, or some patients may not like the side effect profile, and they will be even in a higher need of some treatment. Whether they come to the centers where we are recruiting, all open questions, but I think doctors and patients and other caregivers will be sensitized to new options for small cell lung cancer, and that was something missing so badly for the last decades. So hopefully it will help. We are open to other DLL3 overexpressing tumors. Note that the overexpression levels are relatively low, so we have to make the best, highest affinity agents and the best T-cell engagers, but I'm sure there is a cross-fertilization.
Eventually, we are hoping that we can go first line because we will sensitize this tumor to an immune response, and that's also something Christian just reported back from SNMI that's emerging now. We have been in immune oncology for many years. Hopefully, we can use the two powers of the body, the immune system, and the radiopharmaceutical damage, to make even patients go even better in the future.
Great. Well, I don't wanna neglect your Novartis partnership. I know there's not much you can say about it, but maybe broad strokes, can you tell us a little bit about how it's progressing and the breadth of that effort?
Yes, I'll quickly start. So remember, we had a very tight and successful collaboration with Novartis on ensovibep. So we like them. They are based in Switzerland, as we are. We have a good, deep, trustful relationship. But then, of course, you face reality. There's research, there are ups and downs, and I think it's a very good partnership to tackle difficult targets on the long run. Orano Med impressed us with really high throughput. Smaller company, relatively speaking, we are high on the priority list. Within Novartis, of course, there are other competing forces. We accept that, and we really like to go forward with them. Before handing over to Christian, I unfortunately have to step out a little bit earlier today, Michael. Sorry for that.
No worries.
My colleague who was supposed to speak is on an airplane that got canceled, and now I have to jump over. So-
No problem.
Sorry for that-
Thank you for your time.
But you're in very capable hands. See you next time. Thanks, everyone.
Cheers.
Thanks, Michael. Yeah. No, but honestly, Christian, all deference because, he's been leading and is the relationship manager on the Novartis side as well, so it's imperative, please, that you kinda give a little thought on that as well.
Yeah. So I think with Novartis and Orano Med, I think we are really in the fortunate situation to work with really two companies that have a lot of expertise. I think that both—I think I would consider both of them as pioneers of the field, but the nature of the collaboration is, is obviously different. I think with Orano Med, we really have this almost one team that works hand in hand. I think we managed really to completely, or almost completely remove the walls between the companies, so it's a really back and forth, really efficient process, and that, that's, yeah, that as a small biotech, you cannot do this with, with a, with a big pharma company, but still collaboration. We have excellent relationship. I think it works well, and we're very happy with both approaches.
Yeah, and maybe for the sake of the audience, too, because it is a bit. We were a little early in that. So the relationship with Novartis began through our relationship on a COVID antiviral we had been working on with them. NIBR was also getting familiar with us at the time, saw all those innate properties that Michael was talking about before: short half-life, high affinity, super stable, in and out, all those things, 15 kDa and small penetration. And they had suggested that we try to work on two targets, which we were not working on at the time. You know, we think it would be fair to say that these were targets that they were already pursuing and weren't getting to work, and we were able to provide them with DARPins toward those.
To that end, that led to $20 million upfront, $560 million of milestones associated with those programs, up to double-digit royalties, should they actually, you know, make it to approval. So really great initial validation and really spurned our work again prior to 2007, 2008, when, you know, Christian and Michael were working on the original publications we were doing, but really pushing it forward to the pipeline and the program that we have today. So all credit to Novartis for really pushing us to think hard about this and for our team to immediately say, "You know what? If we're really building a platform here, kidney has to get solved right away.
And from there, we can work on tumor targeting, we can work around half-life and all these other things, but if we're building a platform here, let's do it right. So it really kinda set off the whole thing, which was great.
Great. So you also have an internal pipeline of radio DARPin candidates. You haven't yet disclosed those targets. When might we learn more about those efforts?
Totally. And I know we're wrapping up on time almost, but very happy to not disclose those today, but to point out... but we are definitely in pursuit of multiple targets in the background, building a pipeline of these. And not only are we looking in that sort of place where the unligandable universe of where protein therapeutics as binders can really bring out additional targets within radio, not the PSMAs, not the SSTR2s necessarily, but really looking at unique things.
And DLL3 is a place where we could go, where you might not ligand or a small molecule, but ultimately, we're going to push beyond that, and the things we're looking at now are places where DARPin can make a distinct differentiation, whether those are just binding regions that other antibodies, fragments, or mini- proteins won't be able to get to based on their design, or a peptide, certainly maybe not. But even beyond that, what does it look like, whether that's bispecifics or multi targets on a single DARPin, if there's some sort of tumor, you know, heterogeneity that we're trying to overcome for some reason, does that allow us a more specific binding? We've been there, we've worked in multi-specifics, and we are presently in the clinic with multi-specific DARPin binders.
So there's a lot that we can do that others will try to get to, that hopefully we'll be able to show in the second half of this year and beyond.
Great. Well, exciting 12-18 months ahead. Well, we look forward to following you all with some anticipation, and thank you for your time.
Thank you.
It was nice talking to you.
Appreciate it.
Thank you, Michael.