Okay, can you hear me in` back there? Okay, great. Thanks everyone for joining us, and thanks for the folks listening in or who will be listening in. I'm Mike Nedeljkovic. I'm a member of the pharma research team at TD Cowen, and I'm very pleased to be joined by Patrick Amstutz, the CEO of Molecular Partners, and Philippe Legenne, the CMO of Molecular Partners. This is a company that I'm very fond of, and a lot of the work that they're doing is very impressive. Actually, the next 12 to 18 months will be a very exciting span of time. This will be a name to watch for sure. To lay the table, Patrick, you actually have a really nice slide in your corporate deck that is Molecular Partners at a glance. Maybe you could give us the verbal version of that.
Sure. I said a bit loud, maybe tone me down a bit. Great to be here. I do point out it's been now 10 years since we listed, and Cowen has been a supporter for all those 10 years. Big thanks to Cowen and you for covering us and all the work you put into that. With those 10 years, we actually have the 20-year Molecular Partners anniversary. We have been working 20 years on DARPins. DARPins are small proteins that we can tune to multi-specifics or just small-sized target binding. Molecular Partners at a glance is really first about this modality that is governed by a strategy to make drugs that matter. We keep that simple. We go for high medical need. That's where we belong with this technology.
Early clinical readout means single-agent activity, and all of that built on the DARPin difference. I think the next 30 minutes will be all about exploring what the DARPin difference means. It comes with time. We have now seven DARPins overall in the clinic, so we have learned a lot about the modality, what to do, what not to do, and how to really exploit the difference for patient benefit.
Philippe, anything to add?
I guess, first of all, hi everyone. Not so much at this point, because in fact, you know, it's all about moving our developments in those two big different areas, the T-cell engagement, you know, the immunotherapy aspect, which we have been in for a longer time, and then for the past two years developing this good pipeline, large pipeline of radiopharma. All steam behind those two initiatives.
Great. Let's dive deeper into the latter segment of your business. The radio DARPin platform is unique in the industry, and DARPins themselves would seem to be one of the best modalities to attack radiopharma. I assume you think it's the perfect modality. Why would you say that? Can you summarize your efforts in this area, and why are DARPins so well suited for this?
Sure. I wouldn't say it's the perfect, but for some targets, it's the perfect or the best. If we zoom out and say kind of where is radiopharma working, where you find a small ligand, a peptide, or a small molecule that works, that actually works well. That's why PSMA, SSTR2 has literally hundreds of compounds against those. DARPins are perfect to take that promise from those two targets and broaden the target space. First of all, the DARPin has intrinsic properties that are good, small in size, so deep tissue penetration and fast clearance. Second, high affinity and specificity to a target. That alone doesn't do the trick. We had to adapt the scaffold and make radio DARPins that we engineered for on top of small size, high affinity and specificity, fast kidney clearance. We call it kidney stealth.
We have to give it some half-life engineering tuning to bring up the tumor accumulation to reach the positive tumor-to-kidney ratios that you need in this field. With that, kind of with this tuning, I think what we try to do is bring the promise we have on the targets like PSMA to many more targets. That is what Philippe was pointing out. That is the growing pipeline that we are now building. We think with the stealth for kidney and the half-life engineering, we have a platform at hand that really can bring this promise to many targets.
Great. Coming out of that platform as your first clinical candidate, can you describe that, the target, stage of development, next catalyst, et cetera?
Yeah, maybe I'll kick off and then hand over to Philippe for more the medical side. The target is DLL3. We chose that target a few years back actually as an antibody drug conjugate. It was the first part we did at that time with ImmunoGen. We were moving forward with DARPin drugs. When that unfortunately came to an end, when ImmunoGen stopped their research efforts, we had the binders. When we looked into radio, we said, that's actually a great target. It's very clean. It rapidly internalizes, which will allow us also to load the cells with radioactivity. Let's give it a shot. That was before Tarlatamab, before the other ADCs. We still believe that in this field, it is a great target, and radiotherapy has a big say in there.
Maybe Philippe can add some words on why we're excited about radio in small cell lung cancer on DLL3.
Yes. Obviously, we are building on a proven target. You know, ROVA initially and then Tarlatamab have now confirmed this is a valid target for clinical in small cell lung cancer first. You know, we still think that despite the recent success of Tarlatamab, there is still unmet medical need in small cell lung cancer. I think let's think of small cell lung cancer. It's a high unmet medical need. Patients are progressing quickly. What Tarlatamab has showed the way is that it's active. You know, it's the in-relapse refractory. It's 40% of the patients that are responding. It's great, but it's only 40%. We need to do more than that. Potentially, there is an aspect of durability that can also be improved there. Great target, unmet medical need in a patient population, which is sizable, small cell lung cancer.
On top of that, and for this one, likely we would need to have a diagnostic tool on top of for the neuroendocrine cancers, prostate, neuroendocrine cancer is an important unmet medical need, completely unserved for the moment, and then other neuroendocrine tumors. It is a potential large development starting in small cell lung cancer.
Great. I should have said for folks in the room, if you have any questions, feel free to raise your hand and jump into the discussion. You have a wide-ranging partnership with Orano Med, which supplies Pb-212, the radioisotope of choice for some of your programs. Can you describe that partnership and why Pb-212 is the right isotope for some of these targets?
Yeah, that's a great question. The first discussion we had is sort of which isotope, or actually it was even one above. Do we do alpha? Do we do beta? I think from the half-life, everything, and just from where the field was going, we believe alpha is more powerful than beta. We said, let's invest in the future of radiotherapy, which we believe is alpha. When you then go to alpha, you have to ask yourself, as there is no approved product at this point in time, where will you get your isotope in the amounts you need to not only fund your late-stage development and commercial, but also many products in parallel. When we looked at that space, and it was really our scientists, they found Orano Med sitting on their thorium supply that is decaying into lead and then bismuth on a regular basis.
They have the world supply of it. It was mostly driven by access. We started the collaboration. Orano Med is a great collaboration partner. It really works super well with them. It was a bit the engagement piece that we had. We do the DLL3, MP0712 with them. We're doing a mesothelin DARPin with them. They get another two targets to choose. We just recently added another six targets where Molecular Partners is in the lead, and Orano Med can opt in in two. I think from that point of view, we chose the company that has the biggest supply. What happened in summer, which was strategic value for us that we didn't control, was that Sanofi has heavily invested in Orano Med. Overall, $400 million to build, call it the last mile of late-stage and commercial supply.
I think with that, Orano Med on the thorium supply plus the funding stands out. There are many others to come, and we bank on that. We will also likely branch into other isotopes when we see that the availability is there and the accessibility is there. For now, that was the logic. On the technical side, we like lead because it decays fast. If you think about trying to extinguish a fire and you have a hose that drips a bit or a real hose that puts out a lot of water fast, that's lead. Lead decays fast, and all energy is deposited more or less in 24 hours, and then it's gone. That allows not only to kill tumor cells fast, but also not to kill the incoming immune cells.
We believe it will also have a better tail end, so better effect on the tumor cell, not killing immune cells. More also on the safety side, we believe alpha is the way to go. Having said that, the question, or let's add one benefit, which is waste management. You don't have to be afraid because everything decays fast. Also your waste is not going to be radioactive forever. That's easy. You need a good supply chain. That goes back to my first point. We believe in Orano Med, and we're also glad that they have that deep funding to build that supply chain.
What is the strategy from a supply perspective? That last mile, is that multiple production sites kind of scattered throughout the country, or is it one or two, and it's just getting the isotope to the point of care quickly?
It is one or two and getting it quickly. They are following the lutetium approach that Novartis did. The one thing that struck me first, I thought 10 hours, that's not possible. Actually, it's more or less the same as for betas because no hospital stores radioactive material. It is always delivery on demand. Every patient gets the dose manufactured as needed and then overnight delivery and shipment. That is the same. The simplicity of manufacturing makes it possible.
Great. What is the current status of your lead candidate, MP0712, for small cell lung cancer?
First of all, I think we can say we are curing mice. You know, now it's all about translating this into human. It's important to start there. Translating this into human. We are very close to reaching the clinic, in fact. We are taking a two-step approach, you know, which is one is the imaging part with the lead-203, which is the optimal partner to treatment lead-212. Our phase zero, phase one are ready to go, in fact. This will be in the clinic in the next few months.
Okay. After that, when should we expect the next update and what form might it take?
We will get an update before the end of the year. Depending on how we can field the imaging part, the phase zero part first, potentially a bit before that. I think we are currently, we have a plan A, which is we are preparing for those studies in the US, but not neglecting some risk there, and also having a lot of contacts with different European or other region, in fact, capacity to deliver. We just want, we have a plan A, yes, but we are also working on our plan Bs for execution.
What does the future hold for the radio DARPin platform? Your initial candidate is relatively simple. It's a DLL3 binder with a linker and the radioisotope. DARPins can get pretty fancy, and they can do all kinds of things. Would you apply the types of approaches you've taken in other segments of your portfolio to the radio DARPin platform? Maybe you could describe the ways in which you manipulate DARPins.
The one point, DLL3 in principle, it's also ligandable. There's also peptides out there. The first step was to go to mesothelin, which is where we are targeting a membrane proximal epitope that after cleavage of the full protein is still there, and our binder is not inhibited by the shed form. Very unique binding. We will not be distributed by binding soluble mesothelin, one step. You were pointing out the next steps, which is two-in-ones. We can do multi-specific radios. Obviously, thinking further, switch concepts, pre-targeting, and all the fancy stuff is also in the works.
Great. Okay, let's move on to the immune oncology portfolio and talk about MP0533. You mentioned multi-targeted DARPins. This is one of them. Can you just briefly describe this DARPin and where it stands in development?
Yeah, I can give it a shot and then hand over to Philippe as this is really his program, and he's on a daily base moving it forward. It's a tri or tetraspecific. We are targeting CD33, 123, and 70 times CD3, so a T-cell engager with half-life extension. We gave it a very good safety profile by downtuning the individual affinities to get an avidity-driven selectivity for AML cells. The first results are really encouraging after we found a tweak in dosing. I think that's where maybe Philippe can give a bit of an update on the data and also an outlook where we're steering with it. As you said, this is a big year for us, and this is one of the readouts that we are very excited on.
Yes. We are well advanced in our dose escalation development for the moment. As Patrick was saying, first of all, we've learned a few things in our first seven cohorts. In fact, we've learned that the drug is safe, safe enough that it can be escalated, and that it also works because we had across several cohorts, we had effect on the blast, very in a high proportion of patients, and we had several ELN responses. We knew that. Still, we had not yet unlocked the potential of the drug. We realized that, in fact, we need to have, especially in AML, which is a rapidly growing disease, you need to really hit early and hard. In fact, initially with our step-up dosing, but mainly weekly approach, we did not hit early enough and hard enough.
What we have done is that we have started to tweak, in fact, this schedule administration to go very quicker into effective dose in the first week. In fact, now is where we are. In fact, started to add some additional doses. We have seen the results of that, which are very encouraging, where we have really started to get more ELN responses and some of them durable. We are happy about that, and we take this as a very encouraging signal. That being said, we need to have more, and we need to have longer duration of responses. We have prepared a new amendment where we really do densified administration, and we want to be in effective dose range within the first week, the first few days, in fact.
We think we can do that because up to now, the drug has been safe. We can approach that densification. We are in very, very close range of implementing this new amendment. We should have unlocking moment of truth, if I may say, around this summer, and certainly before the end of the year for the fuller data package. We will know at that moment whether we have been able to unlock the potential of that drug or not.
Amazing to me was this collaboration with the clinical sites. Maybe Philippe adds some words on with whom we're working and how this came about as we were stuck and our investigators pointed us the way how to go forward.
Yeah, so we work, our phase one, we work in Europe for the moment with a team of nine sites across three countries, Switzerland, France, and Lithuania, and the Netherlands, sorry, based on the HOVON, which is really an AML group. We have several advisors coming from the US, where hopefully we'll go soon. We have close advice. At some point, we were a bit, as Patrick was saying, okay, we see activity, but it's not good enough. It's not long enough. This was really encouraged by the expert who said, yes, but you really see it. So guys, get your acts together and push it. This is where we got colleagues from the usual suspects, but basically the MD Anderson team, the Memorial team, or we have a problem, we just call Gail.
When it comes, we have very, very strong support from very knowledgeable people. They are guiding us, and we are in constant relation. We are extremely well supported by an expert team here.
Okay. It is always a good sign when the treating physicians want to use the drugs.
Exactly. Exactly.
They also help you on the protocol that they want to then use. It is not you as a company or developing something in thin air, but with the clinicians that will be using the drug, they will say what is feasible, what not, how do they want to use the drug. That is directly feeding into this new protocol.
Yeah. The team we work with is an expert in T-cell engagement. Overall, they work with CAR-Ts, and they've seen the misery of difficulties that others have faced. They are really trying to integrate all their learnings into these programs because they believe that it has potential.
When we get to this moment of truth in the summer before the end of the year, what is the bar in your mind? Perhaps you won't want to quantify, but if you could, that would be very much appreciated. Response rate, durability, what should we be looking for when you give us the update?
It is actually rather simple, and this has not changed. It has to be above 30% response rate and well above three months, let's say five, six months is what they are looking for. This has not changed. I think the 30% is in really this all-comer type. It is not a genetic predisposition. It is not singling out the high-risk patients. If we in a high-risk patient population get 30%, that is what they would be using because they simply have nothing. If you have obviously the specific mutations, you will get other drugs. Most patients today are totally underserved in this indication, and that is what we are looking for. If we reach that, I think we have to go. If we do not reach it, it is also clear.
Yes. I think we have studied also to understand the patient, the ideal patient profile that this type of drug can help. Basically, we're a patient with a lower disease burden. Basically, either you take your patient who has been in first line, typically as a VEN, a first line, and then when they are just starting to relapse from it or on consolidation to it, that's one aspect. That's the main patient. I would say that's a big part, that's a big patient population. There is also the other patient part, the other subpopulation, which is the pre-transplant patient, which you want to improve the MRD status of. Basically, we have two or three places where we think this type of drug can be highly relevant. Again, it's very much mutation agnostic.
I think there is real potential for such type of drug. And it's not just us saying, the experts are very much guiding us towards that.
On the safety side, what are the AEs of interest? I assume they're immune-related. What are you looking for there? Is there a bar in your mind as it regards safety?
So far, we have been content with the safety profile, meaning that we get frequently IRR and CRS as the T-cell engager usually triggers. We see this during the first cycle, and then it disappears, which is, I would say, a typical manageable T-cell engager profile. That is mainly what we have seen. So far, the drug is considered manageable and again, has allowed us to go a bit higher. I think it is not so much that we want to go much higher in terms of dose. It is more about the densification now. I think we have teased the maximum dose that we want to have. We can still further fine-tune, but I think we are pretty much there. It is all about now optimizing the schedule of administration and making sure we work on the duration.
You mentioned that the investigators in this trial have significant experience with other immune oncology drugs, T-cell engagers, CAR-T. In their sort of anecdotal experience, are they seeing that your DARPin is safer, that the therapeutic window has been broadened by the selectivity, or is it just too difficult to tell because of all the nuances and small numbers?
I guess the constant is that the drug is safe and manageable. That has been always the one enabler. That's why we can keep pushing it, and that's why we can keep exploring improvement or fine-tuning of the schedule of administration. That is the solid basis where we start from. This has always come as an encouragement from the investigator team, which everyone has said, "I've worked on this one and this one, and we couldn't go higher, and we had to stop." That's been always a recurrent frustration. We are not, we are beyond that. That's very meaningful. It was always, "Guys, you have a safe drug. You need to improve, find a way to improve and to grow your efficacy.
I think it is fair that the others were not there. The others tried to push dosing, and it did not happen. They were less safe overall. This is unique to this drug.
Great. Okay, we'll look forward to that update. We only have five minutes left, but you have an entire other segment to your portfolio. Maybe you could talk a little bit about the switch DARPin effort. That's a little bit earlier, but very interesting.
Let's do a step back. We're now in the T-cell world. We have this trispecific or tetraspecific for avidity-driven selectivity. We were not the only ones seeing the potential of T-cells and wanting to unlock that. One simple way is you mask your T-cell engager and you locally activate that. Companies have tried that, CytomX, for a long time. It did not have a real breakthrough until last year when it was Janux and then also Vir that acquired the Sanofi portfolio came out with results that were really, really nice. I mean, we saw responses and dosing that we had never seen before with these types of approaches based on proteases that cleave a masking peptide.
We had hoped for such results, and we said, "Let's build something beyond the protease approach because proteases are very different from patient to patient, so you have high variability." What is always the same is the target binding. So we built a switch DARPin concept built on target binding, where a DARPin has two binding sites. One binds the T-cell engager and creates an off switch. The same DARPin right adjacent has a target binding site that has to now choose, either I block the CD3 DARPin or I bind my target. In circulation, this is off. A third DARPin brings now this construct to the tumor cell. There, the switch DARPin will now find the other target where a higher affinity happens. It starts to bind this other target, releases the CD3, and upon binding, you're activating the T-cell.
We have the same mode of action, if you want, as the protease cleavage of the peptide, everything on binding. That's what we call the switch DARPin on T-cells. Our first program there is moving, so we're going towards candidate selection this year. We again took the mesothelin approach there. Mesothelin in ovarian cancer has the problem that it's immune silent. We believe there are T-cells, but they're not active. What we added is a T-cell engager and next to the T-cell engager, another DARPin for co-stimulation because just engaging the T-cells might be not enough. Let's also co-stim these cells. Now we're in a switched co-stim T-cell engager situation that really should be the next thing for T-cell engagers.
That is for us the future, a switched co-stim T-cell engagers that hopefully can bring the promise of T-cell engagers to tumors that we would consider cold and make that promise for more patients valuable. That is where we are. Super exciting results and a platform to be exploited.
All right. That's so cool. For the mesothelin candidate, what's the next step there?
This is an array of individual DARPins. We are literally screening through that matrix to find the best. We have singled out a few. We also had some learnings how to make better T-cell engagers, and we will talk to that a bit later in the year. There are still some patents pending there from 533, some learnings we are building into this next generation that we will talk about. With that, we hope to be able to select a candidate for development in the second half of this year. That would then mean another good year into the clinics, but we are confident that we can make that.
All right. All right. A lot of news to come. In our final minute and a half or so, I'm curious if you have a view on the broader ecosystem as it relates to R&D in the pharma industry. What amongst the unfortunately myriad political and regulatory risks rises to the top of your list of things we should be focusing on?
Yeah, I think at the moment we are in a very unstable global situation on many dimensions. I think as a Swiss company, we are sort of, let's say, in a very neutral jurisdiction. I think the benefit we have is that we can spread our risks. As you know, we run clinical trials in Europe and in the US. I think that becomes a real advantage to us that we are not hinged to one jurisdiction or country. Maybe Philippe, you can also say a bit more about, especially in the radio space, how we're going about there. We are also working in Switzerland with the regulators how we could change environments to become even more attractive. Maybe Philippe, a bit more on the global approach of us.
Obviously, we are looking into development in the U.S. for two programs. We have planned FDA interactions in the next few months, in fact, on both sides. That being said, again, for our immuno, we have already a footprint in Europe. For the radiopharma, we are looking at several European countries. They are also early and very valuable sites, like for example, in South Africa, which are well known for high-quality work, and we have those relationships.
All right. Is the concern in the U.S. that FDA may be less responsive as you move through early clinical development because perhaps of layoffs or whatever? Is that the case?
Yes. I think we're mostly afraid of layoffs and loss of talent because the FDA is the best agency because of the best talent. That's what we're afraid that if that talent is lost, the quality could go down or delays can happen. We don't hope that, but we just want to be prepared if that happens. I also think even now I'm having my Swiss biotech hat on. I mean, we'll be happy to extend some job offers for people who are looking for a job in Switzerland. You're joking, but I did bring that forward to the Swiss agencies that this is a good moment to recruit, maybe even for Molecular Partners in the US.
Yeah, yeah, yeah. That's unfortunately a strategy I think a lot of folks are going to be taking. Thank you so much for your time. This was enlightening and enjoyable as always. Folks in the room, if you have questions, I think the team will be around for a few more minutes. Thanks so much for everybody's time.
Thanks.
Thank you very much.
Cool.
Other questions?