Good afternoon, and thanks for tuning in to the HCW BioConnect Conference. I'm Robert Burns, the Managing Director and Senior Biotech Analyst at HCW. I'm joined by Seth Lewis, Head of IR for Molecular Partners. Seth, thank you for joining us today.
Really appreciate the invite. Glad to be here.
Awesome. For those who might be unfamiliar with Molecular Partners, can you provide a brief overview of the company, the pipeline, as well as the platform?
Certainly. Molecular Partners is now a 20-year-old company founded out of the University of Zurich, ETH. The concept behind the company, which is still true today, is based on the platform of repeat proteins that they discovered and have been categorized called DARPins, which stands for Designed Ankyrin Repeat Protein. The proteins that we deal with effectively could be imagined as a brick or a LEGO, around 15 kDa, a small protein, no FC, largely working on the binding properties of the DARPin to elicit the therapeutic response you're looking for. In our pipeline today, we are oncology-focused. We have had programs that have been licensed to other companies, including Allergan for wet AMD, which was a singular anti-VEGF DARPin, which had a four-month duration. Others that we've worked in, including an anti-spike trispecific that we had licensed to Novartis to the tune of $150 million.
We are particularly working in two distinct areas. One, radiopharmaceuticals, where we are using explicitly the binding property of the DARPin to find it, bind it, and kill it using radioisotope, both program and DLL3 with lead-212. We are also working in multispecific DARPins where we have our AML program, for example, which is in phase I right now with data coming, two data sets this year, actually by the EHA, and then one later on in the year as well, using a CD3 DARPin binder, but also going after three hallmarks of AML. We will talk about this program a little bit more.
What we do there is actually use the binding properties of the DARPin to avoid monomer-expressing cells that are otherwise healthy targets, and then use the avidity-driven mechanism to find those AML blasts that are expressing multiple targets or the leukemic stem cell, which is expressing multiple targets, but preferentially sparing the healthy cells.
It's pretty much a conditional activation.
That's a conditional activated T cell. We do have other logic-gated immune cell engagements, which are earlier on. We presented some data earlier this year at AACR showing that we could actually lock a DARPin in conformation for CD3 on solid tumors where it won't open unless it's actually on the target in the cancer cell.
You know while we focus on radiopharma for a little bit, because obviously this has been a hot topic as of late, you know I did a massive deep dive on it last year. You know why don't we start with your collaboration with Orano Med, as well as you recently announced that you expanded this collaboration in January 2025. More specifically, I really want to understand what makes the DARPin platform so ideal for targeted radio flagging therapy.
I think what makes it ideal is that the first iteration of success that we've seen in radiopharmaceuticals has largely gravitated continually back toward PSMA or SSTR in those initial targets. The reason is simple. You have a beautiful binding pocket there that you could go after, and you could create a small molecule or a particular drug that will give you great binding, good uptake, good kidney clearance, all the things that you don't have to worry about when it comes to using a protein like a DARPin, which is fair. We have to confront those issues. If you can find a target with a beautiful pocket and you can create a structure that could go there and do that, go for it. We're not going to go after PSMA.
What we are looking at effectively is the unlike-handleable universe where we can start to say, you know what, for the right protein binder that's 15 kDa, so small, you will get some good tumor penetration, a really fast half-life that could be adjusted with certain half-life properties that you can install on it. You know certainty that you know that you're binding exactly what you want to bind to and getting very low off-target toxicity, you're now expanding that universe. Because we believe that that first iteration of companies that were acquired where you saw a lot of end-to-end manufacturing and drug development capability in there, you're going to get a lot of square footage of a lot of isotope production coming online in the next few years and very few targets for them to go after.
From that perspective, we're deploying forward into saying, you can start with DLL3. This will go into clinics this year. That isn't an entirely DARPin unique target. It's a low copy number. It's difficult to get to, but there are other targeting ways you can get there. We've seen it with peptides. We've seen it in other technologies as well on the T cell engager side and the antibody drug conjugate side. When it comes to things like our next iteration of programs, mesothelin is one that we did a poster on this year. It's looking for differentiated ways where we can expand. We don't go after mesothelin full stop. We go after the membrane proximal portion of mesothelin to not compete with shed mesothelin.
You're actually really getting onto the cancer cell and providing cell killing and not having to compete with the rest of the shed mesothelin.
Now, with regard to the Orano Med collaboration, obviously you expanded upon that in January 2025. Talk to me a little bit about the economics here. How many programs does it completely entail?
Certainly. If you're not familiar with Orano Med, this is a partner we've been working with now in excess of two years. They are a private French biotech with operations here in the U.S. They are completely based around the utilization of lead-212, which is an alpha-emitting isotope, which has a very quick half-life, but a very powerful energy emission. It is a 10.5 hour half-life. They have built themselves out of, born out of the Arano Group, which is a nuclear power provider and manufacturer in France. They literally have a mountain full of thorium-232, which is the precursor of lead-212. Over the past 15 years, they've been developing a biotech within themselves to be able to utilize this for medical purposes. They are in the clinics already. They are in phase III.
They have a licensing deal both with Sanofi on the asset that they're deploying phase III right now, which is SSTR, and also a $300 million investment they took on this year to further work out their late-stage manufacturing and logistics. We wanted to work with a partner that had clinical ambitions of their own and had been there before. We're only one half of the molecule being the DARPin. Finding Orano Med, we found somebody with a similar hunger, a logistical capability that had been proven into the clinics before, and a supply at a time where many people are still in the starting gate theoretically discussing whether or not they could actually go into clinics right now. We didn't have to have that differentiation. We're very excited to work with them.
The first program and up to six of our programs can be developed in 50-50 with them. We own the commercial rights to the DLL3 and to the mesothelin, the first two. They have the rights to the next two. We could split thereafter. We do have and expanded our partnership up to 10 actual products. It is not target-based if there is a product that makes it or if there is a product that does not make it. That is what the question is. It is not, oh, TGF beta did not work. Cross it off the list. You only have nine targets now. It is, can you get to image work? Can you actually show that this program has merit? Yes. Now that is part of our collaboration.
You know, obviously, this collaboration with Orano Med is focused around 212 Pb, right? Lead-212. I can think of already two other radiopharmaceutical companies that are focused on lead-212, Perspective Therapeutics and Arbio. Obviously, you know, Perspective Therapeutics is building out a network of distribution facilities here within the U.S. Arbio, you know, they're still private, so we're not as privy to it as much as to what they're doing. Talk to me a little bit about how you're thinking about, or how Orano Med and you are thinking about the distribution network here within the U.S., because like you said, it's only a 10 and a half hour half-life and the shelf life is, you know, it drags the efficacy dramatically increased with time.
Correct. What's really interesting, and as we all learn as we go, when it comes to radiopharmaceuticals and it comes to the treatment of the patient, everybody, I don't care who you are, delivers on the day of and treats the patient the day of because you're always working toward your decay. Yeah. It doesn't matter if you're Pluvicto, it doesn't matter if you're Orano Med, it doesn't matter whoever you are in between. As far as the end user is concerned, the day of treatment is constant. What Orano Med has built in the U.S. already and is building now in parallel in Europe, they have a manufacturing facility outside of a FedEx mega hub in Indianapolis. They produce overnight and then at 11:00 P.M., ship, deliver day of, and administered.
Really, obviously a logistical hurdle, but at the same time, because it's lead-212 and it's not a reactor-based production, it is a chemical production, they produce daily. Even if by chance you had low blood counts that day or there was a snowstorm, they can make up a patient in two or three days thereafter. You don't have to wait for the next cycle of collection, the next bill. They're always producing, which is a great thing to be able to make up, especially in clinical trials, to not lose the patient over that time. Where they are right now in Indianapolis, I believe, don't quote me, but I believe they say they can get to about 70% of, you know, continental U.S. From there, it's not a religion thing. They're not afraid of building multiple centers in the U.S. to deploy. They will.
That's sort of like for a prospective is to them.
True. I will say, I won't speak for Orano Med per se, but they have said over the past 15 years, they have learned that centralized is working for them. If they had started in a decentralized model and they found it to be very cumbersome, things broke down, they didn't have as much control. For them, it works in a centralized model. They could get a wide touch across multiple centers of excellence that allows them to get as many patients as possible. They're not afraid of building more than success islands.
Okay. That's completely fair. You know, one of the things that, let's, why don't we take a broad view of the radiopharmaceutical market, you know, because there is this belief that, you know, where radiopharmaceuticals is now is where the ADC field was 10 years ago. And there is a lot of overlap with the targets that could potentially be prosecuted. I wanted to get your thoughts as to, you know, the logistical strengths about deployment, as well as the 2%-3% risk of TRT-related myeloid issues. You know, how are you thinking about radiopharmaceuticals in parallel with ADCs while taking those two aspects into account?
Yeah. All credit really to Novartis for being the one who's actually pushed radio to $1 billion+ industry and will continue to do so. The fact that we're having that conversation is really based on the success that they've seen. I think we'll continue to see a broader, we are seeing presently a broader adoption of radiopharmaceuticals and more docs coming to that and more patients seeing it as a viable treatment option. I think that that's a large thing. I'm not a scientist, but I would argue from a development standpoint, you learn a lot more, a lot faster in radio than you do with ADC. I can, from a development standpoint, I would argue I like the pathway because you're going to fail faster.
I think with ADC, we do see a lot of dose escalation to the point of we haven't seen anything and wow, you know, you get a dramatic safety signal at times. I think they're both viable options. I think that they will be part of the treatment paradigm for small cell lung cancer with DLL3 and other places. Because as clever as ADCs are and as good as they've gotten, in certain cases, the durability will be questionable. We will need to see the data for the durability because obviously we know small cell is chemosensitive with a high response rate, but then the durability turns out to be very important. I think we all are excited to see what the durability will be.
You know, one of the things that I've been sort of wrapping my brain around is obviously that there are different types of conjugate therapy tied to radioactive payload, right? You got the small molecule platelet ligand payloads. Obviously, you go with antibody fragments and DARPin platforms. You know, and what you said before really is a really important aspect that I don't think a lot of investors might not know, right? That half-life modulation of DARPin is really important. Why? Right? Because it's the prolonged circulation of radioimmunoconjugates that leads to these off-target toxicities specifically within the kidney and the bone marrow. You know, at the same time, we also see these pre-targeting systems that are being developed by, you know, the likes of Wynand or Perspective.
I'm curious whether Molecular Partners is also thinking about a pre-targeting system or because of the half-life modulation that you guys already have in your DARPin platform, do you get around that issue?
I think we will see all those approaches, but just as we have our AML program, which is our first CD3 that's in the clinics that works through an avidity-driven mechanism to open up a treatment window, we have a closed-loop CD3 with co-stim that will only open at the right moment in the right tumor. Now, it's just technologies afford us different things as we progress. I do think that a pre-targeting approach, if it can work, is beautiful and elegant and makes a ton of sense. I certainly can see a future where those things will be part of the conversation. That said, in the meantime, yes, you're matching, you know, the closer you get to an antibody, the more you're worried about prolonged half-life.
The closer you are to the smallest of peptides, the least amount of encoding you could do in it when you work on your next program. With DARPins, you know, we have one randomized surface and the rest of it is effectively like a brick. It's fairly constant. We can actually create a number of alterations into the backbone of the DARPin itself, knowing that we can downtune the kidney reabsorption so that the next time we start our next program, we have those built-in learnings that we can start to encode in the DARPin before we actually figure out what the right tumor uptake is or what those things are. It's just getting to a point where if you're building a platform, you want your repeat cycle to be faster every time.
Yeah. You know, at AACR, you presented some quite intriguing posters. Three in particular. It was a mesoteric radioisotope, targeted radionuclide therapy, DLL3, and then obviously your conditional CD3 Switch-DARPin. So, you know, give us a high-level overview of each. Why don't we start with DLL3 because then we'll take it step by step.
Sure. DLL3 going into phase I the second half of this year and already doing image work through a compassionate use program that we were asked to participate in in South Africa. Really, the latest of these assets that we're discussing, that poster was really just another demonstration that in comparison to the high-expressing DLL3 model versus more of a low-expressing model, which is more realistic to what a small cell lung cancer expression of DLL3 would look like. It's a very low copy number. You want to make sure you're actually not fooling yourself in your early animal work. That was very encouraging to us to know that in that model, we saw consistent, if not just as good tumor uptake. You know, we're not getting as many off-target effects, which was encouraging.
The mesothelin concept, as I mentioned before, we are targeting the proximal membrane portion of the mesothelin. Even if it is a shed mesothelin or if it's a full-length expression of the mesothelin protein, we're binding to the portion of it which is closest to the cell. Therefore, whether or not it's shed, we're only landing on the cell. We're not competing with the rest of mesothelin throughout the body, which has been an unfortunate sink for a number of other approaches. I think mesothelin is a good target. It's just how you go about doing so. We presented on that as well. We're not competing with the shed.
Finally, on the logic-gated CD3 switch, we've actually shown that the DARPin will bind to another DARPin in the molecule up until the CD3 will bind and stay in closed conformation until the point where it gets to the tumor. There's a two-in-one DARPin and it makes a choice. It will bind to EPCAM in this case, releasing the CD3 off of that DARPin. It will stay on EPCAM. It will not reattach to CD3. The molecule then opens for CD3 binding, but also we include a CD2 co-stim. In that, we've shown that we can reduce T-cell exhaustion and we can create greater cell killing.
It's important to have that closed-loop system right there with the DARPin locked on itself because if you do it as a full open chain molecule, you wind up with fratricide where the CD2 and the CD3 just destroy each other and the molecule is useless. It really does show, and it's been great to be able to see the likes of Janik's and Veer now showing that certain conditional activation and cytomics now.
Yeah, with the EPCAM.
Yeah. That in this program, the one we're describing from the AACR poster is an EPCAM mesothelin CD2 CD3. Yeah, at that point, you kind of build these constructs. You realize that they do have to be guarded and protected against themselves so that you actually do need to lock it in and close it before you can deploy it in the body.
Yeah, I know. That makes a lot of sense. Why don't we focus on your DLL3 targeting for the time being? Obviously, I am aware of one other DLL3 targeted radiotherapy that another company is developing. When we also think about the DLL3 landscape overall, obviously we've got Imdelltra, we've got these DLL3 targeted ADCs. I'm curious because we haven't seen as much data on this front, is whether prior ADC utilization will then subsequently impact negatively the efficacy of a radiopharmaceutical product if it were to be received after the ADC. I want to get your thoughts around, you know, just that competitive landscape overall.
Sure. You can have my thoughts, but again, I'm not the scientist. However, what we have seen so far from some of the literature is that, you know, even within Imdelltra being approved right now, I think we're looking at a 40% response rate. Now we're seeing the response with certain survivability and all this. We don't know what the other is. We have a very high response rate at this moment, but again, chemo has a high response rate as well. What's the durability? We have not seen a large diminishment of the expression of DLL3. We do see that it seems to be fairly rapidly, you know, internalizing and then reappearing over and over and over again. We don't see people who have gone past the Amgen CD3 necessarily not being an expressor of DLL3.
I was just wondering whether there'd be upregulation of DNA repair mechanisms. Obviously, with an alpha emitter, you're going to get these double-stranded breakage. If you have an ADC in the prior line setting and you have this upregulation of DNA repair mechanisms, would that negatively impact the efficacy of your DLL3 targeted radiopharmaceutical?
Yeah.
I guess that's a question that has to be answered in time. I know MP0712 is going to enter the clinic relatively soon with data in the first half of 2026. I believe that that first data set, it's biodistribution and PK, right? If I recall correctly.
Before the end of the year, we'll have data showing some of the image work that we've done and early dosimetry. Into the first half of next year, we'll have dose escalation data.
Okay. For the dosimetry data, are there certain tumor-to-kidney, tumor-to-blood ratios or thresholds that you want to see right out the gate?
My team certainly does. No, I think, you know, T to K, one-to-one minimum, you know, we've seen that as our threshold. Obviously, anything creating tumor, much better. We have often seen other companies' T to K in mouse models end up improving toward the tumor in humans, just a slower metabolism. You get a better tumor uptake. There's no reason to not think we might see the same thing. When it comes to blood and red marrow, you know, there are certain limitations of how many gray to get to in the marrow. With a fast half-life and a fast, well, fast half-life of a DARPin and the fast half-life of lead-212, it's the next concern after kidney, you know, but from what we've seen so far, still moving into the clinics with confidence.
Because we're at the time of shortening my question list. While we shift to MP0533, obviously we're expecting data at EHA from cohort eight of this trial. Help frame the expectations for investors around this data set.
Certainly. Again, this is our first CD3 into the clinics. We were very careful with that asset, moving it forward, starting with a very low dose each time and then obviously escalating throughout those dose cohorts. Cohorts one through seven, we did not see a very consistent trend with dose increase and response. What we saw over time was actually that we were getting very little dose into the patients in what we would consider the therapeutic range. Literally talking matters of hours over that period of time of probably 15-22 days. Took that to our KOLs. They said, "You need to start at a higher dose. You need to implement additional dosing days in there to really get this.
The fact that you saw anything is a miracle. This is cohort eight where we were able to amend slightly to add another dosing day and to start higher. That translated in us seeing three out of the eight evaluable patients into CR or CRI. We will update that data at EHA. We are now approved for our next protocol amendment, which allows us to dose up to 14 days consecutively in the first two weeks of treatment for those patients. You would have to receive at least five treatments to be considered a patient on the study. These are relapse refractory AML patients. They're in the hospital setting already. They would be there for the 14 days regardless. You can move to a maintenance setting. It is really about, can you drive them to a CR as fast as possible? Can you maintain them?
The initial date of enrollment's open. We would expect before the end of the year.
Last question for me. So considering the potential of the CD3 Switch-DARPin, how should investors be thinking about the long-term pipeline development of Molecular Partners? Obviously, you have the radiopharmaceutical platform, but you also have these T cell engagers as well. So, you know, what sort of split can we expect here? Or is there going to be a shift towards one or the other?
If they both work, we have a wonderful choice to make. Ultimately, you know, when it comes to things like the CD3 switch and what we've been showing in these AACR and other posters, those applications for solid tumor CD3, many of them can extend far beyond our investable appetite at this moment. That's okay because it's inviting a lot of conversations with other people who are very interested in what we're starting to see from Janik's and Veer's cytomics. We may have a better mousetrap there. People are pretty excited to discuss that.
Yeah, no, I certainly agree with you, Seth, for joining us today. I really appreciate it.
Rob.