Welcome, everybody, once again to TD Cowen's 6th Annual Oncology Innovation Summit. I'm Mike Nedelcovych. I'm a member of TD Cowen's large-cap pharma research team, and I am very pleased to welcome to our panel today Molecular Partners top management, Patrick Amstutz, who is the CEO, and Philippe Legenne, who is the CMO. Thank you, gentlemen, for your time.
Thank you. Thanks for the invite.
Thank you. Thank you very much, Michael. Happy to be here.
Of course. We have a lot to cover. There's a lot of very exciting developments at Molecular Partners in just half an hour. Maybe we could start, Patrick, if you could, for those who are less familiar with the Molecular Partners story, give us an overview of the company's platform and pipeline.
Yes, sure. We work on DARPins. These are small natural proteins that we have built platforms from. These are small binding proteins that we can select to any given target. On the one hand, we have built a Radiotherapy DARPin platform where we use the small size to deliver a radioisotope, and we will talk about that in our discussion. On the other side, we have built a T-Cell Engager platform where you can do not only a Bispecific, but up to a Tetraspecific, so targeting multiple tumor antigens and then engaging a T-Cell and bringing that to the next level, a Switch platform where we can do co-STIM, in-circulation, off-logic gated, on-tumor, on-switches for a next generation of T-Cell Engagers. From those two platforms, we have two candidates that are now, I can almost say, both are now almost clinical.
MP0533 and AML has been clinical. We'll talk about that. We just had an EHA abstract. And our MP0712 DLL3 Radio DARPin is about to be tested in a clinical setting and then a full phase I in the second half of the year. Those are the sort of the highlights and the platform. We have been doing this 20 years, so we have a lot of understanding of DARPins. Maybe a bit on the side, we have DARPin generation 3.0, we call it. We have now implemented all the learnings from the clinical trials in an upgraded version of DARPin. A lot of things to cover in this call.
Great. Let's not waste any time then. Let's start with your radio DARPin platform. Why are DARPins the right modality for a radioligand therapy approach?
They are a modality. Now we can speak about the right for what. Because if you have PSMA or SSTR2 or a target where you can find a small ligand, a peptide, or a small molecule, then actually, I would not take a DARPin. Use that ligand because they go in fast, have high specificity, and for those clean targets, they work actually quite well. The problem is that we think 70%+ of the targets are not easily ligandable. If you just think about the space has been wide open now for Radio Ligands for three, four years, still most people are targeting the same two targets. DARPins can be selected to any given target with one drawback. They are larger proteins, meaning they will be reabsorbed into the kidney.
We have spent a lot of time to engineer DARPins that do not reabsorb into the kidney and have an appropriate half-life engineering to reach good tumor values. We think we have now a solution for those targets that are not readily peptidable. That is where you want to take a DARPin approach. DLL3 is the first. We have a mesothelin DARPin, which is even more differentiated in the sense of not peptidable, and then a pipeline building on the back of that.
Let's start with DLL3 and hone in a little bit there. You mentioned MP0712 is your first clinical candidate. Phase I start anticipated later this year. Can you talk about that molecule specifically? Why DLL3? What's the indication you're most excited about? When should we expect the next update?
I'll just do sort of the intro and then hand over to Philippe as he is really now preparing the medical work. DLL3 is a target that we knew well from DARPin drug conjugates. It was a collaboration with ImmunoGen in the day. We knew it was a clean target. There was some data of Rova that wasn't so good, but we thought that's more the antibody, not the target. This goes back many years. When we started to work on that, we looked at it, liked how low copy number, high medical need in small cell lung cancer, and hopefully radio-sensitive application. That is what we were looking for, a triangulation of clean target, high sensitivity, and a high medical need. We went ahead, and I think we can say we're in the class of the first Radiotherapeutics on DLL3.
In the meantime, Tarlatamab was approved, great data with the T-Cell Engager validating the target. When we started, it was not yet validated. I think now there is more and more also ADCs building. We are excited because small cell lung cancer is very chemo-resistant, and a radio approach makes a lot of sense. Now, maybe Philippe, a bit more about that side.
Yeah, so high medical need in small cell lung cancer, or let me step back. DLL3 is a marker of Neuroendocrine Tumors. And one of the tumor types where it's the most expressed in the most homogenous manner is small cell lung cancer, where there is still a very high medical need. Therefore, it's really in a way the first place which needs to be tested in. We are planning to do that, in fact. Our phase I is really written now, has been discussed with the regulators. Again, we are on our way, I would say, to open it in the second part of the year. That's one aspect.
In fact, we have also, aside from it, discussed and enabled some type of compassionate program, which is a name which is under the Section 21 in South Africa, which has been used by others also in the past for supporting early approach to patients and also at the same time generating important data. We have enabled that, and that is ongoing. We are also very happy to see this moving.
Great.
Sorry, I would just want to add one thing is that beyond our phase I, it looks at a small cell lung cancer patient first in the relapse refractory, but also has a component of other Neuroendocrine Cancers aside from it, from small cell lung cancer concomitantly.
An interesting aspect of radioligand therapy is that you can get different endpoints very early, imaging, dosimetry, and then, of course, efficacy readouts. For your two parallel tracks, the compassionate use and the ultimate start of the phase I , when should we expect what type of data and when should we expect from each of those programs?
I guess we expect first, obviously, to get images, images that will document biodistribution, where does that go, where does the drug go and does not go, and establishing also informing for the future dose to be used in the therapeutic step. We anticipate, in fact, to have that in the early part of this in H2. On the back end of that is the phase I start, which should start dosing patients around the end of this H2. We anticipate to get in the effective range or early pointers early on during next year.
Maybe just to add for those who are maybe less aware, the images can lead to the dosimetry. We can calculate how much DARPin and how much radioactivity was on the tumor and in the different organs. That will give you a very, I'm not sure if I could call it a biomarker, but it will give you a very good sense if you have a therapeutic window or not. If we do not see a therapeutic window, we can call it a day before we have treated the first patient. If we have a higher kidney than tumor, that would be a reason to stop. At the same time, if we see more on the tumor than in the kidney and the blood level that is not prohibitive, we can go forward with a lot of confidence.
The de-risking you get from an image that we will have from South Africa on a few patients will be very large versus any other approach. That is one reason we like Radiotherapy in general, because you can actually have good guidance if you are on the right way or not from the image before you are spending all the money and putting up the full trial. First, we had planned the phase zero. In the discussions with FDA, they did allow us a good starting dose. Mike Suttigie from South Africa asked us if he could do the compassionate setting. We said we do not have to do the phase zero, so we can save some money there, still get the data from Mike, and guide what we will be doing in the phase I.
I think it was a win-win situation for all of us.
You mentioned you could generate sort of relative dosimetry ratios in tumor versus healthy organs. Are there any absolute thresholds that would be informative to predict whether or not we'll see efficacy based on dosimetry, or is that too far afield?
I think we have to qualify a bit, so we will not have absolute, or it's difficult to think. As we are working with lead and alpha-emitter. I think if you're in Lutetium world where you have an approved product and you have a lot of understanding, you have a reference point. Even there, the references are changing because it is a new field. The dose limits are changing. I would say over average, the dose limits are maybe too conservative now. Patients in real life get more doses than are allowed because the toxicity is not that high. They go 10 doses, 12 doses, up to 20 doses, I have heard, on a dose where usually you would say after six prior doses, that's it. I think the field is on the, call it too conservative side.
We will take those numbers into our calculation, but to your point, it's not going to be absolute, but we will have a good understanding if we're on the right track. From the dosimetry, you can calculate how much energy will be deposited in a tumor. If you're there in a level where you say, okay, that makes sense to kill the tumor, you have a very good surrogate to think to go there. Absolute, it will not be. You will still have to run the trial, but I think you do it with a different level of confidence. That's me. I'm not an expert, but maybe Philippe, you've been on so countless calls with all these experts and listening to them.
Yeah, so maybe it's difficult to find what is the right exact ratio that we want to have. What we could say is that that ratio has to be above one, obviously. That's, I guess, I'm not defaulting here, but it has to be more in the tumors than in the organs at risk, as we call them. How much is it? And also how much is it in different tumors? It's very interesting to see that there is no absolute. We can see that there is variation across metastasis. Some metastasis need more, some others absorb a bit less. We don't know exactly. There is not yet a good book that tells us how much we need to deliver by med to do that. It's early days. It's early days for Lutetium. It's early days for Actinium.
It's even earlier days for lead. We are here pushing the limits in terms of background. That being said, we have had those discussions with the regulator. They understand that. At the end of the day, we've had very constructive discussions so far to build a very effective, we think, clinical trial starting at fairly high dose and obviously monitoring tightly so we can start high. That's good for the patients. That's good for the efficiency of the trial.
Great. You have mentioned lead now a few times. Lead-212 is the therapeutic isotope that you are pairing with your DARPin. It was an interesting choice, and the advantages, I think, have been made clear by your management team a few different times, but they are distinct. Maybe you could go over why the choice of lead-212 and maybe provide a few details around your partnership with Orano Med, who will be the supplier of that.
Yes, yes. I must say we spent in the beginning quite some time more on the question alpha versus beta, so Lutetium versus Actinium and lead. Our team was of the impression we want to go alpha, shorter killing range, but more killing. In a way, safer and more effective. We said alpha. The problem we see with Actinium is mainly the supply at this point in time as everybody is running after Actinium supply. All the companies that we would have partnered with have now been acquired, maybe except for ITM. Eckert & Ziegler is also now building supply, but literally Actinium is sort of out of stock. We were looking around what else there is, and we found lead. We found Orano Med, which at that point in time was still under the radar. Nobody knew of Orano Med.
They have, call it unlimited lead supply from their mother company, Orano, which is the French nuclear power company that had mined thorium back in the day in the 1960s and has 22,000 bbl of thorium that is decaying slowly into lead, radioactive lead over time. They can harvest, I think they even call it milk, those barrels and produce. For us, the first decision was really it is available. It has a few very attractive elements. One is that it has a short half-life. You can give a lot of energy fast, but then also the tumor cools down and it will not kill the incoming immune cells. We as also, maybe that is then the segue to our other programs, the T-Cell Engagers. We believe in T-Cells and immune cells to clean up the damage radioactivity has made.
The other is the waste because the short half-life, the waste management will be easier. Orano Med is a strong partner in the supply. We're not investing in that, but Orano Med is investing literally hundreds of millions in building a commercial supply system. They have the money, A, from their mothership, but also second from a large deal with Sanofi that gives them the means to build it. In our view, that is likely the best supply of an alpha you can have as a biotech. That's why we have entered into a 10 product agreement. We have 10, worth 10 products, with Orano Med that we can move forward.
Maybe just to add one little feature on top of the short half-life, which is the fairly clean decay chain, meaning that there is little risk for unwanted effect, if I may say.
What about supply chain, considering the half-life, how to supply at the point of care, and then waste cleanup as well?
I think supply, we understand better than waste. Waste is also very different from country to country. In some jurisdictions, there are much easier or laxer regulations about waste management than in others. On the supply, it is that Orano Med will have a daily manufacturing. Because the way they manufacture is very low, call it energy scale. It is very cheap because they just harvest the lead that has formed by decay. As the precursor is on a column, there is a decay and lead is freed. They literally just collect the lead that has been freed from a column. It is very low tech. They do this next to, I think, a FedEx hub. They can then send directly to the different centers. It has to be overnight delivery.
They will maybe end up with four sites in the U.S. to distribute to all the major centers overnight. It is a requirement. An MD Anderson will say Friday, we'll have four patients. They'll get four doses, 12 patients, 12 doses. The lead anyway decays. It's not that they have to make it. They just have to collect it from that column. I'm intrigued because this is the same logistics as Lutetium has. Lutetium, you also manufacture. You manufacture every two weeks, but the shipment always happens overnight to the site. If a dose is not used, it's shipped back because nobody stores radioactivity. I think here the benefit is lead after 24 hours is not dangerous anymore. De facto, I think the decay is so fast that you don't care too much about the waste management.
Yes, it is a challenge to work with such a short half-life, but Orano Med is a big industrial partner. They know what they are doing. I think they are ahead. They are also, as we speak, preparing their phase III, multi-center, multi-region. I think they are ahead and will have a well-established for the trial when we'll be in that moment of phase III.
When we reach phase III, they should be well on the market, this area,
Yes, across different regions.
Yes. Great. Thanks. Let's talk a little bit about MP0533. Can you describe that multi-targeted DARPin in a little more detail and the phase I AML trial that's underway as well as some of the adjustments you made to that trial protocol recently?
Sure. I can quickly describe the molecule, and then Philippe can talk about the clinical update. We're talking about AML. The problem in AML is that there is not one clean target. There is no CD20, CD19 as for a B cell for an AML cell. There are targets that have a preference to be on these cells, and even more, they have a preference to be co-expressed on these cells. What we built is a Trispecific, Bispecific, or Tetraspecific targeting CD123, CD33, and CD70, three targets on the AML cell times CD3. We have engineered the affinities that those cells that co-express these targets will be killed more readily than the monoexpressing cells. We have created a therapeutic window over those healthy cells that only express one. We think it's around a hundredfold. It's meaningful. We made the molecule.
We went into the clinics. We did a dose escalation. We were surprised by two things. First, we did not see so much activity, also not so many side effects, and we reached the top dose. We only had sporadic responses. We looked at the data because the responses were there. We also saw blast reduction. There was a longer discussion with really KOLs that were supporting us. I think that's where the idea came to give this a second chance. Philippe, please tell us about what we have changed from the dose escalation to the dose intensification and what we're seeing there.
Yes. Thanks, Patrick. The big learning from the first part of the dose escalation was that we need to have a more dense, so more frequent administration to establish quickly a good exposure for the patients and go through the antigen sink, as we call it. That was very important. Also, for a proportion of patients, improving the duration of that exposure. We did that. In fact, we did it in two steps. There was a step, I would say the first step of that is what I would call the.
Intermediate.
Yeah, intermediate one, which is basically quart eight, where in fact, we only did this a little. In fact, we were very happy and impressed by the results where we turned into a 30%+ Complete Response rate at that moment, where we had three out of eight evaluable patients that turned into response. One of them at seven months still is in response. It really encouraged us to think that I think we may have found a key here through this densification. Now we are turning another part on that key, and we are doing it full-blown, if I may say, where we're pushing it, in fact. We are going to do a more dense every day, in fact, for a little period.
Of course, not all the time, but to really try to maximize that rate of response, higher rate of response, deeper responses, and also making sure that we have, you know, we can have durable responses by some premedication. We are very encouraged by what we have seen in quart eight, very optimistic. Now we need to see whether it is necessary to do that second turn to really get the full potential. In fact, we are going to see that very soon because we have now started to include patients on that new part.
Maybe just to echo because it was interesting, you always think of dose intensification by a higher peak dose. You go to a higher dose, higher dose. Because we had Target-Mediated Drug Disposition, the higher dose was just sucked out like a sponge out of the system. Our KOLs came back and said, give it more frequent, but lower the peak dose. It should in a way also be more safe because we're not giving those bolus injections. It's a lower dose, more frequent. If you think also of Blincyto that was first given in a pump, it's not so different. The idea of driving the response into CR, and then you don't need because also the TMDD is gone because you're not in a CR.
You can then reduce, obviously, the frequency, but it was quite interesting to see how that developed in collaboration with the KOLs.
Yes. Yeah, we had a lot of those discussions, including pump or no pump, and we ended up with alignment to say we do not need a pump, we think, because we want to densify, but not for all the time, again, for a couple of weeks. We want to also make sure that we do not exhaust by continuous exposure. At that moment, we will want to revert to intermittent, I would say. We are excited. It is happening as we speak. I think we will have good data emerging around the back end of the summer or in the summer and ready to present at the end of the year.
Great. Okay. We'll look out for that update. We're at the top of our half hour here, but I want to leave maybe the last minute for you to describe briefly your Switch-DARPin platform with the logic gating that you mentioned, and then any final comments you'd like to make before we wrap up.
Yeah, no. Actually, if we would have had the Switch, we would likely have designed our AML drug as a Switch because that is the even more elegant way to come over this gating. As we said, we use avidity-driven selectivity. In principle, you want logic gating. We want smart drugs. We have all these biomarkers. We have all these targets. I think the tools to use that knowledge to make better drugs was lacking. What we built is a DARPin that binds two targets, but it has to decide. One of these targets is going to be on a surface antigen on a tumor cell. The other is a CD3 DARPin. In circulation, there is either/or DARPin that has to decide will block the T-Cell Engager part. It is off. Another DARPin will bring this to the tumor.
This either/or DARPin will also bind to a target on the tumor. It can be the same or a different target. It can be just it can be an end gate or an or gate if you want. Logic gated release the CD3, then the T-C ell is engaged. The beauty of this is we can add on top a co-STIM function, a CD2, a CD28 that is also off because the T-C ell Engager is off. We can augment the potency of a T-C ell Engager beyond what you would be able to do. This all in one molecule. This is sort of our next generation of T-C ell Engagers. We are closing in on defining a first candidate of that.
We hope this year to have a first candidate that would then go into formal development to be in the clinic, maybe not next year or end of next year. It is not quite as fast as the radio part, but it is on its way towards the clinic. It is also generating some interest by potential investors and by pharma partners as that is one way to capitalize on all the knowledge that is in the field with solid tumors.
Great. Plenty of data to chew on between now and then, which we'll look out for. Thank you so much for your time, Patrick, Philippe. We appreciate it. Thanks to everybody on the line.
Thanks, Michael. Take care. Thanks. Bye.
Bye-bye.