I'm required to draw your attention to certain disclosures regarding the relationship between Piper and Monte Rosa, which are listed at the back of the room and also at the registration desk. It's an exciting time for Monte Rosa, where the company's proprietary QuEEN platform rationally designs molecular glue degraders, or MGDs. The company is conducting a phase I study of MRT-2359, targeting GSPT1 for MYC-addicted tumors, and also developing a rich preclinical and early clinical pipeline, including MRT-8102, targeting NEK7 and others. The company just partnered MRT-6160, targeting VAV1 for autoimmune disease. They also have some other partnerships, including with Roche for oncology. Really a lot going on at the company right now. Here from Monte Rosa is Dr. Markus Warmuth, CEO. Markus, thank you, sir, for being with us.
Yeah, thanks, Ted, for having us here today.
So we spend a lot of time digging into the QuEEN platform, and I really hate to say, I think what you guys are doing is very differentiated. Maybe you can start off by telling us how you're using AI to design MGDs and how your discovery capabilities differ from other degrader companies.
Yeah, no, happy to. Obviously, I could talk about this for many hours, but in a nutshell, yeah, we're doing molecular glue degraders. So we're hijacking the cell's intrinsic capability to get rid of proteins. However, obviously, we're targeting through small molecules to very specific proteins we want to deplete. The way molecular glue degraders work more specifically is they bind to that destruction complex or a component of that complex, a ubiquitin ligase, and then literally reshape that surface so the surface becomes a perfect match for the protein we want to get rid of. So we always say, like bringing two proteins on a date with the set outcome that one of these proteins gets shredded.
The AI component of that, and we usually don't talk much about AI machine learning for the company because there's so much more to it, but it is based on our sort of discovery recognition that there are ways for us to predict surfaces and how they can interact in protein-protein interactions. It's obviously informed by lots of experimental data that we have generated over the first five years. I would say it's one of the uniquenesses of our AI platform versus some other AI-centric companies. We, for the most part, only use our own internal data to feed into algorithms, and obviously, we have plenty by now.
But yeah, that really puts us into a position by now to predict for any given ligases, for any given ligase alone or in conjunction with a molecular glue degrader, how that surface actually changes and what some of the matching proteins are or the other way around when we have a protein and we understand some of the surface structure, how we would need to reshape a ligase to make that a perfect fit.
Yep. Yeah, really cool stuff. And we put a note out on this earlier this year. That went into some good detail on it. But what I love about it is now you're really at that point where the engine is very productive in terms of cranking out candidates and really high-quality ones. So I'm going to start with your lead candidate, MYC is a validated, undruggable target for cancer. Tell us about the biology around GSPT1 and why it makes sense to degrade for MYC-addicted cancers.
Yeah, so GSPT1 is a translation termination factor. So in simple terms, when new proteins get synthesized, GSPT1 sits at the back end of that process. There's obviously ribosomes that read a messenger RNA, and at the end of this, at the stop codon, obviously that complex needs to come apart, and GSPT1 actually catalyzes that last step. You could argue that it should be essential for the synthesis of any protein in any given cell in the body, but we've learned over the last five years that that's not true. It really literally is a bottleneck, mostly in MYC-driven tumors. There's actually three different MYC transcription factors. They're notorious oncogenes. There's c-MYC, L-MYC, and N-MYC.
Obviously, in cells, in cancer cells that are driven by MYC transcription factors, there's so much strain on that machinery that once you start to degrade GSPT1 and you lose that efficiency, you sort of stop that machinery to come apart. It's essentially lethal for the cell. That's really what we're utilizing there in regards to biology.
Yeah. And you guys have reported some early phase I data. Maybe you can remind us about that. And when should we get the next update?
Yeah, so the first batch of clinical data actually was released about a year ago, last year in October. And it was really supposed to show sort of early PK and how that relates to pharmacodynamic effects. So can we degrade GSPT1 and can we degrade it safely to a degree we wanted it to be degraded? The short answer to those questions with the data actually was yes, we were able to degrade GSPT1 at safe dose levels. We also had seen some interesting hints of activity, although admittedly that was still on a fairly small data set. Now, that first batch of data actually we were utilizing a five and nine regimen. So we're dosing patients five days on, nine days off, five days on, nine days off in a 28-day cycle.
The reason for that being that while we didn't have any concerns based on preclinical data, there was a competitor molecule already in the clinic that had shown some toxicities that typically kicked in around day four, so we wanted to have a schedule where we could potentially catch those toxicities early on. Now, long story short, we didn't even see any of those toxicities, and so decided to go to a much denser regimen, 21/7. We're dosing 21/7 in a 28-day cycle, 21 days on, seven days off. The next round of data coming out, obviously, will be a lot focused on that 21/7 schedule and any results we have there around PK, PD, and safety. Then, of course, again, activity if there is any, but obviously that is something we would be expecting.
Current guidance is to put data out or an update out this quarter, so coming up soon.
Great. And again, it'll obviously depend on the data, but it's right around the corner here. What do you see as next steps for this program?
Again, I mean, this is a new modality, if you want. It was literally the first molecular glue degrader put into a solid tumor setting. You probably know that BMS/ Celgene actually has molecular glue degraders, not just in the clinic, actually approved some of them being blockbuster drugs, but they're all in heme oncology, right? So this was the first time a company went into a solid tumor setting. And so the trial with a new modality being tested in solid tumors, new biology, novel biomarkers, of course, in phase I was set up to mostly look at safety, PK, PD, and early signs of efficacy. The next step actually would be to go into the phase II expansion arms, which are for the most part set up as initial signal finding expansions, right?
So there's a stage one pool design where the first 10 patients in a much more defined population then tell us, is there any signal or not? And then from there, of course, any further development could be contemplated.
Great. Now, switching gears, MRT-6160, congrats on the Novartis partnership, really great deal. Firstly, tell us about VAV1 as T cell and B cell target and the preclinical data that you guys presented at EULAR this summer?
Yeah, so super interesting target. Should start with sort of VAV1 and where it's expressed, and interestingly, its expression is extremely restricted to immune cells and in particular T and B cells and to some degree in monocytes. You're not finding it anywhere else in the human body. It's downstream, as you mentioned, of both T and B cell receptor signaling, and so very unique in a way in the immune system, and so obviously, when we realized through our platform that VAV1 is a targetable protein, we were all pumped up and started to work on it, but to be fair, even back then, we didn't expect it to work out quite as well.
So as we had molecular glue degraders in hand and started to probe its activity, its phenotype, we realized that by degrading VAV1, we actually disrupt the communication of a subpopulation of T cells, Th17 cells, with B cells in autoimmune diseases, right? So you literally disrupt that antigen-driven activation of T cells feeding into B cells and secretion of autoantibodies from those B cells. Really compelling efficacy preclinically in a variety of models that represent that biology. We've tested it in an antigen-driven model of rheumatoid arthritis. We've tested it in the classical antigen-driven EAE model, which in some ways represents multiple sclerosis biology, an IBD model induced by transfer of auto T cells. And so lots of compelling evidence up until here that that T cell, B cell Th17 biology is the sweet spot of VAV1 and any VAV1 degrader that you use later in the clinic.
Nice. Excellent. And you guys recently have begun dosing healthy volunteers. Remind us the terms of the Novartis partnership and where does it make sense to develop this?
Yeah, so fantastic deal for us, of course, in particular on a target that's quite honestly not as widely known in the field, at least not sort of in the sort of outside investor world. It was interesting for us to see as we sort of started to socialize our portfolio and in particular VAV1 with larger companies that pretty much everyone seemed to have taken a look at it before, but it is an undruggable target. The deal for us, as I said, super validating, and sure, I mean, the economics also, of course, made a ton of sense for us, but to be honest, it was even more now sort of the opportunity we have to explore 6160 very broadly in a variety of different indications.
Obviously, now within that partnership, the specific indications haven't been disclosed, but it was really great to see how well aligned we were between Novartis and us on where to take this. So I'm really looking forward to the next steps in that partnership. As you mentioned, we're obviously in the clinic conducting a phase I healthy volunteer trial, have guided towards Q1 for top-line results of that trial, and then would expect sort of more information during the course of next year on where we will go next.
Nice. And will that switch over into Novartis's hands then after the phase I?
Yeah. So after phase I, operationally, this will be in Novartis's hands. They will conduct phase II, phase III development. We obviously have agreed on a P&L profit share for the program. So we continue to own 30% of the revenue for the U.S. market. Although our actual cost share of that only kicks in once we are in phase III. So phase II will be all operated by Novartis and on Novartis cost.
That's great. Really great deal. Now, you guys are planning on filing an IND for MRT-8102 in the first half. Tell us, if you could, about NEK7's role in the NLRP3 inflammasome.
Yeah. So again, a pathway that's been well studied by now. Actually, loads of clinical proof of concept events for IL-1, alpha and beta targeting agents, biologics. Some other companies in this field doing NLRP3 inhibitors. NLRP3 has an ATPase function. NEK7, actually, in this complex is a scaffolding protein that's absolutely essential for assembling the NLRP3 inflammasome. And so what you do here is rather than inhibiting the already assembled inflammasome or neutralizing the downstream outcome, which are the downstream cytokines here, you're blocking the actual assembly of the inflammasome. So instead of the inflammasome firing and you inhibit it, it's not even active and assembled once you degrade NEK7. Really interesting. There are situations where inflammasome assembly is NEK7-dependent and independent. And so I think that also gives us an angle in regards to more specificity, selectivity around some parts of the immune system and inflammation versus others.
But I think, long story short, being further upstream and having a degrader with more sustained PD modulation, obviously, we believe that this could be superior to some of the other modalities. So I would like to say you're basically getting antibody-like pharmacodynamics, but with a small molecule that's now being the furthest upstream node rather than being very downstream.
Yeah. Very interesting target. Where does it make sense to think about developing this? And what is your early development plan here?
Yeah. We haven't really been specific on where we will take them. Expect that to come out with the announcement of the IND filing or acceptance. That said, sure, as I said, there's proof of concept out there. There's positive clinical proof of concept for antibodies in pericarditis, in gout, some other diseases. There's certainly, as I said, other companies using inhibitors in this space, and there's probably some clinical data coming out in the near term from Roche and Novartis, and so I think all of that will be important guidance for us, of course, where to go exactly, but pericarditis and gout, of course, since I mentioned them, obviously, you can tell those are indications we're considering quite seriously at this point.
Yep. Very cool. Switching gears again, cyclin-dependent kinases or CDKs play an important role in regulating gene transcription, but also cell cycle. CDK4/6 target, blockbuster for Ibrance and some of the other cancer drugs. What is the role of CDK2, and what are your plans to pursue that with an MGD?
Yeah. So yet another super interesting target, right? You can tell we're going from translation in cancer to T and B cells to inflammation back to cancer. And so it tells you a lot about sort of the power of the platform and diversity of targets we can and want to address. So CDK2, super interesting. You've alluded to estrogen-receptor-positive breast cancer, the efficacy of CDK4/6 inhibitors there. It's believed that CDK2 cyclin E is a salvage pathway there. And so companies in the space have been looking for potential triple combinations here with CDK4/6, plus, of course, anti-estrogen agents and then a CDK2 modality. Great to have two shots on goal there. We have molecules that specifically degrade CDK2. They're very selective for CDK2, way more selective than CDK2 inhibitors. But we also have a cyclin E1 degrader.
And so an interesting opportunity here to just see what's the modality that actually works best in sort of what particular context. There's beyond the breast cancer scenario, obviously, also cyclin E-amplified tumors in particular, ovarian cancer to some degree, endometrial cancer. You can certainly find it elsewhere as well. And so another very unique opportunity for us to look into in particular then with our cyclin E1 degrader.
Since you bring it up at the Triple Meeting, EORTC and NCI-AACR, you guys profiled 50969, which is not a development candidate yet, but just an early program that showed highly selective potent degradation of cyclin E1. Tell us about that data. And I hadn't really put the two together. So will it be best one advances, or how do you think about all of those fitting together?
Yeah. I think it could be either/or, right? I think it could be like, let's look at the best opportunity within that complex. That said, each of these CDK2 MGDs and cyclin E1 MGDs come with interesting, unique properties. And so it might be actually worthwhile to think about developing both of them. The presentation or poster at the Triple Meeting obviously had focused on cyclin E1. Very interesting, right? Because it is a cyclin E1 degrader. It doesn't even touch cyclin E2. Again, I think that's going to be a huge advantage in regards to avoiding some of the toxicities that you certainly get when you inhibit CDK2 and sort of take out any CDK2 cyclin E complexes. Really great efficacy. We have seen in cyclin E1-amplified tumors. There was always a concern that when you degrade cyclin E1 selectively, compensatory cyclin E2 expression might override this.
We haven't seen that at all so far. I think that also makes sense because while there's loads of cyclin E1 amplifications, there's literally no cyclin E2 amplifications in cancer. So these are not just redundant and overlapping. I think E1 gives you a lot of opportunity to be very selective and well tolerated for as long as you can target it very selectively.
Yep. Very cool program. So to the extent you can, tell us about the Roche partnership. Again, another big deal you guys signed a year or two ago. What are you guys working on together there?
Yeah. So another great partnership and, of course, interesting, right, being a company that originated in Switzerland in Basel. Somewhat proud, of course, how we utilize sort of that unique footprint to forge partnerships with both of the big companies in town. Very different flavor from the partnership we're dealing with Novartis here. It's a discovery deal utilizing our QuEEN platform to come up with molecular glue degraders for targets that Roche has nominated for the collaboration. That deal, I mean, it's about a year old, didn't include any of our existing public or non-public pipeline, right? These are all novel targets that Roche nominated. Super interesting back then for us then beyond oncology, which you mentioned, it also includes neuroscience. So even before Novartis sort of buying into us as a company in immunology, Roche did by committing to half that collaboration being in neuroscience, certainly a disease area.
We wouldn't necessarily have gone into it ourselves in the near future, and so it really gives us a unique opportunity to extend our scientific footprint into that direction as well.
Yep. Very cool. So with the Novartis upfront, we estimate Monte Rosa has pro forma cash of just shy of $400 million. How long does this fund the company, and what's it enable you to accomplish?
Yeah. So our current guidance is cash runway into 2028. That actually doesn't include any of the future phase II milestones yet for the Novartis partnership. Obviously, it puts us into a really great position in regards to seeing through 2359, 6160 itself, of course, and whatever we get in phase II. Put 8102 into the clinic through multiple inflection points as well. But obviously, most of all, also now allowing us to further utilize our platform internally for more, yeah, just very cool, unique targets that have been on everyone's radar, but just super, super hard to drug.
Markus, when you think about the platform, what do you think your productivity is? Do you have, "We'll file one IND every year or something like that"? How do you think about the yield that'll be coming out of QuEEN?
Yeah. I mean, quite honestly, I mean, that's not something we've projected that particular way. I could say two INDs a year. It's also a function of cost of capital, if you want. I think the platform offers a lot of opportunity, meaning this is not a one-target, two-target, or three-target platform. This is like a multiple dozens of target platforms that we can address. And so that becomes the number of INDs per year. At the end of the day, it becomes a function of how successful we are overall. And then, of course, in regards to lowering our cost of capital. But from an opportunity point of view, there's a lot to do. I always like to compare us to RNAi platforms and sort of that unique capability in regards to going very broad because druggability is no longer an issue here, right?
It's really more a function of, yeah, where do we best apply that platform now to make a huge impact.
Yep. Awesome. Markus, thank you very much.
I appreciate it.
Appreciate it. A lot of exciting stuff to come.
Absolutely. Yeah.
Great. Thanks, everybody.