Good afternoon, everyone. Thanks for attending Jeffrey's Healthcare Conference. My name is Clara Dong, one of the academic analysts here on the biotech team. So it's my pleasure to welcome Markus Warmuth, CEO of Monte Rosa Therapeutics, joining us today for this fireside chat. Welcome. Sounds great. Yeah, thanks for the introduction. I'm obviously very excited to be here today. Great. So before we dive into your interesting pipeline individual program, maybe you could provide a brief overview of your pipeline, your molecular glue degrader platform, and where do you see the differentiation from other protein degradation technologies, especially PROTAC. Yeah, sure. Happy to give you some insights. Yeah, as you said, we're working in protein degradation. We're utilizing what we call molecular glue degraders, which are small molecules that bind to ubiquitin ligase, so sort of the protein that initiates degradation. By binding to the ligase, these molecules reshape the molecular surface to a point where that becomes a perfect match for a protein that you want to get rid of. Differentiated in a way from modalities like PROTACs, where obviously PROTACs are more heterobifunctional molecules. You have something that binds to a ligase still, but then also need to find a pocket in your target of interest, and then you put a chemical linker in between. Very, very smart approach. Of course, it does mean that the target you're going after needs to have some form of a pocket that you can bind into. Your target space is still attractive, but obviously becomes more limited than what you can do with molecular glue degraders. The company is about six years old now. We've established a pipeline based on our internal product engine that's quite significant by now. I'm sure we're going to talk about some of them. We have programs in oncology, 2359, our GSPT1 degrader. We're working on CDK2 and cyclin E1. We also have programs in the autoimmunity space, VAV1, MRT-6160 are the target and the respective molecule. We're actually just about to put another molecule in the clinic that's targeting NEK7, which is a component of the NLRP3 inflammasome. Lots of progress, really clear validation of the platform and its productivity. I'm excited about what's happening and obviously also what's going to happen in the future. Great. Just as you mentioned, you have both oncology and INI programs. Maybe just on a high level, could you discuss your strategic consideration across those two different therapeutic areas? Yeah, I mean, we just generally see this platform able to operate across multiple different disease areas. We're not of the mindset that we have to focus in one particular space. I think there's great opportunities across oncology. There's great opportunities across INI. We're starting to look at targets in cardiovascular indications and metabolism. For us, it's really more, where is this engine best applied? It's obviously where there's undruggable targets in high unmet need indications. That's really what we're keen in regards to venturing into. Great. Let's start with the GSPT1 program. You recently announced prioritizing the castrate-resistant prostate cancer as a leading indication for the GSPT1 degrader, 2359. Maybe could you elaborate on why the mCRPC will be the rationale of selecting this indication and why mCRPC could be the more suitable indication for this degrader? Yeah, so maybe just sort of a couple of steps back. MRT-2359 targets GSPT1. GSPT1 is a translation termination factor, so sort of catalyzes the last step of protein synthesis by essentially separating mRNA from ribosomes and new proteins. During the course of the program, we figured that this modality degrading GSPT1 has the most growth and survival impact on cancer cells, where those cancer cells are driven by transcription factors and in particular by transcription factors of the MYC family. When we started our clinical program, we had multiple hypotheses in mind. There are cancers, in particular, various different types of lung cancer that are driven by the expression of L-MYC and N-MYC, two members of that notorious MYC family. There are also cancer types that are driven by high expression of c-MYC, or at least c-MYC is a co-oncogene. That is really how prostate cancer, metastatic castrate-resistant prostate cancer, came into the picture. That is a tumor type that generally is characterized by very high expression levels of c-MYC, and where c-MYC actually cooperates with the androgen receptor to drive disease. We had seen preclinically that prostate cancer cell lines were among the most sensitive cell lines, most sensitive to MRT-2359. We have done a bunch of preclinical xenograft models as well where 2359 alone, but even more so in combination with the androgen receptor antagonist, actually showed great efficacy. Everything sort of lined up after our dose escalation for us to then sort of pivot into prostate cancer and focus on that indication. Got it. For the updated data expected in the second half of the year, could you help set some expectation of what investors should expect and what kind of efficacy and safety profile would support the decision to further advance the degrader to the next step of development? Yeah, so obviously I'm starting with safety. Yes, we absolutely want to see a compelling safety profile as a monotherapy. 2359 actually showed a very compelling safety profile at the doses that were eventually chosen. I mean, we more or less were grades one and two adverse events only, obviously at higher doses. We had some level of heme toxicity. Now obviously we want to reproduce that tolerability profile in the combination setting because that prostate cancer expansion arm is a combination with enzalutamide. From an efficacy point of view, we're actually casting a relatively wide net here, meaning we will have heavily pretreated patients that very likely will have seen multiple standard of care agents. Some of them will have seen both abiraterone and some version of an androgen receptor antagonist and some other later line therapeutics as well. We will actually be able to report most current genomic data as well, actually profiling all these patient samples that we get from the trial for AR-V7 expression levels, for Ligand Binding Domain mutations in the androgen receptor. Based on sort of that clinical profile, it's really hard to give any guidance around a% of responses we want to see. Obviously, we are looking for true PRs. We are trying to get as many RECIST evaluable patients into the trial as we can. As a result, we are requiring measurable disease as an entry into the trial. We are really trying to get an idea here in the trial what the potential of 2359 in combination with enzalutamide is to shrink tumors. Great. And then maybe from a landscape perspective in the CRPC treatment paradigm, where do you see 2359 and estrogen receptor inhibitor combo might be positioned, and which patient population do you see the best fit for the combo? Yeah, I mean, it's probably a bit too early to give you a definitive answer because we're early in the exploration of that core. Obviously, we have some ideas. I'll start with, sure, at the end of the day, a combination with an androgen receptor antagonist might not be the only possible combination to begin with. That's our start point. We're starting to think about other potential approaches as well. You can obviously think of further development that is more driven by genomics. Let's go into AR-V7 and LBD mutant subsets. Interestingly, one of the three patients, actually a patient with a PR in the first data set that we've released, has an LBD mutation. I think there's potential there. I think you can also start to think about other combination approaches in earlier line settings, maybe as an alternative to treatment with an androgen receptor antagonist after abiraterone. You come in with a combination either with an AR antagonist or with something else. I think there's multiple opportunities once we do understand the safety picture and of course also where we get the best responses. Fantastic. Let's switch the topic a little to the VAV1 program. For those who might not be familiar with the VAV1 targeting strategy, since this is a first-in-class degrader targeting VAV1, could you just talk about the potential of this targeting strategy? Also, you have a collaboration with Novartis, so maybe walk us through the details of the deal as well. Yeah, so it's a super interesting target in autoimmune diseases. VAV1 is actually downstream of both the T cell and B cell receptor. Undruggable. Also, we know that companies have certainly tried to create inhibitors for VAV1. Didn't pan out. Not a target probably because of the fact that it's undruggable. That's sort of super high on everyone's radar. Nevertheless, very intriguing data that we were able to generate with our MGD that at the very least, at the very least got Novartis intrigued enough to enter into this partnership. Very compelling preclinical package we were able to generate around TH17 biology and how VAV1 degraders could have an impact in autoimmune diseases that are driven by TH17 and eventually also B cells. Last year in October announced that partnership that we're super excited about. It does, beyond the financials, of course, give us the opportunity to explore this asset much, much more broadly and aggressively than what we would have been able to do ourselves. The phase I data that we have just released a couple of months ago further supports that. Molecule worked great, gave us the expected degradation levels of around 90-95%. Really no safety concerns coming out of that phase I healthy volunteer trial. The partnership is really off to a good start. Obviously, we did publicly announce and we received $150 million upfront payment for that. There are other things around the partnership, again, including the fact that we can now very broadly explore this asset that got us excited. Fantastic. You mentioned the healthy volunteer study, the healthy volunteer data. Maybe you could share some key findings from this study and which part of the data make you really excited and give you confidence of the program's potential to address INI indications? Yeah, I mean, there's probably three major points here, right? The first is really good PK and associated with it, obviously also good PD. Degradation of VAV1 that's deep and actually sustained, which is important because sure, that does give you flexibility around dose regimens or, to be more concise, regimens that are potentially less than once daily dosing. There wasn't sort of an obvious in vivo biomarker to measure, but we did ex vivo stimulation of both T and B cells that we isolated from these healthy volunteer subjects. By doing so, we saw that the depth of degradation that we were able to achieve translated into very nice, greater than 90% inhibition of cytokine release from both T and B cells. That's an important component, of course. Thirdly, the safety profile, there was really nothing to be concerned about from this healthy volunteer trial, essentially confirming what we had seen preclinically in our GLP tox study where we had not seen any findings, any tox issues despite the fact that we have dosed up to 500-fold the efficacious dose. Got it. You just mentioned you use ex vivo simulation assay to evaluate the impact on cytokines. Maybe if you could just elaborate a little bit more on this, what's the rationale behind this approach and what are the advantages and potential limitations you see compared to directly measuring cytokine changes? Yeah, I mean, again, in healthy volunteers, because you do not have disease, sometimes scientists just like measure the biomarkers that you would love to measure. Here we had to just make sure that through ex vivo stimulation, we trigger some of the signaling cascade and that then we are able to ideally fully inhibit those signaling cascades and the associated cytokine release. We were paying most attention to IL-17 and interferon gamma because we felt this is probably the best, at least benchmark data out there suggesting that when you hit these cytokines, you can expect efficacy in a human disease setting. It was very gratifying to see that on those two cytokines. We actually did really well, but sure, it's a surrogate for later measuring that in patients, no more and no less, but definitely very exciting and obviously creating a lot of confidence and momentum around sort of our discussions around clinical development with our partner. Perfect. For VAV1, what are the other indications you and Novartis are considering? Maybe you can talk about what are the selection criteria when you're using for selecting indications for phase two trials? Yeah, so we haven't publicly disclosed what the clinical development plan will look like. I believe it's safe to assume that it's not going to be dramatically different from what we had talked about before we entered into this partnership. We had talked a lot about IBD in particular, you see. We've talked a lot about arthritis in particular, rheumatoid arthritis, but certainly also some other forms of arthritis, certainly other types of rheumatoid diseases. Essentially, wherever you have a sense that T cells in particular, TH17 biology and B cells on top are an important driver, lupus, Sjögren's are some of the other diseases that would come to mind. I'm not saying that we're doing all of this all at the same time, but again, fair to say that we entered into this partnership to not just start with one indication or two, but really go very broad from the get-go in our phase two program. Fantastic. VAV1 also has functional overlap with multiple other immune targets such as JAK, TIG2, IL-17, and TNF. Just remind us, are there any similar targets in the clinic that might validate or de-risk the MOA of VAV1? Yeah, I mean, you know I would see VAV1 sort of be almost more specific than JAK kinases or the inhibitors. We look at this mostly as mimicking on a small molecule basis, some of the IL-17 and IL-23 targeting agents. That is really where we are looking sort of for benchmarking as we start to go into the clinic. Got it. Okay, let's move to pivot the topic a little to the next program, MRT-8102. So maybe for those who are not familiar, could you briefly introduce the MRT-8102 targeting strategy and how is it differentiated from directly inhibiting NLRP3? Yeah, so super interesting, very exciting pathway here. We're talking NLRP3 inflammasome multiprotein complex that drives production and eventually secretion of IL-1 alpha, beta, IL-18, and actually has a few other signaling effects. A complex that's triggered by various different agents, a complex that you can actually inhibit through small molecules. Our approach here is actually degradation of NEK7, which is a component of the inflammasome. It's essential for its actual assembly. You take out NEK7 now instead of inhibiting an already assembled inflammasome that obviously can keep firing once your inhibitor goes away. With NEK7, you're inhibiting the actual assembly, right? Even if your drug starts to go away, because the protein takes a while to be resynthesized, there will be no activation of the inflammasome. We think that gives you a much deeper, more lasting blockage of the pathway. There's probably also some differential here in regards to what stimuli actually do rely most on NEK7 versus not. Certainly some differentiation around what diseases to go into, but also in regards to what adverse events to expect. Great. Remind us, what's the status of the program and when should we expect their first clinical data? Yeah, so guidance for MRT-8102 is that we'll have IND clearance first half of this year, which now technically means this quarter or this month. Long story short, it's imminent. That means we'll be able to start the healthy volunteer trial early in the second half of this year, of course. We haven't given guidance yet on when to expect clinical data, but that obviously will come out with the IND announcement. Perfect. The NEK7 degrader, it also shows ability to penetrate the blood-brain barrier in human primates. How do you plan to leverage this feature in your future development strategy? Yeah, I mean, fair to say then in general, like this pathway has been implicated in many different inflammatory diseases triggered by many different types of stimuli. Our initial clinical program with 8102 will focus a bit more on peripheral inflammatory diseases, probably with a focus on cardiovascular, cardiovascular immunology, pericarditis is certainly high up on the list, but other indications in that space. There is an opportunity to also do central indications later. There is also more chemistry that we're doing to potentially come up with a second molecule. I think we have a guidance out there to have a second molecule at some point ready next year as well. I think we learn a lot from this healthy volunteer trial, which will certainly also measure exposure in the CSF to decide whether or not there is a path forward in central indications. You're certainly an area that just in general around the inflammasome is now having a lot of traction and also, of course, an area where more and more now we're seeing reliable peripheral biomarkers to undertake reasonably sized POC trials. Got it. Let's talk about the rest of the pipeline. You also have a CDK2 degrader and a CCND1 degrader in the pipeline. How should we think about their respective suitable indication selection? Could you just briefly talk about your development strategy for those two as well. Yeah, so an interesting program, right? Here we have two proteins that form a complex and drive cell cycle progression in cancer cells and now back in cancer. Interesting that we were able to find degraders for both CDK2 and cyclin E1. Interesting also that our CDK2 degrader does not touch cyclin E1 and our cyclin E1 degrader does not touch CDK2. I think that creates just like a unique opportunity to explore efficacy profiles preclinically and toxicity profiles preclinically on either/or. Our current thinking is that we could focus on one program, but if these molecules are sufficiently differentiated, also possible that we are bringing both programs forward. When you think about indications, sure, certainly cyclin E, amplified high expressing indications like ovarian endometrial cancer come to mind. Certainly a more compelling, more sizable indication would be positive breast cancer. We're more and more data points through CDK2 cyclin E overriding CDK4, but that's also a more complicated therapeutic and regulatory landscape and certainly not going to get any easier. I think our first step here would be exploring best possible single agent activity in the amplified setting and then consider whether it's worthwhile going into the larger breast cancer indication. Got it. What's the timeline? How should we think about the timeline of the next update for the program? Yeah, so here, I mean, this is much earlier than the other three programs. We're in the midst of profiling our development candidates. They'll be formally announced at some point later this year, targeting an IND for next year. I think the timing is great because we're starting to see some really compelling POC data in the pathway with CDK2 inhibitors. Our picture obviously is that with cyclin E1, we can be more selective and safer. I think that's a good setup in regards to timing and moving into the clinic after we have the IND cleared next year. Fantastic. Lastly, what's Monte Rosa's plan for the rest of 2025 and next year, 2026? What are the catalysts investors should look forward to in the next 12 months? Yeah, I mean, good news. I mean, our partnership with Novartis has put us into a fairly comfortable position if there is ever one in our industry from a balance sheet point of view. Our cash runway guidance is into 2028. That gives us the runway for many inflection points. Obviously, the most significant pieces of news coming out this year is, yeah, what is that VAV1 clinical development plan? It's certainly not going to be a niche indication, I can say as much. I think it's going to be very compelling and very meaningful indications. 2359 update on what we're seeing in prostate cancer. As I said, we haven't guided on MRT-8102, but sure, starting next month, we're starting to see at least internally some of that data and the potential for the molecule roll in and then certainly more inflection points coming in 2026 and beyond. I'm really excited about our current setup. This is a very productive product engine, as you can tell from our portfolio. I think we're now in a position where we can be just really spoiled and sort of moving forward, pick the best opportunities. Great. We will wrap up our session here. Thanks everyone for joining. Sounds great. Yeah. Thank you.