Hi, good afternoon, everyone. I'm Eliana Merle. Thanks so much for joining us at the UBS Targeted Protein Degradation Day. Very happy to have Monte Rosa Therapeutics here with us today for a fireside chat. Joining us from Monte Rosa is Markus Warmuth, Chief Executive Officer. Markus, thanks so much for making the time. Maybe just to start out, I guess, what is your philosophy on protein degradation with molecular glues? And in particular, there's a lot of companies now emerging in the private space looking at molecular glues. I guess, how do you view your approach as differentiated from others? Yeah, so as you said, I mean, we're, we're not the only ones in the field. If you break down protein degradation, so from a high level, there's PROTACs, and there's molecular glue degraders. We're obviously focused on molecular glue degraders, really because we thought and found this to be an attractive approach to get rid of undruggable proteins, right? So those that do not have an obvious pocket to engage. As you might know, PROTACs usually need to find a ligand first for a target of interest, to then design a molecule. Have built a platform that by now is super productive. It's based off on the one end, in-house built machine learning and AI that really allows us to learn about protein-protein interactions and surfaces, protein surfaces, that mediate these interactions. And, of course, we're sort of applying that to the interaction of a ubiquitin ligase with a target of interest, but then, of course, also an experimental platform between our screening approaches and targeted and unbiased mass spec, you know, producing a lot of data that eventually feeds back into our machine learning and AI approaches, and designing and optimizing our algorithm. And so, we really think that that is a unique combination that we're not necessarily seeing in other companies for a platform. From the early days, we decided to start with a ligase known as Cereblon because there was some good information, and I think it's by now really, really paying off. So, at a high level, really have learned to understand these protein surfaces, how they interact with each other, how we can make them act with each other through molecular glue degraders, and have really now taken this to the next level. Makes sense. And there's a lot of discussion around sort of moving to novel E3 ligases beyond Cereblon. Maybe can you sort of elaborate on that comment, of why starting with Cereblon is really paying off? Yeah, definitely moving to other ligases makes sense, but starting with Cereblon even made more sense, simply because, as I said, there was information out there, and, of course, a lot to learn, in regards to, what it takes, to bring these two proteins, like a ligase and, a new substrate, on a date. I think we've learned enough by now, to extrapolate this to other ligases, and clearly, what's so special about Cereblon and where it engages its new substrates is, that surface has very high PPI propensity, right? So it really likes to form protein-protein interactions, and we've actually used these insights in our AI to look across the 600 or so ligases, simply asking, "Okay, what are the ligases there that has that PPI propensity?" But then also, of course, where you have these interaction surfaces, you also need a pocket for a molecular glue degrader to bind in. So long story short, we have started to work on other ligases as well, but clearly, Cereblon, there's still a lot to do, and our current portfolio as in the public domain is all driven by Cereblon to begin with. Mm-hmm. Makes sense. Can you give us an overview of your pipeline, both in the clinic and preclinical disclosed targets and sort of the timelines across the programs? Yeah. So, one molecule, MRT-2359, in the clinic, dosing patients as we speak. This is, molecular glue degrader, MGD, for a protein known as GSPT1. So we're in oncology, with this one, tackling, tumor types that are driven by, transcription factors, in particular, of course, c-Myc, as, maybe the, most infamous, oncogenic transcription factor with, still, a lot of unmet, medical needs. As you might have seen, we've just filed an IND for, our second molecule, to go into patients. This is, for MRT-6160, and that's a molecule that's actually degrading, a protein called VAV1. So we're now in immunology, autoimmune diseases, VAV1, is important, downstream of both the, the T and B-cell receptor. So, have seen preclinically a very unique profile in regards to how that molecule, by degrading VAV1, disrupts T-cell-mediated B-cell activation, some compelling efficacy data preclinically as well. We have a development candidate for another program in the I&I space, NEK7. This is an important factor for the assembly of the NLRP3 inflammasome, actually targeting Q1 of next year for an IND filing, and then an interesting duo of programs between CDK2 and Cyclin E. So two proteins that form a complex, but we have degraders for each of them. And that would obviously take us back into oncology applications in breast cancer, ovarian cancer, endometrial carcinomas, and beyond. Mm-hmm. Great. Maybe as you think high level around target selection and indications, are you sort of more focused on inflammatory targets going forward and the I&I space, or oncology? Yeah. Honestly, we still see huge opportunities in both oncology and in I&I. We also see huge opportunities for the platform beyond those two disease areas. And so really what's important for us is for the target, of course, to be undruggable or to have something about it that we think we can solve with our approach that no one else can solve. So, CDK2, as an example, sure, you could argue that's druggable, but we do actually think with our approach we're uniquely positioned to dial in levels of selectivities that others can't. And so for us, it's really about, hey, is there something special we can do with that target? And of course, in the indications you would be going, is there, the high unmet need, but, we're certainly not pivoting from one area to the other or honing in on one particular area at this point. Mm-hmm. Absolutely. Makes sense. I guess, moving to your lead program with GSPT1, I guess, can you give us an overview of the data seen to date and what we can look forward to in the update guided for the second half of this year? And so again, program, in the Phase 1 dose escalation, as you know, we put out data last October, early data, in a dose regimen where we were dosing the molecule 5 days on, 9 days off. At that point, we had actually identified 2 dose levels that gave us optimal PD modulation, that were absolutely safe. But from there, then decided to actually now go to a denser dose regimen, 21/7, so more than double the dose intensity. And just, we are recently updated that the initial dose level, which was the same dose strength as for 5 and 9, so 0.5 milligrams, that the initial dose level was safe, essentially showing a similarly favorable AE profile as we had observed for the less dense dose regimen. So what does that mean for the second half of the year? Of course, we want to define the eventual or final recommended Phase 2 dose. We're currently dosing, as disclosed, at 0.75 milligrams. And then, of course, also in the second half of the year, update on what we're seeing for efficacy in that dose escalation. What should we be looking for in the data update in the second half? Yeah. So, you know, again, in regards to the types of patients we're enrolling, the strategy hasn't changed. We're mostly in lung cancer and neuroendocrine tumors. We're looking for tumors that have high expression of L-Myc and c-Myc. Biomarker positivity, we were not selecting in the initial readout, was about a third of the patients, and so I would expect a good number of additional patients now, of course, as we continue to explore regimens and also use backfills with about the same ratio of biomarker positive versus negatives. And, of course, we continue to look for what type of clinical signal we're getting across the various different patient populations we're probing in this trial. Great. Moving to VAV1, where you recently filed an IND, can you elaborate on the rationale for a molecular glue degrader here, and how this could be differentiated versus other approaches, and maybe high level, how you think about indication selection? Yeah. So, a target we're super excited about. It's certainly a target that's not on everyone's radar. I think the reason for that mostly being it's an undruggable, right? So for the industry, up until now, there wasn't really a way to tackle this target. I know for a fact, because I worked on it in a prior life, that companies have tried to come up with inhibitors, but the pockets you have available there are just too shallow to come up with something that's potent and selective. And so degradation here is the path to go. It's undruggable, it has a dominant scaffolding function to begin with. So, the question is, would an inhibitor even do what a degrader can do? As I mentioned earlier, lots of compelling preclinical data here, where degradation leads to disruption of T cell-mediated B cell activation. That's really where VAV1 plays a significant role, especially when that process is driven by strong autoantigens. have by now seen a very nice efficacy in a variety of different autoimmune models, preclinical models, an IBD model as an example, that's driven by T-cell transfer. We've seen efficacy in an RA model, and we've seen efficacy in a model of multiple sclerosis. So, as we were thinking about the clinical development, obviously, we have to start with a healthy volunteer trial here. But as we started to think about where to take this molecule in the future, of course, you know, that process was really driven by, "Hey, what do we know about a variety of different autoimmune diseases on a molecular basis, and which of these are truly driven by this T-cell-mediated B-cell activation?" Clearly, in that context, diseases like IBD and rheumatoid arthritis rose to the top. There were some others, but of course, another consideration here was, okay, what are the indications, the diseases where we think in a let's call it a Phase 2a proof of concept setup we can get to a clinical signal within a reasonable timeframe? And so again, all combined, for sure, IBD and rheumatoid arthritis have risen to the top for proof of concept trials, but there's certainly still other things, Sjögren's syndrome, a few others that we are considering. But as I said, first step here is a healthy volunteer trial. Of course, looking at VAV1 degradation and some other biomarkers, both in vivo, but also from ex vivo stimulation experiments. Mm-hmm. Great. Yeah, I guess in terms of the healthy volunteer study, maybe just, like, I think you've said first quarter next year for data- Mm-hmm. What should we be looking to see from maybe a biomarker perspective that could inform potential on disease activity in patients? Yeah, so again, it's, it's a true healthy volunteer trial. Mm-hmm. We decided not to include patients, mostly because, our goal here was to get to the actual Phase 2a trials, across multiple, indications as soon as possible. It's a SAD, MAD, a single, and then multiple, ascending dose. We're looking at VAV1 degradation, right? That's important, in this field. But then also some additional biomarkers. There's a few, cell surface markers, like CD69, that we can measure. And then, of course, also, induction of cytokines or lack thereof, in in vitro stimulation assays, and we'll be looking at, IL-2 and IL-6, but certainly also at, IL-17, BAFF, and some other cytokines that are typically being, released, when, when, T and B cells get activated. Okay. But so we can look at those cytokines and markers, but presumably because it's in healthies, we won't see as much of a change as we would theoretically in patients. Well, because we're doing ex vivo stimulation, of course, yes, we should see good signals. And so- Okay I think that should give us confidence that the levels of degradation we're achieving translate into inhibition of that pathway. But then, sure, the actual test in patients comes as part of our Phase 2a PoC approach. Mm-hmm. Okay, that's helpful. That makes sense. I guess, what, like, is the optimal, like, proportion of degradation? Do you wanna fully degrade VAV1 or partially, what are you hoping to do? Yeah, that's always a tricky question to answer because level of degradation sometimes depends on the assay you're using. If you look at our corporate deck, I mean, by Western, we can certainly get to 90%-95% degradation and more. In the actual SAD/MAD study, we will likely be using targeted mass spec and flow cytometry. In those assays, we think that at about 80% degradation, we start to see then efficacy, or in other words, 80%-90% degradation is where we want to get to expect efficacy. Mm-hmm. Makes sense. And you alluded to this before, but I guess why is this such an attractive target? You mentioned working on this at a pharma company that wasn't able to develop a molecule. I mean, particularly in the I&I space, there's a lot of approved therapies. What do you think about VAV1 that could be potentially differentiated? Yeah, I mean, a few things here, right? I mean, I'd say a lot of what happened in recent years in regards to approvals are biologics trying to go after single cytokine pathways or their receptors. So I think here you have a unique opportunity with a small molecule, so there's the convenience of oral dosing to tackle multiple really relevant cytokine pathways at a time. We've seen impacts on IL-2, IL-6, IL-17, and sort of taking these back to their normal physiological levels, that's really what VAV1, being sort of at this intersection of T and B cells, can do. For diseases like UC IBD in general, that we call sort of multi-cytokine, or there's not one dominant cytokine, there's multiple cytokines at play, we think this should be super, super attractive. Makes sense. That's exciting. Turning to NEK7, I guess, can you elaborate on the rationale behind this target a bit more? Yeah. So as mentioned, we're still now in the I&I space. NEK7 is a very important component of the NLRP3 inflammasome. I mean, so now you can say, "What's the point? There are inhibitors," but what NEK7 does in the signaling pathway is it's actually triggering the assembly of the NLRP3 inflammasome, or in other words, no NEK7, no active inflammasome. And so we, again, think this is a mechanism of action that's super attractive, right? Rather than inhibiting a already assembled inflammasome, now you can just wipe out inflammasomes altogether. We're obviously impacting the release of IL-1 beta, but also IL-18 and IL-1 alpha through a proapoptotic cell death into the environment. And so, you know, been able to come up with a very nice molecule, MRT-8102, which we think has all the properties that we need to have an impact on this pathway in vivo. The molecule actually does cross the blood-brain barrier, and we were able to measure NEK7 degradation in the brain preclinically in monkeys. So again, a molecule we feel very good about and that we think is highly differentiated from the actual inhibitors out there going after the pathway. Mm-hmm. Interesting. Maybe what's your latest thinking kind of on the potential indications where you might explore NEK7 first? Clearly, it could potentially be involved in a lot of different indications. Yeah, absolutely right. I mean, we've been looking, of course, at perhaps some of the the IL-1 beta and/or IL-1 alpha/beta antibodies worked, and what can we learn from that? So, our thinking as we sort of launched into this program, of course, was mostly peripheral inflammatory states or diseases like pericarditis, gout, and some others. But, obviously, as you know, a lot of talk and even buzz recently about a potential involvement of this pathway in obesity. Certainly not a hard indication to look at even early on in a Phase 1 proof of concept trial. I think we're really well set up here to go after the types of indications I've mentioned first, and this is what the program was originally designed for, but I think there are opportunities, optionalities now with that information about blood-brain barrier penetration to go into some of the other indications as well. What CNS indications do you think would be applicable here? That's that's interesting on crossing the blood-brain barrier. No, and so, obesity, actually, the idea is that for that, you have to cross the blood-brain barrier. So, it's going after a central function of the NLRP3 inflammasome. I think the more classical CNS indications for NLRP3 or that inflammasome has been involved, of course, are Parkinson's disease and, of course, also Alzheimer's. So more the neuroinflammatory, the classical neuroinflammatory diseases. Mm-hmm. And what's the latest in the timelines to the clinic for NEK7? So current guidance is for an IND filing in Q1 of next year. So I'm in the midst of IND-enabling studies, making good progress there. Mm-hmm. Maybe just a broader question for both NEK7 and VAV1. I guess, what's your confidence in the safety of degrading these proteins, particularly as we look at more chronic indications that are non-fatal? I mean, at least based on preclinical data, super high. We've released some of the, the VAV1, GLP tox data. It was really, really gratifying to see that, even at, at doses that represent more than 500-fold, what we think is necessary for efficacy, we literally had no tox signal. I know there was a lot of, debate, and probably still is, around cereblon and just targeting cereblon alone, potentially leading to toxicities. All the data we have on VAV1, and even, like, the shorter-term toxicity studies we have on NEK7, do not support them. There's no bone marrow toxicity, that we have seen. I think when you see bone marrow toxicity, with a molecule that utilizes Cereblon, that is most likely because of the targets, the proteins you're degrading, but has nothing to do with Cereblon itself. So, long story short, feel really good and confident about the safety profile of those molecules. Mm-hmm. Great. And then turning to CDK2 and CCNE, I mean, maybe just starting with CDK2, you alluded to this before, but you really see a, you know, potential differentiation from degrading versus inhibiting. Can you elaborate on that? I mean, it's for us, it's really all about selectivity, and of course, I know that companies that are pursuing CDK2 inhibitors typically call them selective, but they're really not that selective. And you know, certainly have a limit in regards to differentials you see between CDK2 dependent and independent lines. Certainly something you can expect us to talk more about also in the second half of this year. With our molecular glue approach, we're clearly not touching any other cyclin-dependent kinase, but we're actually not touching any other kinase to begin with. As a matter of fact, just like all the other programs here, we're talking about pretty much monoselective molecules. And so again, based on all the data we have compiled pre-clinically, we think this could be a superior approach, in particular, in the context, of course, of ER-positive breast cancer, where you're probably gonna wind up doing triple combinations between an estrogen receptor-targeting agent, a CDK4/6, and then eventually a CDK2 targeting agent. And so I think safety there will be most important, and I think our approach can actually deliver then. Mm-hmm. Makes sense. And how should we think about the timelines for this? I know you mentioned having a development candidate this year, entering the clinic next year. Is that a fair assumption? Yeah. So the current guidance is development candidate this year. You can tell from the data we have put out that we have very nice molecules in hand. We haven't really guided yet towards an IND filing and that timeline. I mean, typically, from having a development candidate to an IND filing, it's about 12, sometimes 15 months, depending on how difficult a CMC campaign is. So that should give you roughly an idea where the IND filing will land. But certainly once we have that development candidate, we'll give more concise guidance on when to expect the IND and then moving into a clinical trial. Mm-hmm. Great. Well, we're at the top of the hour, but Markus, thank you so much for joining us today. Great learning more about the programs and, for those on the line, thanks so much for joining. Sounds great. Yeah, thanks, Ellie, for having us today. Yeah, thanks. Talk to you soon.