Thank you, everyone, for attending Jefferies Healthcare Conference in London. My name is Kelly Shi, one of the biotech analysts here. In this session, we are very pleased to have Mr. Markus Warmuth, CEO of Monte Rosa, join us. Thank you, and thank you for joining us. Maybe before we dive into each individual program, could you give us a high-level overview of why you chose molecular glue degrader platform versus a lot of your peers actually working on the three-way protein degrader molecular approach? Yeah, no, happy to comment on this. And so for those of you who are not familiar with targeted protein degradation, there's a couple of different approaches. I think the one that, at least in public perception, had most traction early on are PROTACs or heterobifunctional degraders. And so to your point, there are literally two molecules in one. You have something, a scaffold that binds to the cell intrinsic protein destruction complex. It's typically a ubiquitin ligase and then some other components that you need there. And then you have another scaffold that binds to your target of interest, and then you put a chemical linker in between. So very smart, but obviously complex molecules. And you're always required to find a pocket, a binding site within your target of interest. Molecular glue degraders are very different. I mean, they still work through the same complex, but they now bind to the complex and literally reshape the entire surface of that complex. So it becomes a perfect match for whatever target you want to destroy, for whatever target you want to get rid of. And so what does that mean? Very simple. There is no pocket required on the target of interest side. And so you can really go after lots of proteins that are just like not accessible to a PROTAC platform. So something we liked, it sounds very fancy, but of course, we knew there was a molecule out there at this point when we started, marketed by at that point, BMS, lenalidomide. Actually, they had a few other molecules. We knew this was going to work, but it obviously required us to build a platform that can now expand into lots of other targets. Great. And a follow-up question here is, would you be able to leverage a broad range of E3 ubiquitin ligase for molecular glue as what a PROTAC actually can do? Yeah, absolutely. And so again, obviously lots of talk in the field early on, okay, in this destruction machinery, there's about 600 ubiquitin ligases. Technically, each of these could be used for destruction of interesting targets. It's not that simple. We don't really think there are many that are like the one we're using right now, Cereblon. There's certainly some. We're making good progress. We've learned a lot in our first five years. And so I think certainly more to come. But we think of this more as maybe a handful of other ubiquitin ligases in this space that can be reprogrammed. Fantastic. Now moving to GSPT1 program as the data imminent. So initial data from the phase 1 dose escalation, even at the lowest dose level, you actually have shown partial response and stable disease, very encouraging signal. On the other hand, you also show the PK saturation and 60% of the GSPT1 degradation has been observed. And we feel like no clear dose response has been observed. So curious, what should we expect the efficacy in the at a higher dose or maybe in the by using like a modified dosing regimen? I mean, schedule. Yeah, great question. I mean, maybe just for background, the target for this program actually is GSPT1, the molecule known as MRT-2359. GSPT1 is a translation termination factor. So it's a protein that helps separate ribosomes as they produce protein that helps to separate ribosomes from new protein and mRNA. It is a mechanism that we think is particularly important in solid tumors that are driven by transcription factors known as the MYC family. And so the 60% degradation level that we actually see in the clinic is something we had optimized for. Why is that? Because we figured degrading GSPT1 to 60%-70% is good enough in a MYC-driven tumor. They just need that 100% level to survive. Obviously, if you degrade to 100%, protein production is important in pretty much every cell. You push it too far, right? If you have 100% GSPT1 degrader, you see some more widespread general toxicity, and so the goal really was, let's get to 60%-70% in the clinic, and so we did. We didn't see a dose response because the molecule was also safe enough preclinically so that our starting dose already gave us the 60%-70% degradation level, which also means even now with the schedule change, we've gone from a sparse schedule five and nine to now 21, seven. We're not expecting deeper degradation, but of course now we see 60%-70% over more days in a cycle, and obviously that's important in a five and nine cycle, so it's five, nine, five, nine. If a patient misses two or three doses, it's impossible to make up for that, right, so your five and nine, your total of ten days can easily be reduced to seven days. At 21/7, obviously if patients miss a couple of doses, it's not a big issue. Making sense. And so your target initially, the MYC positive tumors, maybe help us to understand how big this market opportunity is and what has been the challenges. And also moving forward to next phase, what kind of efficacy bar do you set? You feel comfortable to move forward? Yeah, so again, MYC family transcription factors really well validated oncogene. So interesting that despite a lot of effort over tens of years, there's really not a drug yet out there that addresses these tumor types, at least not an approved drug. Part of that obviously is MYC as a transcription factor is very hard to drug. And even we haven't been able to go after MYC directly just yet. That's at GSPT1 and this mechanism obviously has a lot of promise. The market potential is significant. If you only look at, like, where is MYC or any of the three MYCs overexpressed. That said, of course, we don't think that that particular mechanism is relevant and important wherever MYC is overexpressed. We have biomarkers to actually find that out. Our initial focus has been lung cancer, actually both small cell and non-small cell lung cancer. We think these opportunities are quite significant. From a clinical development point of view and efficacy bar, obviously the first step here was to do a phase one dose escalation with a primary focus on safety. The patient population is fairly heterogeneous because we enroll patients with small cell, non-small cell. We actually also allowed patients with neuroendocrine tumors in because there was an idea that those would have high expression of two of the three MYC family members, L-MYC and N-MYC. So long story short, heterogeneous patient population, we didn't set an efficacy bar by percent, at least not pre-specified. But of course, we want to see some level of efficacy to be confident to go into expansions. Actually, the expansions then that are set up in a two-stage design. Each phase two expansion has a stage one and stage two, where the first 10 patients have a predefined efficacy bar to move on and then enroll the entirety of the expansion arms. But obviously, we haven't disclosed yet what these efficacy bars are. I see. And for the next data update, can you provide some metrics in terms of patient number and the follow-up time and what should we focus on? Yeah, I mean, just sort of high level. I mean, we haven't disclosed the specific number of patients on the trial setup in the basket design, which allows us to enroll up to 18 patients per cohort. Six of these go typically into safety assessments. And then we can actually have backfill cohorts per dose level as well. So just sort of ballpark, given where we are in two different schedules, certainly a good number of patients and more than double than what we had reported actually in our initial data release last year in October. I would say based on that, we were expecting solid representation of biomarker positivity. So I think all in all, I think this is going to be a fairly meaningful data set. And again, I have guided to this coming out by the end of the year. Great. And GSPT2 actually shares some homology to one. Curious if you have targeting to two, it is more of a liability or benefit, any like a functional redundancy you saw? Yeah, we don't see it as a liability. It's fair to say that while there is a GSPT-2, it's not as widely expressed. We don't really see it a lot in solid tumors. When we degrade GSPT-1 and there is a GSPT-2, sometimes we actually see it downregulated, whether that's direct or indirect, because you're impacting that translational machinery. We haven't fully understood yet, but at least based on all the preclinical data and also based on what we have disclosed so far on the clinical AE profile, we don't see any issue with that. Great. Moving to immunology programs. First, congrats on the recent deal you announced with Novartis, VAV1, VAV1 program. Maybe first share with us the details for the deal and also where do you see this VAV1 targeting strategy to tackle I&I indications? Yeah, so I mean, obviously a fantastic deal for us. Honestly, not just because of the economics of the deal and what it does for the longevity of the company, but also because we felt from the very first conversations that it's almost a perfect match between how we think about VAV1 and how Novartis thinks about VAV1. And I'll talk in a second sort of where we see this going from an indication point of view. In regards to deal terms, just at a high level, and obviously that information is in public domain. It came with $150 million upfront. The total milestone package, both development and regulatory, is in the order of $1.5 billion. There's obviously also sales milestones. Most of all, we were actually able to retain a 30% profit split or share for the U.S. market. Europe obviously will be covered by royalties. And so between now being able to develop VAV1, MRT-6160, MRT-8102 way more aggressively, broader, deeper. As I said, obviously this partnership also giving us very significant revenue to increase our forward planning. In regards to where to go, super interesting preclinical data that you can find actually also to some degree in our corporate deck. VAV1 is actually downstream of both the T and B cell receptor. Importantly for signaling, but it doesn't mean you're wiping out all T cell receptor signaling and all T cells. The actual biology really is within Th17 subpopulation of T cells, in particular when they are hyperactivated, as well as in B cells. And so when people ask me like what's the best comparison here, I would say it's probably a combination of a non-liver toxic BTK inhibitor. So something that blocks B cell receptor signaling and IgG secretion and then is active on the Th17 side. So anything that's in the IL-17 signaling cascade, any of the biologic side. So it's a very cool combinatorial mechanism that at least based on preclinical data was extremely well tolerated in all the tox species we utilized. Great. Super insightful. It's a very broad range of indications we can think of, as you mentioned, if it's a BTK and Th17 combo. In the past, you also mentioned ulcerative colitis and rheumatoid arthritis might be the indications for VAV1 program before the deal. Just curious, are these two still the priorities for future development? Yeah, obviously a lot harder now to comment on them. There's going to be a joint development committee as typical in these types of collaborations. They're certainly still very high on our priority list. I think these two indications and others make sense based on the biology I described, but obviously to be discussed once the teams have formed, and then we'll certainly start to talk about this again more next year. Okay, great. And moving to NEK7 program, maybe not everyone actually knows it is in the same signaling axis of NLRP3, which actually made some headlines recently. And so maybe first from the biology perspective, could you help us to understand how is it similar or dissimilar compared to targeting NLRP3? Yeah, so a very well-known and in many ways highly validated pathway. There's literally approved drugs in the pathway on the IL-1 alpha/beta biologics. The actual NLRP3 inflammasome obviously is upstream of those antibodies. NEK7 in that cascade is the furthest upstream. NEK7 is important to assemble the NLRP3 inflammasome. And so the best way to describe the differentiation is an NLRP3 inhibitor obviously inhibits the already assembled constantly firing inflammasome. And then of course, based on the PK of your molecule, you will be on and off in regards to inhibition. With NEK7 degradation, obviously the inflammasome can't even assemble. And one of the huge advantages we have with degraders in general, but in particular molecular glue degraders, are long-lasting PD effects. We know and it's actually true for VAV1 as well. After a single dose of our NEK7 MGD, MRT-8102, we get rid of NEK7 for 48 hours plus. So it's a very robust PD effect. And we think in the setting of inflammation for as long as we're not immune suppressive and nothing points into that direction, this is going to be a huge advantage. There's also sort of special stimuli where NEK7 is particularly important. And again, we think this is going to be really key for clinical development. So again, having something long-lasting, not immune suppressive in the inflammation space, I think will have a huge impact. Great. And you also have shown that this molecule has the ability to penetrate the blood-brain barrier in non-human primates. Curious, how would you leverage this feature for the future clinical development? Yeah, I mean, there's definitely quite a few central indications where this pathway seems to be important. Parkinson's disease and Alzheimer's are out there as indications in public domain and certainly being pursued by some of the inhibitor companies. Talk recently about obesity and sort of inhibiting central inflammation to have an impact on obesity as well. 8102 actually has decent blood-brain barrier penetration. That said, by now we have molecules that do that even better. Again, a huge advantage of doing it with the degraders. We can measure degradation even in the brain, obviously not in a human being during the trial, but we can do this in preclinical tox species, which will help us to better define what's the dose we will likely need to have an impact on the CNS inflammasome. We can actually also measure it in CSF. So I think a lot of upsides here for using NEK7, but yes, the central molecule will probably be different from MRT-8102, which will focus more on peripheral indications. Okay. Have you disclosed which indication will be prioritized? We haven't disclosed that yet. I can say sort of coming back to some of the proof of concept in the field for IL-1 alpha/beta, you have data in pericarditis. There's data in osteoarthritis. There's data that would support development in gout. And so I think there's plenty of choices here, obviously more to come in the next few months and as we enter the new year. Obviously, this molecule MRT-8102 is slated to go into an IND filing and then into the clinic first half of next year. Okay, great. Maybe moving back to oncology pipeline, you have both CDK2 and CCNE1 degrader under development. They are actually the binding partner and the regulatory cell cycle arrest. And on top of that, there are actually multiple CDK2 inhibitors under development and in a more advanced stage. What would you say the CDK2 degrader actually can do additionally compared to CDK2 inhibitor and also why you pursue both given that they probably elicit similar functions? Yeah, so an interesting duo we have here, right? So these are two different molecules. We have one that degrades CDK2 and one that degrades cyclin E. The CDK2 degrader doesn't degrade cyclin E and vice versa. So I think that gives us some interesting opportunities and also differentiation. The inhibitor question, it's a good one. Many companies, as you know, are out there advertising selective CDK2 inhibitors. They're relatively selective based on biochemical assays. They definitely favor CDK2 over other CDKs, but they're not perfect. We definitely see in cell line panels like CDK2 dependent versus independent defined by CRISPR, but genetic tools that with CDK2 inhibitors, you just don't get as good differentiation as compared to what we see with actually both our molecules, our CDK2 degrader and cyclin E degrader. So we think the key advantage of the CDK2 molecule will be higher level of selectivity and hence better tolerability, which I think is key in regards to where we want to go. We've developed this so far and still obviously preclinical to go into positive breast cancer and ideally a triple combination. And I think key to this obviously will be safety. I think this is a patient population, first line metastatic breast where safety, given how long you now treat those patients, is going to be key. cyclin E, obviously the intention there is to focus a bit more on any of the cancers that have genomic alterations in the pathway, in particular those that have cyclin E amplifications. Great. Timeline wise, when do we expect the first clinical data? So, for those, we haven't given any guidance. They're obviously still in lead optimization. We've guided towards having a development candidate for CDK2 this year. And so we will cyclin E, everyone in the company knows it's one of my favorite things. We're working super hard. It's not too far behind. So again, I think cyclin E, given that this is completely undruggable, obviously has a lot of the same sort of flavors as VAV1 has. So a really interesting, cool defining target for us. Great. And as now you have both oncology and I&I programs progress very well, and could you discuss your strategic thinking across these two therapeutic areas? And also on BD front, would you actually rely on external effort on certain areas or it's more like individual asset-based when you think about organic and inorganic growth in long term? Yeah, so it's literally that, right? For us, it's more asset based than disease area based. I think in each disease area, and we're not even limiting us to ONC and I&I, there'll be targets with indications that are relatively straightforward to develop and then indications or targets that will be harder to develop. And then there will be situations like with VAV1, which at some point we realized it's almost like too big to do for any small company. And also I obviously use the term too big to fail, right? I just wanted to see this teamed up with someone where we felt it's set up for success. And so we look at us as a platform company. Also, that's not always a popular term, but I think we have a very unique, differentiated, highly differentiated product engine. We try to apply that engine wherever we think it's best applied, be it ONC, immunology, cardiovascular metabolism. Then we think about partnerships or not just based on clinical development plan. Would we need combinations or not? Who on the other side actually is there that would make a great partner? Is there anyone at all? Fantastic. We're going to wrap up here and thanks for a very insightful discussion. Thanks everyone for attending. Sounds great. Yeah, thanks for.