All right. Good morning. Thank you everyone for joining Jefferies London Healthcare Conference. My name is Clara Dong, one of the biotech analysts here at Jefferies. So sitting next to me, we have the Chief Executive Officer of Monte Rosa Therapeutics, Marcus Warmus. Welcome. Yes, thanks. Thanks for the invite. Pleasure to be here. So Marcus, before we dive into your individual programs and pipeline, maybe could you give us a quick overview of MondeRosa? What's your molecular group, the greater platform and what really makes your molecular group the greater is an attractive therapeutic modality? Happy to. And so as you pointed out, we are active in targeted protein degradation. So we take out proteins that are acting up in disease driving cells. We can do this very selectively now with our platform. The secret to success there was really to understand how we can design these molecular glue degraders so they bind to ubiquitin ligases very selectively and in a way that they reshape the ligases surface to now become a perfect match for a protein we want to take out. We've done this now multiple times. We actually have three molecules in the clinic, and each of these molecules actually is exquisitely selective. So really think this is an up and coming modality. The big upside here also is it's induced protein protein interaction. And so we do not require the target to be druggable. There's no need to have a pocket a binder to the target. It's really, again, reshaping a ligase to become a perfect and sticky surface or match for the protein we want to take out. And I mean, obviously, the concept of protein degradation is not completely new, but how is molecular glue differentiated from other protein degradation technologies, especially PROTECT? Yes. So interesting, Rob, because in some ways, protein degradation was invented through molecular glue degraders. I'm talking about a drug known as thalidomide and then lenalidomide. Also they weren't actually known to be molecular glue degraders when they were discovered and originally developed. From there, actually, some companies developed a pretty cool smart approach where instead of doing molecular glue degraders or smaller molecules, you do hetero bifunctional molecules. You have something that binds to that ligase that we're reshaping, in this case, just a binder. You find something that binds to your target of interest, and you put a chemical link in between. And so a very smart process. But as I like alluded to, you need to find a binder to your target of interest first. And so the target needs to be at least somewhat druggable. And so many times, of course, then when you look at portfolios of these companies, they're redrugging druggable space, and these molecules still have a lot of advantages, essentially taking out the protein, achieving deeper pathway suppression. But you can't really do what molecular glue degraders are doing, which is go after the completely undruggable target space. Great. And then I want to talk about your VAV1 program first. I mean you have a partnership with Novartis, and we recently saw the partnership expansion as well. Maybe just walk us through your collaboration with Novartis in this high level of this program. So let me actually start by saying, VAP1 is one of these prototypical targets we'd like to go after. It was very well known to the industry for many years. I actually worked on it in the early 2000s when I was still with Novartis. Completely undruggable, no one was ever able to find an inhibitor or even a binder. And so we came up with this beautiful molecule, MRT6160 degrades WAF1 very selectively, actually spares WAF two and three, which is really important to avoid toxicities. Eventually, entered into this partnership with Novartis. It seemed to be the perfect match where, obviously, we knew that Novartis had invested on the inside into this target. They had publications on BAPH1 early on describing its role in autoimmune diseases and what its potential is. And obviously, we're now looking forward in that partnership to move MRT-six 160 into Phase II trials. And then you previously reported some healthy volunteer data with So maybe just give us a walk through of that data and maybe what which part of that data set gives you the most confidence that VAV1 degrader has this potential to address multiple indications in I and I? Yes, couple of things. I mean, it was a classical SADMAD study, so we're mostly looking for PKPD and safety, of course. So do we get enough drug into the system? Does it degrade VAF-one enough for us to be confident that it can achieve efficacy? And actually, can we do this in a safe way? We then also isolated immune cells from the participants in the trial to stimulate those cells ex vivo just to see as we degrade RAF1, can we also block signaling in T and B cells? We looked at a couple of different pathways and actually cytokines as a readout. We looked at IL-seventeen, which we feel is important because that's where VAP1 plays a huge role in Th17 biology. We actually also looked at interferon gamma just to sort of benchmark against some of the existing drugs. Many of the IO23 agents actually in similar assays use interferon gamma. I mean I would say we're benchmarking extremely well against some of these other molecules currently being developed. And so I would say based on that and what we had seen preclinically in mouse models, a fairly high conviction that moving forward into those Phase II trials makes a ton of sense. So let's talk about those Phase II trials. So what are the key selection criteria for determining the indications for Phase II? And when should we expect Novartis to announce indications for those trials? Yes. So I'll try to address your last question first just to get that out of the way. We can expect Novartis to announce initiation of the trial when they announce initiation of the trial. I was listening to my colleagues from Avinas before, and I was smiling because I think they were talking about data being released by Novartis, and they will hear about it first. So I will just say we will hear about it first when they initiate the trials. I'm just kidding. We obviously know what the plan is, but agreed with Novartis to not disclose any details on the actual indications and time lines. We are very happy with the clinical development plan that we have seen as obviously a joint development committee between Novartis and us. From selection criterias for those, it's pretty straightforward, like wherever you have a sense that Th17 biology is important. Obviously, Novartis, with them having developed Cosentyx, has a lot of experience in that field. This is also where we, as as I alluded to, mostly focused our preclinical studies. So anything Th17 driven where we know T cells, autoimmune T cells activate B cells to release autoantibodies makes a ton of sense. And then I also want to quickly touch on the second partnership you have with Novartis. And maybe just walk us through that new collaboration at a high level? What are you aiming to achieve with the new target? Yes. So an interesting sort of follow on obviously tells you that in the year, we collaborated around sixtyone-sixty. We really started to appreciate each other's know how and drive. And so that second collaboration made a ton of sense. The agreement actually has a license on a target that I think was a huge interest on both sides. There's know how on both sides contributing to the program. So we decided the most straightforward path forward here is a licensing deal. And then there's two options on existing preclinical programs within Monte Rosa. And so this is not a classical discovery partnership where Novartis would give us a long list of targets to screen. This is really more intended for Novartis to have access to an option to things we're already working on. From our point of view, I can say our platform queen has been incredibly productive. So we weren't given everything away we have. Look at this as sort of an overage of targets, again, in spaces where we felt development on our own would be extremely challenging. So a lot of the same features here as you've seen with 6,160, right, like assets that eventually will be applicable across a broad range of autoimmune diseases. Got it. Maybe let's move on to NEX-seven program. And maybe to set the stage, just tell us what is this NEXT seven targeting strategy? How is it different from directly inhibiting an RP3? Yes. So just to throw it out, wholly owned still, so I can say whatever I want, kind of. Really excited about the pathway and, in particular, Nx7 as a target. It's obviously a crucial component of the NLRP3 inflammasome, one of the key inflammatory pathways in the human body. As a component of that inflammasome, it's essential for the actual assembly. So when there's no NAC7, there's no active fully assembled inflammasome, which we think is a superior strategy. And so instead of inhibiting the foliassembled inflammasome on and off with inhibitors or even going after cytokines downstream, you've basically now completely quieted that signaling pathway. And so we do believe that by degrading NAC7, you can achieve deeper inhibition of the pathway. There will be longer duration of inhibition as far as you're not with your PK working against too low trough levels. We're at the end of the day, at least some inflammasome activation will come back. And then we did see that a recent NLRP3 inhibitor actually shows some proof of concept data. It tells us that the pathway seems to reduce the cardiovascular risk. So maybe tell us what you've learned from that data set, that proof of concept data and what's the read through for your NEX-seven? Yes. I mean, obviously, encouraging to see the excitement around that asset. This is Ventix's NLRP3 inhibitor. All that said, we didn't need to see that data, right? I mean the earliest proof of concept for the pathway and that it can influence cardiovascular outcomes comes from canakinumab, Novartis' IL-one beta antibody. That antibody actually did show a signal in an ASCVD trial. It just had too much infection risk, lethal infection risk to make it to a label. But certainly, was a nice proof of concept. Obviously, it had also helped to establish reduction in CRP as a key biomarker to predict a positive outcome. And so between what we historically know about canakinumab and now sort of the more recent data from Ventix, we're obviously very excited about, a, the pathway but also feel extremely good about our approach to inhibiting the pathway through NEX-seven degradation. And you do have your own initial data reading out next year as well. Maybe just help us set the expectation for that data readout. And what kind of what level of degradation you are targeting? And then what kind of biomarker signals should we watch for? Yes. So again, Phase I SAD MET trial, but somewhat different compared to what I was describing for MRT6160 in a sense that we have a Part C there, which we actually called a CRP POC trial. You might just as well call it a mini aCVD trial, right? So we are looking in individuals with elevated cardiovascular risk and elevated CRP levels, whether we can drop CRP back to more reasonable levels. I mean it's a four week study for now, so it's not the full twelve week or six month study. But I would say, so far, if you look across various different assets, kind of canumab, other molecules, sure, if you get to a CRP drops within four weeks, they will certainly be maintained nicely following through with longer treatments. And so I think that, that POC study can be extremely informative on how much NEX-seven we need to degrade to achieve efficacy. Preclinically, in models, we've actually seen full efficacy with, let's say, as little as 60% degradation, which is interesting. There's probably a threshold level of NEX-seven that's required for inflammasome assembly, so you don't need to wipe it out to 100% to inhibit the pathway. So at around 60% degradation in a mouse, we get equivalent efficacy to what you can achieve with NLRP3 inhibitors when you dose those actually very highly, more or less to full inhibition of the inflammasome. That doesn't mean that's going to be our limit in the clinic. We can certainly get to higher levels of degradation. I'd say our target would be somewhere around 80% to 90% degradation, I see, as sort of the optimal range to get robust longer term pathway inhibition. So moving forward, would you consider a combination strategy with GLP-one for cardiometabolic diseases as well? I think that's definitely a feasible strategy. At the very least, from a preclinical point of view, MRT-eight thousand one hundred two is extremely safe. We haven't really seen any toxicities. I mean, our four week GLP tox study, obviously, the longer term studies are underway. And so we think this is combinable with other agents. Certainly would be very logical, but there's other combination approaches that we're also considering. Great. And you also have a next gen, next seven degrader that does have a blood brain barrier penetration feature. So how do you plan to leverage this feature in the future clinical development? Yes. There's a couple of reasons why companies, at some point, a couple of years ago, decided to a brain penetrant. Let's call them NLRP3 pathway agents, small molecule agents, so be it like we as a Nex7 degrader or NLRP3 inhibitors. There's obviously a validated role for the NLRP3 inflammasome in neuroinflammatory conditions like Parkinson's and Alzheimer's. But at least prior to Ventix's data release, I believe that there could be a direct effect, single agent effect on obesity and that, that would require penetration of the blood brain barrier. Now obviously, that data or the trial read out negative for obesity doesn't really mean for sure that it can never work. But obviously, that's the two reasons, like neurodegenerative and obesity, why you might want to have a CNS penetrant molecule. Great. And maybe let's move on to Jazz PT1 program. Maybe just give us an overview of where the program where which stage this program is at and why pursuing castration resistant prostate cancer for this program? Yes. So I mean, again, just to sort of frame and recap the program, MRT-two 359 targets a translation termination factor called GSPT1. When you take out GSPT1, you essentially stall ribosomes. And this becomes extremely critical in the context of tumors that are driven by MYC transcription factors, and that's something we have shown over and over again in preclinical studies. There's three different MYC transcription factors. There's L MYC and N MYC, smaller population, and then there's also C MYC, that's the one. Most everyone usually pays attention to. It turns out that prostate cancer, AR positive prostate cancer is one of the tumor types where C MYC is most frequently overexpressed, highly expressed and actually interacts with androgen receptor signaling to drive development and progression of that of the tumor type. So felt to us that this was a natural place to go if you wanted to probe activity of 2,359 in the context of c MYC as a key driver in cancer Earlier this year, in March, have disclosed some early data from that expansion. Admittedly, a small number of patients was only three patients. But within those, we had actually seen one PR and two stable diseases. The PR was in a patient with a mutation in the ligand binding domain. Patient actually was heavily pretreated. The other two patients, the two with stable disease actually had were positive for ARV7 transcript. So felt that, that data was remarkable enough to warrant further exploration. We've now expanded that to 20 to 30 patients and planning to actually put at least some of that data out before the end of the year. And in terms of the data you're planning to put out at the end of the year, maybe just help us frame the expectation for the data as a scoop of data we should expect to see in terms of efficacy and safety? Yes. So by the time we put the data out again, we expect to have at least enrolled roughly 20 to 30 patients. We've treated the first patient, I think, last year in October. So for some of these patients, we'll have longer term follow-up as well. We made it particularly hard on us by requiring every patient to have immutable disease, right? So there will be no patients with bone only, which also means there will be no patients where we only have PSA responses. Everyone will have a response or at least potential response assessed through imaging, which we felt is the right way to go. We really wanted to know, can we shrink tumors with that modality and not just lower PSA temporarily. We've done a lot of biomarker workup as well. Every patient will have a fresh set of ctDNA data. So we know what the most current ligand binding domain, mutational status is. Every patient will have ARB7 transcripts and protein freshly assessed in circulating tumor cells. So I believe this will be a very meaningful data set that hopefully paves the path for how to move forward with that asset. And maybe for the last minute or so, I also want to touch quickly touch on your other early stage programs. You have a CDK2 degrader and CCNE1 degrader. So how should we think about the opportunities for those two? Yes. It's a very exciting package, I mean we're in the fortunate position that we can take out selectively either CDK2 or Cyclin E. And interestingly, as we explored those two assets, sure, they didn't turn out to be equal. We actually do think that CDK2 degradation will have the best effect in ER positive breast cancer. Really interesting convincing results here in a triple combination preclinically, of course, with CDK4six inhibitor and fulvestrant, Extremely well tolerated, which, again, speaks to the selectivity of the molecules we can create. Cyclin E, probably best suited for cyclin E amplified tumors, in particular, cancer. For both programs, we now have molecules that qualify as development candidates. So certainly on track to move one or both forward into INDs in the future. And maybe lastly, let's talk about your balance sheet. What's your cash runway? Yes. Current cash runway guidance is through 2028. So I'm in a fairly comfortable position, if comfortable is ever a thing or term in biotech. But we feel very good where we are today. And what we can do with that cash runway certainly funds us through multiple Phase II proof of concept studies for our portfolio programs. Sounds great. I'm looking forward to it. So that brings to the end of our discussion. Thank you, Markus, and thank you, everyone, the audience in person and online for joining us. Enjoy the rest of the conference. Sounds good. Yes. Thanks, Sarah, for the invite again. Thank you.