All right. Good afternoon. Good evening. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. Our next presenting company is Monte Rosa Therapeutics, and presenting on behalf of the company is CEO Markus Warmuth. There is a Q&A after the presentation. If you have a question, just raise your hand. We'll bring mics to you, and for those tuning in online, feel free to submit questions via the portal, so with that, Markus, thanks for joining us. Sounds great. Yeah. Thanks, Eric, for the introduction. And most of all, thanks for having us at this fantastic conference here in San Francisco. And so today, I'm going to present on behalf of Monte Rosa and the entire company, obviously, to give you an update on what's happened, in particular last year, but of course, also to give you an outlook on what we're up to this year. And so first, maybe to kick it off, and for those of you who are not as familiar with the company, we're active in the field of targeted protein degradation. So we're taking out proteins. There's a variety of different ways you can do this. We are doing it through molecular glue degraders. And I have a slide coming up that actually explains that. We do think of ourselves as the leading company in that molecular glue degrader space. We've built a platform called QuEEN. That's a very cool combination of AI, machine learning, but of course, also experimentation. We have labs in Boston and Switzerland that do active work. Everything we do actually is done in-house, except, of course, some of the chemistry that we're outsourcing. I think the best evidence for the innovation for leading this field is our portfolio, and again, I have a slide on that. It's a unique and differentiated portfolio that we have built over the last five, six years within the company. Last but not least, on this slide, we have actually a very strong financial position at this point. We have a cash runway that we're guiding towards lasting into 2028, and this will certainly get us through multiple additional value inflection points. What are molecular glue degraders? Just very briefly, as I said, these are molecules that help to take out proteins. And we can do this very specifically, as you will see. These molecules, these are small molecules. They're orally bioavailable, work by binding to an E3 ligase. So that's part of the cell intrinsic protein destruction pathway. And by doing so, they reshape the surface of that E3 ligase to a point where that surface becomes a perfect match for a protein we want to take out. From there, obviously, it gets ubiquitinated, so tagged for destruction, and is eventually taken out, as I said, by the cell intrinsic protein destruction machinery. A few words on why we are so excited about this modality. One, of course, is it allows us to go after undruggable proteins. And so for this matchmaking between an E3 ligase and a protein we want to take out, we do not require a pocket on the side of the target, the neo-substrate, as we like to call them. So in that context, obviously, very similar to what you can do with gene editing or RNAi, just here, you can do it with small molecules. And we can do it at the same level of selectivity that RNAi or gene editing provides. So a very compelling story. There's a few other advantages that I'll bring up as we go through some of our additional science. Definitely not enough time today to talk about the platform, how it differentiates. And so really just two simple slides that, in a way, encapsulate why we think we are now the leading molecular glue degrader company. So one thing we decided to do early on, and that we realized is that to understand how to do this, we really needed to find ways, computational ways, algorithms to understand protein surfaces. And so we've established quite some know-how around geometric deep learning that now informs how the surfaces of ligases, but also neosubstrates, are shaped, but even more so how they can be reshaped in the context of molecular glue degraders. And of course, that has now led to a point where, within the ligase, we've initially worked on Cereblon. We have greatly expanded chemical space, but also neosubstrate space. But we have also utilized the insights from these exercises to expand to additional ligases. We haven't named those ligases yet, but expect us to start talking more about this in the next month and years. And so a huge space that we have opened up, obviously, now thinking way beyond where we initially were in oncology. I think where we are with our technology, with the selectivity we can dial in, certainly any disease area has become open to us. And so here is our portfolio. I keep it brief on this slide because I bring it up again at the end of the presentation to talk more about upcoming milestones. So again, rather than going through this target by target, let's actually get into the programs and the science around them. The first one I want to talk about is our GSPT1 program and a molecule known as MRT-2359. And so GSPT1 is a very interesting protein in the protein translation pathway. So it's important in the synthesis of new proteins in a cell. And we figured out that it's particularly important in the synthesis of new proteins in tumor cells that are dependent on MYC transcription factors, MYC actually being very key drivers of cancer, very notorious oncogenes that so far really haven't been addressed therapeutically. And so the cartoon here really shows how we think this works. You have MYC driving protein translation, obviously transcription first, and then from there, translation. Interestingly, there are three MYC transcription factors, L-MYC, N-MYC, and C-MYC. They actually all provide the components that you need to initiate translation, but they do not induce termination of protein translation. That's really where GSPT1 comes into play. Translation termination factor, really there to help catalyze the separation of new protein from mRNA in this process. Lots of preclinical work that we have shown in prior years that validates the slide that I'm showing you right now. And so with 2359 in hand, obviously, we did quite some translational work to set us up for the initial clinical trial. Some of the initial work and even the initial dose escalation focused a lot around L-MYC and N-MYC as sort of less frequent alterations or highly expressed MYC transcription factors. More recently, we've become also more interested in tumor types and subsets of tumor types that are C-MYC driven, typically larger populations that potentially don't even require preselection of tumors. And so one of these tumor types is prostate cancer. Lots of literature out there on prostate cancer suggesting that C-MYC on its own is an oncogene there. But C-MYC actually can also modify what androgen receptor does in the context of androgen receptor-positive prostate cancer. It can amplify AR signaling. It can alter AR signaling from a more differentiating signature that AR induces to a proliferative signature. Eventually, C-MYC can actually also cause drug resistance. So some interesting data that I'm showing you here, obviously, we have a lot more in two prostate cancer cell lines that are actually either partially or completely resistant to enzalutamide, actually also resistant to other antiandrogens. Interestingly here, in combination, but even as a single agent, we see a very significant activity in this setting. But we're also seeing the actual androgen signature, and that's not shown on this slide, but we have the data, the androgen signature being downregulated. So there's a clear interference with this pathway by downregulating or degrading GSPT1. So a quick glimpse into where we are in clinical development. Obviously, a phase 1 dose escalation has been initiated a little bit more than two years ago. We've reported late last year that we now have identified a couple of safe dose levels. We were actually testing two different dose regimens, a five and nine schedule. So we were dosing five days on, nine days off, five days on, nine days off, but also a more dense 21/7 schedule, so 21 days of drug administration with a seven-day dose holiday. Again, both regimens were safe. For both regimens, we found safe dose levels, and having identified a recommended phase two dose, beyond the tumor types we have tested as in the single agent dose escalation, we're now also exploring ER-positive breast cancer, and most of all, following onto the last line, AR-positive prostate cancer so trial, obviously, still recruiting in that setting. We've actually guided towards an additional data update in Q1, so not too far out from today. Switching gears to another very, very intriguing program or target. We have one molecule behind that is known as MRT-6160. And so 2359 was actually the first molecule, the first molecular glue degrader to ever be tested in a solid tumor setting specifically. This is now the first molecular glue degrader being explored in a non-oncology setting, more precisely in autoimmune disease. This is a program that in October, we announced, we licensed to Novartis. The actual ongoing phase one trial is actually operated by us. And you will see on a slide coming up that just like for 2359, we've guided towards a Q1 data readout. So it's going to be a busy Q1 for us. So what is VAV1? Why are we so excited about it? Why actually is our partner so excited about it? It's a signaling protein in immune cells. Its expression is very restricted to immune cells, T and B cells, and a few others. Interestingly, one of the few proteins out there that's actually involved both in T and B cell receptor signaling. We're not aware of any other protein that really sort of crosses these two cell types as much as VAV1. And so what you can accomplish here by degrading is obviously inhibiting at least parts of the downstream signaling of T and B cell receptors. But as a result, we're also inhibiting the crosstalk between T and B cells altogether, in particular, of course, those T cells and B cells that are hyperactivated by autoantigens. Lots of, again, preclinical data we have. I think this slide sums it up very nicely. When you look at the actual mechanism and what VAV1 degradation does by sort of interfering with T, B cells, their interaction, in particular, TH17 cells, you see a lot of overlap with the existing approved biologics. And so we look at this as an oral opportunity to eventually look much like many of the biologics that are out there. But instead of taking a single cytokine pathway out, obviously, here, you have the opportunity to also work in what we like to call multi-cytokine settings. So where multiple cytokines in a more heterogeneous situation drive autoimmune disease. Just to recap a few of the highlights of our partnership with Novartis, this was a deal we truly got excited about around the potential to develop 6160 much faster and more broadly. But of course, also importantly, financials. We actually received an upfront payment of $150 million. In the course of the development, we're eligible for up to $2.1 billion in development and regulatory milestones. And of course, there's sales milestones. And that actually begins upon initiation of phase two studies. We're essentially approaching the end of our phase one study. These are things we're already starting to think about. There will certainly be more information coming out later in Q1. Then in the course of this year, we're going to take this molecule moving forward. Just a quick word on the actual phase one study. It's a pretty boilerplate, SAD, MAD, healthy volunteer study. So single dose and then multiple ascending dose. We're obviously looking there at, can we degrade VAV1 to levels we actually want to degrade VAV1? How long does that degradation actually last? In simpler terms, PKPD, and then, of course, also safety. We are looking at biomarkers ex vivo. This is also obviously a healthy volunteer study. So there's not much to measure in regards to cytokines in vivo in patients. But we can isolate their immune cells, stimulate them ex vivo, and then basically correlate degradation levels to levels of functional inhibition in those ex vivo assays. And in that context, we'll certainly look at cytokines like IL-2, IL-6, IL-17. And so again, just to reiterate, phase one study ongoing. It's a boilerplate, SAD, MAD study. And we're expecting top-line results to roll out in Q1. It's not our only IND program. We actually have another one that's about to go into the clinic. We've guided towards an IND filing within the first half of this year. The target here is NEK7. And so what is NEK7? Where is it important? It's actually a very critical component of the NLRP3 inflammasome. I'm sure this is a pathway you've heard about, very essential for a variety of different inflammatory conditions. Pericarditis is one that's been out there, gout, but certainly a lot of others. Lots of talk about the role of the NLRP3 inflammasome in all sorts of cardiovascular conditions and obesity as well as in neurodegenerative diseases, including Alzheimer's, and so lots of opportunity there. What is NEK7 good for? Obviously, the inflammasome is a multi-protein complex, and NEK7 really is essential there for the actual assembly, so you take out NEK7 inflammasomes, NLRP3 inflammasomes do not even assemble accurately, so this is not inhibiting the assembled inflammasomes. It's trying to avoid that they even become active. Somewhat different from VAV1, there's existing clinical proof of concept for the pathway. There's biologics out there that address IL-1 alpha and IL-1 beta, and so quite some good guidance on where to potentially take NEK7 degraders. Cardioimmunology, certainly some good information there, some good proof of concept. Gout, I've mentioned, osteoarthritis through some of the biologics, and so on and so forth. So again, a validated pathway here being addressed with a novel modality that we think will be superior to NLRP3 inhibitors. And so a few data points, and I think this really showcases the quality of molecules we can generate. On the very left-hand side, you actually see the degradation of NEK7. We're essentially talking like single-digit nanomolar degradation, EC50s or DC50s, as we like to call them. Now, that's great, but a challenge we always got early on was how selective can you be? If you look at the middle panel, that's a proteomic experiment. So we're literally measuring in a cell when we expose that cell to our NEK7 MGD, what are the proteins that go down in expression? And it's literally only one. I think we can clearly conclude here that within 10,000-12,000 proteins, we're monoselective for NEK7. And that's quite astonishing because NEK7 is not the only family member. It's a kinase. There's nine other, actually eight other NEK. We're not touching any of these. So quite astounding and certainly something that with kinase inhibitors, with things that bind the ATP pocket of a kinase, would be very hard to accomplish. And then last but not least, of course, when you go in vivo, also important to know how long does the degradation last? And this is something we're now seeing over and over again, unless you have proteins that we synthesize very fast. After After a single administration of, in this case, MRT-8102, we have very long-lasting PD effects. The protein's taken out for multiple days. Obviously, that gives us a lot of opportunity to think about patient-friendly dose regimens as well. Clearly, patients prefer to take a pill less frequently if possible. Degradation, right, obviously, you also want to see functional impact on the pathway. I keep it brief here between measuring the activity of Caspase-1, which actually processes IL-1 beta intracellular, and then the actual secretion of IL-1 beta. We see a very nice functional impact. That's actually in human monocyte-derived macrophages. On the right-hand side, a very cool flow cytometry-based assay where we actually can measure the formation of the inflammasome in cells. In this case, it's actually in human whole blood. Again, you can see very nice, more or less complete inhibition of inflammasome formation. And then last but not least, of course, so if you want to see does that work in vivo, we've done a study. I start on the right-hand side in rabbits where you can induce a gout-like pathology by injecting MSU. And you can see very nice efficacy here in regards to treating joint swelling. We use prednisone here as a control. It's actually dosed at levels that are much higher than what you would be giving in the human setting. And so here, very well tolerated doses of 8102, very comparable efficacy to super therapeutic doses of prednisolone. On the left-hand side, actually a study in cynos where we treat cynos with 8102. Obviously, these are not diseased cynos. So just like what I described for VAV1 here, we took samples from these cynos. We did ex vivo stimulation. And you can see that with the level of NEK7 degradation we got, which was more or less complete. It's not shown on the slide. We got complete functional inhibition of the pathway. So lots of evidence that this pathway or this modality works in the pathway. As I said, this is approaching IND filing. We're sort of final stages of wrapping up some of the work and report writing. And this should go into the clinic first half of this year. So third program for us to take forward into clinical trials. And so then last but not least, want to spend a little bit of time on yet another oncology program. As you can tell, we look at us as a company that's not oncology only, not I&I only, not even oncology and I&I only. I think this platform is going to be applicable across a variety of different disease areas. And so here, Rebecca, in oncology, we have a very nice duo of molecules, one targeting CDK2 and another one targeting Cyclin E1. And so why is that exciting? Sure, these two many times work together in a complex. But it's also important to understand that while they many times work together in a complex, CDK2 has functions that are Cyclin E independent, and Cyclin E has functions that are CDK2 independent. So it's really important for us to have these two different shots on goal here. Some of the tumor types that are relevant in this program are ovarian cancer when Cyclin E is amplified, but also ER-positive breast cancer, in particular post-CDK4/6 treatment, where this pathway and CDK2 in particular seems to drive continued progression of at least a subset of these tumors. And so to show that CDK2 degradation, I'll start with CDK2 first, is a potential modality in this context. We ran an in vitro experiment where we do a long-term culture of a breast cancer, an ER-positive breast cancer cell line with either ribociclib or, then, in a combination. And you can see, obviously, while single agent ribociclib, that's a CDK4/6 inhibitor, works somewhat, you do actually get outgrowth of resistant clones. And by adding on MRT-9643, which has development candidate-like qualities, you can very significantly delay that outgrowth. Now, that's great, but in vitro, I mean, what does that mean? So sure enough, we went into in vivo studies. This is a study in an ER-positive breast cancer model in vivo where we're looking at tumor size reductions. In this context, we did ribociclib, so CDK4/6 as a single agent, and then all sorts of double and triple combinations. The focus here, obviously, is on the triple combination with 9643, ribociclib, and fulvestrant. You can see very nice efficacy, definitely better, improved from the double combinations, and in particular, improved from the ribociclib-fulvestrant combination, which you could consider standard of care. Now, that enhanced efficacy, of course, correlates to lots of interesting PD readouts that we have done. A couple that are on this slide, obviously, you look at downstream pathway phosphorylation of Rb. We can very nicely suppress that in this triple combination. We can actually also, and this is based on an RNA-seq study from those tumors, at the end of the study, it can very nicely repress the entire E2F pathway around. So again, very compelling data that for a triple combination, one will be better than just the double combination. I think the most important thing I almost forgot to mention, for the triple combination here, it was extremely well tolerated. We tried some of these CDK2 inhibitors that are out there as well. Much more toxicity there as compared to our degrader. And so, as I mentioned, MRT-9643 has development candidate-like properties. There's a couple of other things we have to do. There's another molecule we're profiling, but we've guided towards this or whatever other molecule becoming our development candidate in the course of the first half of this year. And then last but not least, since I mentioned it, we're also working on cyclin E. I keep it brief to this one slide. A unique opportunity for us, some data here on the left-hand side, a cell line panel where we're testing cyclin E amplified CDK2 dependent cells versus non-amplified independent cells. You can see very nice separation here in regards to cell growth effects, much less of a separation with a variety of different CDK2 inhibitors, including Blueprint and Pfizer. Really great in vivo efficacy as well. As a single agent in this case, we're starting to see significant reductions in tumor size. And so this program is a little bit behind CDK2, but you can tell from this slide that we have molecules already that show very decent oral bioavailability and are getting close to development candidate profiles. And so with that, just a quick summary. I've mentioned a lot of that already on the go, but just to recap, this is going to be a very busy year and in particular, a very busy first half year. For Monte Rosa, GSPT1, MRT-2359, we're working towards an additional data disclosure during this quarter. And this will have lots of data from the monotherapy dose escalation, of course, including some of the efficacy data that we have seen. But we'll certainly also start to include some of the combination data that we are generating as we speak. VAV1, again, similar situation, top-line results here for the phase one coming out in Q1. And then, of course, in the course of the year, more guidance in regards to where this molecule will be taken in phase two studies. NEK7, IND filing, first half of the year. And then, of course, initiation of our phase one healthy volunteer study. Certainly, some more information with the IND filing coming out on the design of that phase one study and a potential development path. And then CDK2 cyclin E, as I mentioned, each of these headed towards development candidates as well. And so with that, I really want to wrap it up with sort of a longer outlook, something, again, I've alluded to in the course of this presentation. I think in the last four or five years, we've really shown that this platform is a true product engine. It's not just like a one, two things, and then there's nothing else to do. We've really built a very compelling portfolio. Our initial focus was on oncology and autoimmune. Really great to see. And again, VAV1, first molecule ever to be specifically developed in autoimmune. Really great to see that we can create molecular glues that have the quality, that have the selectivity, that have the safety profile to actually be successful outside oncology. And so obviously inspired within, as we start to build more portfolio, disease areas like cardiovascular, metabolic, genetic diseases, all of these are in the picture in discussions. And so again, expect us to start talk more about even some of the early targets later this year. And so with that, obviously, I would like to thank you for your attendance and would like to open it up for questions. Great. If there are any questions from the floor, just raise your hand and we'll get a mic over to you. But Marcus, maybe just to set the stage a little bit for the VAV1 healthy volunteer readout coming, one of the two key readouts coming later this quarter. Can you just talk a little bit about sort of the dose and period you're evaluating in the MAD portion of the study and sort of whether you expect to observe a bit of a dose response as you look at both degradation and cytokine activity profiles? Yeah, so we haven't disclosed the exact dose levels. That's an yes, we are expecting a dose response, in particular in regards to sort of onset and sort of offset of the PD effect. And obviously, we're assuming that that will translate from protein degradation into what we see in the cytokine assays. As I said, and alluded to before, one of the big questions for us is how long lasting is that PD effect? Because again, while daily dosing obviously is pretty much standard, of course, with a long lasting PD effect, we would have quite some opportunity for less conventional, but more patient-friendly dose regimens as well. Okay, and I guess, is it kind of the first of perhaps multiple readouts from the healthy volunteer study, or is this sort of the full data set? Yeah, I mean, the plan really here is like the full top-line results of the entire SAD-MAD study. Got it. Okay. And just now, as a partnered program with Novartis, I guess, how would you orient or set expectations in terms of your freedom or the cadence of disclosures on the part of Monte Rosa as the program sort of proceeds through additional phase one, phase one B development? Yeah, I mean, I think there's agreement between the two parties that continued disclosures obviously are important for us. This is not, I mean, it is a licensing deal, but we have actually retained a 30% US P&L split, and so obviously, for us moving forward to fund our share of the work, it's pretty clear to our partner that continued disclosures are going to be important. That said, I mean, there was certainly an upside for us in this partnership. The actual funding requirement on our end will only start to kick in in phase three. Okay. Great. And maybe just a question on the NEK7 program. There are a number of, seems to be a growing number of NLRP3 inhibitors, also kind of focused on the inflammasome that are in development or that are entering the clinic. I guess, can you talk about how engaging the inflammasome at the level of NEK7 is potentially distinct from that at NLRP3? And to what extent sort of you've been able to interrogate this preclinically? Yeah, I mean, I think there's a couple of things we see as an advantage. I think biologically, the obvious one is we're further upstream. So as I said during my presentation, instead of inhibiting on and off an inflammasome that's assembled and that wants to constantly fire, here we're essentially upstream blocking the assembly of the inflammasome altogether. Now, on top of that, and again, I spoke about this with the longer lasting PD, of course, we think the inhibition of the pathway altogether will be more robust. But we also will have the opportunity to think about, as I said, more patient-friendly dose regimens. All that said, even from an IP point of view and owning that chemical space and the number of molecules we can generate, I think going after NEK7 is a huge advantage. I mean, to our knowledge, we know a couple of other companies have tried, but to our knowledge, we're one of the few companies that are still in the NEK7 target. Okay. All right. I think we'll have to leave it there for time. So thanks so much, Marcus, for the presentation. Thanks, everybody, for tuning into the session. Sounds great. Yeah, thanks, Eric.