Good morning, everyone. Thank you for joining, those of you in the room as well as those of you on the webcast. My name is Faisal Khurshid. I'm one of the senior biotech analysts here at Jefferies. We're her e at the Jefferies Global Healthcare Conference in New York. Really pleased to have with us the management team of Monte Rosa Therapeutics. On stage with me, Dr. Filip Janku, CMO of the company. Filip, can you start by giving an overview of the company? Yeah. Monte Rosa Therapeutics, we are specialized in the development of small molecules called molecular glue degraders, which are given as oral therapies for the two areas of interest are I&I and oncology. We have several programs in the clinic, which are at a similar stage, at the phase II stage. We have MRT-6160, which is the VAV1 degrader, which is a regulator of T-cell and B-cell signaling. That has been out-licensed to Novartis, with the anticipation of the several phase II programs as a next milestone this year. We have the program of molecular glue degrader targeting NEK7. NEK7 is a protein which has a scaffolding function in the NLRP3 inflammasome. By degrading NEK7, you prevent NLRP3 inflammasome from being assembled. We have a molecule in the clinic, which is called MRT-8102, which has been now tested in the proof of concept study, which is called G-FORCE-1, which is in a patient population in cardiovascular risk defined by obesity and elevated CRP. Some of the early data were actually shared back in January when we showed pretty profound effects on the CRP reduction. We do also have actually the follow-on molecule in the next generation, in NEK7, which is currently in the preclinical stage to become clinical soon. In cancer, we have MRT-2359, which is our oldest clinical program, GSPT1 degrader, showing some pretty exciting data in metastatic castration-resistant prostate cancer with underlying AR mutations. We have had the updated ASCO GU a few months ago, showing quite interesting signal in population with AR mutations, with significant amount of PSA responses. In fact, we have seen five PSA responses in five patients with these mutations. The next step for that program, which is pretty imminent in the next quarter, per our guidance, we are hoping to start a phase II study, which will specifically look at this AR mutant population to confirm that signal. Programs which are approaching the clinic is our CDK2 and Cyclin E1, which is guided towards IND later on this year. Okay, great. I want to talk about NEK7. I think this is one of the more interesting parts of your pipeline. Can you explain the rationale for targeting NEK7, relative to inflammasome pathways, and why targeting NEK7 might be a better approach than targeting NLRP3, and also the downstream targets, IL-1, IL-6? Yeah, this is an excellent question. I touched on that a little bit when I did my overview. The NEK7 has a scaffolding function in NLRP3 inflammasome. If you degrade NEK7, if you deprive the NEK7, you prevent NLRP3 inflammasome from being assembled. By doing so, you achieve very sustained level of NLRP3 inhibition, which has its downstream therapeutic effects, including effects on otherwise pathologically-driven cytokines. What differentiates us, I might start from cytokines and then move to NLRP3s, because I think there are some important distinctions to be noted. If we compare how we differentiate from, let's say, IL-6 anti-cytokine therapies or IL-1s, you target the inflammation at much more proximal fashion at the level where this pathological inflammation is actually triggered, instead of dealing with the ultimate effectors of that pathological inflammation, such as targeting IL-1 or IL-6. That has some important distinctions which can be impactful for both efficacy and safety. By preventing inflammasome from being assembled, you not only impact the cytokine levels, but you also have impact on inflammatory stimuli or inflammatory processes which are more upstream in the pathway. One of them which would be very important is pyroptosis. Targeting NLRP3, whether it is with NEK7 or other molecules for that matter, you reduce the pyroptosis with consequential release of pro-inflammatory stimuli, which neither cytokine would do. That's one important distinction. The second important distinction is when you have, let's say, IL-6 antibody, but the same would apply to IL-1, you effectively deprive or reduce the levels of that cytokines in very dramatic level. There is no necessarily situation that IL-6 is just sourced by that NLRP3 inflammasome and the IL-6 can be a consequence of many other processes, some of them might be actually needed. The same applies to IL-1. The IL-1 can be the consequence of other inflammasome beyond NLRP3s to be activated. If you completely deprive or eliminate all the molecule of the cytokine, you might be also preventing some processes to happen which are actually needed and desired, such as pathogens defense. That's something which the NLRP3 NEK7 targeting wouldn't have. The differentiation between NEK7 and NLRP3 itself. As I mentioned, we prevent NLRP3 inflammasome from being assembled. While targeting NLRP3 directly, you target the activated NLRP3. The NLRP3 inhibitors also are dependent on the occupancy-driven pharmacology, which means that the drug is only effective as long as it's occupying its binding site. With the inflammasome being activated and with the expected pharmacokinetic of the small molecule inhibitors, you can probably expect more on-and-off effect of this inhibition compared to preventing NEK7 from being assembled and having inflammasome constantly shut down. Yeah, that makes sense. Filip, if I can push on that a little bit. If that's the case, then why for some of these kind of next generation NLRP3s, like the BioAge drug, you see roughly comparable levels of CRP reduction to what you're seeing in your own phase I study? There is a quite important distinction. You have to use higher doses, I would say. I can put it a little bit in the context. When you look at some of these NLRP3 programs, and I don't think I need to go to any of them specifically because it's kind of applicable across the board, you typically see that these high effects on the CRP reductions are associated with the doses, which are pretty close to the maximum doses, which were determined in the dose ranging multiple ascending doses part of the study. That seems to be universally applicable across most of these programs, at least as I am aware. How we differentiate from that standpoint is that if you look at our program in multiple ascending doses, we test the doses between 5 mg and 200 mg, and the dose which we released the data for in January was 40 mg. It's actually 20% of our maximum dose, which was determined as safe in the multiple ascending dose. Clearly, for the effective inhibition, you can use much lower doses, and consequentially, if you use the higher doses, you potentially run a risk that certain adverse consequences, whether it's propensity to more off targets, might be something which potentially can be a liability. Got it. I actually think it's in line with this thesis. Yeah, that makes sense. As you think about this kind of pretty interesting catalyst path here with regards to the targets in this pathway, we recently saw a second IL-1 antibody with encouraging phase II data in HS. I think that the catalyst that investors are very focused on right now is the upcoming data from Novo in a study called ZEUS for ziltivekimab, their IL-6 antibody. Can you tell us about how you think about how you guys are seeing that readout, and the potential read-through to your program? First of all, we think that the targeting of the axis or the pathway to some extent is de-risked, at least from the efficacy perspective. There is a variety of data that modulating CRP does impact the future cardiovascular events, including the old and dirty drugs such as colchicine or even to some extent CANTOS. Again, we have to keep reminding everyone that CANTOS didn't fail on efficacy. CANTOS failed on safety or didn't meet the expectations on safety. That's why the drug doesn't have a label. What we expect from ZEUS as a good result is if the efficacy bar is met and there are not any concerns in other areas such as safety, so t hat would definitely help to further energize the field, which is already energized. At the same time, I have to admit that there is not a complete equivalency between our program and IL-6. Let's say some of the liabilities for potential safety, which can result from the complete inhibition or near complete inhibition of the IL-6, we actually shouldn't have because we just inhibit the NLRP3. There is not a complete equivalence. It is important to understand the distinctions, but definitely, I think the good result of ZEUS, which I just defined, would be good for the field for patients. Got it. Based on the level of validation that exists for IL-6 in ASCVD, would you expect success in that study? I would, yeah. I absolutely would. Again, the CRP is a very well-validated marker to the point that American College of Cardiology actually kind of issued a new updated guidance on the CRP. The relationship between the future cardiovascular events and the CRP level seems to be very well-defined. To many extents, actually, CRP seems to be a better predictor than even things which are well-documented, such as LDL. Yeah. It's kind of interesting that if your CRP is less than one, even if your LDL is elevated, it doesn't really matter that much. I actually think there is a lot of validation that if you do something to CRP, it matters, and IL-6 antibodies clearly reduce the CRP. Yeah, I think there were actually, even just in the last couple of weeks, some interesting publications on the relationship of CRP reduction and IL-6 reduction to MACE outcomes. Are you referring to those more recent studies, or what specifically kind of gives you confidence on that? I mentioned CRP, but as you pointed out, there are actually even data for IL-6 that reduction of the IL-6 itself reduces the future cardiac outcome. Again, on the efficacy front, I think as long as the drug is good, speaking of IL-6, and well-designed, the study should be successful. Again, when it comes to the long-term safety, that's something which we have to wait for ZEUS. Got it. Coming to your own data for G-FORCE-1, early in the year, you had data on CRP reduction for the 40 mg cohort. Can you set expectations for the data up that you have coming later this year, the dose ranging data set, and what investors should expect? Yes. I will start maybe first why we decided to expand the study, the proof of concept to study which we now call G-FORCE-1, which stands for that we added two additional dose levels with corresponding number of placebo. It will be total of four arms, three dose levels, and one against placebo. It's a 28 days administration, as I pointed out, in individuals with the high cardiovascular risk as defined by obesity and the high CRP level. What we've shown back in January is that 40 mg does have a profound and sustained reduction on CRP, which in fact from week one seems to be only strengthening back all the way to week four. That's also a little bit differentiating to a lot of comparable programs, which often see a drop in the CRP with a little bit of rebound. We were pretty pleased that we haven't seen that rebound. In fact, the evolution between the week one and week four showed the deepening of the CRP response with the highest reduction at week four, which was at 85%. That gives us a confidence that in this expanded study testing multiple doses, we can actually have a pretty good assessment of the dose relationship and the CRP relationship. That was really one of the main motivators as well because that can allow us to plan more efficiently the subsequent phase II study. In addition to that, we obviously hope that the CRP data will replicate, and we have a good understanding of the relationship between different doses. We haven't guided what these doses are, but the expectation is that the doses are lower than what we tested. Other thing which we will get out of it is in January, we released obviously everything is blinded, so it was just blinded safety. We expect in the next disclosure to include the unblinded safety plus in addition, some additional biomarker data such as IL-6, which we just spoke about, and others. Got it. Can you explain, you had 40 mgs as the dose that you disclosed. You're saying the extra two dose levels are both lower than that. Would you expect to see any dose response given that on target degradation, you're in the range of full degradation anyways? That's why you do the experiment to actually see how it plays out. In the MAD dose escalation we had, we achieved a target NEK7 degradation, between the lowest dose, which was 10 mg, and the highest dose, 200 mg, which was roughly similar. In other words, each dose actually achieved the target degradation. This is something which is not a bug, but feature of the molecular glue degraders because with the catalytic mechanism of action, when one molecule of the drug can actually degrade thousands and thousands of your target, you can actually achieve the target degradation across very wide spectrum of doses. Not necessarily. Obviously, we might potentially find a flaw for the CRP. That would be the good outcome as well. Really the whole point is that this will inform and helps to streamline the subsequent G-FORCE- 2.. Great. Let's talk about that in terms of your phase II. I think you guys have guided two phase II initiations in gout, in ASCVD, and in HS, as well. I think HS, the phase II trial design is maybe a little bit more straightforward, a little more precedented. For ASCVD and for gout, can you talk to us about what your phase II designs there might look like? I think the atherosclerosis phase II designs have been quite established as well over the last few years. These are typically studies which are also CRP studies, except for they are given for longer period of time to generate enough safety data to make people comfortable to move phase III. Our G-FORCE- 2 will be also a CRP study with the three months administration, with potential of the three months extension. Obviously that's longer than G-FORCE- 1 w hich is given for 28 days. It's also population which, in the cardiovascular or atherosclerotic risk, which you can probably expect how these patients would look like based on the prior experience. I think it also gives you a lot of opportunity to look at some other additional exploratory endpoints, which can be very informative for potential additional avenues of development, whether it's looking at the liver inflammation or liver fat or anemia or weight loss, A1C and all of these. I actually think that we will be in addition to a primary focus, such as the CRP reduction and safety to make this asset phase III-ready for atherosclerosis. I think we can generate actually a lot of valuable data which can potentially also provide additional data informative for additional avenues of development. Got it. Okay, gout? The gout is guided towards the Q4 or to Q1 of the next year. That's for the phase II, which would be considered as a proof of concept in the acute gout flare situation. We do expect in that study also actually produce some data in terms of the recurrent flare frequencies because it's planned to be given for prolonged period of time. Really the main endpoint is the acute gout as a proof of concept. What we like about gout, although there are often externally mixed reactions, some people are excited, some not, but we actually feel that it's a huge opportunity to innovate, especially when it comes to anti-inflammatory approaches, especially a huge opportunity for drugs which are not expected to have any kidney liability. A lot of gout patients, chronic gout patients, have underlying kidney insufficiency, which limits what therapies can be used currently. When it comes to anti-inflammatory agents, there is not really anything out there except for colchicine, which is similar to cardiology, heavily underutilized because it's a drug which is not fun to take, especially if you don't have problems at that given time. It's a kind of a tough sell to accept the certain problems which perhaps are not overwhelming, but can be perceived as a bothersome, such as diarrhea and stuff like that. We presume that there is a really huge opportunity to innovate. There has been quite a momentum with the urate-lowering therapy, and urate-lowering therapies are definitely useful. There are certain things which, again, limit their use. Definitely the uptake of urate-lowering therapies is lower than it should be. One part of it is that actually, paradoxically, especially from the short to intermediate perspective, the urate-lowering therapies can actually result in an increase of gout flares. Again, it can be a little bit off-putting for people to stay on them. We see that this is a really huge gap to innovate, and I think we are in an excellent position to do so. Great. Across these three phase II opportunities that you have with ASCVD, gout, and HS, which one is your favorite? Which child is your favorite, right? I think we like all of them. I think all are areas of critically unmet need. I haven't spoken much about HS, but the HS makes a lot of sense as well. It's a disease which is characterized by very high activity of NLRP3 inflammasome. In fact, if you look at inflammatory conditions, it's one of the conditions with the highest level of NLRP3 inflammasome. We set diagnosis we have been thinking about for quite some time, and definitely our conviction was strengthening as lutikizumab data were coming up a couple of years ago with recent further evidence from IL-1 beta antibody segment from Avalo. It obviously has some challenges, but I think these challenges are more and more understood. I think with the right selection of the size, the right training, the right KOL makes, I think, the certain challenges, such as unpredictable placebo, can be actually managed. Great. You've done a nice job partnering your VAV1 program. For NEK7, especially given the initial CRP data that you've shown and the potential to build on that later this year, you mentioned yourself that CRP data in some of these diseases is very validating for downstream clinical benefit, how do you see the kind of partnership potential for this asset? At the moment, we plan really to hold on to and do the next stage of development ourselves. The phase II, which is ahead of us, is very doable and to large extent, I would even argue that getting these programs to the finish line is doable as well, even for someone of our size. Definitely for HS and gout. When it comes to the atherosclerosis, people sometimes get a little bit skeptical because they see the efforts such as CANTOS or even ZEUS. One thing which we have to keep in mind that what makes CANTOS or ZEUS large is the effect size which you can expect, and also the time which it takes to have an event. That's what makes these studies long. There is evidence for several parameters, whether these are laboratory parameters or imaging parameters or biomarkers, which can suggest that you might identify the population in which that effect size and expected hazard ratio can be perhaps larger, and the time to the event can be shorter. That might reduce substantially the path to that indication and to that phase III indication. Maybe the path that you start with the more high-risk population, get your drug on the market, and then expand with the more broader populations subsequently might be actually the path if it's something which we do all the way to the finish line, avoiding doing such large efforts such as CANTOS or ZEUS. Filip, just to push on this, a lot of investors look at the situation and make the conclusion that as you look through the rest of the year, if ZEUS works in ASCVD, if the lutikizumab phase III works in HS, if you guys show consistent CRP reductions at a larger N size in your G-FORCE-1 readout, the strategic interest here will have to be overwhelming. That's what investors are saying. Do you think that's a fair way that investors are thinking about this? That's definitely fair. There is definitely a lot of interest. We are having a lot of discussions. The way we are thinking about it is that at the time, we would like to hang on to that and keep creating the value. Again, you are exactly right. The interest is significant. Got it. Let's shift gears. Let's talk about VAV1. We just have a few minutes left, but just to start on just high level on the target, can you just explain how VAV1 degradation is differentiated from other T and B cell targets, for example, like JAK inhibition or BTK inhibition? The degrading VAV1, and just going a little bit back to mechanism for people who might not necessarily be that familiar with that, because it's a target which hasn't been much on the radar since we haven't really had the drugs to target that. It was on the radar of pharma, but that's why Novartis went into such a lucrative deal. The VAV1 is crucial. It's a gap, which is crucial for mediating the signaling from the T-cell and B-cell receptor. By degrading the VAV1, you modulate related T-cell and B-cell signaling, especially for these T-cell, B-cell mediated disorders. It's also a therapy which appears to be quite safe. T he safety data which we had from the phase I, as well as preclinical data, was showing that this therapy is more immunomodulating rather than immunosuppressive. I think there is definitely potential for additional oral drug, which the JAKs are great, but they are not perfect. They have some liabilities or certain things which at least clinicians find off-putting. We definitely think that for the type of a drug with this type of a mechanism of action, there is actually a really broad spectrum of applicability across multiple autoimmune diseases driven either by T-cell or T-cell, B-cell biology. Okay, great. I understand the program is in Novartis' hands, so you guys might have some limitations in what you can say on it. At least from the Wall Street perspective, there's been a little bit of a gap from when the deal occurred to starting the phase II studies. Can you comment at all on e xpectations for when those phase II studies will start? It certainly feels that way, although on the other hand, when you look at the deals with the large pharma, it's often not unusual, especially when there is expected that the next wave of the clinical development is relatively substantial. At the moment, we are in constant communication with Novartis being included in the development team, so we obviously know where things are going. Novartis at this point decided strategically from understandable reasons that they wouldn't be that outspoken about it. Part of it is also to protect the IP and potentially not facilitating the competition. The guidance is the multiple phase IIs in this year and w e believe once this one is out, people will be quite excited about it. Got it. Any hints on indication selection? Again, that hasn't been released by Novartis. I think one thing which I can say that we socialized in our prior disclosures and public decks, multiple studies, especially the in vivo studies looking at several indications. These studies looked extremely promising, so that's something which people can potentially refer to as a potential development opportunities without not getting specific on what's really happening next this year. Great. Hopefully, I don't get you in trouble by pushing for an answer. Well, I think I didn't say anything which is not out there. On GSPT1, your prostate cancer program, just remind us what's the next catalyst there, and what would you need to see to support further development? In the next quarter, we are planning to initiate the phase II confirmation study. The previous step was that we tested MRT-2359 in kind of an early phase II in an unselected population of metastatic castration-resistant prostate cancers, and we've seen this pretty strong signal in AR mutant heavily pretreated patients. The study required RECIST measurable disease, so 27% of patients had liver mets, heavily pretreated selective population. These AR mutant setting, we've seen PSA responses in all five patients. Two of them had PSA 90. Latest disclosure was at ASCO GU. At the time, still two patients continued on therapy. We've seen two RECIST responses. That actually look like a pretty competitive data in that population comparing favorably to AR degraders or let's say, CYP11A1 novel inhibitor, which is in the development. We definitely felt that this is something which is worthwhile pursuing. The AR mutant thesis would be pretty suitable to biotech of our size to take it to the finish line. The next step for the phase II is really to confirm that signal. That will be focused only on AR mutant patients only. It will enroll up to 25 patients, assuming that the activity is maintained, or it doesn't have to be 100% PSA response rate, but the activity remains high. If this one is accomplished, we confirm the signal, the drug will actually proceed forward on the drug development trajectory, which how it exactly would look like would probably depend on the conversations with the regulators. Got it. Great. Then just one last question to wrap us up here. The nice thing about companies with degraders or glue approaches is that it's really a platform approach. You can continue to innovate and generate drugs off of that. Given that you have a couple of interesting programs in the inflammation side and an interesting program in the oncology side, when should we expect a new program disclosure from you? Are you more likely to lean more into oncology or into inflammation? There is a lot going on in the target discovery, definitely in the inflammation space. We do also, which I might mention, have the two partnerships, right? I mean, with the recent option deal with Novartis, which is I&I-focused, and also older deal with Roche, which is looking at oncology and neurology. There's a lot going on. Although we will be probably maybe a little bit less prone to disclose these targets early simply for the fact not to help competition to get into the space early. I think we are in the position that it kind of makes sense from the standpoint where the company is. Got it. Well, I think that's all we have time for. Thank you so much, Filip, for joining us today.