Hi, welcome to the next session of TD Cowen's Immunology and Inflammation Summit. We're really happy to have joining from Monte Rosa, Filip Janku, their CMO, where we will discuss a couple of different programs of theirs that fit in the I&I bucket, both the NEK7 degrader as well as a VAV1 degrader. We'll probably diverge a little bit from the INI topic at the last few minutes to also quickly discuss their GSPT1 degrader that has an oncology update in the next couple of weeks, just because that will be kind of the next catalyst. Maybe to start off with, Filip, do you want to just kind of give us a high-level kind of status update overview of the company for people who may be a little bit less familiar with the story? Thank you, Mark, and thanks for having me. Monte Rosa Therapeutics is a biotech which is focused on the development of molecular glue degraders. That is within the protein degradation space modality, which is actually quite attractive because it opens up a significant proportion of the targets which otherwise would be considered undruggable because the mechanism of action of molecular glues does not require to have a binding site as you would need for either small molecule inhibitors or even if you stay in the protein degradation space, for PROTACs. We are based in Boston and Basel, and our main focus is inflammation and immunity. We also have some presence in oncology, as actually Mark just pointed out. We have three clinical programs, MRT-6160, which is the first in class and I believe the only- in- class degrader of guanine nucleotide exchange factor VAV1, which is otherwise a regulator of T- cell and B- cell signaling. That has been licensed to Novartis last year and is actually expected to go to Phase II. We have NEK7 degrader, MRT-8102, and that's been in the clinic as well. That's focusing on inflammation and targeting of inflammation, inflammasome, and IL-1 signaling. Last but not least, we have in the clinic MRT-2359, which is a molecular glue degrader of GSPT-1, which is currently being tested in prostate cancer in combination with enzalutamide. Okay. I and my team have come up with a whole list of specific questions that we'll get into in a second here with Filip. We do want it to be interactive to the extent possible. I would remind the investors on the line, please do submit questions via the online portal, or you can email me directly, and I will add those into the list as well. Maybe with that, we'll start with the wholly- owned asset, MRT-8102, the NEK7. I think this is a target that maybe investors aren't very familiar with because there haven't been a number of programs against this before. You can just start out, why is it an interesting target? In particular, why does it need to be degraded, not a traditional approach to drugging it? That's a good question, Mark, because NEK7, as you might know, is actually a kinase. Its function in inflammation and in the activated NLRP3 inflammasome is actually structural or allosteric, if you will. NEK7 is a necessary component of the NLRP3 inflammasome assembly. In other words, if you degrade or deprive the cell of NEK7, then the NLRP3 inflammasome cannot be assembled. This is also what is behind the major differentiation from other strategies in the field, such as NLRP3 inhibitors, that by degrading NEK7, you are essentially preventing inflammasome to be assembled while the inflammasome inhibitors, the NLRP3 inhibitors, they essentially inhibit the inflammasome which is already firing, which is already activated and firing. Okay. I guess what would the theoretical risk be of degrading NEK7, either that blocks some of its kinase activities, but also blocks that scaffolding function in the assembly of the NLRP3? Is there a way that too much inhibition could be a bad thing? We haven't really found out any risk in our studies, including the toxicology studies. There is obviously more NEK kinases. I mean, NEK7 implies that there is more NEKs. So there is over 10, I believe, of different NEK proteins. And some of them may actually play roles in other processes, such as mitosis. Even though there have been some suggestions from some older publication that it might be the case for NEK7, we actually didn't confirm that. We certainly don't see that. We see from the safety perspective that degrading NEK7, actually, as far as we know, has very low liabilities. I mean, but typically when you go after a new target, you often get these questions, right? I mean, what are the risks? What potentially can happen? We actually did something which perhaps is not done that often, but I mean, as a part of our corporate presentation for the last number of months, we actually do include the data from or the summary of the data from the GLP studies in the relevant species, such as Cinos and rats as well, in which actually we in both, we determined that we essentially had no relevant findings up to the highest doses. The highest doses were more than 200 above potential equivalent human exposure. At least based on this data, the molecule actually seems to be very low- risk. Obviously, it's a GLP study allowing the Phase I. It's a 28-day study. The longer toxicology studies are happening as we speak. So far in the clinic, we haven't disclosed anything. The disclosure is planned for the first half of the next year. I think I can say that we are actually quite pleased with the progress of the program. Okay. Before we get fully into the Phase I, just, I mean, you mentioned that there are other kind of NEK family members. Were those the hardest things to design the molecule to not inhibit? Or are there other kind of related kinases that maybe were more difficult, particularly when you think about preventing off-target toxicities? I mean, like when you have a molecular glue degrader, I think one of the advantages is that the interaction with your target protein to be degraded is through the protein-to-protein interaction. You actually do not really utilize any binding site, which usually might have a liability that it can be conserved across the entire family, across the entire family of the proteins, which we quite often see. From that standpoint, you have advantage when it comes to selectivity. For many people, it sounds a little bit contraintuitive because glues are actually often seen as not that selective. Some of that actually is really just based because of the history and how these modalities evolved, right? The first clinically used glues were IMiDs, whether it was thalidomide, subsequently lenalidomide. Even when lenalidomide, which is relatively not at all drug, I mean, got approved for multiple myeloma, the mechanism of action hasn't been actually really elucidated. These medicines have never really been designed with the understanding of mechanism of action. Therefore, the selectivity wasn't necessarily front- and- center. If you look at, and again, we disclose that information publicly, if you actually look at our proteomic experiments, when the cells are actually exposed to high concentrations of 8102, and you look at what's the impact on the expression of the different proteins, you essentially see that on this TMT proteomic experiment, the only thing which comes down as degraded, hence reduced in expression, is actually the NEK7 itself. You are not touching any other proteins in the NEK family. Okay. In the preclinical data, you mentioned this kind of difference between NEK7 mechanistically versus an NLRP3 inhibitor. I guess preclinically, how does that manifest in terms of true efficacy in animal models, but also maybe are there key kind of PD markers that we should also be thinking about tracking that would also translate into a human and show that differentiation early on? We actually, in our preclinical experiments, which we disclosed, benchmarked the data to sel noflast in many experiments when we look at actually the release of the relevant cytokines so that the information is actually available. We do fare well. Even more importantly is when you actually come to the treatment scenarios when you dose your inhibitor to humans. I mean, with inhibitors, you always have it's a different pharmacology, right? I mean, it's an occupancy-driven pharmacology. Essentially, the effect is happening for as long as that binding site is occupied by your small molecule inhibitor. This is one thing which often leads to the discussions: who has more prolonged mechanism of action, who is longer above certain concentration, which actually can result in efficacy. At the same time, the NLRP3 inflammasome is already firing, right? Whenever your concentration goes below what is effective, you might actually have the episodes when the coverage is not ideal. You're not going to really face that with the glue at all. That is for a variety of reasons. One of them is the inflammasome doesn't get assembled. The second is also the mechanism of action itself, how the glues work. They have a catalytic mechanism of action. Actually, the one molecule of 8102 can probably degrade thousands and thousands of NEK7 molecules of the NEK7 protein. That effect actually continues for whatever is the duration of the compound in the system. Even when the compound is actually out of your system, still the NEK7 doesn't come back instantly. It actually takes several days for the NEK7 to come back. You actually have a far more controlled and sustained inhibition without this kind of potential on-and-off liabilities, which you might be more likely to face with the inhibitors. Okay. Is there a PD marker that we should be thinking about that really shows that increase, maybe a bit more depth, but also that kind of durability and reliability of that inhibition? There is. I mean, I wouldn't mention one, but I can mention quite a few of them. Actually, many of them are implemented in our Phase I program. One thing for any degrader, I mean, you would look at whether you are degrading what you are supposed to degrade. We are obviously looking at the NEK7 degradation in our healthy volunteer study. When it comes to the markers which are more kind of maybe linked to the mechanism of action, I think the CRP is actually a pretty good marker. You can obviously do it without any manipulation. There is no need for any ex vivo stimulation or anything like that. It's actually a relatively simple lab test. Also, which is a good thing, that for NLRP3 IL-1 axis, there has been the expected effect on CRP has been kind of established in studies which already validated at least the efficacy of IL-1 NLRP3 targeting in different scenarios. I mean, what I mean by that, I mean, if you look at, let's say, canakinumab and the CANTOS study, the Cantos study did not result in registration of canakinumab for prevention of major cardiovascular events, but it actually was not because of the lack of efficacy, it was because the safety margin was not met. There were just too many serious infections to FDA liking to approve it. For the safety, the canakinumab actually met its endpoint in that study. The CRP reduction in kind of an intent- to- treat analysis was about 60%. If you look at the recent data from Ventyx, which was just released a couple of weeks ago, which was a 12-week study in obese subjects in cardiovascular risk and elevated CRP, the cardiovascular risk was defined by the obesity. The effect on CRP was actually quite similar in the intent- to- treat analysis. I mean, when they did some modified analysis, which excluded some patients which had suboptimal or not detectable PKs, I mean, then the CRP effect was a little bit higher. Again, it's been quite established what you can see. I think it's a good marker, which kind of sets the benchmark. You can also look at the cytokines, whether it's an IL-1, whether it's an IL-1, probably IL-1 beta, IL-18, IL-6. The downside with cytokines in healthy volunteer study is that you need to use ex vivo stimulation for that. It's somewhat a little bit more artificial experiment because the cytokine levels are too low in the healthy subjects. Yeah. Yeah. Yeah. When you look at the CRP, do you think is there an ability with this to show that it is more effective on that PD marker? Or is it really, particularly when you're not in very disease-heavy patients and things, you're going to have threshold effects? It's just really the goal is just to match those ones for now and then show clinical endpoints in larger and longer studies. It's always tricky when you do cross-study comparisons. The studies are always a little bit different, right? I mean, canakinumab was obviously the CANTOS was a long-term Phase III study. Ventyx, which I mentioned, was a 12-week Phase II study. We are doing the Phase I at the moment. I mean, you have kind of a benchmark when you need to be. If you are at that benchmark or better, I actually think at the stage where we are, that means that you are in a good spot. Okay. Okay. You have kind of touched on the Phase I trial design in a couple of different comments, but do you want to just kind of put that all together and just walk through what the design of the Phase I is and the latest on kind of where you are progressing through the different parts? The Phase I study, it consists of three parts. There is a classical SAD and MAD, which there is nothing really out of proportion in that. I mean, it's a fairly standard SAD/M AD. Again, all the relevant PD endpoints are incorporated in that, including the CRP, although keeping in mind that often the healthy volunteers actually have pretty low levels of CRP. Then there is a Part 3, which is focusing on treatment of patients in cardiovascular risk, again, defined by the obesity. There are some similarities with some studies which I mentioned from our peers and elevated CRP. That's all one package. It's all done under one protocol. The guidance that we will share the data in the first half of next year is actually intended that it will include the entire Phase I package, so SAD, MAD, plus the CRP study. The study is actually progressing really well. I think we press released the initiation in July of this year, and it is moving really well. Okay. Next up, we'll presume we would hopefully be that there's successful data and therefore Phase II. What does that Phase II program look like? Is it likely because you mentioned that there's a lot of different areas you could take a NEK7 inhibitor over time in terms of different autoimmune diseases or inflammatory diseases. Do you run just one proof- of- concept trial, find a dose, and then worry about expanding into additional areas? Are you planning to run multiple in parallel? Just what's the approach there? I mean, as you pointed out, Mark, there is definitely kind of a broad spectrum of indication where you can potentially go. I mean, we went through quite a lot of the diligence process and narrowed it down to maybe the four indications, which we see as kind of our favorite. These are indications which I'm not necessarily saying they're all of them, but probably the combination of them we will be exploring in the Phase II once we release the plans for the next step. That includes a large kind of disease indication such as ASCVD or MASH. I mean, the MASH, there is quite a building evidence that targeting the NLRP3 inflammasome can actually be a relevant approach for MASH. ASCVD MASH would be the large- ticket indication. The smaller indications, but again, very scalable and potentially very scalable from the perspective being taken even to the finish line by someone like us with our resources, would be pericarditis and prevention of the pericarditis flares and the prevention of the gout flares. The gout sometimes has a little bit of mixed reaction. I mean, some of it is probably negativity is probably driven that there have not been successes, but I think the success at some point will happen. It is a disease which has 10 million people in the U.S. I mean, half of them have recurrent gouts. Still, a significant proportion of them actually has to be managed by rheumatologists because they have three or more flares per year. That is certainly a population of unmet need. Even though there has been some advances with the urate-lowering therapies, I mean, they do not necessarily help to reduce the flares, not at least from the short-term point of view. These are kind of four areas we are pretty excited about. Do you think there's one likely to be kind of one optimal dose that's used across all of those? Or are those diseases in the biology so different in the different diseases that there's a good chance you're going to end up with different doses for different diseases? I think there will definitely need to be a dose exploration for them because I wouldn't be surprised if there are different doses. I actually think even from kind of a strategic development that actually might be even things which will be even helpful from the development standpoint. I mean, if you look at it just from the inflammation levels, the inflammation levels in pericarditis are different than inflammation level in gout or than inflammation level in ASCVD or MASH. Kind of moving roughly from the highest levels of inflammation to the lowest. My expectation would be that those explorations would need to happen separately for each of these trials, which quite frankly is not really that much a problem and likely would be required by the regulatory agencies anyway to do it as a part of the Phase II. Okay. I know we're running up on time, but since it is the next callus and it's a couple of weeks away, do you want to kind of just on the oncology side, we're going to see some data in prostate cancer, but mostly prostate cancer shortly for 2359. Just frame up kind of how people should think about patient numbers, the follow-up, and what's really the kind of relevant success criteria given the patient population that you were actually enrolling. When we had a previous release, I mean, we just included super- early data on three subjects with prostate cancer, which included two stable diseases, one PR combined with the PSA9 response. They were all in patients with AR alterations, which included AR ligand-binding domain mutation or AR-V7. This was a heavily pretreated population with prior chemotherapy and Pluvicto. That obviously was super- early, but quite encouraging. I think we are guiding and planning that there are not that many weeks left in the year, but I mean, that there will be between 20 and 30 patients as the current guidance with the guidance on what are the next steps. The study is actually enrolling well. We are trying to make sure that that cohort represents different kind of scenarios of castration-resistant metastatic prostate cancer because the expected efficacy somewhat differs based on what population you have, whether it's a population which is more naive, perhaps with prior abiraterone but not prior enzalutamide, versus a population which is heavily pretreated, maybe had chemo, Pluvicto, or the patient with ligand-binding domain mutation. We try to kind of balance the enrollments so that we have a reasonable representation of all of these potential subsets that we can actually determine based on the observed efficacy on the next steps and guide towards that. Okay. In terms of response rates, for that, maybe at one end of the extreme, that heavily pretreated has seen Pluvicto, has seen chemotherapy, what would you view as interesting data? Maybe at the other end of the spectrum where there is much less AR experience, even let alone chemo. It's not that super straightforward, but I mean, I can give some guidance, right? I mean, for abiraterone pretreated, enzalutamide, or similar naive, we have data from Mever-Metastat from Pfizer. So that kind of gives you the guidance, what you need to see in that population in terms of resistant PSA response rate. For, let's say, LBD population, Ligand-Binding Domain population, there are data from AR degraders or CYP11A1 inhibitors. So that gives you that. Essentially, any good signal after Pluvicto in general, regardless of everything else what I said, is probably a good thing. Okay. Okay. That, unfortunately, we're going to have to cut it off. We could keep talking for a while, I'm sure, but we will have to stop it here. Thanks a lot, Filip, for joining, as well as the investors on the line. Thank you so much. I appreciate you. Thanks. Thanks.