Hey, great. Good morning, everyone, and thanks for joining us for our third annual virtual I&I forum here at CFOL. I'm Alex Thompson, Biotech Analyst. Happy to have Markus Warmuth, CEO and President of Monte Rosa Therapeutics, kicking things off this morning. I'm going to kick it over to Markus to give a quick overview of Monte Rosa and then maybe a brief update on the new Novartis deal that they announced this morning and what it means for the company, then we'll get into a Q&A. Markus, thanks for joining us and over to you. Yeah, sounds great. Thanks, Alex, for the intro and, of course, thanks for your invite to this very exciting conference. Maybe just a few brief words on Monte Rosa Therapeutics. I'm still a very young company. I'm about six, seven years old now, active in the field of targeted protein degradation and in that space with a particular focus on molecular glue degraders. Over the years, I've built a terrific platform. We named it Queen, mostly after the actual rock band Queen, because it's so awesome. We have learned through this platform how to program our molecular glue degraders to just exquisite selectivity and into a target space that's fairly unprecedented. All things combined, of course, have used that engine to now create a portfolio of assets, with three of them in the clinic with a focus on I&I, but I'm certainly not exclusively I&I. We also have oncology programs, and I'm sure we might find a second to touch on at the end as well. Big news this morning. We've actually entered into another collaboration with Novartis. Some of you might know that we signed a deal with them last year around our lead asset in the I&I space, MRT-6160, which is a degrader of a signaling protein downstream of both T-cell and B-cell receptors, VEF1. I think this extension probably reflects the mutual respect we have grown for each other in our capabilities. Very excited to now sort of work on the next round of programs with our partner there. I guess maybe another high-level question here. With some of these large markets in I&I, one of the challenges for a biotech like yourself is always how to balance standalone as a company versus partnerships to sort of expand the platform, expand the indications that you can go after. How do you think about that as it, like, what it means for Monte Rosa Therapeutics as a standalone biotech company? I mean, it's certainly the thinking that sort of first led us to partner with Novartis, which we believe has massive potential across a variety of different autoimmune diseases, pretty much anything that's validated to be TH17-driven. Huge markets, big drives that are necessary. The part of our undisclosed preclinical portfolio that's become part of this new deal obviously falls into a similar bucket where we're certainly also working on targets, and Next7 is a disclosed target we're super excited about, where we believe we're much better set up as a small company to develop ourselves. I really believe that, you know, knowing whom to develop with as early as possible helps, right? I'm sure there's a lot, even in a collaboration with a big company, that needs to happen. Without losing time, obviously, the earlier you can partner, the better. Yeah, makes sense. Maybe before we get into specific programs, I wanted to kind of touch on sort of a nuanced description here about how you think about a molecular glue degrader versus sort of the historical small molecule degrader classes like the PROTACs, et cetera. What are the key similarities and differences and the pros and cons? Yeah, you know, it's relatively simple, right? It's interesting because, you know, many times PROTACs are being referred to as sort of the older class. Actually, the ugly truth is molecular glue degraders were out there before PROTACs and some of the early insights into glues were used to actually create the PROTAC concept because it was thought doing glues based on rational design would just be like impossible. What's the difference? Molecular glues actually bind to a ubiquitin ligase, like the cell intrinsic protein destruction complex or like the proteins that initiate protein destruction. They reshape the surface of a ligase and then basically make it a perfect match for a protein-protein interaction. It's really induced protein-protein interaction. PROTACs are slightly different. These are heterobifunctional molecules. One end binds to a ligase, the other end actually binds into a druggable pocket of a target of interest, and then you just put a chemical linker in between. The big limitation, of course, of PROTACs being you always will have to find some pocket on the target you're trying to get rid of. That's different from molecular glues because, again, that's induction of a protein-protein interaction, so no pockets required there. Okay, let's dig into the programs, maybe starting with VEF1. Maybe let's lay out why this is an exciting target and maybe why this has historically been such a challenging target to drug. Yeah, super interesting target and certainly been around for probably in the order of 20 years as an I&I target. Maybe not sort of the most well-known one simply because, sure, it is, in a sort of classical sense, not druggable. It has a catalytic domain, but not really a good pocket to attack. It wasn't necessarily like high on sort of the radar in the investor world, but as we started to work on it and were able to find our first degraders, we realized quickly that this is something that big pharma strategics had thought about for many, many years. It's a target that's actually downstream of both the T-cell and B-cell receptor. We do believe the major role here is actually downstream of the T-cell receptor. Really, in a space where we know this is where autoimmune diseases start, it's activated autoimmune T-cells essentially driving disease. Lots of validation from the early 2000s in knockout mice suggesting that these are viable, actually healthy, but completely protected from autoimmune diseases. Really, the data, the level of validation that we typically want to see for a target to start investing in it. I guess maybe to pull that thread a little bit more, obviously with the degradation space, the question usually is, what's your therapeutic index? How comfortable are you with fully degrading that? You mentioned knockout mice. What else do we know about the safety of fully inhibiting VEF1 or knocking it out? Yeah, I mean, knockout mice, of course. Certainly, what we have learned so far from our own program, right, we're obviously past the IND-enabling tox studies. The results were quite remarkable, as a fact at the highest dose used in our GLP tox study, which was hundreds of fold above the therapeutic dose. We didn't see any toxicities. I many times get the question in conversations, what was the DLT? I mean, your preclinical tox studies, and it's just like I didn't find anything, right? I mean, it's like one of the cleanest tox reports I have seen in my entire career. No hints there. It's interesting because sure, it is an immune signaling, but it does not seem to cause severe immune suppression. We're not seeing depletion of immune cells. We believe VEF1 is particularly important where T-cells become hyperactivated. Sure, that is in a way in autoimmune disease, right, where you have sort of chronic T-cell receptor signaling hyperactivation of the pathway. Long story short, between the preclinical package and then what we have seen in our Head Cell Volunteer Trial at this point, there's no tox concern whatsoever. What do you think are the most important preclinical validation models for you here? There's obviously a handful of TH17 or T-cell models out there. Yeah, I mean, a couple of models that we obviously like and results that we got excited about. The EAE model, as much as you can debate whether that is a multiple sclerosis model or not, is certainly very well validated to be T-cell and in particular TH17-driven. We had preclinical data on a rheumatoid arthritis model. We had a T-cell transfer model as well for IBD. There are actually more models that we have run since that we're planning to publish soon. The common theme always was T-cell and TH17-driven. Many times we weren't just looking at the actual efficacy in a preventative and a therapeutic mode, but of course also into sort of gene expression changes and some impressive results that we have shown in posters and talks and also in our corporate deck around modulating TH17 signatures in many of these disease models as well. You're in a phase one. Based on the phase one data, how confident are you in the ability to select a phase two dose or doses moving forward? I mean, very, very confident. Obviously, great results there, as I mentioned. First of all, no safety concerns, which we always tend to forget that that's what a phase one study typically is about, trying to determine safety. Then, of course, look at biomarkers as much as you can. We've actually seen pretty much complete degradation of VEF1 across several dose levels, which gives us a wide therapeutic index. Of course, plenty of different dose levels and regimens to eventually pick from. That's ongoing work with our colleagues at Novartis, of course. What are the next steps here moving into phase two and sort of how does this Novartis partnership functionally work? It's been a great partnership, right? I mean, part of it is the proximity. I mean, our Swiss office is actually on the former Novartis campus. We're literally a five-minute walk away from each other. We meet very regularly at all levels. The next steps, obviously, to initiate phase two, are the typical steps that you need to take, right? Like you need enough material, you need protocols and get them cleared by the FDA. Of course, also the longer tox studies done, depending on how long you would like to treat patients in your phase two. Obviously, the longer you can treat, the better, even for competitive reasons and being able to enroll quickly. Do you anticipate that indications will be disclosed, or is this going to be more, you know, TBD from Novartis' disclosure perspective? Yeah, I mean, they will certainly be disclosed. We obviously all post our trials at some point on clinicaltrials.gov. I can't give you an exact timeline because we agreed to keep that confidential, but certainly when these trials initiate, the information will be out there. For now, all I can say is sure it's a very broad, aggressive development program. We obviously see it as the plans develop across in sort of line with what we talked about before, large, super high-value indications. Yeah, makes sense. Maybe pivoting to Next7, I guess it'd be helpful to put Next7 into context within the broader NLRP3 or IL-1 pathway set, because I think a lot more investors are familiar with those targets than Next7. How is this differentiated among those targets? Yeah, I mean, let me first start with the pathway overall, right? I kind of like to say this is probably one of the most underappreciated pathways in I&I right now, despite the fact that there's such great proof of concept out there from the biologics like Canakinumab and the like. NLRP3 inflammasome drives obviously secretion of IL-1 alpha, beta, and IL-18, and then triggers a cascade of IL-6 and eventually CRP secretion. There's more, of course, like immune cell activation. Next7 actually sits at the very top of that cascade. It's actually necessary to assemble the NLRP3 inflammasome. It was shown in mouse knockout studies that if you do not have Next7, the inflammasome isn't even there assembled and active, which we believe is a huge advantage when you can degrade Next7 versus having an inhibitor, right? Where you might have sort of based on peak and trough levels on and off pharmacology here, and we've shown this in cynos, once Next7 is gone, the pathway is just silent and shut down. We think still that that is very well tolerated without some of the infection risk that came with Canakinumab and the likes. These antibodies take out IL-1 beta or alpha, depending on whether they're sort of monospecific or can target both. They're taking out IL-1 from all sorts of sources, and the NLRP3 inflammasome is not the only pathway that's activating those. I'm really a target that we are super excited about and now moving forward through this phase one study as well. I think the other question for this pathway in particular is just indication selection. How did you come to indication selection choice, and where do you see moving on from here? Yeah, I mean, in a way, two buckets, right? One, sure, as I mentioned, biologics have been out there. Canakinumab, Rilonacept, obviously in pericarditis. Some development molecules are also now showing some promise, and you can learn from there. Certainly, Canakinumab showing activity in gout, actually in ASCVD as well, which was too high of an infection risk to get approved there. You can lean on that, but then sure, there's certainly also some of the internal learnings. We really think that this pathway is particularly important where metabolites or crystals of metabolites drive activation of the pathway. This would be MSU, for example, in gout, oxidated phospholipids, cholesterol crystals in ASCVD, NASH, and the likes. Then it's unfolded proteins. This would probably be then more for central, but certainly some interesting learnings there internally that have helped sort of shape our plans for how to move forward after this phase one study. For the part three study in particular, these CKD patients, like what does good look like, and how does that then inform where you go next? Yeah, I mean, you know, you can simply look at some of the benchmarks. Some of it is sort of apples to oranges, right? Canakinumab, as I said, showed promise, just had too high of a lethal infection rate. Yeah, got to around 60% inhibition of CRP. That is certainly something that on chronic administration of 81 or 82, we would at the very least like to meet, if not exceed. You look at some of the IL-6 biologics now out there, they can get to 85%, 90% after longer treatment. That is a little bit deceiving because it's kind of the last step in the cascade, of course. Sure enough, close to CRP, but there's other things in between that, of course, IL-6 agents won't be able to take care of, right? They're certainly not necessarily feeding back into inhibiting the actual inflammation. Bottom line is sort of 60% plus is our base case. Of course, if we get to the 80% plus level, even more exciting. You also have an earlier stage CNS-penetrant program. Where do you envision this going in the future? Yeah, as I said, a lot of good evidence also in CNS diseases for misfolded proteins to drive pathway activation. Also, now a body of evidence around obesity and sort of inflammation in the brain, sort of driving obesity. I don't necessarily think there's absolute certainty around it yet, but certainly between those two hypotheses and having large chemical space available for us to work in, we were inspired to sort of work on that second round molecule as well. I guess if the NLRP3 is working in obesity, is there any reason why Next7 shouldn't work? I would say absolutely no reason, right? As a fact, we're assuming that because of the steady pathway inhibition without sort of daily rebounds, as you approach trough levels, the efficacy should be even better. Okay. Maybe what's next on the I&I side? It seems like you're thinking about larger indications like VEF1, partners, Next7, sort of these smaller indications with standalone. Is that kind of the blueprint for Monte Rosa Therapeutics moving forward? Yeah, I mean, it's certainly a model that we like, right? I think there's just markets that will be super hard to penetrate. We've talked about it at the beginning for a small company, especially when big pharmas have existing franchises there. There are areas that I think are quite manageable, and that's how we like to split up the work. Again, view this partnership as Queen is extremely productive, and why not leverage that in other ways? Not just to generate more dollars, but literally to bring additional medicines to patients in the future. You obviously also have an oncology portfolio. How are you thinking about resource allocation between I&I and oncology, and how does that play out moving forward? Yeah, I mean, honestly, there's not a defined way we want to spend X% in onc and X% in I&I. I think if you just look at the sheer potential, clearly VEF1 and Next7 is something we're very focused on right now, but we also do think that opportunities exist in oncology, and why not pursue them? I think in general, we look at Queen as an engine that can go across multiple disease areas. We're starting to look into cardiovascular more. Next7 in many ways is already at this intersection anyway, right, between inflammation and cardiovascular, potentially even metabolic indications. Really a lot to do with the science and the engines that we have built. What are the next major inflection points for oncology for you internally? Yeah, we have additional data coming up for our GSPT1 molecular glue degrader, MRT-2359. We had actually put some data out there, just three patients, so small data set earlier this year in March. We were in prostate cancer across three patients. We had seen a PR and two stable diseases. Remarkably, those patients actually either had an ARV7 transcript positive readout or a mutation in the androgen receptor ligand binding domain. All alterations that typically lead to resistance to anti-androgens. I think in that context, certainly encouraging, we're expanding that cohort. We're actually able per protocol to expand that to 20 to 30 patients, and the goal is to put some of that data out by the end of the year. Certainly something we continue to be very excited about. Our protocol actually requires all patients to have scans, so we'll have RECIST data on every single patient that's going into the trial. Do you see this as a program that you move forward on your own, or is this an opportunity to potentially do some more partnership work? Honestly, it's not too dissimilar from our thinking in I&I, right? I think to look at the totality of the data and then see, okay, this is a small sort of more orphan subsection of prostate cancer, or again, could this be larger in combinations? There certainly would be advantages to use the capabilities of a large pharma company. For now, that's how we continue. Okay. I guess you also have a Roche partnership. Can you sort of touch on what that looks like and what indications you're looking at there potentially? In a way, different from our newest Novartis partnership in a sense that that was a true discovery deal. Targets being nominated by Roche as our partner, and then we screen or find other ways to find initial hits to a target. Obviously, targets haven't been disclosed. The partnership is between oncology and actually neuroscience. Again, something we liked because that helps us to better also understand that neuroscience field if we ever wanted to go there ourselves as well. Great. I guess maybe final question. You obviously got $120 million upfront with this Novartis deal. You're not providing new cash runway guidance yet, but where are you in terms of pro forma cash, including your 2Q report now? What did you have in 2Q? Yeah, it was just below $300 million in cash. Our runway guidance was into 2028. Okay. I think a good way to look at today's deal is certainly going to extend our cash runway, but of course also allows us to pursue some of the things we were doing more aggressively. Great. Markus, appreciate you taking the time. Thanks for joining us. Sounds great. Awesome. Good. Yeah, thanks, Alex. Yep.