All right, everyone, I think we'll get ready here for our next fireside. My name's Derek Archila. I'm one of the biotech analysts here at Wells. Very excited to have Monte Rosa Therapeutics. From the company, we have Markus Warmuth. That's about correct. That's all right. Very close. CEO Markus, thanks so much for joining us. For sure. Yeah, thanks for inviting us. Excellent. Well, maybe just to start off, maybe give a high level overview of what you guys are working on at Monte Rosa. We can dig into the questions after. Yeah, no, happy to. Just sort of high level, company's active in the space of targeted protein degradation. We like to just destroy, take out proteins. We're not inhibiting them. Within that field, we're sort of singularly focused on what's called molecular glue degraders, as opposed to heterobifunctional molecules. How do these work? These are small molecules that bind to the protein destruction complex, or a protein in that complex known as ubiquitin ligase. Reshapes the surface, and then eventually creates affinity for a protein we want to take out. We've applied this now across several dozens of proteins. Obviously, not all of that work is in public domain. Have built a clinical portfolio by now with three assets in the clinic, and actually more to come over the next 12 months or so. Excellent. So maybe let's talk about the lead program, MRT-8102. NEK7 program. I guess, why do you like NEK7 as a target, and what utility does it have across broad I&I indications? Yeah. NEK7 is a protein involved in the NLRP3 inflammasome, so we are in inflammation. Lots of evidence out there that that inflammasome is involved in sterile inflammation mostly, so it is not so much host defense, really sterile inflammation in the human body, across a spectrum of diseases. I am sure we will talk about some of them, like the ones we are focused on for our indications. NEK7 in that complex actually is a scaffolding protein, so we have learned over time that when you take out NEK7, that inflammasome cannot even assemble. Which is really cool because, sure, there are companies that are working on inflammasome NLRP3 inhibitors, like NLRP3 inflammasome inhibitors. That is inhibiting the fully assembled inflammasome. We obviously take the scaffold away, so basically no risk of that inflammasome to become active at any time during the day. Got it. I guess you guys are working on developing NEK7 in cardiovascular inflammation. That is kind of the lead indication. We saw some results from the ZEUS trial. I think this is a different target, IL-6, but also kind of trying to target that inflammation cascade. It failed. I guess, what are the key learnings from that trial, and how do you kind of expect to apply this to your program in the future development there? Yeah, no. Great. How much time do I have? All the time. I'm ready. Just kidding. Maybe let's start, like why ASCVD for that asset? The amount of literature, the amount of evidence connecting the NLRP3 inflammasome with ASCVD is overwhelming. That goes from preclinical data to human genetics, to clinical evidence that by interfering in this pathway, you can actually change the outcome of ASCVD cardiovascular disease, more or less in general. That's really the data that convinced us that this is where we should go. Also, really cool, right? It looks like an ASCVD, that is the pathway, right? You don't have three, four different immune pathways all playing together. Atherosclerotic plaques, they're essentially driven by activation of the NLRP3 inflammasome, that's why we believe MRT-8102 will work there. Then comes ZEUS, of course it hits on a Friday, I think we were all like, "Oof". Eric was on vacation. Here goes our weekend or vacation. Like, how could this happen? If you think about the pathway, for years and years we've been oversimplifying it, right? We've been saying, okay, there's lipids, they oxidize, they go into vessel walls, start to build plaques, by activating the NLRP3 inflammasome, which then spits out IL-1 beta, which then leads to secretion of IL-6 from immune cells, which then leads to secretion of CRP and a bunch of other things from the liver. Very oversimplified, because what I think everyone keeps forgetting is at the level of an atherosclerotic plaque, it's not just IL-1 beta. There's IL-1 alpha, there's IL-18, there's proteins called DAMPs, things like HMGB1, calprotectin, Calgranulin C. All of these are probably more important to change vessel walls and keep driving that inflammation in plaques and induce thrombosis on top of it. All of these are super important. Most of all, they're not impacted by taking out IL-6. I think at the end of the day, IL-6 was probably just not the right target to pick. It's very far downstream. It's essentially, in a way, the second messenger between the atherosclerotic plaque and whatever you induce for an acute phase response in the liver. Got it. I guess for some of the things that you just mentioned in terms of the DAMPs and the calprotectin- is this something that you could measure in your current trials and get an understanding if that could have a potential impact in these patients? Yeah, no, absolutely. Not all of them, but many you can measure. Some of them do actually like to stay very local resident in the plaques and the vessel wall. But calprotectin, calgranulin, relatively easy to measure. They do go into plasma. HMGB1 typically is. I will point out, though, that our population in GFORCE-1 isn't ASCVD. It's patients that are obese and at risk of developing ASCVD over time. Some might already have it and not know, but it's not a population that was diagnosed with ASCVD. I'm saying it just to ensure not every of these biomarkers will already be up to a point where you can then measure its inhibition. But I would say for the vast majority, we have data available by the time we roll out GFORCE-1. Got it. What does this say about CRP at this point in terms of a biomarker, given that Yep that's what was really potentially the stratifying factor in ZEUS? Yeah, again, super interesting sort of looking at this sort of after the fact, right? I think there was a confusion in particular after Novartis' trial with their IL-1 beta antibody canakinumab, known as the CANTOS trial, where the big finding in the analysis was that for those individuals in the trial whose CRP was above two and then dropped below two, there was a significant outcomes benefit. I think that led to, at least for some, to the conclusion that CRP is a disease driver, and that the goal needs to be to down-modulate CRP. That's not at all true. CRP isn't a disease driver. As a fact, you can make many arguments that CRP is secreted in an acute phase response by the liver to protect inflamed tissues. It is still a very, very good biomarker, right? You dampen inflammation of any kind, CRP will go down. We're still looking at CRP, and we have to, despite the failure of Zilti or the ZEUS trial, because if you now go further upstream, you will still down-modulate CRP, right? Look at it more as your PSA in prostate cancer, right? Which sure, in any prostate cancer trial, you probably want to bring PSA down, but then depending on what target you choose, you might eventually have a read-through into overall survival or not. So excellent biomarker. It's not a disease driver. You could probably take it out by using, I don't know, a knockout method in humans or as siRNA is, and you would not see a MACE benefit. Got you. Then let's on the flip side, talk about the safety. of kind of targeting NEK7. Ultimately what was interesting about the ziltivekimab data in ZEUS was potential infection risks there. So I guess, how do you marry that, particularly given the fact that NEK7 sits upstream of IL-6? Yeah, and so again, very interesting, and there's clearly also evidence from other trials. It's all related to the type of target you choose, right? Yes, and we only have the high-level top-line results, but no, we did report an infection bias across their trial. We had seen this actually in the CANTOS trial as well. In CANTOS, there were lethal infections. What we're hearing was that these were mostly occurring early on in the trial until everyone knew about the infection risk, and it was much better handled. Now, the issue there is both IL-1 beta and IL-6 aren't specific for the NLRP3 inflammasome, right? They're mediators of all inflammasome. There's many. There's NLRP1, there's NLRC4, there's AIM2, and then there's other immune pathways, even like Th1, Th17 biology will eventually lead to the secretion of IL-1 beta and IL-6. You take IL-1 beta or IL-6 out indiscriminately with an antibody, of course, you are hitting all these immune pathways, and at some point, your host defense kind of collapses, and you create an infection risk. As I alluded to in the beginning, NLRP3 is mostly there to handle sterile inflammation in the human body. When you inhibit NLRP3, you have all the other inflammasomes left, you have all the other immune pathways left to still take care of your host defense. Or maybe in slightly other terms, while with an antibody, you take out all IL-6. What you do ideally with an NLRP3-targeted agent, like an NEK7 degrader or inhibitor, you bring IL-6 back to the normal physiological levels, right? Which then indicates you have managed the inflammation in your atherosclerotic plaque. Got you. So I guess, with ASCVD, kind of trying to get proof of concept there with the GFORCE-1 trial, maybe talk through the way that trial is set up, what we should be looking for in the next update here. Yeah, it is a phase I proof of concept. It is four weeks of treatment across three dose levels with a four-week safety follow-up, so it is a total of eight weeks of safety observations, which is somewhat unusual for a phase I. Many of the other companies in this space have not done it, but it gives us an early idea on whether there is any infection risk or not. We will be looking at more than just IL-6 and CRP, obviously. We will be looking at the DAMPs we can measure. We will be looking at some of the thrombogenic factors that are important as well for the disease. Since there has been a lot of talk about sort of the IL-6 receptor protective allele and some of the pathway genetics, we will also have some data available on SNPs that are risk factors or protective alleles and small N, so we do not know how this works out statistically. But should there be any correlation, obviously we would be able to draw those conclusions as well. So I would say for a phase I, it is going to be a fairly deep, fairly informative data set. Informative in a way, like helping us to set up the G FORCE-2 phase II trial. Got you. So maybe talk through your indication selection. You have talked about Hidradenitis suppurativa, you have talked about gout. How strong mechanistically should we be thinking about a NEK7 degrader in those indications and ultimately kind of lay out for us the development path in those indications? Yeah. So when we had MRT-8102 in hand and we needed to decide on where to go clinically, the exercise we did was we collected as many RNA-Seq data sets as we could get our hands on from tissues, and ask, okay, in which of these indications is the pathway most upregulated? ASCVD actually came in as number two. Gout was number three. For a while in our slide, we had the number one not disclosed because we were not quite ready to commit to HS. I got the question, like every single time we met an investor who was like, "Okay, so what is number one?" And then at some point it was, "Okay, we should probably look at number one. It is HS, right? Yeah. That is how we picked indications and then sure, is there any existing evidence in each of these indications from clinical trials that the pathway can be targeted and the drug works? For HS, obviously, you have now two IL-1 antibodies that have positive phase II data. ASCVD, yes, we talked about ZEUS, but there is a couple of trials with colchicine, which targets NLRP3. There is CANTOS, and I could make the argument that even lipid-lowering drugs actually work through inhibiting inflammation, right? Because it is essentially the trigger for the inflammasome. And then gout, very similar situation. That is how we set up our clinical program. Obviously, there are indications four, five, and six as well, Ryan, but we did not want to start any more than three trials for now. Gout, we are going into phase II. It is a relatively simple setup there. We are basically looking at frequency of flare recurrence after treatment of an acute flare. So the treatment will start with a patient having an acute flare, but the important readout is really after that has been managed, can we actually suppress recurrent flares that would occur over the next three to six months? Should lead to a POC outcome in sort of relatively short amount of time. HS, obviously, a little bit more complicated, sort of with the HiSCR score, and so on and so forth. But sure, it will not be too different from some of the phase II trials that have been run in this space. Obviously, in the sequence of events, that will be the last trial to initiate, so we are still sort of interacting with KOLs and working out some of the details of the trial design. Got you. Okay. Beyond these indications, what's kind of the dream scenario? We even just heard Dr. Gottlieb talking about inflammation, cardiovascular, and NLRP3 specifically. This could be a broad-ranging kind of mechanism. I guess what's the overall potential, and are we kind of still at the cusp of really understanding kind of how inflammation really impacts a lot of diseases? Yeah. I do agree, this is probably a pathway that has very broad applicability. Maybe in the interest of simplifying it, I'm seeing like three, four, maybe five big areas where there's really great evidence, either pre-clinically or again, from human genetics and existing clinical trials, that there's a point to be made. Obviously cardiovascular, maybe even metabolism, right? Obviously, a huge interest in inflammation in fat tissue. I'm not talking obesity, I'm more like MASH and the likes. That's one. Then crystal-induced inflammation. Gout would fall into that. But obviously, there's other metabolites that form crystals and can trigger pathway activation. Autoimmune diseases in general. Many of them, and that probably includes HS and IBD at the very least, have very strong signals for NLRP3 activation. And then allergic diseases. Asthma, atopic dermatitis, and obviously there's medicines there, right? At least subsets of asthma, in particular neutrophilic asthma, which doesn't respond too well to Dupixent, to a huge degree, is driven by the NLRP3 inflammasome in neutrophils in this case, actually. Lots of additional opportunities to go into, even if ASCVD at some point turned out to be too much of a heavy load. Got you. So maybe just shifting gears to some of the other programs in the pipeline. You have a collaboration on MRT-6160, your VAV1 molecule. Maybe just a little bit of background about that mechanism. What do you think really drove Novartis to see the promise there and enter into this collaboration on the program? Yeah, so interesting protein, and again, one that's not broadly known, at least it wasn't in the industry when we started to work on it. That wasn't the case for Novartis. Turns out they had started to work on VAV1 probably more than 20 years ago now. There's publications out of Novartis on VAV1 knockout mice, knock-ins of functionally dead VAV1. So they've spent a lot of time thinking about the target. But fair to say, they were never able to find an inhibitor or a degrader for it, which obviously speaks to the power of our platform. That signaling protein actually sits downstream of both the T cell receptor and the B cell receptor. So, when people ask me what drug would you compare it to, like what existing drug, I always like to say it's the mixture of a combination of Cosentyx and a BTK inhibitor, like remibrutinib. Now that probably explains where the interest of Novartis is coming from. Obviously, they have an existing and a growing franchise in that space, and they definitely see VAV1 MRT-6160 as something that can add to them. Got you. They activated a Sjögren's, trial. How do you feel about the mechanism in that indication, and what's the rationale there, given the underlying disease pathology? Yeah, clearly a disease that's driven by sort of this interaction of Th17 cells with B cells. Obviously Novartis has been active in Sjögren's, with their BAFF receptor antibody, something where they have a great network, a huge interest. Definitely the right indication to go into. We actually did a preclinical mouse model, for what it's worth, on Sjögren's, disease. The efficacy was just stunning vis-à-vis any of the standard of cares that we could use. Standard of care is a little exaggerated, because there isn't really anything out there. We've tried a CD40 antibody. It was just like day and night difference. Falls into the lupus disease complex. I think if Sjögren's, is positive, there's definitely then additional things even in that disease complex to think about. Yeah, actually just last week also activated the psoriatic arthritis phase II as well. Do you think there's generally a future for VAV1 in a lot of those more kind of typical type of autoimmune indications like psoriatic arthritis, psoriasis, RA? Do you think all those could be on the table? Yeah, definitely. If you look at our corporate deck and even some of the older versions of then where have we spent our time, where did we run models, Sjögren's as I said, Sjögren's lupus, arthritis, and we actually did a rheumatoid arthritis models also would make sense. And then IBD. There's definitely more. Actually, we also had an MS model, multiple sclerosis. As I said, anywhere where you have very strong evidence that Th17 cells drive B cells, that's where you want to go. I guess in terms of your collaboration, what sort of involvement do you have in terms of participation or the communications coming out of these trials? And ultimately, how should we think about the cadence of new trials and milestones associated under the collaboration? Yeah, I'll start with the last part of your question. Obviously we said from the get-go and then reiterated at the beginning of the year that Novartis is going to go very aggressive and parallel track here on indications. We had guided to multiple phase IIs kicking off this year. You could argue two are probably already multiple, but sure there's more coming. In other terms, Novartis isn't going to wait for these first two trials to read out to pick the next indication. So really, really happy on that end. We do have, obviously, a lot of interaction. For those who do not know us yet, we do have an office in Basel. It's literally right across the Rhine from Novartis's campus, so it's taking me roughly 5 minutes to walk over and see our colleagues there. So it's a really good, really tight interaction. We're super aligned on where to take this. It's just around communication. Yeah. Obviously as a small company, we would love to talk about daily progress on the program. Novartis is like, "Why would we? We're just going to inspire our competitors to do the same thing." I can't really comment on sort of the plans on how to communicate out results from those trials. But sure, there is a plan. I guess now that your VAV1's out there, it's under collaboration. Have you seen any other companies reveal programs, whether it be a VAV1 inhibitor, if that's even possible, or other degraders? Yeah. Inhibitors, I would say impossible. I haven't seen anyone, and I know for a fact because I did work in Novartis too, that sure, we've tried, we, Novartis- Yeah And it was impossible. From a, is there anyone out there doing degrader? Sure. Once something looks cool and you get $150 million up front, there will be Chinese companies trying to do the same thing. There are. That's just the world we live in. I haven't seen anything from a U.S. pharma or biotech company yet. Even if there are Chinese companies, I feel very comfortable. The scale of development, the amount of resource that Novartis has put to work here is stunning. I wish everyone good luck. So maybe just shifting gears. You have another program, MRT-2359. This is, again, an in-house program. You are developing this in prostate cancer. Maybe talk a little bit about the target here, GSPT1. It has gone through a little maze of the development, through a couple indications. I guess what gets you confident here on its journey in prostate? You have got probably an updated data set coming out, I think, later this year. What should we take away from that? Yeah. We like the data we have in hand. Admittedly, it is a small number of patients. To your point, we went through dose escalation. We had not focused on prostate yet. That focus came in an expansion cohort. It totally makes sense. The hypothesis behind the drug is targeting MYC signaling, and prostate cancer is a great space to test out that hypothesis, because pretty much every tumor that has high androgen receptor has high MYC signaling. What we saw in that expansion cohort was that the five patients so far that had mutations in the androgen receptor and active androgen receptor signaling had a PSA response. So we literally have 100% response rate. It is not going to stay 100%, but it is okay for now. It would be stunning if it did. Even better, and this was the right thing to do for us, we required every patient to have measurable disease. So everyone who has a PSA response, we now also have a RECIST scan on. All these patients showed tumor shrinkage. Not all to the level of a full PR, but two had. But those tumor shrinkages were durable. So they were not just two months and then they progressed. So, at the very least on these five patients, again, all androgen receptor mutant, we think we have a very clean signal. We have guided through the last data update on this trial, in the second half of this year. There are six patients now that we will be able to read out on. The trial is now closed, so there will not be any additional patients. We have moved into a confirmatory trial, and that actually just initiated a couple weeks ago. We're still seeing the first patient. Got you. How should we think about that confirmatory trial and ultimately, maybe talk to us a little bit about benchmarks that we should be looking at in terms of the line of therapy you're working in. Yeah, the population we've treated in this phase I expansion, and it's not going to be different in the confirmatory phase II, is late stage. So they'll have seen chemo. Definitely everything, androgen receptor antagonist, chemo, some probably multiple rounds, in this expansion arm. I think 60% actually were also post-Pluvicto, and some had already seen experimental bispecific antibodies as well. So it is super late stage, which makes the data even more exciting. A 100% response rate in that setting isn't something you should be expecting. So that's the setup. It's hard to compare. Obviously, there's some data out there on next-generation androgen receptor antagonists like Arvinas's and BMS and the likes, with their PROTACs. BMS 's PROTAC I think had a PSA response rate of about 40%. That was at a time where Pluvicto wasn't even as broadly used. I'm pretty sure they had a still better, less heavily pretreated subset of patients. I would say anything around 40%-50% plus in now this new setting, post-chemo, post-Pluvicto, would be extremely encouraging. It's obviously all about RECIST and durability of responses to run. That's super important. When should we get an update around the confirmatory trial, and I guess, would you guys give an interim update on how it's enrolling? Yeah. Sure. It's an open label trial, so we'll obviously be in a position to report as the trial progresses. But sure, we're not going to raise our arm every single patient that's coming through. It's set up as a stage one, stage two. Stage one has 10 patients. I would say sure, by all means, if the first 10 patients coming through confirm what we have seen in the expansion arm, we would definitely give an interim update. Got it. Okay. Then maybe with the last few minutes, we've seen an evolution of these companies who focus on degraders, like yourself, over the last couple of years. You guys took the more risk of going like with the target risk, which seems to be paying off, which is great. So I guess, how do you think about new targets and what the platform's actually capable of at Monte Rosa? Yeah. A platform, obviously, is amazing, right? For many times when you have these platform or product engine companies, your first two or three programs are the thing, and then you're kind of running out of ideas, things to do. That's not at all the case here. We're making continuous improvements. It is heavily AI-based, so we're never making a big deal out of it, and I still don't want to. The cool thing is, sure, we're accumulating a lot of internal data that's super high quality that we can use to sort of model these ternary complexes and predict how we need to design our molecular glue degraders to make them more broadly applicable and extremely selective. So lots of interesting targets that we're working on. We're obviously now in a time we're coming back to competition abroad. We're not as inclined to talk about them as early as we did before we even went public. But yeah, there's more to come. It's really great because beyond feeding our own pipeline, of course, we've been super active on the BD side. I think our platform can continue to also feed our bank account through some of these additional targets and then partnerships. Does that remain a near-term priority to partner out more programs or at least the platform to some degree? No, I wouldn't necessarily say it's the top priority, but it's obviously good to have that optionality. We did the VAV1 partnership, not just to bring the dollars in, but because we realized that that is an asset where you'd want to go very broad in exploring your indications in phase II. I think when we arrive for something else, at that point, we're like, okay, this is probably better done in partnership with someone else because it's like exploring. There isn't sort of this crystal clear path. Why not, right? But sure, we're maturing, and we're keen to hang on to assets for as long as possible. Should we assume that any new targets or things that are largely under investigation in kind of the early stage pipeline is focused in autoimmune disease or immunology and inflammation and oncology, or are there other areas that you'd look to explore? Yeah, those are the three main areas. That's diverse enough. It's a lot. Our CMO is here, and he grew up as an oncologist, so did I. Then I turned him into an immunologist and then a cardiologist. I'm hesitant to turn him into a neurologist, but I think he's keen to learn new things all the time. Got it. Then maybe just the last question in terms of the funding. What are you kind of funded through in terms of being able to generate additional data from the overall pipeline portfolio? Yeah. Cash runway is into 2029. That would essentially take us through pretty much all the phase II studies that we've talked about. For the ones that Novartis is performing, we're getting all these milestones, we don't have to pay anything. This is all being paid by Novartis. We own 30% of the U.S. P&L. It was a particularly nice feature of that collaboration. Enough cash runway to see through the 6160 trials, MRT-8102, and then of course, also MRT-2359, and probably some of the early phase I stuff for some of the targets we're moving forward with as well. Excellent. Well, thank you so much for the conversation, and I think we'll leave it there. Sounds great. Yeah, perfect. Thanks, Derek. Thanks, Mark.