All right, welcome to this next Fireside Chat with Monte Rosa Therapeutics. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it's my great pleasure to welcome Marcus Warmuth, CEO of Monte Rosa. Marcus, welcome and thanks for joining us. Yeah, great, thanks for inviting us. Maybe just stepping back for one second for those in the audience that are less familiar with Monte Rosa, can you just explain what molecular glue degraders are and why Monte Rosa is pursuing that technology? Yeah, no, so a very interesting modality. I can't even say it's a new modality because it's actually a blockbuster drug out there, lenalidomide, pomalidomide, blockbusters for as long as they were still having exclusivity. That operate this way, although they weren't exactly known to be molecular glue degraders when they were discovered. What do molecular glue degraders do? They actually engage the Cell Intrinsic Protein Destruction Machinery. They bind to a type of protein called ubiquitin ligase and then reshape the surface of the protein in a way that it becomes the perfect match for a protein that you want to get rid of. What are the big advantages? This is induced protein-protein interaction. There is no binding initially to that protein you want to get rid of, which means you can actually apply it to absolutely undruggable proteins. There are obviously some neat examples in our portfolio where we have done that. Great. Maybe then just want to talk about your pipeline, starting out with your INI pipeline. The term biologics in a pill has recently gained traction in the Degrader Industry. Your most advanced program here, which is partnered with Novartis, targets VAV1. Maybe just stepping back again, what makes VAV1 an interesting drug target and how well validated is it today? Yeah. So target we obviously like. We do believe it's extremely well validated, at the very least through mouse genetic data. There's knockout mice where it's been shown that these mice are protected from Autoimmune diseases despite still actually having a Full Vaccine Response. There's no human validation yet outside of obviously what we've done in the clinic so far. Interesting protein in the sense that it's downstream of both the T and B cell receptors. It's involved in two pathways, mostly when that pathway actually gets Chronically Hyperactivated. We do believe then this is a great target in the context of a variety of different autoimmune diseases, in particular those that are driven by either strong T cell components or T and B cell components. Given that broad implication across both, as you mentioned, B and T cell biology, do we need to worry about potential off-target AEs and how do we think about the safety profile with VAV1 programs? Yeah, so I mean, at least as far as we can tell, no concerns on off-target toxicities on these molecules. And it's not just true for MRT-6160, extremely selective. We're not hitting anything else but the intended target. We haven't really seen much issues with molecular glue degraders around nonspecific binding to other proteins, CYP induction, HERC induction, and so on and so forth. Your major concern would be, of course, on-target toxicities with VAV1. Again, mouse knockouts suggested it's going to be reasonably safe. We obviously have long-term tox studies by now, four-week GLP and three-month GLP tox studies that actually support this. It is a mechanism that's immune modulatory, certainly not immune suppressive. As I said, the molecule is extremely clean, so no concerns so far. Right. I meant to say on-target tox by the way. Thanks. As we think about the potential size of the VAV1 degrader market opportunity, there are numerous indications that could be implicated here. I guess which of these opportunities have the lowest translational risk in your opinion? Yeah, I mean, to be fair, hard to tell right because there isn't sort of the VAV1 biomarker. We might talk about CRP for our other INI program, NEK7. The CRP for VAV1 doesn't really exist. You have to rely on what do we know about what VAV1 does, so it inhibits very nicely Th17 biology. That has been the constant theme across multiple animal models we have run. You obviously then have to think about, okay, where is Th17 T cell biology most important? Certainly some examples that we have put into our deck. We have great data in various models of Arthritis. We have great data now in a model of Lupus/Sjögren's syndrome and also great data in IBD. Certainly those have all been very well validated as diseases driven by that mechanism and those pathways. Okay, makes sense. You did present some phase I data earlier this year in healthy volunteers. Yeah, maybe just remind us of the key learnings from these data, including some of the Biomarker Analysis that you've done. Yeah, no, I think that that study turned out as well as it possibly could. It was a classical set met PKPD Safety Study. I start with safety, extremely clean safety profile, nothing to worry about. On the PKPD side, really nice dose linear PK. We have actually not disclosed the actual dose levels, but I can say they're sort of in the single-digit milligram range. Part of not disclosing obviously is related to being able to file IP dose per indication. We got to VAV1 degradation across multiple dose levels that was pretty much at maximum. The same was actually true when we then looked at Ex Vivo Cytokine Stimulation Assays. Overall, again, safe full PD modulation across multiple dose levels and a very nice setup to now sort of pick doses for various different indications. Okay. There are several phase two studies that you're planning with Novartis that could cover different disease areas. Yeah, maybe talk about the process of selection. Which phase two studies are being considered and yeah, what are next steps for the program? Yeah, I mean, in some ways I've already alluded to that, right? I mean, that's sure. Novartis has a lot of experience in that biology. They do have an approved drug there with Cosentyx, so a lot of expertise in regards to assessing targeting Th17 biology makes sense. Obviously, there's all our in Vivo Exploration in mice. The data I alluded to and all of that actually contributed to selecting the indications that are now moving forward. I mean, I'm pretty sure there will be more to be added in the future. Okay. What are the next data disclosures in the program that we should look forward to? Yeah, I mean, data obviously depends on sort of phase two initiations, which obviously we have the timeline, but I'm not in a position right now just to maintain confidentiality to talk about it. I think once we are able to talk more about the actual indications, the clinical trial designs, we'll come up with guidance on when to expect data as well. Okay. And then yeah, maybe shifting to your 2nd program, the NEK7 degrader, MRT-8102. Yeah, perhaps talk about the target itself. So what drove your decision to target NEK7 by means of with the goal of inhibiting NLRP3 at the end of the day as opposed to directly going after NLRP3? Yeah. So very interesting signaling pathway, obviously great validation from multiple agents, biologics in the clinic, mostly downstream actually absorbing Cytokines that are being produced and then secreted through stimulation of this pathway. It's a multi-protein complex. NEK7 actually plays a crucial role there as sort of the assembly factor for the entire inflammasome. When you take out NEK7, obviously a cell will not have a fully assembled inflammasome, hence no active inflammasome. These are the inhibitors which obviously target the fully assembled activated inflammasome. Of course, based on the PK of your molecule and how high you can dose, you will either get or potentially not get reactivation of the pathway at trough levels. We do believe that by just disassembling the inflammasome, you get deeper and prolonged pathway inhibition, hence the efficacy of a biologics kind of, but obviously at the convenience of a small molecule. Obviously, the additional advantage over biologics in this space being then you do not necessarily have to pick, do I want to go after IL-1 alpha, beta, IL-18, or various different combinations of these or further downstream of IL-6? You are essentially just shutting everything down sort of at the highest possible point of interference. Okay. So in terms of differentiation from inhibitors, so it sounds like deeper and more prolonged inhibition, is that correct? Correct, yeah. Great. Yeah, how would you prioritize potential target indications for MRT-8102 and what is the size of these opportunities? Yeah, I mean, a huge span of potential indications here where the inflammasome has been implicated. Lots of talk these days about pericarditis. Certainly an attractive indication, small of course, but certainly feasible for a small company. We do actually quite like indications where the biology is driven by formation of crystals and then those crystals stimulating the inflammasome. Gout is a good example where MSU crystals trigger the pathway. It's essentially the cause of flares in gout. There is also a sort of developing story in MESH and ASCVD where Cholesterol Crystals and also Oxidated Lipids can activate the pathway. There are other indications to think about. Also, we haven't spent too much time like Asthma versus Ceramides activate the pathway. We do like, as I said, the indications where there's a very well-defined Metabolite on its own or in form of a crystal stimulating the pathway where we have really great evidence that NEK7 is absolutely essential to drive the pathway. Gotcha. And then so this is in phase I. Could you just help set expectations for the upcoming data disclosure next year? Yeah, so that will be the entirety of the phase one study. This is designed a little different from VAV1 in the sense that we have a single and multiple ascending dose arm, but then also a part three which actually looks into the impact of NEK7 degradation, MRT-8102 on CRP levels, individuals that have elevated CRP levels because of obesity and a higher Cardiovascular Risk. Obviously a short duration, it's only four weeks, but still meaningful way to achieve proof of concept for the pathway early on. Okay. Is there, based on preclinical data or mechanistic data, what level of NEK7 degradation at a minimum do you think sustained do you think is necessary to drive clinical benefit? Yeah, I mean, from the PKPD studies we have in CNOs, we believe that actually 70-80% degradation are sufficient to achieve more or less full efficacy. It doesn't mean that we're only getting to 70-80%, but that's what the data tells us. We have sort of similar observations in mouse where again, 70%, even a little bit less can lead to efficacies that are comparable to what you can get with NLRP3 inhibitors. There seems to be a threshold level for NEK7 under which when you fall under that threshold level, obviously the inflammasome is just not efficiently assembled anymore. Gotcha. You also have a second-gen program, a 2nd-gen NEK7 Degrader. Yeah, maybe talk about differentiation from 8102 and what opportunity you see for that molecule. Yeah, so I'll start by saying, I mean, one of the big competitive advantages we have here on NEK7 also versus inhibitors is we kind of own at least for now the actual chemical space. Inhibitors are all in a fairly narrow universe and so gives us lots of opportunities to think about follow-on molecules. There is sort of a story out there that NLRP3 inhibition, be it by inhibitors or NEK7 degradation, can have an impact on obesity. Also, it hasn't really confirmed in a recent study by another company. The CNS molecule in some ways was intended towards obesity, but also with a potential to treat neuroinflammatory diseases. We do know that 8102 has exposure in the brain in CNS. What we are doing as part of the SAT-MAT study for 8102 is we look at exposure in the CSF to see whether we feel there is enough getting in to believe it could work there. I think if that is true, we will probably repurpose the 2nd-gen molecule to something else. Certainly have seen the opportunity and have shown some data that show we can increase Blood-brain Barrier penetration with our chemistry. That would certainly also be an opportunity. You did have a couple of partnerships. You have a discovery partnership with Roche and then the product partnership with Novartis on VAV1. How do you think about potentially balancing, retaining value on the NEK7 program versus partnering that as well to perhaps expand the opportunity space? No, I mean, and clearly, I mean, two fantastic partnerships with Novartis and one with Roche. I think we've shown that we can leverage our platform to create revenue. I'm always trying to avoid non-dilutive because there's different types of dilution, but all the partnerships we've done clearly made sense. Now that has put us into a position where for NEK7, obviously we feel like we're in a position to carry the clinical development program forward ourselves. I'd say sure, if we're successful in ASCVD at some point, that would have to be partnered with someone else. Those are monumentally sized trials at the end of the day. I'd say that aside, all the indications we're currently contemplating, we feel we can execute on ourselves. Right. Then obviously you do have also your GSPT1 Degrader Program, one of your earlier programs, 2359, which I think you've been focusing phase one studies now on Prostate Cancer and Breast Cancer. Yeah, maybe talk about how those two studies have been enrolling and any expectations for these upcoming data disclosures. Yeah, I mean, enrollment has been going really well. Probably remember the data so early and only a few patients we had shown on prostate with a PR and two stable diseases on the 1st few patients coming in that has certainly created enthusiasm with investigators. Made it fairly straightforward to recruit. Also, the sites are mostly phase one sites rather than Prostate-centric sites, which obviously can create a little bit of a challenge there. By the end of this year, which is what we have guided to at the very least for prostate, we will have a fairly decent data set. We were actually able, based on efficacy, to expand to somewhere between 20 and 30 patients. We won't have all patients enrolled and durability data on all of them. If you assume, I think we've dosed the 1st patient last year, September, October, at least for a good portion of these patients, we will not just have initial efficacy, but also some sense of how durable responses are. We certainly see this as a great potential opportunity. I think combinations, and this is a combination with enzalutamide, combinations in Metastatic CRPC are the next step. Obviously combining two small molecules makes a ton of sense from a mechanism point of view because we're still targeting MYC in a way as a pathway here. Even combinations in the future with radioligands could make sense as well. Looking forward to the data release and then we'll see where we can take that molecule from there. Is there a particular, maybe just maybe stepping back to what types of patients are in the studies? Is it mostly post-chemo or Pre-chemo perhaps, Post-AR? What level of efficacy would you want to see to advance this into a phase two setting? You know, it's a great question. I mean, fair to say, and this is kind of why I brought up the phase one site issue, if it's an issue at all, sure you tend to get more heavily pretreated patients there than in, let's say, prostate-specific centers. I think I would assume that there's a fairly high rate of definitely prior Androgen Receptor Inhibitors and abiraterone, but also of course chemo. Certainly a good portion of these patients we already have seen the Pluvicto and some of the Investigational Bispecifics. Okay. Are we, is it mostly PSA responses or do you have Radiographic Assessments as well? Yeah, so in a way somewhat an outlier here in the field because we wrote the protocol in a way that we require every patient coming in to have Immutable Disease, Visceral Disease, which again obviously biases you towards a bit less favorable patient cell. We really wanted to know whether we can shrink tumors and not just have a short-term impact on PSA. We obviously have PSA as well. I think through every patient having a RECIST assessment and then hopefully also an assessment of durability, we'll get a pretty good read. I'm always cautious in the small sample set to define a percentage to be seen to move forward because again, it depends a lot on what's the actual molecular makeup and of course also what's the pretreatment overall history of that sample set we're getting. As we think about your earlier stage pipeline, which programs are you most excited about and which ones are closest to IND filings? Yeah, I mean, obviously closest to IND is our CDK2 Cyclin E1 package. We're super excited about Cyclin E1. Doesn't mean we're not excited about CDK2, but sure Cyclin E1 in some ways is special, right? It fits this undruggable kind of theme. We've also learned that by engaging Cyclin E in Cyclin E Amplified Tumors, we codegrade CDK2 because it's a small complex. When it engages with that ubiquitin ligase, actually you see ubiquitins tagged onto both Cyclin E and CDK2 at the same time. There are lots of new programs emerging out of our discovery engine, mostly in the INI space, many times fitting sort of this theme of undruggable and being a signaling node that takes care of multiple Cytokine signaling pathways at a time, right? It's not sort of the single Cytokine in a pill theme. It's really more beyond biologics in a pill where we go after Central Nodes. Right. Great. Thank you, Marcus. I think it's time to wrap up, but appreciate the time and looking forward to hearing more about the exciting pipeline later this year and the next. Thank you. Yeah, sounds great. No, exciting times. Thanks again for the invite. Awesome. Thank you.