Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yas Rahimi. I'm a Senior Biotech Analyst here at Piper. Thrilled to be featuring the team from Ventyx Biosciences. Thank you for being here and being part of our conference. We have lots to discuss over the next 25 minutes, and we have an incredible 2025 ahead of us. So maybe a good place to start off is just maybe for investors who are revisiting Ventyx or kind of looking into 2025, what are some of the key inflection points and milestones ahead? And then we'll go into each specific program. Yeah, sure. Thanks, Yas, and great to be here. So you made very clear about our strategy starting in January of this year, where the clinical focus is now on taking our two NLRP3 compounds, the peripheral molecule and a truly brain-penetrating compound, the 3232, into multiple trials. Some trials are to explore, I would say, hypotheses that are based on some data there, whether it's in vitro data or animal data. And then the other is trials. The RP trial in particular is based on biology of IL-1s, IL-1 beta, the IL-1 alpha/ beta traps, and positioning our compound as an oral drug in the rilonacept, Arcalyst pathway. So three trials, one in RP, one is a cardiovascular metabolic obesity trial, and the third one is a biomarker trial in early Parkinson's patients. And all these trials would have started at the end of this year. Parkinson's has already started. We announced that. We have the RP trial and the cardiometabolic obesity trial starting at the end of this year. Then the readouts are going to be in the same order, which is Parkinson's first in the first half, and then obesity, cardiovascular metabolic, and the recurrent pericarditis in the early second half of next year. Okay. I think for a lot of investors who are excited about the CNS-penetrating NLRP3 molecule, they're seeing a number of other compounds in development, one by NodThera, one by BioAge. Could you maybe talk about sort of the differentiation of your compound versus some of the other CNS-penetrating ones? Yeah, I think if you look at these compounds and talk about the competitor, I think they're all bona fide NLRP3 inhibitors, right? They all hit the target. They all block IL-1 beta suppression in various assays, right? I think we focus on our compound. I think our CNS compound is a truly brain-penetrating compound, right? We don't have to dose it at sort of untenable doses in either nonclinical studies or in humans from what we've seen of these compounds in the public domain, right? And so, but they're all bona fide NLRP3 inhibitors. So I think the data generated from those compounds is standalone, valid data, again, be it in sort of the phase II-A studies being disclosed, albeit not a complete set in some of the animal work. But our brain-penetrating compound is truly a CNS molecule. It's not some dosing that you have to do to get it in. And it's not just even the Roche compounds or oral small phenyl ureas, and they're not really brain-penetrating, right? So that's where we stand with that molecule. Okay. Could we maybe talk about, I think investors recognize that this mechanism has pleiotropic effects, right? Inflammatory effects, fibrotic effects, metabolic parameters. It could truly be positioned for metabolic syndrome across the board. One of the things that's unclear to investors is whether this mechanism should be a standalone mechanism for patients with metabolic syndrome, especially the high- risk, versus more positioned on top of an existing therapy. I know in your studies, you're going to be evaluating both strategies, but would love to hear what your thoughts are in the future. So good question, right? Especially in the CNS area, it's not clear. There's a strong biology behind Parkinson's and the role of NLRP3 in the microglia, and then subsequent release of cytokines. Post that, it's not clear, right? So the astrocytes to damage in the neurons is established, but this link between microglia and what happens downstream is not established, right? So people believe it's a disease-modifying therapy. That's what the belief is. But also a lot of, for lack of a better word, skepticism because there's so many failed trials, and how is it any different. And I think this is a place where one's going to have to see, first of all, monotherapy, right? Not saying completely abrogate the disease, but to actually see a meaningful effect on Parkinson's, especially folks that have progressed to a point where you start to see motor function issues. In the cardiovascular space, I think, there's not a lot of drugs out there in the MACE prevention area. There's not a lot of drugs out there in the risk reduction area. So there could be a unique position for an IL-1 beta-based biologic or an IL-6, which is what people are not quite, I think you folks have recognized that, but the stuff that Novo is doing with their trials, the stuff that another company is doing with their IL-6 extended molecule all fits in with the role of NLRP3 in driving IL-1 beta, which drives IL-6, which drives hs-CRP. Where it goes on, right? There's fibrinogen, right? There's plasminogen, there's PAI-1. There's some understanding about lipoprotein(a). So there's a lot of mechanistic speculation, but I think with our trials, with some of the other data out there, the picture will start to get a little clearer, right? Okay. Could we maybe talk about sort of logistically where you are with some of the current tox package with VTX3232? What has been completed? What's left to do? We're done with the chronic dosing. So we have nine months in primates and six months in rodents complete. We've established a very large therapeutic window with this drug. Our doses that we've shown that completely block the target in the CNS are about 10-15 milligrams q.d., right? And so we believe we have a very high window. Yeah. So I think we've done all the tox work. We've done all the CMC work. We're on our way to starting these trials now with 3232. In terms of your obese population, just some broad color on what is the size of the study or the number of patients per cohort, how many doses you're contemplating of exploring? So we haven't disclosed sort of the details of the trial, but if you can think of a classic or standard weight loss trial that's been run in the last year or so, a couple of years, whether it's from the GPCR, whether it's from the New York oral company, it's a really classic trial. So we have a placebo-controlled monotherapy arm, and we have a placebo-controlled combination with an incretin there as well, right? It's powered to detect significant weight loss. So anywhere between 3% and higher, sort of the bar with an oral drug. We're not going to starve these patients with caloric restriction. That's not a weight loss trial, right? You're going to make them very angry, but they will all lose weight. So that's not the way we will run it. I think it'll be a definitive answer on whether this mechanism has any real basis for weight loss in humans, given the data we saw from competitor compounds, our compounds in mice, which was actually pretty compelling in terms of weight loss, right? Do you foresee, because we've seen difference? We have seen four-week studies in obesity. We have seen 12-week studies. Given that the tox package has been covered, do you foresee that your obesity study would be more like four-week or 12-week study? It's a 12-week study. So again, we're going to run this study to really define this mechanism. I think the mouse data excited people, but there was a lot of confounding stuff after that that people just said, "Oh, there's no weight loss mechanism." Again, not really appreciating that the study that was disclosed was not a true weight loss study, right? And so we moved from a four-week study to a 12-week study. We moved from a smaller study to a well-powered study, and we moved from a mono to a combo. Okay. And do you expect the population stratification to be just pure obese? Obese with high-risk markers, maybe a certain level of CRP, a certain level of lipids? You're just making this up. Since the driver is CRP, so there'll certainly be a CRP threshold. Of course, there's a BMI bracketing of these patients, nothing different from what the other trials you've seen. There'll be another cardiovascular risk factor, right? Remember, we're doing this trial in obese subjects, right? There's a given in terms of certain elevations. The lipids are elevated. Many of these folks are going to be borderline prediabetic, right? There's going to be effects on the liver, and you're familiar with this, fatty liver. There's certainly renal issues with GFR, right? Our goal, just like we did in the mouse study, is sort of look at this as a model where, yes, there's a gross weight loss component to it, but it's also look at lipids, right? Triglycerides, LDL, HDL, glucose, insulin, HOMA-IR, OGTT on that end. Look at renal function. Look at liver in terms of enzymes. We have an MRI-PDFF component. We have a cT1 portion to look at whole-body scan. So you really get a picture from this as to not just weight loss, right, but also on the edge of cardiovascular risk, on the edge of diabetes risk, on the edge of fatty liver, and also what happens to the whole body in terms of inflammatory control with an NLRP3 inhibitor. What is left to do, and are you going to stratify on obese, diabetic, or non-diabetic? Or will they all be non-diabetic? Well, they'll all be non-diabetic. But most of these patients by nature are going to be elevated glucose on the borderline of HbA1c. Yeah. It's hard to convince the agency to go into a diabetic population and mix trial like this. I think you guys have commented that initiation of the study is expected sort of year-end. Are we just any minute waiting for the announcement? Enrollment has begun, and maybe an NCT number to look at some of these design details. So we don't dose on the day we start, but yeah, we are on track to initiate these trials this year. And this year's got a few weeks left to it. A few weeks left. And then top-line data, what backup? Top-line data is about, yeah, so early, early second half of the year, and the trials are different, so the RP trial, it's done more at academic sites, and there's a lot of understanding the patients and the flares to make sure you do it right, and that has its own logistics because of all the IRBs. The cardiovascular metabolic obesity recruits much faster, but again, there you have, we have the sites. We have to make sure each site has the capability to do the MRI-PDFF with the cT1 scan, so we're leaving no stone unturned in this analysis, in this trial. I think it's easy for investors, once you start your obese high-risk population study, to figure out what's the bar, and expecting the data. But I would love to kind of spend the time to educate the market on A, the RP opportunity, and what would be a product profile that would be competitive, so what is the RP market opportunity that exists, and two, what do we want to see in sort of a strong proof of concept? Yeah. So I'll take the latter, and maybe Thomas also jump in on the market opportunity. So the RP trial is really tracking an oral drug for RP that's based on the success of rilonacept or Arcalyst. This is the Regeneron- Kiniksa drug. And in our understanding from both the commercial analysis, from speaking to KOLs, there's very few folks that are true KOLs in this space, right? It's a rare disease. And the opportunity to do what rilonacept does, right, and more, both in terms of the patients and geography, it's not approved in the EU, is compelling, right? And I think Kiniksa has made a good case for how they've built the patient population and the market for this drug. And that's really where we need to be. And I think even the path forward in terms of doing the phase II study and a much speed-to-market approach with the phase III, it's well laid out. So that's how we feel about this. There's obviously, it's never done until it's done. So we want to see the data come out. But here's where we really, truly believe we can move this very quickly depending on the outcome of the study, right? In terms of market opportunity? Yeah, market opportunity. I think you take a step back and look at the treatment paradigm in RP, right? You have NSAIDs, you have corticosteroids, colchicine, which is kind of viewed as a non-selective oral NLRP3 inhibitor, but has some other kind of liabilities. And there's a huge gap between colchicine and where Arcalyst is from an efficacy perspective. So if we can hit anywhere in that window, preferably closer to where we are with Arcalyst, I think there's a huge demand, certainly from clinicians and patients to have this is a disease that's really, it's an acute disease, but it's treated chronically. If you look at the market data that Kiniksa has put out around Arcalyst, I think the average duration of therapy at this point is around 24 months. So patients will treat their acute flare, they'll stay on drug at some point, they'll come off, flare again, and then get right back on drug. And so as we talk to KOLs, a lot of interest in anything that can get you close to that efficacy profile. And then since it's a chronic disease, having an oral option that's safe and effective, but isn't kind of a weekly injectable that you have to reconstitute and administer, is very attractive. I think total market opportunity, it's consensus for Arcalyst is around $1 billion. I think Kiniksa and we think that the market can be even bigger than that. It's a large 40,000-patient prevalent population, orphan pricing, and coming in with an oral molecule and being able to expand the pool of treated patients. I think there's a lot of places we can play there. What led you to pursue RP as one of the indications? What evidence in terms of the preclinical model or the pathophysiology of RP was like, "Yep, that's what we should go for"? I think you have a couple of playbooks, right? You take the canakinumab playbook or the Ilaris playbook, or you have some of the mixed compounds like the rilonacept, which is an IL-1 beta-alpha trap, right? And then you look at the data and you look at some of the studies done with canakinumab, which is also effective in RP, right? And then you, of course, have some in vitro studies people have done, and that at least alleviates your concern about, "Hey, this is alpha-driven. Where is going to be the impact of a beta drug?" People also don't appreciate the fact that NLRP drives IL-1 beta through caspase-1, but there's a feed-forward loop in terms of IL-1 beta then driving IL-1 alpha, at least from the NLRP3 domain, right? So that analysis and the fact that the couple of areas where you can go into is, of course, the secondary prevention of MACE, which would be in an ASCVD population, high-risk population. You have to do certain mutations that tend to. And I think there, and then what becomes, even for us, right? So biomarker studies showing reduction in CRP in these populations then really begs a large outcome study, right? Which I don't think, at least at this point, we're set up to do. RP is a bona fide mechanism. It fits in with our profile. And it's an area where if we choose to, we can take this thing speed to market with a phase III trial, right? While we do some of the other work around cardiometabolic space with our CNS drug. Think of the CNS molecule as in two parts. One is the CNS aspect. And in that study, it's a very straightforward question. Does hypothalamic control of inflammation give you effects on feeding, right? Definitely answer the question. Second is the second half of the compound. Think of it as a peripheral molecule because it also has strong peripheral exposure. And that's where we're going to dissect out the cardiometabolic parameters. And it may turn out that our peripheral compound then goes into those indications, right? Because this whole IL-6 story is just developing, right? And we want to be one up in an NLRP3. And so when the Novo studies read out, when some of the other stuff with, for example, Tourmaline is doing, we are positioned with our compound right there as an oral IL-6. Thank you. Yeah. I think the first CRP reduction study to outcome is expected end of 2025, early 2026, so to have a significant read-through to the NLRP3 and the IL-6 pathways. You also earlier this quarter announced your partnership with Sanofi in regards to their commitment. Was it an interest in just the NLRP3 program and just the CNS? What aspect? Was it the CNS aspect that drives them for NLRP3 inhibitor or metabolic? Yeah, so I think historically. A combination of both? I think it's both. But I think from a scientific perspective, much more understanding on the neurodegenerative side. I think Sanofi is of the same belief that neurodegenerative diseases really are they follow a neuroinflammatory signaling. They believe that, right? And I mean, you've seen the success with the BTK compound. There's a number of companies like Sanofi that are heavily invested in finding a cure for Alzheimer's, for example. For MS, certainly there's been a lot of progress for. So I think these companies recognize that we have the best molecule out there and to sort of, I'd call it a handshake with them. And we learn from them in terms of what they expect. And they sort of loosely follow us. It's a deal which has the rights of first negotiation. So there's nothing that obligates us to disclose data before you guys see it. But clearly, I think what it points out is that these companies are interested in these pathways. Now, in terms of the cardiovascular, of course, they have a readout on the CNS molecule. So whatever comes out of the metabolic study, they'll get a look at it as well. But the real interest from them is this pathway that says neuroinflammation will control neurodegenerative diseases. So that's the primary angle for them. And in terms of cash and cash runway to kind of get you to both the RP study and the 12-week obese high-risk group? Yeah. So we ended Q3 with about $275 million in cash and equivalents. That's inclusive of $27 million proceeds from the Sanofi investment. And what we've said is that gets us into at least the back half of 2026. And so hopefully by certainly second half of next year, hopefully early in the second half of 2025, we'll have read out all three trials: Parkinson's, cardiometabolic, also recurrent pericarditis. And we should have at least kind of a year of capital at that point to play with and can be kind of flexible and opportunistic around these data points next year to supplement and finance if it makes sense to do so. Great. Well, team, thank you so much for being part of our conference. Our pleasure, yeah. We really want to say thank you. We look forward to an awesome 2025. Thanks. Applause to team. Thanks. Thank you.