All right. Good afternoon and welcome to day three, the final day of the Barclays Global Healthcare Conference. My name's Carter Gould, covering U.S. Biopharma. I am pleased to welcome Ventyx Biosciences to the stage, joining us from the company, CEO Raju Mohan, and CFO Marty Auster. Guys, thank you. Welcome. Raju, I think you're gonna make some opening comments and then we'll launch into Q&A. Yeah. Well, first, thank you for having us here. It's, you know, it's a pleasure to do this and, and speak to where we are as a company today. You know, we had an Investor Day last week and exciting programs, new programs that we are focusing on the clinical path. So, happy to chat about that today. And thanks again. Okay. So let's talk about the recent Analyst Day. You shared a number of data points on the NLRP3, which we, frankly, hadn't seen much on prior to this, and announced sort of next stage in development plan. When you think about the I don't know if you wanna take it, one asset at a time or make some overarching comments first. Maybe highlight your takeaways, or what investors can take away from the recent updates. I think that take-home message is that, you know, we have a portfolio. We have a pipeline of compounds. And the focus last two, three years post our Ventyx formation has been so much on TYK2, right, externally. And, you know, we always believed that we had a pipeline. It was not just the TYK2. It was the S1P1. And then we've been developing the inflammasome inhibitors, NLRP3, both peripheral and in the CNS. And, you know, it's not something that we pulled out of a hat three weeks ago. You know, we've always had a conviction that you have to look across a broad range of immunology pathologies. And yes, we were an I&I small molecule company. I think now we think of ourselves as an I&I and potentially a CNS company as well, right? The take-home message is there's a robust pipeline. As we look at the TYK2 program and its really focused way of deciding a path forward in Crohn's disease, we've had the S1P1 now, which is phase III ready, but we were definitive about finding a partner to have any kind of capital spend on that and then refocus or focus or prioritize our portfolio to now go, you know, go into this exciting area for NLRP3 where, honestly, a year ago, six months ago, people had no idea, not just what this target was. They had really no understanding of what we had built. And we had promised folks data from our CSF trial with peripheral. We had promised folks data from the phase I trial. And we put those out last week. But orthogonally, there's a huge interest in this area now from the metabolic space but focused really on obesity as well. And so that's another exciting area for us. So, I think we just want folks to know that we have a pipeline, and the pipeline will continue to grow. And there'll be areas that we have to look at carefully in terms of commercial viability. But are we competitive? You know, even the TYK2 space, the psoriasis trial actually met an endpoint. Just didn't feel the drug was competitive. S1P1, we think we have the most differentiated molecule out there. But again, given the stage, we would want to find a partner. And then NLRP3, you know, we can talk more during this discussion. Great. So I definitely wanna get into some of the strategy questions. And, you know, I think going into the past week, I think the key thing people knew about these assets is one sort of is peripheral. The other one is CNS-penetrant. As we just think about the basic chemistry behind these, can you talk about how distinct they are, different backbones, etc.? Any other details we should be aware of? Sure. Yeah. So, so the interest in small molecule NLRP3 compounds started about, I would say, six, seven years ago. And this was after Novartis published the CANTOS trial. Right. So a lot of interest in finding ways to block the biology of IL-1 beta in particular. The inflammasome was set up. And then within the inflammasome, NLRP3 is probably the most well-characterized compounds. A lot of flurry to find these molecules. There was a lead, early lead called MCC950. And people jumped upon that. And everybody sort of wanted to carve out their IP space. Intrinsically, the sulfonylureas, which is the MCC950 scaffold, are not brain penetrant. And there was an interest in CNS biology of NLRP3. But the CANTOS trial has sort of focused people more on the peripheral side, the cardiovascular side in particular. So early-generation compounds, our peripheral compound are all based off the sulfonylurea scaffold. We have an issued patent. We managed to optimize it into a well-behaved, well-characterized NLRP3 inhibitor. At the same time, we realized that taking a compound like sulfonylurea and trying to create a CNS molecule is just not viable, right? And so our strategy for designing the CNS molecule was to look at a very different chemotype set. Molecules that penetrate across the blood-brain barrier have their physicochemical characteristics that are very different. That was the basis for designing our brain-penetrant compound. As we've talked about over the last few years, all our compounds are internally designed. We own all IP, all commercial rights. So by design, these two compounds, 2735 and 3232, are distinct chemotypes. And that's what we showcased last week on how we plan to take this opportunity, exploit these differences in having a clear peripheral disease indication approach. And then on the CNS side, we outlined our initial phase II- A programs. Okay. And I guess as we think about sort of, as you think about the PK profile, and maybe draw some contrasts on maybe the things that are working in the favor here that maybe were a little bit more complicated with TYK2. I think for TYK2, for S1P1, you know, these were well-characterized pathways, right? So TYK2 in particular from IL-23 biology but from work that had been done with deucravacitinib now as a TYK2. So, you know, you have a blueprint. You have a map of how to approach the disease indications and what kind of target coverage you need to get. Same thing with S1P1, between a ozanimod, the first-generation compound, a etrasimod. The biology of S1P1s has been studied for decades in MS. Right. Here, it's slightly different. Yes, the biology of IL-1 beta is understood in a number of disease indications from the biologics. The path with an NLRP3 compound in disease indications is still; it still needs to be mapped out. And I think what you need is a good selective drug that can, you know, thoughtfully probe proof-of-concept trials like we did or mechanism like we did in the CANTOS trial and then design other trials efficiently to go understand sort of how to connect these dots. Eventually, you have to show efficacy in a longer-term trial in a disease-modifying endpoint. Okay. So let's focus on the, on 3232. And I think we all can appreciate why you chose obesity. But you had a host of other indications you could have chosen from, prioritize Parkinson's and obesity. Can you maybe talk about why Parkinson's is a good, you know, first initial effort? Yeah. So, more and more in the literature, there's an understanding that neurodegenerative diseases really are triggered by neuroinflammatory signaling. So in the case of Parkinson's, the aberrant signaling in the microglia is believed to be one of the trigger points for eventually what causes neuronal death. And so people have been again connected dots in early in vitro studies and the work in understanding the role of these molecules, showing potent effects on microglia, showing effects on downregulation of cytokines like IL-6, like hsCRP. And so there's a growing body of evidence that amongst the various diseases you can look at, whether it's Parkinson's or Alzheimer's or progressive MS, even more orphan diseases like ALS, there's a body of evidence that Parkinson's is where much of the weight of evidence exists. And so we've always planned to move this compound into a proof-of-concept trial. This was, prior to obesity, excitement. And then with the emerging data on the role of, or potential role of NLRP3 in, controlling feeding mechanisms and, weight control, we think we are really well set up to, again, use a good compound, a compound we know is CNS penetrant. We can have a PK/PD calibration to explore this hypothesis because none of this has been proven before. There's no tried-and-true path. So if you do this, you will have this outcome. Okay. When you think about the data that supports moving into obesity, can you talk about the different supports? I think there's obviously been a big focus on some of the external data that's been generated by a competitor here. Definitely some questions around that data. But there's other data points that are supportive as well. And maybe just draw that map for us. Yeah. Maybe, Marty, you wanna talk about some of the other data points supporting it? And I'll take the. Yeah. I'll start. And Carter, I just wanted to thank you once again for inviting us to the conference. It's always one of our favorite firesides of the year. So good to be here. And you're asking about obesity. So, I mean, obviously, in the obesity setting, you've got upregulation of NLRP3. You've got a bunch of kind of clear biomarkers downstream of NLRP3 activation that are elevated consistently in obese patients. You're talking about IL-1 beta, IL-6, hsCRP. So there's kind of long been known sort of a linkage between obesity and inflammation. And you see that both centrally with kind of new evolving evidence kind of showing hypothalamic inflammation, both driving and potentially contributing to obesity and potentially being a mechanism by which you can sort of reverse that cascade. and you also have a lot of a weightier amount of evidence, with peripheral inflammation that occurs, as part of metabolic syndrome and obese patients over time. So you see that in the adipose tissue. You see that, you know, kind of broadly throughout, the systemic setting. Yeah. So in terms of the recent animal data that was published by a competitor, if you look at that study and that mouse study, the obese mouse study has been used as sort of a catch-all study for a number of indications, so whether it's insulin resistance, whether it's obesity, other aspects of metabolic signaling. So it's a question of what endpoints you want from that model. No model, as you know, can truly mimic what happens in human disease. But if you look at the aspects of that model, you have proper controls in that study, you can then have a good assessment of what the path you're looking for in terms of making sure your compound is truly CNS penetrant. It's driven by CNS NLRP3 CNS inflammatory signaling. We think that data that was published is consistent with what has been shown, which is the role of NLRP3 and by conversely blocking it, an inhibitor, the effect on weight, with controls, with semaglutide as a control as well. For us, however, you know, as we showed with our compound 3232, we have an extremely well-behaved compound. We can dose it at meaningful doses QD and further build upon this evidence in our own studies with our own controls and further validate this part of the program. I think, again, eventually, you have to show this in a human trial. We pointed out our plan is to go into a biomarker study. You have to have a basis for establishing the neuroinflammatory part of this, whether it's in Parkinson's, whether it's obesity, because if that's a trigger, that's a starting point for your connecting the dots. And then we'll also look at these are small trials. And we'll look at, potentially effect on weight as well. But the primary focus of these trials, these short trials, is to establish robust biomarkers in periphery but equally or more important in the CSF. And I think that are. And sorry if I could just add also. In the obesity, the initial study, we're looking at a 28-day study. We'll be looking at that in patients with elevated cardiovascular risk factors as well. So we'll be looking at patients with a high baseline hsCRP and other factors that'll be used as a screen and a cutoff to make sure we're enrolling appropriate patients that are amenable to the mechanism. Right. So with the existing GLP-1s, there's been debate around how much is the impact on inflammation directly from the molecule, how much of it is downstream from weight loss and other, you know, improvement, other markers. What do we know about that? I mean, certainly, semaglutide showed impacts on CRP and in their outcome study. When you try to untangle this, where do you sort of use your anchor points in terms of then what you need to show to be, you know, be relevant in the conversation then coming out of your phase I? I mean, I guess, you know, again, there's a lot of science that needs to still be. There's still a lot of unknowns here. Right. Our thinking is that the inflammation and the obesity are sort of tied. And there's a feedback mechanism that exists that's obesity is driving inflammation. Inflammation is driving obesity. And it's sort of an unhealthy cycle that's occurring. And kind of intervening and breaking that at different points could be useful. There's also potential to sort of mechanistically, I think, combine given the well-tolerability of the NLRP3 obviously, we need to still establish safety along with some studies. But the drug was very tolerable in phase I study, really no GI symptoms to speak of whatsoever. So kind of an interesting also potential accompaniment to GLP-1 therapy. Okay. And so that study's gonna start when, and we're gonna get data when, Marty? We'll initiate the 28-day study in the back half of the year. It should be a fairly quick study to conduct. So, you know, for now, we're thinking we'll have a data point in early 2025. And as we get closer to enrolling that study and finalize the protocol, we'll be more specific about timeline expectations. Similarly in Parkinson's? Parkinson's will initiate around the same time. It's gonna take a little longer to enroll. We're doing, you know, more invasive measures. They're obviously doing CSF sampling pre and post 28-day treatment. That'll take longer to enroll. We'll have that data later in 2025. Okay. Maybe if we come back to the peripheral acting, you know, program, maybe just put in context kind of how you think about, you know, what would be a, you know, put that data, I guess, in the context of what we've seen with CANTOS and MACE already. Yeah. Why don't you start with that? Yeah. Absolutely. So from the cardiovascular perspective, there's a couple data points that I think are sort of driving our interest in this and I think driving industry's interest overall, right? So the CANTOS study, what I believe it was, 2017, you saw a 15% MACE reduction. You saw, you know, kind of a healthy 30+% reduction in hsCRP. And kind of, I think, it validated this idea of IL-1 beta inhibition driving kind of, again, reduction of CRP through an IL-6 mediated mechanism, as a potentially potent impactor on MACE. You've seen since then, you've seen follow-up data from some long-term studies with colchicine, right, where you've seen 20+% MACE reduction, more robust. And colchicine is thought to have sort of an indirect NLRP3 inhibition effect. So I think that there's a very strong argument that there's a high expectation to expect benefit with a direct NLRP3 selective NLRP3 inhibition in the post-MI kind of secondary prevention setting. What there isn't is a well-tolerated oral, easy-to-use, you know, simple molecule. So I think that there's, kind of a very, you know, nicely partially de-risked pathway that we can kind of follow behind. So for phase II, you, you'd wanna just kind of establish, look at biomarkers, make sure you're achieving, the sorts of reductions in key biomarkers that you'd expect. We're looking into some possible imaging modalities as well to kind of further support evidence of efficacy. And then from there, you'd look to do those longer-term outcome studies, which, again, will, when we complete phase II, we'll kind of assess where we're at. But that may be something we wanna do with a partner given the size of those studies. Okay. So in the backdrop of all this, you still have the S1P and sort of talk about urgency to partner that, particularly as you're potentially turning over some cards that could, you know, be transformative for the company. Yeah. So, you know, we believe we've shown the data. We showed more data that continues to support the endoscopic image we showed in the induction part of the study. We've taken a small subset of folks in the open label and showed continued improvement in these endpoints. So, yeah, we have an urgency to actually move this into phase III. We're phase III ready. We have the CMC in place. We have an end-of-phase II meeting in early second quarter. And, you know, we think this molecule can, you know, add to the frontline therapy that's needed for UC patients. It has a differentiated endoscopic remission profile. It's an endoscopy score of 0. So that's, you know, we've started the initiatives. We'll continue to approach the partners. Be clear about that. And we'll come back and let you know where we are on our second IBD trial. This is the Crohn's ongoing Crohn's trial with VTX958, the TYK2 inhibitor. As we disclosed, we've now modified it. First of all, we changed the endpoint from a co-primary of endoscopic response to a primary of a CDAI score with, of course, secondary endpoints. We are now enrolling approximately 93 ± a few patients. And then we hope to have, so we have, complete enrollment in the next couple of weeks. And then we'll read the data out in the mid-year timeframe. And we'll have a good look at both the primary endpoint and the secondary endpoints. And based on the outcome, if there's a positive read, we will decide what the path forward is for this, whether it's our own development efforts or partnering this molecule. But we're not setting any external expectations until the data reads out. The data will speak for itself. Right. Maybe switching gears back to obesity, you know, you guys were very focused, not that long ago on, on INI. When you think about the in-house capabilities to, you know, to run the study and, I guess, maybe even more importantly, think about the potential next steps, is there additional build-out or, you know, bringing in either new people, consultants, etc., to help you with this process? Yeah. So, you know, we have an amazing network of external KOLs. We had that in the I&I space. We had that in dermatology. We have that in IBD. We just added a couple of folks that we showcased at the Analyst Day. So Ted Dawson and Marty Pomper. We'll continue to add external folks to build upon our knowledge in these areas. In terms of operational aspects, we have an amazing development team, so the CMC folks, the regulatory people, all the supporting QA, QC work, the trial ops people that actually manage these trials, and the people that design them. Actually, we have that infrastructure. Now, of course, as we transition into some of these newer areas, we will have to build in regulatory translational expertise and bring in clinical folks to add to that space. In terms of sort of the operating infrastructure, we've got a very competent team, very passionate about what they do. We'll add all needed resources to then make sure that, you know, we have an immaculate execution of these trials. Okay. And are you gonna be going back and doing some of that preclinical obesity work? Or at this point, it's gonna focus on sort of what the clinical improvement is? Well, you know, we've guided folks, as Marty said, to the commitment is to start the obesity trial in the second half of the year. Yeah. But we will continue to build the understanding in a non-clinical space. We are running the animal model that we just talked about. We'll have data for that model, again, mid-year. Other aspects, so again, I said, connecting the dots. We will continue to do that. But the phase II-A trial is independent of the animal work. Okay. Maybe just the last question. As you think about the strategic optionality that this obesity piece opens up, a lot of different directions you could go in. You know, we'll have two individual, kind of enrollment-free assets, which, I guess, open up avenues to potentially partner one or the other. Any reason why that wouldn't be foreseeable in the future or why, you know, having both would, you know, restrict you in any way? No. Because we, you know, we plan to develop these compounds orthogonally for separate design applications. There's different commercial pricing, opportunities for both of these drugs. And I, you know, there's different paths for this molecule. In the near term, as I said on the, on the Analyst Day, we don't we're not focused on primarily focused on partnering. These are focuses to execute laser, laser-focused on executing it. But again, you know, we look at every opportunity that, that comes our way. But the true value creation really is at a phase II. You've shown efficacy and safety in a disease population. And I think there's a mix of folks that have an interest in peripheral diseases. There's clearly a focus on obesity now with certain folks. And there's folks that have interest in a sort of a broader control of, of, metabolic inflammation. I think, you know, our goal is to make sure these compounds establish a robust proof of mechanism as we plan to do. Then, you know, we'll take other opportunities as they come. Okay. Well, we'll leave it there. Ventyx, thank you very much for joining us on stage today. Yeah. Carter, thank you as always. Pleasure.