Good morning, everyone, and welcome back to Oppenheimer's 34th Annual Healthcare Conference. I'm Jeff Jones, one of the senior analysts here on the biotech team. With that, I'm delighted to welcome, Raju Mohan, the CEO, and Marty Auster, CFO of Ventyx Biosciences, to give us an update on the story. Thanks, Jeff. Thanks, Jeff. So, I guess the place to begin is, obviously on the, you know, sort of transition from 958, and as we're focusing in now on the S1P program. Why don't we talk a little bit about the S1P program, refreshing on the data you've shared to date and sort of as we look forward into phase III? Yeah. Well, thanks again, and a pleasure to be here with Marty. So, refreshing the S1P1 UC trial data with VTX002. As you recall, we had presented the 13-week induction data with this compound. We had two doses, the two active doses, 30 mg and 60 mg. Both doses met the primary endpoint of clinical remission, which was the primary endpoint. We had a 17% clinical remission at the top dose, with both doses meeting stat sig in that trial. We also had an endoscopic remission for the top dose, 60 mg, at placebo-adjusted 22% and a 29% absolute endoscopic remission in that trial. And that is unmatched. The most you see with almost all the drugs in that 10% range, with the only one that approaches this magnitude is Rinvoq. We also showed concurrently a thread of data that would support this, so both in terms of of clinical remission, endoscopic remission, double remission, as we called it, histopathology that would align itself with these data and lymphocyte reductions that we had shown early on where, again, we have achieved the level of of PD biomarker suppression with this drug, again, not seen with the other S1P1s in this class as well. So we had laid that data out, including the exposure response, the PD markers, the clinical response that I just mentioned. So what we have now, and we've talked about this, there's two other sets of data that would come out. One is the open-label, reminding folks that in this trial I'm not gonna go into the nuance there, but let's, for clarity, we had a bolus of patients that went into the open-label extension after week 13. And in the first part of the protocol, these were all everybody who completed 13 weeks went into the open-label trial. So you would have a cohort of patients that were on placebo. You'd have cohorts of patients on the 30 mg, and you had cohorts of patients on the 60 mg, right? And when these folks complete week 39, so this is a total of 52 weeks now, post the 13 weeks, we will now have similar data that you saw before, which was the clinical remission, the endoscopic remission, all the other ancillaries that come with it. So the PD markers, the biopsies. And there, again, we hope to show the response we showed before, so durability, hopefully maintained, if not improved, across all of the cohorts, right? And I think the key would be when we zone into the placebo cohort, which is now would have been on the 60 mg dose for 39 weeks, what is the clinical remission? What is the endoscopic remission in particular with these? Because that will then also add to the strength of our data before. And perhaps a few folks that look at this response and say, "Well, you achieved it. Now show us how this can be reproduced." Obviously, we believe it'll also reproduce in phase III trials. But showing this in this cohort in particular, the placebo cohort, will be a validation of that data. And then, of course, we have the long-term extension, which was the second part of the protocol that we had to amend, was that folks that responded that had responded week 13 continued on their original dose for additional 39 weeks. They would complete the full, full 52 weeks. And that data would come out sometime in a very early part of the second half or early part of the third quarter. We should have that data. So that's when the, as you recall, the last patient went in last year, May timeframe, we announced the completion of enrollment in both trials. So a year after that, one year, you will see this data now. And so sometime in the June, July timeframe, we will have that. So that's the flow that you would, see this year. But the first part of the first additional data that we would present would be the open-l abel extension and the further validation, we hope, of the endoscopic remission and maintenance and durability, and hopefully improved durability of that data. Right. So the open- label extension data, when would we be looking for that, do you think? So we've guided folks towards a number of data points in the first quarter of this year. So, that's about as specific as I'd like to get today. But that's, you know, we're just not. If we're halfway through, that makes, you know. Correct. Certainly, near term. Second half of the first quarter. How about that? There you go. So, not today, necessarily. And as we look at where an S1P sits in this universe, you know, for other UC products, and you mentioned the JAK inhibitors, some of the other, ozanimod obviously being on the market, that one being a little more complicated, and etrasimod just recently launching. Sort of how does this fit, as you think about the injectable, the oral story, and then the story amongst the orals? Yeah. And, you know, let me just lead off, and I'll have Marty add to this, because this is an important point, I think, for folks to understand. So number one, the S1P1 class now has hundreds and thousands of safety patient data, right? So relative to drugs in this class and JAK inhibitors in particular, but even the newer modalities coming in out there, there isn't this level of safety data that's been put out there. Our titration regimen shows that you pretty much mitigate any cardiovascular concerns, both on the conductance side as well as the bradycardia side with this drug. And there is virtually little risk of infection that's been shown, again, with a number of trials, not just in the UC space and the MS space, right? And as you know, JAK inhibitors have a line of use restriction. So we believe, and I think this is the thesis that Pfizer put out a week ago, that, you know, the goal is to have position this molecule as first-line therapy. And I think we should stop thinking as S1P1 for us necessarily as, you know, behind etrasimod. I would like to think of this drug as best in class, if not best in therapy, right? And the data bear out. And two points there is the phase II data we showed shows unmatched endoscopic remission, which is sort of a key aspirational goal for gastroenterologists to get a score of zero, right? Perhaps in the near-term setting is, you know, less consequential, but long-term effects on disease pathology with a score like this has much, much better prognosis than any other parameter out there, the endoscopic remission. So again, we believe that we have an unmatched endoscopic remission. Phase II data in these trials of phase III data has, in most cases, maintained the effects you've seen, and that's been shown with a number of drugs, including etrasimod, with the endo remission in the 10% range was maintained across the phase II trials. And then the two phase III that ran the UC12 and the UC52 there as well, right? Marty, you want to add to the positioning of this drug in particular? Sure. Yeah. I mean, I agree with what you were saying. I think there's a number of slots this can fill into, Jeff. You know, as Raju indicated, there is a clear need for folks, especially in sort of the moderate and moderate to severe, that are needing a more potent therapy than maybe mesalamine or some of the less effective early-stage therapies that are used. There's a lot of reluctance to go to an injectable. You've got a safe oral molecule with competitive, if not competitive, plus, efficacy to some of the biologics that are frontline, like HUMIRA. So, this is a pretty attractive slotting in for frontline for those patients. If you look at more treatment-experienced patients, the durability and sustainability of remissions and even the achievement of remission in the induction phase with the biologic agents, on a gross basis is often in the 20s% and 30s% range with a delta in the 10%-15% range versus placebo. So you're clearly many patients, most patients are not achieving kind of a peak clinical response. And certainly, that's not being held up as durable over time, with some of these therapies to varying degrees. So there's opportunities there. And then finally, I think long-term, you're seeing more and more interest from clinicians and as well as from industry in exploring combination strategies. So again, the ability to add on a safe therapy that's oral, could be combined with a biologic, could be an add-on. You could end up seeing induction with sort of a combination approach and then maintenance with kind of a long-term, oral approach that could make a lot of sense, too. So we're starting to think more and more about those types of regimens. Okay. In terms of the end- of- phase II meetings with the agency, kicking off the phase III, where do you guys sit as we start to look at, I guess, short-term and longer-term timelines around the program? Yeah. So we've planned the end-of-phase II meeting in the sort of the Q1-Q2 interface. That a lot depends on the agency and their availability in this world we live in today. So that's on track. And then, we've been planning for a phase III start in the early third quarter. And we remain on track for that. So again, all the talks and the CMC work is all in place. You know, we've got a very efficient machinery here to run these trials. You know, our recruitment in this trial was, again, very efficient. And so we're all on track for what we've guided the folks. CMC, I assume, as well in terms of material availability and scale. Everything. Yeah, everything. So both the API and the drug product, which is the tablets, all in place. Then have you guided it all in terms of timelines that you're thinking about for the phase III to run? Obviously, it's a long-term study with and relatively large. Are we thinking, you know, 2026-type readout? I think once we've had our FDA meetings and we're further along the planning phase, we'll probably talk more about sort of our design thoughts and things like that. But I think it's important to get through that step before we project timelines. Fair enough. Okay. Pretty standard phase III trial, though, you know. Yeah. In terms of 958, you know, you still have, as we think about Q1, you've still got, you know, this, the Crohn's readout anticipated this quarter. I guess any updates there? Is Is that still on, still planning to read that out? We have planned to read that out. You know, we've always targeted a certain number of patients to complete this data. I remember the original trial was 132 patients that we've guided folks with two active doses, right? And we've told folks that we would do a, called an interim analysis. But we want to make sure this analysis then powered with, you know, sufficient number of patients, right? So that'll determine sort of the timing of when these folks will complete the 12-week induction data. So stay tuned, because we, you know, we, that's where we are right now. So once we reach that point, obviously, it starts the clock with the 12-week, and then, of course, there's all the processing. So just stay tuned. Got it. I mean, any issues with, you know, maintaining those patients and/or enrolling those patients given the psoriasis results or, you know, the strategic decisions you had to make around the program? None. Right? So remember, each of these trials is a standalone, our relationship with the CROs. And, you know, obviously, patients, just like in the psoriasis trial, we had no problems enrolling there because people want oral therapies. And the same goes here. So again, the moderate to severe Crohn's folks want an oral therapy here. It's a different value proposition. There is no really a safe, I would say, a safe and effective oral therapy. So no, it's just a typical enrollment in these trials, as you see, sort of the hockey stick phenomena. And what happens? I mean, the trial was, you know, well designed. So no, there is no effect of psoriasis trial. And we handled that very professionally with our sites. And so again, there's no issues with what we did with the psoriasis style, no bearing on the Crohn's. Okay. And then the other thing we really have coming out this quarter is the NLRP3 programs, the 2735 and 3232. You know, obviously, some really interesting opportunities there. Can you sort of update on where you are on those and what you're thinking about those programs strategically? Yeah, yeah. Super excited about the program. You know, here's a case where, you know, we're sort of pioneering. I would certainly say the clinical path with these drugs. You know, these NLRP3 inhibitors have been around for, as you know, Jeff, for many, many years. The small molecule compounds were initially the IFM, Novartis, and then Inflazome and a bunch of other companies. And we've always strong belief in the safety and efficacy of these compounds through the non-clinical work that we did. It's just the focus has been so much on our IBD drugs, S1P1, Crohn's, and the 958. So, we're super excited that we managed to now complete two major milestones with these drugs. So with the peripheral compound VTX2735, we are wrapping up our CAPS study. So remember, we had shown phase I data for this compound a couple of years back. We initiated a CAPS trial, which is a proof of mechanism. This is a direct effect of a gain of function mutation of NLRP3 in these patients. Not an easy trial to run, given the small number of patients and folks that are on biologics. But we've managed to complete this trial. We will share this data as part of our Q1 update that we promised folks last year. So that's with the peripheral compounds. That's 2735. That's in CAPS patients. Again, you'll have the data that's germane to these patients that we'll disclose. On the second compound, VTX3232, this is our CNS penetrant molecule. Again, reminding folks that there has never been a true brain penetrant compound disclosed. Often, folks have taken the peripheral compound at large doses and shown effects in the order of small distribution, low distribution in the brain. So here we have a compound that we've shared some data, and some of it is on our public disclosures. Very potent compound. Non-clinical data has shown a balance, a really balanced distribution between the periphery and the central compartment. Certainly, we can do invasive studies in animals. But in our phase I study with this compound, which is in healthy volunteers, but here, we have not only a measure of peripheral circulation of this drug, we also have level of exposure in the CSF. CSF is a surrogate marker for brain exposure. So a free fraction in the brain is measured by CSF levels. And then we have biomarkers both in periphery as well as in the CSF. So this trial, again, is now complete. And we're wrapping up all of the data for this trial. And we hope to present, again, a PK safety biomarker in periphery, as well as drug exposure in the CSF, calibrated to our IC50 and IC90, both in whole blood, as well as in human microglia. So that's a very important calibration, because we've run this assay in primary human cells-derived microglia as well. And then, of course, biomarkers, IL-1 beta and other biomarkers, both in blood, through an ex vivo assay, and sort of a de novo response on baseline levels of biomarkers in these folks, so pre-dose and post 14 days of dosing. So very comprehensive safety exposure readout that we will share with folks. And then also our plans to progress these compounds into further studies, phase II studies, both on the periphery as well as the CNS molecules. So expect a very comprehensive update. And again, as you started out by saying, it's very interesting compounds. We've just never given them the day in the sun, partly because the focus has been on, you know, on our phase II studies we were doing last year, both for the UC compound as well as for the 958. And also because we've completed key studies here, a proof of mechanism in one case, and certainly CNS, CSF exposure, which has again not been shown by other folks that we hope to show. Right. Okay. In terms of strategically around the NLRP3 programs, you were just mentioning potentially moving to phase II. You've also talked about outlicensing at different points, you know, depending on the emphases in the Ventyx story at different time points. So how are you thinking about these programs strategically, in terms of next steps once you have in hand data packages, both in CAPS and safety for the 3232 compound? Yeah. So, you know, certainly we have a lot of interest from folks over the years in orals and our ability to develop safe and effective oral compounds, a lot of interest from people. NLRP3 is an area where a number of companies have acquired or developed compounds that have stalled in phase I studies, really haven't seen much progress. I don't think that bears on the target. I think it's simply, I think, compounds that went in too soon hit some hurdles in phase I studies and sort of go back and reengineer their compounds. So again, you know, these are large indications, eventually, you know, belong in the hands of folks that can accelerate development. But we also believe that the true value of compounds really for us is once you've shown efficacy and safety in patients and proof of concept, right? Whether it's the CNS side or it's the periphery side. So we'll explore all options, but we certainly have the ability, like we had for 958 and 002, to move these compounds through phase II proof of concept. These are, you know, studies that are, again, well within what we've been planning with these compounds. So we're not going to go into, you know, how and what we do with these compounds eventually. But we are prepared. We are geared. We will show you our development plan through phase II with these molecules. And I think anything beyond that, you know, will remain on the strength of the data we generate with these compounds. Marty, anything to add to that? No, I think that's well said. Okay. Okay. And obviously, yeah, I guess interesting timing with VTX2735 with the CAPS, the CAPS study serving as proof of mechanism, proof of concept there. So that could be something maybe that there's earlier interest in. But you certainly have the capabilities to run phase II trials and, you know, picking the right indication. Yeah, I mean, these phase II trials, as you know this, are biomarker trials. They are mostly safety exposure and, you know, relevant biomarkers, whether it's in a, you know, in a spectrum of peripheral indications or some of the neurodegenerative studies that have been done, there's certainly a precedent out there. And, you know, I think this having a molecule or both molecules, certainly the 3232 with the CNS side is I think it's a, you know, it's a first mover in this class and super excited about that. Okay. In terms of, you know, you've talked in the past a little bit about your pipeline beyond the NLRP3s. You know, is there anything on the horizon in terms of near-term IND filings and other programs you might be talking about? Yeah, so we haven't disclosed specifics of our discovery pipeline. We typically do that as we get closer to development compounds. So again, stay tuned. I think what I would say there is, as we get into the CNS space with our compounds and a sort of a broader set of pathways that triangulate towards the neuroinflammatory space, we continue to look at newer opportunities there and, you know, bring our chemistry engine to that space. In some cases, these are complementary to the inflammasome pathway, so to speak. In some cases, they fill the gap that exists between various pathways and what's expected in sort of disease remission as well. So just stay tuned. We will certainly talk about these compounds in the next, I would say, in the next few quarters as these mature, right? Okay. Just a clarification question that came in online. For both 27 and 35, do you anticipate those updates, clinical updates coming in Q1, or do you think those will be Q2? Q1. Okay. Thank you. And then in terms of financials, obviously, you've got a pretty substantial financial position at this point, but looking to drive into a phase III study, a long-term large phase III study. So can you comment sort of how you're thinking about runway and sort of the longer term? Yeah, Marty, you want to take that? Yeah, I can take that. So at the end of Q3, reported $300 million in cash, Jeff. I think what we've said holds true, which is that the burn rate will be a bit elevated due to some of the wind down of the 958 psoriasis psoriatic arthritis trial in Q4. And that'll start to dissipate out a little bit and reduce as we get into 2024. Runway wise, we've, you know, provided guidance for capital into 2025. We've also said that with the changes to the psoriasis program, we expect that to extend out by several quarters. So we'll be more specific as we make our phase I updates and kind of lay out the next steps clinically over the coming month or two. We'll be more kind of specific about what that runway looks like and what we hope to achieve with the capital on hand. Certainly, as we're looking to embark on kind of the next steps, phase II trials with the NLRP3 program, phase III with 002, we're very mindful of sort of where we're and where our capital needs will be and we'll be making kind of our strategic decisions in line with that. Yep. Appreciate that. And obviously, you know, 1Q's reporting's coming up soon. So we'll well, not 1Q, 4Q. So we'll get those end-of-year updates and your latest thinking in the coming weeks, more or less. Gentlemen, I think we are almost up on time. And I think we will close it out if I don't have any additional questions coming on. So, operator, why don't you take us clear? Yeah. Thanks, Jeff. Thanks, guys. Yeah.