All right. Good afternoon, everyone. Thank you for joining our Piper Sandler Healthcare Conference. Excited to have the team from Ventyx Biosciences here with us. We have lots to cover in the next 25 minutes, so let's get started. Let's get started. Let's do it. Raju, Marty, wonderful to have you. Maybe a good place to start is to talk about Crohn's data upcoming in 1Q 2024. As you could imagine, I think, investors and analysts, which we were surprised on the discontinuation of PsA and psoriatic arthritis. But we're looking forward to the Crohn's data, and I think the first fundamental question that exists is, what is the strongest data in your view right now. Mm-hmm. That warrants moving forward with this asset in Crohn's? We'll talk about all the other elements of the readout, but we'll start there. Yeah. Yeah, good. Yeah. Thanks, Yasmeen. Happy to be here. So first, you know, we discontinued the trial for psoriasis and PsA for reasons that really are more business reasons. Mm-hmm. The idea that this compound didn't meet the expectations— Mm-hmm. We had for efficacy in psoriasis, and we had a read-through into PsA. Mm-hmm Based on other people's data, so that was the reason we're discontinuing it. It wasn't because the compound didn't meet its endpoint, it did. Mm-hmm But it just wasn't something that we want to develop ourselves or raise capital around a phase III study. So that was the reason. Now, in terms of the Crohn's study, look, we don't have any data to support us saying that this is going to be viable in Crohn's, right? Mm-hmm. The way we look at it, Crohn's, the Crohn's is a whole different value proposition than psoriasis. Mm-hmm. It's a much bigger opportunity. There's no real safe and effective Crohn's drugs out there other than RINVOQ. Mm-hmm. The incremental cost of doing this study, the interim analysis. Mm-hmm Is single-digit millions. It's, we'll look at it thoughtfully in terms of the readouts. Mm-hmm. It'll have to be a convincing readout for us, based on certain endpoints, that we understand from the IBD space. Mm-hmm. We'll decide to then, either discontinue like we did. Mm-hmm The other two trials or outline a path forward once we have that data. But it's really an opportunity. Mm-hmm. It's the trial is, what? 40% recruited already. Yeah. So, you know, we'll have a good 50-60 patients by the time we— Mm-hmm We read the trial out. And, I mean, we do have a hypothesis. Mm-hmm. I won't say hypothesis, but we have data from non-clinical distribution studies of VTX958— Mm-hmm That show that we have much higher levels— Mm-hmm Of drug in the gut wall. Mm-hmm Across the different components of the gut wall, relative to drug in— Mm-hmm Plasma. Mm-hmm. So that's, that's objective data. Now, when there's a— If and when there's a positive outcome, we'd like to understand is that what's causing it as best as we can. Mm-hmm. So that's really the reason for— Mm-hmm Continuing this trial. Team, what were the factors for deciding not to continue this study to full enrollment and then unblind it? Why do the interim? Is it just to get an earlier go, no-go decision, or what was it? Well, I think. Mm-hmm I think the conventional wisdom or the headwinds is, like, why would this thing work and— Yeah. Why would you be competitive here in Crohn's? Mm-hmm. A, because you didn't quite get what you said you would get— Yeah In psoriasis, number one. Number two, there is this, so TYK2 failed in UC— Mm-hmm Failed in Crohn's, right? Yeah. So I think it's. This is not a pivotal trial. Mm-hmm. This wasn't designed to be a registrational trial. Yeah. We're not taking any kind of a hit in terms of— Mm-hmm You know, if it's a positive read and we'll be thoughtful— Mm-hmm About it, then there is a path forward, and we'll talk about that. If it's not, then, you know. Yeah We would have dealt with it early— Yeah Than sort of running two UC trials. Yeah And a Crohn's trial— Yeah That TYK2 has done. So that's really it. That's the reason. Got it. it. And do you think that, I think the question that investors also have is, given that it's an interim and it's a smaller population, like, what type of signals do you need to see that gives us an inclination, "Okay, this product profile looks competitive, and therefore we should move forward?" Like, what is the, you would see— Yeah, good question. Signal? Yeah, so the trial has co-primary endpoints. Yeah. One is the CDAI index, and one is the endoscopic response rate. So similar to what you've seen with- Yeah The approvable trials of other drugs. If you look at, you know, the comp group for this would be like the IL-23 antibodies. Okay. If you look at recent data from those drugs, you've seen, you know, endoscopic response rates in the high teens into the 20s. Okay Low 20s. Something, something in that ballpark would be— Mm-hmm Sort of a strong signal. Yeah. You know, I think in general, we'll put more, probably more thought and more weight on— Yeah Onto the endoscopic. Yeah Response scores relative to the CDAI indexes— Mm-hmm 'Cause it tends to be a little bit more objective, a little less— Mm-hmm Placebo variance. So. Obviously, there's no chance to detect statistical differences, so the rates that you were referring to is, if they're in that ballpark without showing a statistical— We're continuing to enroll the trial, right? Yeah. So, you know, where we're at at the time of the psoriasis update was, I think Bill indicated that was a little over 40%— Yeah Enrolled. So Enrolled. So that's a reasonable point to sort of— Okay Take a look and try to figure out. But again, we want to have that 12-week— Yeah Endoscopy data for a healthy enough— Mm-hmm Proportion of this trial to make that make sense. And just, you know, obviously looking for a signal. And, another question that we have gotten is, have you— do you guys get a chance to look at blinded Crohn's data? Is it meaningful to look at blinded data if things are tracking in that direction? I think the— or difficult to do so? Well, the clinical group's always looking at the— Yeah Blinded data in terms of safety. Yeah No, and I think just for the questions you exactly asked, which is, you know, we've got to get to a meaningful. I mean, what decision would you make. Yeah From the blinded data, right? And again, the cost of running it, the timeframe from getting to the interim analysis, these are all within- Mm-hmm Real, finite, defined times. You know, we'll get this data out by Q1. Mm-hmm. You've got to have a certain number of patients. Yeah Before you start to really make decisions, consequential decisions. Mm-hmm. Right? So yeah, so, not something that we're going to react to. Is there an opportunity by which, given that your product looked highly safe, like, you could come up with showing, you know, strong data on 25 and 300 mg versus placebo, but could potentially even think about doing another study to dose higher? Is there a reason to. But I guess we'll see when we get to that. We'll have to see, right? Yeah. The whole distribution, if the dist— Yeah. First of all, first of all, there has to be a positive answer. Yeah, yeah. And we're optimistic about that, cautiously. Mm-hmm. Without setting any expectations, Mm-hmm. To make it clear. Number two, we'll have to look at understanding why. Mm-hmm. If it is a distribution model, then I think sort of the exposure modeling and blood becomes— Mm-hmm Less relevant. Yeah. One could argue you could dose lower. Yeah. I mean, we'll have to see. Yeah. We'll see how it plays out, right? Okay. Remember, we have two doses in there. Yeah. Two high doses. Yeah. We'll have to see what the dose response is, if there's a dose response. Yeah. And again, there's a placebo, too. Yeah which I think sometimes when we've had interactions, people don't Mm-hmm Appreciate. Yeah. So, it is a, you know, it's going to be a smaller initial— Yeah Look, but it's, you know, it's a controlled look, so. Got it. And then is there an opportunity to think about, post that readout, to think of other indication for this, for which this asset makes sense? Or let's see the Crohn's data and then go from there? Well, let's see. Yeah. We've got a lot on our plate right now. Yeah. We'll have to look at the entire portfolio. But, yeah, I think that's a fair thing. Yeah. We saw. Yeah, I'm just going to leave it there. Yeah. So let's maybe move on, on your S1P1, which you had a really strong readout. I think the hiccup for the Street is that maybe they don't understand the key differentiation that your product has shown. So could you maybe walk them through, based on the phase IIb data, what is the differentiation versus other S1P1s that are currently on the market? Yeah. You, me? Yeah. Sure. So yeah, that trial was designed to look at— Yeah Dose-response between two dose groups— Yeah Targeting lymphocyte reduction that was sort of— Yeah Similar to ozanimod, etrasimod— Yeah The other S1Ps developed in the class. Yeah and for UC, versus a higher dose, which is going to target— Mm-hmm A higher level of lymphocyte reduction. We successfully achieved— Mm-hmm That biomarker effect. We were able to achieve a high 60%— Mm-hmm Absolute lymphocyte reduction, which was quite a bit, about— Yeah 30% stronger Yeah Than you'd seen with other drugs approved in UC. You know, and then that data then corresponded with— Mm-hmm A clinical remission and endoscopic remission Yeah Rates that were, you know, endoscopic remission rates were best in class. Yeah And really best across across UC development and and controlled studies. So that was really encouraging to us. Mm-hmm. You know, we're pretty happy with the outcome there. Okay. And then, I think in terms of now, since the data that read out, have you had a chance to engage with the agency and discuss sort of pivotal phase III designs? Or if not, if it hasn't occurred, when is those activities going to be in place? Yeah, so that's going to happen around the first quarter timeframe. Exactly— Okay When we won't disclose, but it's on track. Mm-hmm. When we'll do it as expeditiously as possible. A lot goes into that. Yeah. We have to do a lot of population modeling, PK modeling. Okay. Get everything lined up. We don't see that as anything. I mean, this is the third S1P1— Yeah In this class. They're well familiar with the target, but we have to get all our ducks— Yeah Lined up before we do that, and that's going to happen. But no, there's no anxiety around it. Yeah. It's just a process the team— Yeah Had to follow once the data came out. We have an open label— Yeah Extension piece of the data. Yeah. That will wrap up, and, you know, we said we're going to disclose that in Q1. Mm-hmm. That goes into the briefing book. So, you know, the goal really is to have the agency and us agree on a— Mm-hmm Single phase III trial that's going to be registrational, because we believe in our mind that the first one we just completed is also the maintenance part of the— Yeah Two-part trial. You know, we plan to have a single dose trial. Mm-hmm. All that has to wrap itself. For the OLE data that you're going to get, how large is that cohort going to be for when it reads out in 1Q? It'll, you know, it'll be a significant number of patients— Okay That have completed week 39. Okay. There's some nuances to it. Yeah. We don't need to go into how the, t here was a slight change in the protocol. Mm-hmm. There will be a significant number of patients that would have completed the open-label portion of the trial. What do you hope to—which, what should we, historically speaking, when we've looked in S1P1s, like, what we would, we want to see in that at that time point, just continued improvement in endoscopy and clinical remission, like, sort of like a linearity, or even more, could potentially see further improvement? Like, what, what do you hope to see in that- Yeah. Data? Well, I'll tell you. You know, I think that people have really haven't seen too many surprises— Yeah with open-label piece. Each open-label has its own nuance. Yeah. So ours, like I said, we can talk about it some other point. Mm-hmm this particular open label arm has evolved. But, you know, you'd see your biomarkers- Mm-hmm. and lymphocyte data. You'd look at your primary and secondary- Mm-hmm Endpoints, and, I mean, this is a, this is a full look. It's an endoscopic- Yeah Look at it, so, but again, we don't necessarily expect any surprises- Got it In the, based on what's been seen historically with durability Yeah. I would say, let's not even call it open label, with durability of- Mm-hmm Of efficacy with S1P1 molecules. No, that's great. And team, the other question that comes up is: Is your strategy to run the phase IIIs on your own, or is this an asset that obviously, historically attractive partnership, you would be actively looking for, you know, partnering, partnering this for phase III? Yeah. So, you know, this, the profile of this compound necessitates a phase III study. Mm-hmm. We think this is an approvable drug. It's differentiated. It's one of the few small molecules outside- Mm-hmm The S1P1 label that has shown this kind of safety and efficacy- Mm-hmm As a class. Right. Whether we do it ourselves or whether we partner, it is all gonna depend on how the portfolio plays out in the next- Mm-hmm Next quarter, in Q1. Yeah. Yeah, I think that's it. Okay. Whether it's a partnership and, you know, and we have to make those decisions based on where the other Yeah Where all the other assets play out, including the Crohn's readout. But we're planning for a phase III study. Mm-hmm. We've got all the CMC work in place. We're planning- Yeah For the agency interaction in the first quarter, and, and- Yeah And then we'll also look at- Yeah Where we are in terms of other readouts- Yeah Financing. Everything is on the table. Okay. And then who's running the efforts right now, now that will be effective as the chief medical operations? You know, like, maybe if you could talk about, you know, the announcement on, I think- Yeah. So- Last week. Yeah. Yeah. So you actually answered the question of who's running the operations, right? Mm-hmm. We have a very strong clinical group- Mm-hmm That, as it turns out, you know, collectively have run- Mm-hmm At least two, if not three, phase III trials- Mm-hmm For S1P1. Mm-hmm. Right? So we have folks that have- Yeah Done the two UC trials- Yeah For Arena. There's some folks that even have a Receptos legacy. Mm-hmm. The ClinOps group that has done these trials- Mm-hmm. There's absolutely no hiccup there. Okay. Right? And Bill will continue to be part of our advisory board. He's gonna be on the ClinOp board. Yeah. So from that sort of a guide perspective, he's there. But the day-to-day, I mean, I'd rather remind people, when we set up at Ventyx, the ClinOps and the ClinDev- Mm-hmm Were the first people out that we hired. Mm-hmm. There was no CMO at that point. Yeah. And so I think that's the, w e're comfortable with- Yeah With— It's the teams that are operating this now, that it will continue and, you know, nothing will— there's gonna be no hiccup there. And then, of course, Bill is available- Advisor As a CRO, and then we also have other folks on the team, like Sheila, who's- Mm-hmm Who ran the Receptos drug. Mm-hmm. So we have a lot of... And then we have advisors like Bruce Sands- Mm-hmm Who are all there for us as we need it, but. Okay, great. So now, maybe moving on to the NLRP3 program. So we also expect data from the CAPS program in 1Q for that program. Correct. It's a small study. It's in 10 patients. I guess the question also for a lot of investors that are new to CAPS is, like, how much heterogeneity exists in this patient population? Are you gonna get enough of a signal to establish a strong proof of concept to warrant, you know, insight on how this compound is doing? So what do you hope to gain at this data, especially to kind of frame it around? Yeah. You know, again, like more, like, almost like a bar for success for that study. Of course, it's not, we haven't committed to 10 patients. Yeah. We said up to 10 patients. Up to, yeah. Like those discounts you get at stores, they say up to 50%- Yeah But it's not gonna be. Secondly, my understanding, and we have a KOL who's been part of the trial, so Hal Hoffman has done this with biologics, obviously. Yeah. Marty can add to this. My understanding is from these trials, especially with the biologics that have been used, it's a pretty clear efficacy. Mm-hmm. It's a combination of certain biomarkers- Mm-hmm But also patient responses and how they feel. Mm-hmm. Like, once you take them off the biologics. Yeah. So we have two sets of patients, not us, but in general. Yeah. You have naive patients, and then you have patients that have- Yeah Been on biologics. Once you take them off the drug, right- Yeah They flare pretty rapidly. Oh, okay. Right? So joint aches, headaches- Mm-hmm Fever, and conversely, they respond- Mm-hmm Pretty quickly, right? So we should expect to see if the drug works, we should expect to see efficacy in these patients pretty rapidly. Mm-hmm. There isn't that much heterogeneity, at least in this particular subset. Mm-hmm. We haven't really talked about, m aybe we have. We're looking at a particular subset of these patients with a particular mutation- Mm-hmm Which make up about three-quarters of the patients. Mm-hmm. And amongst these, there isn't a lot of heterogeneity. In fact, much of this population actually is familial, so you would see mothers and daughters or husbands and kids that have- Yeah CAPS in the family. Is there any other readouts in CAPS with this NLRP3 that's already available that people can look at, or is there other upcoming CAPS catalysts in 2024? No, I mean, you can refer back to the- Yeah There's CAPS data in the labels for Ilaris- Yeah Canakinumab, as well as- Yeah Arcalyst rilonacept. Mm-hmm. Right? You can look at, if you look at Arcalyst, I believe they- Yeah They looked at like a mean symptom score- Okay Which is pretty similar to the composite mean symptom score we're looking at as our- Okay Primary efficacy endpoint in the phase II. So again, these are all small trials, obviously. Yeah. And some of those are fairly- Yeah Old as well. Those are, those are recent precedents. And, is there, you know, you have also the idea after CAPS is also you could build other indications. So is there an opportunity post that readout also to reevaluate and think about what are pipeline expansions with this program or, or? So we've done a thoughtful analysis- Yeah of potential opportunities for Yeah the peripheral molecule. We owe it to share that. Yeah. Right. But I think collectively, NLRP3 development is a, this is a big ask and, you know, there's a lot of- Yeah Unmet need, big, big markets. Yeah but large trials, some of them requiring outcome trials. Yeah. We can touch briefly about a CNS molecule, but, you know, we may consider a biomarker study- Mm-hmm At some point, but, but again, we'll have to play out the entire portfolio sometime in the first quarter, and we'll come with the guidance. But yeah, you could, you actually could do some early studies with the peripheral compound. Yeah. Okay. And then what about the CNS penetrant VTX3232? Yeah, so that's a- 32 That's a unique compound. There's not, t here's really no truly brain-penetrant drugs out there that have been disclosed. We have a different chemotype. Mm-hmm So it's a completely separate molecule from the peripheral compound. And what, what we hope to show in the phase I data in the first quarter is, again, safety. Mm-hmm Blood exposure, blood biomarker Mm-hmm Which is IL-1β, but then also drug levels in the CSF, cerebrospinal fluid, which is a measure of free drug in the brain. Mm-hmm. So actually look at unbound drug, and then, and then people who understand the biology of IL-1 beta- Mm-hmm Will understand from our assays. Mm-hmm What we've shown, what level of inhibition you would need with the exposure. Mm-hmm. Kind of like IC90- Yeah For TYK2. And, I think that's valid, sufficient for comfort that you've got drug now in the CSF. Mm-hmm. You're going to see the same exposures in the brain- Mm-hmm The free drug, and justifies a trial. And here it's a very different story because the indications that have been sort of understood for this- Mm-hmm Are Parkinson's, Alzheimer's Yeah MS, even down more complicated, more complex ALS, Huntington's. Mm-hmm. I think it really belongs in a small group of folks that actually do these trials. Mm-hmm. But we think our data will be, when we present- Mm-hmm Hopefully, hopefully will be compelling and clear that here's a drug. Mm-hmm in this pathway that has brain exposure. Mm-hmm The thresholds are such that you can actually treat folks. Mm-hmm or on these large trials. Yeah. That's what we're going to show in the first quarter. No, that's great. And then, team, we saw another. I mean, NLRP3 biology has been a very strong interest for large pharma. I think we saw last week also acquisition of another NLRP3 company, Caraway, that was present. So I guess at what junction do you entertain the idea of partnering the NLRP3 programs, whether it is, you know, VTX2735 or VTX3232? Like, do you want to get. I guess, how do you think about that franchise? I think we, you know, honestly, and this has been true even six months ago- Yeah We'll look at every opportunity. Yeah As it presents itself, right? So if it's something that fits with our portfolio- Yeah If it meets our financial model now for where we need to be with the portfolio, then absolutely. Yeah. But we don't need to make any hasty decisions today. Yeah. But you're right, there's a lot of, t here is, and I'm glad you brought it up. There is excitement around the NLRP3 Mm-hmm Just not obvious to people. Yeah. So in our portfolio, myopically focused on- Mm-hmm but people don't realize that there's a- Yeah Whole different world out there that's, that's focused on these Yeah This target. Yeah. Marty, what in terms of cash, like what is the current cash runway and for the company as you guys are executing through a very catalyst-rich 2024? Sure. We reported third quarter results a few weeks back. The capital at the end of third quarter was $300 mil- Mm-hmm A little over $300 million in cash and equivalents. We had previously sort of communicated- Mm-hmm A runway into 2025. Okay. What we said on the psoriasis top line- Yeah Results call was that obviously with the changes. Yeah And discontinuation of psoriasis Yeah And psoriatic arthritis, we'd be expecting to extend that by a couple- Mm-hmm Quarters minimum. Yeah. So we're probably looking to something in the mid, mid to at least mid 2025. But again, we need to sort of refine the plan- Yeah And determine where investment is going to be. Yeah. So, I guess I'm saying that with the mindset of we're in process- Yeah Of kind of prepping to launch Yeah A phase III VTX002 study. So in light of that. Great. Well, team, we come to the end of the fireside chat. Thank you so much for being here with us. A very busy first quarter in 2024, so like right around the corner, so can't wait for all the updates. So just wanted to say thank you on behalf of all- Yeah, likewise Our family. Thanks for engaging us. Yeah. Thank you.