Don't worry, we would not miss this. Never a doubt, Mike. Good afternoon. I'm Michael Yi, a biotechnology analyst here at Jefferies, and very happy to moderate our next discussion with Ventyx Biosciences. We have members of the team up here. We have Raju Mohan, CEO, and. Matt Moore. Fantastic. Maybe it would be a great opportunity, Raju, for you to just make some broad opening comments. Ventyx obviously is executing on the pipeline, and actually we're awaiting some data soon. You have a couple of programs going on, and I would love for you to just start by discussing the key programs. Obviously, again, we're expecting some data soon, so maybe kind of talk about that and what we're focused on this year. Yeah, thank you. This is Matt Moore. Matt's our Chief Operating Officer. Fantastic. Pleasure to be here. Thanks, Mike, and thanks, folks that are here. It is June of 2025, and I think this is really our moment in time in the sense of where we were as a company two years ago, where we started out with the inflammasome, where we are today, and the rest of the year, the next two quarters is going to define us in the field of the inflammasomes in particular and in RP3. We have three phase two readouts coming. The first one is going to be the trial in early Parkinson's patients with our, obviously, the CNS molecule. This is a biomarker trial. We can talk more about that in a bit. This is a brain-penetrant analysis for those that are taking CNS inhibitor. It's a brain-penetrant inhibitor. It's a different brain-penetrant inhibitor. It's a different scaffold from the peripheral compound, VTX2735. This is VTX3232. That trial is going to read out this month. We've guided folks towards the second quarter. Can you clarify that? The Parkinson's study reads out. This month. This month? Yeah. So we guided folks towards the second quarter, and the second quarter is now. The second and third studies are the second one is a study with the peripheral compound in patients with recurrent pericarditis. And this is an open-label trial. It's modeled after a biologic out there, Arcalyst, which is a. IL-1. Rilonacept. It's an IL-1 alpha beta trap. This is an open-label trial. This trial will read out sometime in the second half, sort of the cusp between the third and the fourth quarter. The final trial is our large placebo-blinded VTX3232. Again, this is our central compound, brain penetrant, but also peripheral. Obviously, it's peripheral as well. This is a trial in subjects with obesity and cardiometabolic risk factors. Call it an obesity cardiometabolic risk trial. That's right. When does that study read out? That'll read out again on the cusp of third and fourth quarters. Both these trials will read out. Call it in the fall, I guess you're saying. Call it in the fall. Okay. I think. Formal guidances. Okay. Yeah. It is not going to be the last months of the year. Sometime after the third quarter. That is where we are. We have executed amazingly well. We cannot wait to see the data and share with folks. Multiple opportunities, multiple folks out there also looking for this data as well, right? In a good cash position as we are. We built out the team, so. You have teed it up well. There is a broad array of different types of investors that are looking at Ventyx. I have had a number of people reach out and kind of revisit this for a number of reasons. Obviously, there is data coming up in the next few months. The stock, obviously, is at a very low valuation right now. Trading was around cash, under cash, somewhere in that range on any given day. Also, if I may add a third interesting piece of that, which has caused a lot of people to start asking about Ventyx, is because on the NLRP3 brain penetrant molecule, Sanofi has a right of first negotiation agreement. They put a little bit of money in, right? They own a little bit of the firm, and they have a right of first negotiation on this, which was an interesting deal at the time, but also got particularly interesting because another company that Jefferies covers, Vigil, had a right of first negotiation also with Sanofi, and that actually just got acquired. Given that there is data coming up for Ventyx, and they also have a right of first negotiation, a lot of investors have been looking at this. I think he alluded to not only investors waiting for the data, but obviously, perhaps other strategic people are also looking at it. Maybe we could start with that because that first Parkinson's data comes, and I'm trying to figure out how does the Sanofi transaction negotiation work because that molecule is in Parkinson's, but also the obesity part. Can you just first remind us, because it is timely, what the Sanofi deal is and how that is actually structured? Then given that, that sets us up for let's actually look at the data and what's coming and what is good data. Yeah. The Sanofi deal is a ROFN. For people that are not familiar, it is Rights of First Negotiation. It is not Right of First Refusal, Right of First Negotiation. What that means is that it is a right to negotiate around VTX3232. It is a molecule-centered deal. The ROFN is triggered or starts at the end of the second readout, which is the cardiometabolic readout. Now, to put it in context, we believe. When that data is complete or in-house. Like I said, the third, fourth, the cusp of the third, fourth quarter. That is when they are windowed. Can you clarify that? That's when the formal process starts as far as defined, which is X number of days for them to look at the data, X number of days to come in and say, "We have an interest." Of course, it does. They get to look at it first and go through something. Now, in reality, and we believe this from our discussions with Sanofi and their history with neurodegenerative diseases, with their success with the BTK inhibitor, now their interest in Vigil. They've built a, and they're not the only ones, but the fact that we are a little bit close to them, I call it a loose handshake, if you want to call it. They've got a commitment to a neurodegenerative disease. They made it public. They are not afraid to take on Parkinson's, Alzheimer's, TBI, epilepsy, Huntington's, ALS. To us, the second readout is essentially a, they do not want to look at the data. They want to see the safety. Nothing else. That trial is three months of safety with the same compound, right? Having said that, not to get too much into it because we have not had the data yet. We have not put that out yet. Assuming everything is as planned, they or anybody else can act any time, right? We can't solicit other folks as part of ROFN, but somebody can say, "Hey, look, we love your data because we're going to put it out," right? Once we have it, it's not just going to be cloistered. It's going to be put out to the investors. Can you clarify what you're saying? First of all, again, this is very timely, and we'll get into some of the keys. This is timely because investors are trying to understand this, and this would be very helpful for investors and, quite frankly, the analysts, which is that you said, "Hey, you could put out the data that is, you're going to put out the data." That's great, and we'll look at all the data. Technically, their right of first negotiation is a specific contractual window that they get to open up and be the first to look at it in kind of a structured way, but that's after the second data, which is later this fall. Now, if people look at the Vigil situation, which just happened, that was, I don't know if that was a deal-specific molecule or not, but Sanofi acquired the whole company in that case. First, I guess, since I don't cover Vigil, but someone else, was that a deal-specific situation too, but maybe they only have one drug. It becomes semantics, right? Because they're so damn traumatic. They took the oral, and they gave back the biologic, my guess is back to Amgen is what my recollection is, but that's semantics, right? Yeah. You're saying, look, obviously, anyone can look at the data. Anyone can also look at that. That's public, and we're going to look at it. They can look at a data room, but also anyone can make an offer anytime for anything too. There are some nuances to data rooms and so on, so we do not get into it. Certainly, the public data is available to everybody, right? Exactly. Okay. Exactly. Okay. The last piece I'll say on that is that Sanofi is not restricted to waiting until the second readout. They can have a look at this data at the first read itself. Exactly. That is the way it's set up in here. Exactly. Okay. Let's talk, because I think the point is anyone can look at stuff anytime. Sanofi obviously gets a phone call and gets to look at stuff regardless. Tell us about this dataset coming up and kind of maybe delineate the value proposition here in Parkinson's neuroinflammation versus cardiometabolic obesity, where that's obviously a totally different value proposition. Maybe talk about those two and maybe the risk around that and what is positive. Yeah. If you back up a year and a half ago, before the mouse data came out in obesity, obesity was not on the radar for an inflammasome inhibitor, right? The idea that central inflammation is going to be a player in weight reduction and feeding was not really considered. The link between neuroinflammation triggered by IL-1 beta triggered by NLRP3 in the glial cell in the microglia linked to astrocytes had been established, right? By no means is the picture clear. What happens post that in terms of the neurons dying in Parkinson's or in Alzheimer's, that has yet to be established, right? The fundamental belief in the biology that neuroinflammatory trigger is what's responsible for neurodegeneration is now exciting for folks, including folks like Sanofi, right? That believe that you can perhaps have disease-modifying therapy. Just talking about the trial itself, this trial is an open label. It is a 10-patient trial in patients with early Parkinson's disease. Primarily, there are three things that we would want to see that would define a success factor here. First, of course, is safety. Second is evidence of exposure in the CSF, which is a surrogate for free fraction in the brain. Evidence of exposure where we can cover the target completely, which means we are blocking NLRP3 pathway. The first pathway is IL-1 beta, which then drives IL-6, which drives hsCRP and downstream on and on and on. Clear evidence of blocking the pathway in the CSF. Safety, exposure, evidence of biomarker modulation in the CSF. PD markers. PD markers. Biomarkers of NLRP3. How long is the dosing? It's a 28-day trial. Once daily for 28 days? Once daily for 28. Different cohorts of dosing? Just one single dose level. You, based on phase I, you picked your highest safest tolerance drug. We picked the highest. We picked a dose where our exposure modeling told us we were at least three times above where we would need to completely block the target. Yeah. Based on PK and calculations on how much is getting into the pipeline. PD, ex-vivo, biomarkers. Yeah. So you picked that dose, took it into this. This is once daily for 28 days. Once daily, 28 days. is open label, so no placebo. Each patient is their own control, right? We have a baseline on all the factors. We have post-dose on day 28. Success is defined by exposure, safety, PD in the CSF, right? How much exposure do you need in the CSF? First one, I know how to look at safety. Exposure in the CSF, what's a good level? If this is a level that you need to cover the target, you at least want this level, right? We have three X levels. What is that level? Because I can't really tell. I really tell. I don't want to hear it post-operatively. It depends on, let's say your 100% inhibition, 90% inhibition is 100 nanomolar. You need 100 nanomolar in the CSF to cover it. You know what is the level that you would like to see? 300-400 nanomolar. 300, 400 nanomolar. Perspectively, is plenty of exposure to be covering it. When we get to the end. You have no doubt that you are. Now you're like three times covered. Yes. Thank you. 300, 400 nanomolar is multiple-fold coverage of the target in the brain. That's the amount that you'd see in the CSF. You want it covered at trough levels. It means you want continuous coverage 24/7 of those levels. Okay. You want the trough levels to be 300-400. Okay. Now, if all that happens, then you know it's getting into the brain. The next question is engaging the target and then having the downstream effects to be shutting down the biomarkers. For NLRP3. Sure. What markers are those and what do we want to see? You want to see a suppression of IL-1 beta. You want to see, so then you have a cascade of biomarkers, right? If you start to see a consistent suppression of all of those, then you know it is real clear that I am going to suppress IL-1 beta, which then suppresses IL-6, which then affects down acute phase reactants, which is CRP, serum amyloid A, on and on and on. It's all consistent. All has to. How much IL-1 beta reduction in this would be in the CSF? IL-1 beta is hard to measure in the CSF. So we look at CRP. We can see what? In the CSF, hs-CRP is here. Okay, hs- CRP, that's an inflammation marker. IL-6, which is upstream of hs-CRP. IL-1 beta in plasma. Plasma. Okay. Plasma. Okay. You have got this dynamics of. How much is a good hs-CRP reduction, which is a tricky marker in inflammation because we cover a lot of other? How much in the CSF is good? Wherever these folks come in, and remember they are not severely inflamed, right? Early Parkinson's patients are not people that have infection or, but wherever they come in, we want the levels to go down to basal levels. Basal levels. Towards the lower level of detection, right? How do we know perspectively what's the right basal level of hs-CRP, or do you look at? We look at the basal levels coming in, right? Let's say you're coming in at 2 nanograms per mil, for example. You want it to go down to whatever the basal level is, 0.5, something like that, right? It also has to be consistent with all the other markers. It's not just one marker. The picture has to be unambiguous for us. What's going to happen, and I'm trying to keep it simple, but this is a picture. Investors and certainly scientists will look at it. We want to see consistent reductions of the key markers that tell a consistent message that you have coverage, but also that the biomarkers are going down. You listed off some of those, and we'll take a look at that over the 10 patients. You said 10. And we'll determine if it's active. Correct. What do you do from there? Do you, A, you feel good that you could be de-risking the target. You'd be like, "Oh, I feel good. Now I'll just look at the cardiometabolic data coming later this year." What do you do? I think the Parkinson's team then, the Parkinson's team says, "This is the success factor we defined. We've achieved exactly what we wanted. We've got safety coverage. Start planning for phase two studies," right? Certainly we've got folks out there that are looking at the data as well. Look, in all candor, to get a drug like this, which we think is disease-modifying, right? This is a case for a biotech-pharma partnership, but no other business reasons, just the fact that you need to accelerate this, right? There's multiple opportunities. There's debate around Alzheimer's being more appropriate, sometimes easier in terms of the digital biomarkers available. That is our goal. If we establish this compound to be the best out there in terms of brain coverage, target coverage in these patients, then we've taken the baton all the way to the last person who's going to take it and run. Just as the CEO, but also just you would therefore want the maximal value for your shareholders. If someone looks at the Parkinson's data and says, "It's clearly got great coverage, clearly CNS penetrant, clearly the biomarkers are going down consistently very well." Obviously, if you could wait a quarter or two, we're going to get more information and some form of value based on what we're seeing in cardiometabolic. By the way, that's just more than just obesity. A year ago, we're just talking about weight loss%. There are other things that that drug could be doing in other applications like maintenance of weight loss and all sorts of things. How do you think about that? It's like, "Okay, well, if someone just gave us a really attractive offer based on the Parkinson's, that's a great deal. That also incorporates some value there. Versus, "Hey, if we just wait two quarters, we could get there, but maybe the buyer's gone." Whatever it is. How's that working out? If someone comes to us with an offer, look, we look at all options all the time. Let me tell you, our focus right now, the good thing about where we are is we've got three trials. We've been amazing custodians of our capital, right? We've got somewhere upwards of $200 million. We just closed last time $230 million. And the trials are all baked in. We are in no anxiety to push this in any unreasonable way. You have $200 million. Yeah. We want to play out this story to understand the potential of this molecule, the potential of the peripheral compound, generate really good data, right? Buyers come, buyers go, but our focus right now is really not to focus on that aspect of it. Sure. Okay. So we'll be excited to look at that data. Hopefully, it's positive data. You're looking to put out a press release or whatnot. I don't know if you'd host a call or whatnot, but put out a press release, and you'll come back to us on that. Again, this is an important data point. There is no urgency to transact on this data, but this is important to uncover some of the key here. I'm going to promise you a PR, and I'm going to promise you a call. Okay. There you go. All right. Can you remind me in this landscape, are there other I do recall that Roche is also running an NLRP3 in Parkinson's. Correct. Where's their data? Because it was supposed to come, and then they don't have it presented. What's the landscape right now in NLRP3? Roche, yeah, it's good to talk about that because Roche set the precedent for this type of a trial, arguing that a biomarker trial in 28 days was sufficient. If you look at their trial design, which they publicize now and ours, it pretty much mirrors it, right? It's a biomarker. There's an imaging component in the trial, microglia imaging, but nobody puts a lot of weight in early. It's an exploratory endpoint. We're looking for the data point as well. I was at the AD/PD meeting in Vienna. They haven't put it out. I don't know the technical issues. I mean, you could put out, you'd say, "Look, the compound is safe, but we're not seeing anything." I don't know, Mike. Right. Right. They haven't even commented on it. I think when companies do not have a full picture of the brain penetration of their molecule, right? It is hard to know if they are hitting the target and if because if we do not see exposure in the CSF, you are not going to see the target, right? When we lay out our phase one studies, we show you everything from exposure to calibration of the 100 nanomolar as you talked about, right? It is hard to, I mean, I would love to see the data. Maybe they are in phase two without the data. It is really hard to tell. Okay. So that's one. Are there other NLRP3s that we should be paying attention to, to track? I think there's a lot of companies out there. I mean, I'm not going to single one out, but historically, there's Ventyx. There's one with a name known, NodThera. There's no NodThera. That's cardiometabolic. Oh, they also did a, are they in CNS as well? They did a CNS study as well. Yeah. Okay. Are they doing a CNS study or what? I don't know. Similar comp to what's going on here. I don't know where they are in progressing that thing, but they did publish a phase 2-a study. Again, devoid of any real details, it's hard to tell exactly what was going on in that study, right? I remember the obesity study. Is that what you're referring to? The Parkinson's one. There's a Parkinson's one. They also put out some data. There is going to be a lot of players. This reminds me of those TYK2 days when, well, so. I want to remember those. A lot of, I know, I know. And a lot of people jumped in. I think you see a lot of companies, BioAge. BioAge, yeah. Nimora had a compound, Ventyx. There are a lot of companies. I mean, this is a great target. This is a great target. There is. I mean, the great thing about the CNS, but also the cardiometabolic, is there's various ways to develop it, apply it. How is it going to work? Is it going to be some absolute single monotherapy cure for Parkinson's? Or maybe it should be added on top of an A beta or an early Alzheimer's. Certainly in cardiometabolic too, which I want to shift to as well, which is it's probably not meant to be a replacement for or for GLP-1 and oral GLP-1, but there's ways that that mechanism could be complementary. You've been really reading up on this. I mean, you're spot on. Parkinson's is going to be polypharmacy. Even if this directly is a target, there's going to be therapies in Parkinson's or in A beta in Alzheimer's. That's a real, I think. I mean, in Parkinson's, there's many different drugs going on in various parts of Parkinson's. People have been looking for new developments. I mean, I've covered some of those companies, and they can add on to some of those. Right. That is a different value proposition. It is clear whether we, with who we is, move forward, a clear validation of the approach. Obesity, cardiometabolic. Let's talk about cardiometabolic. Tell me about the design of the study. You hit it right where the study is. It's essentially a signal-finding study, right? That's really hard for investors to get. I get why they don't get it because on one side, we have obesity, which is a clear endpoint, right? We don't guide folks towards any expectations on weight loss, right? The mouse is a mouse. Mouse feeding behavior does not translate into humans. Mechanistically, you could wave your hand and say there is something. We're doing the definitive study. We've got a study that is both monotherapy with a placebo with 3232, and we have a combination arm with semaglutide, also with placebo. Sema is not, but the. How long is this study? Three-month study. Three months. Placebo. Placebo drug. Monotherapy 3232 and 3232 on top of GLP-1. 3232, GLP-1, sugar, GLP-1. Four arms. Got it. Got it. Four arms. Four arms. Four arms, upwards of 40 subjects per arm. 40 subjects. 40 per arm. 40 per arm. That's big. Okay. It's power to detect single-digit weight loss%. Wow. Right? And so additional weight loss, there's a complete whole body scan in terms of chemistry, clinical chemistry, glycemic indices, lipid panels, liver panels, DEXA for body composition, MRI PDFF for body and liver scan, and a corrected T1 scan for liver fibrosis, liver fat similar to what. Can I ask? Akero's been doing. Can I ask you, this is very rare. When this data comes, three-month data, having followed the inflammation space, particularly the IL-1 space, canakinumab, I think that Wall Street has a very reasonable belief that shutting down the IL-1 beta pathway through canakinumab has demonstrated clinically meaningful cardiovascular benefits in large randomized studies. Take a look at that study. Those require long, big studies, and ultimately they got the result. In three months, it's definitely plausible that you're going to see knockdowns of hs-CRP. You're going to see, I don't even know if you'd see lipids and what they're going to change, but in three months, I think you would see various markers change, which would mean it's safe, it's active, it's doing something. What do you do with that? Because you're totally right that weight loss as a monotherapy would be nominal. Weight loss on top of GLP-1 is likely to be nominal. How does one develop that? It depends on weight loss on top of Sema, what that is. I think 30%, 25%-30% above Sema would be quite meaningful. Interesting. Now, let me be clear on three months of injectable Sema, three months. Are these particularly obese people? They are 30-42 BMI. Okay. In three months, you're going to get a few% weight loss. 5%-6%. 5%-6%. You're telling me if the combo arm had 7%, that's actually a 40% improvement. But a percent or two added on top, statistically significant, it's definitely saying it's incrementally helping. That would be meaningful, I guess, over three months. What comes with it in terms of either additive effects on Sema or direct effects of the drug that are not, like for example, Sema's GLPs are not directly active in the liver, for example, right? NLRP3, if I had to guess one target tissue where this is going to have a profound impact, it is in the liver. What effect? Fat reduction or what? Folks have shown effect on lipolysis, fat reduction, potentially effects on lipoprotein A. Again, nothing borne out by human studies, right? Are you doing MRI PDFF? We are doing MRI PDFF. We're doing a CT-1 scan, which is a corrected water scan, right? We're not going to leave any stone unturned. I think the total composite of this picture would come out of where. Remember, anything outside weight is all peripheral in our mind. That's where you have the opportunity with the peripheral compound. The reality is that there are a lot of strategic players with a lot of deep pockets who would need to do these because you're a smaller company, certainly in CNS. In cardiometabolic, if you listen to Merck and others, they certainly are looking at other mechanisms that are peripheral or complementary to GLP-1. Likewise, I think we've done enough with GLP-1. There are other things to add on top to differentiate programs and strategies to be helpful and meaningful in obesity. IL-6, which is something we do not talk about. Companies like, well, a couple of companies are going after IL-6 antibodies right now in ASCVD, right? Yes. Just that, again, canakinumab definitely shows that there's clinically meaningful benefits. An oral small molecule version of this would be great. Correct. Thank you very much. We look forward to data coming up this month. Our pleasure, yeah. Obviously go from there, and we'll have more important data on NLRP3 later this year. Thank you very much. Thank you, Mike. Thank you all. Bye.