Welcome to the UBS call. Trung Huynh, you may begin. Hi, good afternoon to those guys on the East Coast. Good morning to the people on the West Coast. Thanks for everyone online for joining us. It's our penultimate session of the day. Well done for your making it this far. My name's Trung Huynh. I'm the large cap pharma analyst here at UBS. For this session, we have Ventyx. Raju Mohan, the Chief Executive Officer and founder of the company, and also Marty Auster, CFO, who's hanging out on the side there, once an analyst at the UBS Paris. Welcome, gentlemen. Thanks very much for joining us today. Yeah, my pleasure. Great to be back at UBS, Trung. We'll probably do, for everyone online, 30 minutes-35 minutes for this session, to give you a bit of a break and then on to the next one. But I guess, why don't we start with a quick introduction? Raju, I think maybe why don't you give everyone listening an intro into perhaps yourself and Ventyx, and obviously, given today is about obesity, Ventyx's strategic interest in the disease. Yeah, you know, you cut out a little bit, but let me understand. So the question was, what's Ventyx's strategic interest in obesity? Is that? Yeah, well, an introduction and then. Okay, yeah. Your interest in the disease. Understood. Yeah. So, you know, Ventyx is, as it exists today, has been around, about three years or so now. It'll be three years, and, and, it's been 2020. In 2021, we combined two companies with Ventyx, which was a TYK2 company, to form Ventyx, which had three assets in it: the TYK2 inhibitors, the, S1P1 inhibitors, and the, modulators, and then the NLRP3 portfolio. And, we talked about our TYK2 program last year, you know, and where we are with it now in terms of Crohn's disease. We have an S1P1 compound for UC, that's, phase III-ready, and we've talked about that. And the newest member of our portfolio is NLRP3, and, you know, we didn't really talk a whole lot about that over the years. We did talk about phase I for our peripheral compound. We disclosed some non-clinical data for the central compound, which is the VTX3232. But really, I think it's opportunistic, opportune time. Earlier this year, we showcased our NLRP3 portfolio, in particular at our Investor Day, and just talked about different opportunities for this class of compounds, both for peripheral and for the central molecule. And so Ventyx, the history of Ventyx really is a company that's come out of a strong drug discovery platform. All the compounds are internally discovered, internally owned. We have 100% IP and commercial rights to our molecules. And then as the company has grown, the shift from discovery, early development, has now grown into a company that has one phase III-ready asset. We've completed a bunch of phase II trials. We are poised to do phase II studies for the NLRP3. And we've built a company now that's gone from, again, early discovery to having a full, full-blown development platform. Obviously, we've got, you know, the the financial side. Marty is the CFO. We've recently hired a Chief Operating Officer to then manage the operations and BD side. So that's, in essence, what Ventyx is today, a company that has multiple targets, multiple molecules in discovery, the cliché, multiple shots on goal. And I think with NLRP3, it's really a product in a pipeline, or pipeline in a product, so to speak. Now, for NLRP3, and we can go more into the obesity question, I think the biology of NLRP3 across multiple indications has really been evolving over the last, I would say, four to five years. The most recent interest, obviously, is in obesity, but it's been around now for multiple inflammatory conditions and diseases. Okay, so on that, perhaps can you elaborate a bit more about the association between metabolic inflammation and obesity? Like you say, just there in your introduction, you know, you have expertise and history in immunology, the portfolio that you're developing. Actually, it does feel like you're one of the leading biotechs when you're looking at this relationship. So I'm just curious about the inflammation and obesity relationship. Yeah. First, thank you for anointing us to the leading biotech status, much appreciated, and Marty and I will tag team on this one. So, you know, the association between the gut and the brain, sort of the gut-brain axis, has been there for a long time, right? And now, so we are flipping it now and talking about the brain-gut axis here. And obesity in its multiple manifestations has shown itself in inflammatory signaling through to the adipose, to the liver, to the brain, to the islet cells. It's always been a connection between adiposity, adipose tissue, and increased inflammatory response. That's been the one connection. Secondly, if you go back to the CANTOS trial, there was a clear effect of this antibody. It's an IL-1 beta antibody on multiple cardiovascular risk factors. Albeit there was no direct interest or focus on obesity, clearly, there was an interest in reduction in cardiovascular factors now. So coming back to obesity, as we look at now in terms of reduction of hs-CRP, reduction of IL-6. Hey, guys, I just cut to technical difficulties here. It looked like we lost you there for a second. Are you back? Yes, we can hear and see you now. All right, we're gonna take it back live. Sorry, we're gonna take it back live in three, two, one. So what I was talking about was a link between, for example, IL-6 and hs-CRP, and known effects on obesity that has been seen, again, in not trials specifically directed at weight loss, but in trials where people have looked at cardiovascular events and seen effects on obesity. Or in diabetic control and effects on obesity, which is where sort of the GLP-1 agonist progressed from their interest in insulin resistance to now their applicability in reducing body fat and obesity. So the last point I'll make here is that this connection now that we have an interest in, which is a connection between the inflammasomes, in particular NLRP3 and obesity, is a newer area of interest. I think that you'll find a lot of links to NLRP3 across the board with GPR120, another protein implicated in control of food intake and fat. And there's been a lot of links between NLRP3 now and the cannabinoid pathways. So I think as this data emerges, especially in humans, there'll be a much more defined link between inhibition or activation of NLRP3 and a downstream link to weight gain or weight loss and appetite control. I think that is the mechanism that folks are most interested in this pathway. Marty? Interesting. It's interesting you. Oh, sorry, Marty, did you want to say something? Oh, no, no, I think Raju said it well. I think again, just we view obesity as a disease that is sort of has a feedback relationship with, with low to medium-grade inflammation over time, and that's been well known for a long time in things like liver disease and metabolic risks. And then more recently, there's been mounting evidence about the importance of sort of neural inflammation, sort of impacting satiety signaling and things like that as well. So that's, that's sort of where the concept of brain penetrant NLRP3. I think there's been a lot of interest going back to CANTOS, as Raju said, about sort of the peripheral benefits potentially of a, of a anti-IL-1 or NLRP3 inhibitor approach. But the, but the. Yeah. Is a little bit more fresh. Yeah. Yeah, it's interesting. There's been a lot said about the IL-1 pathway, IL-6, pro sort of inflammatory cytokines, the cannabinoids, so there is some work looking at this. I'm curious if that inflammation pathway. Do you think that's more of a risk factor, a cause, or an outcome of obesity, or all three? I'm sorry, trying. You're the, is the risk. I think that. Obesity and inflammation are sort of interlinked. I think as obesity occurs, inflammation's driven, and then you end up getting complications, but I think there's sort of a feedback and a reciprocity there. I don't think. But again, we're looking at a population to study in humans that's going to have a kind of an elevated inflammatory component, along with, you know, sort of an obese condition, but we're looking at patients that are generally going to be at higher risk of sort of metabolically poor metabolic outcomes. Okay, excellent. So let's look at NLRP3. You've talked about it here. It's probably your most advanced product, looking at this. Can you just walk us through the mechanistic rationale of targeting it? Targeting NLRP3 or targeting. Mm-hmm. NLRP3. Yeah, so if you go back to the CANTOS trial, we talked about that, the effect of canakinumab, which is the CA in CANTOS. You know, it's a very large trial, over 1,000 patients, broadly cardiovascular. There was also some look at cancer in that trial. But the effect on cardiovascular risk factors was pronounced and unambiguous in that trial. But it also was seen with something, one in 800 folks had infection, risk of infection. So completely abrogating IL-1 beta through an antibody is certainly leads to, you know, reduction in risk factors, like we talked about, hs-CRP, IL-6, certainly driven through IL-1 beta, but also you're now basically removing any or all IL-1 beta. There's initially the evolution of that has been to. It's a response against pathogens, right? So I think what NLRP3 does is allow, allows you to block NLRP3, an NLRP3 that's implicated in disease progression, without completely removing the protective IL-1 beta that can come from other sources in there, right? So it's a very novel, sort of a selective way of blocking the inflammatory signaling pathways without taking away the host defense that's required in case of any opportune infection that may happen. And so that's the mechanistic aspect we're targeting, and then, of course, where the disease pathology has converged with IL-1 beta now offers an opportunity for this approach to target those diseases, be it cardiovascular, cardiometabolic, kidney disease, gout, and now certainly the interest in neurodegeneration, Parkinson's, Alzheimer's, and then the most recent interest in obesity. So that's sort of the rationale based—and it's no, no different from what has happened in, in the case of many discoveries, right? Whether it's, it's—we talked about TYK2. Interest in TYK2 came from an interest in IL-23s and having an oral drug that would target the IL-12/-23 pathway. So it's a similar paradigm here, where you're using a small molecule approach, the most well-studied inflammasome, in targeting IL-1 beta, where there's been a lot of biology early on with IL-1 beta analogues, be it canakinumab or anakinra, and so on. Excellent. And I know it's early days into looking at this. We have seen some data, though. So in diet-induced obesity mouse studies with NLRP3, from NodThera, they have shown this anti-inflammatory effect. Just, well, how well-validated is this model for human translation beyond the incretin class? Yeah, again, you faded out, but I think I got the gist of it. So number one, the diet-induced obese study that was published by NodThera a couple of months back. So if you look at the study, and there's a number of points in that study. So they had used a brain-penetrant compound. They had a peripheral compound. There was a couple of different studies they had put together in that paper. But if you look at the data from that study, it's very compelling. So each individual endpoint with its controls. So remember, there was a lean control. There's a placebo control in the diet-induced obese mice. There's obviously the drug control. There was semaglutide, the GLP-1 agonist. With all those controls, it was very clear that the CNS-penetrant molecule was having a profound effect on weight loss, an effect on feeding in these animals, although the feeding effect on the animals tends to normalize or start to normalize through some adaptive mechanism. The downstream effect on metabolic parameters, lipid parameters, insulin resistance parameters, glucose, insulin HOMA-IR, effect on steatosis, effect on inflammatory markers, all very consistent with reduction in obesity. So what we talked about in the opening segment here. And then reduction via reduction in fat in the signaling pathways that then trigger inflammation and insulin resistance and other aspects of that. So in our mind, the paper was very comprehensive. Now, in terms of the molecule, and they had talked about it itself, it has a to say, you know, to the least interesting way of accessing the CNS, and so they have to dose very large amounts of this drug. I think it was three times a day in mice, multi-milligram quantities. So that's a different question, but it was, you know, really well-calibrated paper with all the controls, experiment and all the controls. So, you know, we think from the mice study itself, or from the mice study, there's a clear link between an NLRP3 blockage and reduction in weight that then correlates to what's been seen with semaglutide. Understood. And why do you think that CNS exposure is necessary? Well, I think if you go back to, again, we talked about inflammation. CANTOS. In the adipose, right, in the patient liver, and now inflammation in the brain is linked to effects on feeding mechanism, for example. And Marty talked about this early, this sort of feed-forward feedback loop. So always looked at, again, gut-brain axis, but I think here we're looking at a brain-gut axis. So what happens if you reduce inflammatory signaling, for example, in the microglia or in the hypothalamus? How does it now impact signaling that is, results in, for example, targeting ghrelin or leptin and proteins and enzymes that are involved in feeding? So there's a clear convergence of these pathways, certainly in the mice now, that controlling inflammation through an NLRP3 in the brain, potentially in the hypothalamus, is results in impact on feeding behavior, and the weight loss then results from reduced calorie intake in these animals, right? So we're not, we're not changing gut motility. We're not changing gastric emptying time. It appears to be a direct signal from the brain in terms of satiety in these animals. Okay, understood. Your DIO study, can you just walk us through your plans here, just the where you are now, the timing on it? Yeah. So what we've said is we'll put out the results from this study, and we haven't said exactly how we'll put it out. We'll put them out in the second quarter, right? So we're heading to the last month of the second quarter very soon. So, you know, stay tuned for that data to come out in June. In terms of design of the study, I'm not gonna go into the actual design, and you'll see it when we present the data. But these are pretty standard studies, and it's not just been done with NLRP3 most recently, not just with GLP-1 agonists, but across the board, even not even with just obesity agents. But there's a lot of other drugs that have been used. Pretty standard studies. So you have mice that are. Excuse me, mice are not bred to be. They don't, genetically, they're not obese animals, at least not the non-genetic animals. So you have to take lean mice, and you have to feed them a high-fat diet for some amount of weeks. And when you have the appropriate weight gain in these animals, and it's variable from study to study, you then have an impact of a drug. In this study, a placebo, you can use a control, in this case, semaglutide. Oftentimes, you have lean controls, animals that have not been put on a high-fat diet. And all these are controlling for non-specific effects like toxicity or stress, those controls are. But the real control here is the three controls in here, or two controls. One is placebo or chow rats, animals that are just, you know, diet-induced animals that are not given the drug, or diet-induced animals that are given the drug, and then, in this case, an incretin as a control, which is GLP-1. So that's sort of the study. And then we'll have, you know, the impact on weight loss, impact on feeding, everything I talked about before on metabolic parameters, lipid parameters, steatosis, inflammatory signaling, all that should be the output of the study. And, you know, we have, just based on what I said about the NodThera study, a bona fide NLRP3 agonist, certainly one that's as well-behaved as our molecule, and VTX3232 should, and that's the key word, show you the effects that have been shown with other studies, in particular, the one we just talked about with NodThera. Yeah. Understood. Is there anything specific that you're looking at here? If you don't see a signal, do you still think it makes sense to run a human study? I'm gonna sort of. You know, at this stage where we are, you know, a month plus away from that, you know, let's not, you know, speculate on whether or not the study will work. Let's just play that out, right? What we have said is we are planning a study in obese subjects in the latter part of the year, so we are committed to doing that study. We've said that before, right? So I think it's suffice to say that we will put the results of the mouse study out in June, and we'll, and we are on track to initiating a study in obese subjects in the latter part of the year. Okay, great. And have you commented on your thoughts around a phase II? Have you spoken to FDA here at any point potentially approaching looking at mono combos? Could you comment on anything to do with that phase II yet? Well, I'm not gonna comment on the phase II detail plan, but again, the basics of that study is gonna be, obviously, it will be a placebo-controlled study, and there'll be VTX3232 in that study. We haven't commented on any other aspects beyond that. Typically don't need FDA guidance for a study like this. And so this is really not a study that requires a lot of discussion with the agency, and unless you have some issue with CMC or something else, it's a pretty standard study. It's a 28-day dosing in obese subjects, and pretty much follow the guidelines people have done. There are certain BMI parameters. Obviously, we're gonna look at folks with elevated CRP and so on. So, at least for this study, there's no interaction with the FDA required. You have to have the safety coverage for 28 days, and you have to have the drug that's well-characterized, but there has to be all of the CMC work and qualification, and you do have to file an IND in this case, but again, all that stuff is just housekeeping. Okay, understood. And you touched upon CRP. Do you know, are you going to. Again, I realize this is talking about a patient population here, but is there any interest in looking at people with elevated CRP? And potentially, what's that percentage of the obese population that have sort of elevated CRP? Do we know? Yeah, and Trung, so I think what we've indicated previously is that we will. The primary endpoint of the study will be looking at those biomarkers with change in body weight as a sort of a key parameter that we'll be looking at on a secondary basis. We will be looking at obese subjects with background elevated CRP and baseline inflammation. We haven't pinpointed the exact cut-off we're using, but it'll be something kind of in the moderate elevated CRP range, probably not super dissimilar from what you've seen in other kind of approaches with NLRP3 inhibitors or IL-1 and antibodies in this sort of patient population. What was the other part of your question, Trung? Do you know what percentage of the obese population you would estimate to be above that threshold? Yeah, I think. You're looking at a substantial majority. I don't have the exact number, but it's not, there's not a paucity of patients with elevated CRP and baseline inflammation. I think there's some ranging around that, and we'll have to think about sort of initially. We'll be looking at folks with sort of a probably more elevated cut-off. If we see, you know, weight loss, I think we'll look to sort of expand the population we explore over time and then further phase IIs. Great. And then, last one on 3232. So yeah, 3232. What's the differentiation points you think that you have over NodThera's assets? Yeah, so our approach to 3232 was very unique with respect to what folks have done in targeting NLRP3 inhibitors, which is to go after sulfonyl ureas and then to go after modified ureas to get them into the CNS. We started de novo design of this compound, where it would have all the appropriate physicochemical properties of getting into the CNS, so the MPO score, the polar surface areas, and so on. And that sort of led to 3232, which is an optimized drug for the CNS. As we pointed out, it has almost equivalent partitioning between the central and peripheral compartments. We have high levels in the CSF, which is a reflection of the free fraction of the brain. I'm not going to comment too much on that NodThera's compound. They've published the chemistry of that compound extensively in a J. Med. Chem. paper. They've talked about it before. It's a prodrug approach to delivering the molecule and getting into the CNS, and I think much of the molecule is cannibalized, so you don't—you only get a percentage going in, hence the high doses they have to use. So, you know, again, they've done a good job in having a modified NLRP3 inhibitor, but we believe we have a potential best-in-class, just given the PK, the PD of this molecule, the safety of this drug, what we've shown in terms of biomarkers in the phase I trial, and how we're positioning it now across. You know, we've talked a lot about obesity, but, you know, our interest also here is in neurodegenerative diseases, where there's just so much unmet need. And we think Parkinson's could be an area where there could be disease-modifying therapy for a NLRP3 inhibitor, such as VTX3232. Okay, and, we're heading up to time here, but one last one. Beyond, NLRP3, is there anything that's attracting your attention in obesity? Well, we're not going to, you know, either talk about or jump into that bandwagon. You know, the space is very crowded with incretins and G's, and triple G's, and double G's. We think NLRP3 offers an orthogonal approach, you know, potentially a safe, orthogonal approach to weight loss, whether it's induction of weight loss or maintenance of weight loss. So, you know, we'll get into this. You know, it's fair to say this is an opportunistic approach here for obesity, and we will move what we think is the best molecule. But other than that, you know, we'll showcase our portfolio that's, you know, in the discovery development side at appropriate times this year. But right now, the focus is on getting NLRP3 into multiple trials, obesity, Parkinson's, and then potentially later-stage phase II studies. Okay, great. Well, we look forward to the data upcoming soon. Raju, thank you for your time. Marty, thank you for your time and insight. The next session is Terns with Ellie. That starts at 1:00 P.M., so you've got 30 minutes for a quick bite and some time away from the computer. But, Team Ventyx, thank you again for your time and help here. Yeah, thanks, Trung. Good to see you. Yeah, our pleasure. Thank you.