Good morning. Thank you for joining us on our next session. I have the pleasure of having two members of the Ventyx Management Team up here with us, the CEO Raju Mohan, as well as the CFO Martin Auster. Thank you for joining us to talk about all the developments going on at Ventyx. Logically, if I may, I would love to start off with Raju giving us an overview, specifically with a key focus on the developments in the NLRP3 program, which, to be fair, is an important focus for Ventyx in obesity and CNS. And so I would love for you maybe just to summarize your perspective on your NLRP3 program, why it's differentiated. Obviously, you had some mouse data out today in obesity, and the stock is moving right now as I speak. So getting, again, a little more high level, tell us a little bit about your NLRP3 and your potential in obesity. Oh, absolutely. Yeah. Thanks, Mike. So, yeah, let's start with NLRP3, and let's just focus on the CNS penetrant compound for now. So, as we showed in our phase one study, we have, I would say, probably the best in class CNS penetrant compound that has both the safety profile and the PK/PD profile for once-a-day dosing. We've shown at doses as low as 10 mg qd. We completely wipe out IL-1 beta signaling, which is the primary target for NLRP3. And we've shown that both in blood and in CSF, we affect key biomarkers post-IL-1 beta, IL-6, fibrinogen, hsCRP. So everything that aligns itself for us, completely controlling aberrant signaling of NLRP3 in the phase I study. So that's where the phase I stands. QD dosing as low as 10 mg, complete wipeout of IL-1β, and then downstream effects on hsCRP, IL-6, fibrinogen, and other markers that we've shown. So that sets us up now for phase II, phase IIa studies in NLRP3, what we believe are NLRP3-driven disease indications. And in terms of neurodegenerative disease, Parkinson's is the most well-studied, albeit not in humans, but there's more and more data coming out of nonclinical work, in vitro studies, primary microglia studies that link NLRP3, connect the dots all the way to Parkinson's, tyrosine hydroxylase, dopamine, aberrant dopamine, neuronal death, right? So that's the link that people are trying to establish. And we plan to do it with our molecule in a phase IIa study in Parkinson's patients in the early part of the second half of this year. Now, in terms of obesity, there was a paper that came out of NodThera. A competitor paper came out early this year showing weight loss in this diet-induced obesity mouse model. When we looked at that data, independent of the compound and the dosing, if you connect all the dots there, there was enough evidence to show that NLRP3 is causing weight loss in these animals and then all of the secondary benefits on cardiometabolic parameters, right? So we did two studies, one as a monotherapy. Data that was comparable to Sema. To Sema. Just to put everyone's, you know, baseline context. Now, when I looked at that data, and there was a lot of questions about, is it coming from toxicity? Is it coming from in their drug? You're dosing it 100 mg, 3x a day to mice, right? So it's, again, put that aside. The qualitative nature of the data tells you if you block NLRP3 in obese mice, you affect weight loss and you affect signaling and cardiometabolic parameters. That is the take-home message, right? Now, if I were to dose mice 3x a day, I will tell you I'm going to stress them out, okay? So I'd be very hesitant to compare studies that are dosing animals with this amount of mass in their GI 3x a day, okay? So look at that study for what it's worth, which is NLRP3 inhibitor. It doesn't matter how much you dose, weight loss, cardiometabolic control. We did two studies. One is monotherapy with VTX3232 in diet-induced obese mice. The first study was these mice were older and more obese. These were sort of off the shelf, and we took what we got. But again, each study has its own control: vehicle control, lean control, semaglutide drug. So animals on chow, animals on high-fat diet, animals on high-fat diet plus our drug, animals on high-fat diet plus semaglutide. The second study was more controlled in the sense that we were actually able to take normal animals, Black 6, put them on a diet for 15 weeks, really control the age and obesity. But again, they're internally controlled. Both these studies, the second one had a combo arm. Individually and collectively, put a picture out that says, if you block NLRP3 in these animals, you affect IL-1 beta, you affect hsCRP, you affect IL-6, you affect fibrinogen, you see weight loss, you see a complete control of metabolic parameters, lipids, cholesterols, inflammatory pathways, hepatic steatosis, all of it aligns itself. When you add semaglutide to this study, you not only see weight loss with the monotherapy, you now see additional weight loss on top of semaglutide, and you see additional benefits, again, similar to what you saw with monotherapy. Now you see additive benefits on this study, right? So not only can you not compare our own studies from one to the other in the sense of sort of absolute numbers because they are different studies, different age of mice, you certainly cannot compare cross-compound studies, especially when those compounds are not well calibrated. In our mind, this is the experiment we set out to do based on our belief that the Natera data was real and nothing has changed in our approach for starting a human study in early second half. Let me try and see if I at least got two important points that I pulled away. One was in your two preclinical studies that you published today or put out a press release on that you see strong weight loss benefits, stronger weight loss benefits with Sema and in two internally controlled studies. So you feel confident that there are weight loss benefits and metabolic parameter benefits, and you see all of that. Yes, another company also has some positive data in theirs, but you would be very hesitant to cross-trial compare two different preclinical trials with different types of mice, different ages of mice, different weights of mice, let alone their study also use significant amounts of drug relative to the dosing you are giving. And so you think that you just think things can happen when you give that much drug of the others. Without a doubt. Even with the competitor studies they've done in multiple studies, they saw different degrees of weight loss, different endpoints. So each study, again, I'm not knocking the competitor study. All I'm saying is these studies need to be looked at as standalone internal studies as long as you have good control. And then if you do enough of those, in our case two studies, you can really paint this picture. You can connect multiple dots. So the second set of dots was this combo study and what happens in this study, independent of the mice and the age and obesity, because you are controlling it. So no apologies for the first study, no apologies for the second study. And now compositely, we've seen everything that we want to see in going in a human trial where we'll see what happens in a 28-day weight loss. May or may not see weight loss in that 28-day study. We're planning a longer study, but certainly all the other parameters should align themselves, including glycemic control, steatosis, liver triglycerides. Obviously, you don't dissect the humans, but certainly you'll see effects on lipids, triglycerides, and potentially weight loss in a small study. I mean, there's been certainly 1%-2% has been shown with incretins. We'll see what happens there. Yeah, absolutely well-designed studies with the outcome that we expected on weight loss. Remember, if you look at those charts, the data are extremely tight so w e powered them for mice. We had 20 mice per group, and the p-values are down to 0.001 in some of those numbers. It's very tight. It's not like there's a huge variability in these animals when you actually dose them in the internal control studies. So yeah, and I know we don't have a slide here, but you can email it if you want. We were looking at the two graphical charts side by side. Yours, the magenta curve is increasing weight with the placebo. And then in your two Ventyx arms, you see a decline in this sort of teal blue one. And then in the higher dose, I guess, or maybe that's both. That's a combination. That's a combination. It continues to go down and then sort of steady states around 14 days to 21 days. People were asking in your monotherapy goes down, but then by day 10, it starts to go back up. How do I interpret that? I think the first study with these older animals and more obese animals, they tend to have a different feeding pattern. So if you look at what happens post day 10 in these animals, even on vehicle, you have this upward trajectory, which you don't see in the second study, right, where they tend to sort of maintain their weight, and then you start to see a drop in with the compound. That's just a pattern of these older animals. It's probably some adaptive behavior for these older obese animals. Again, with an internal control, you can see our drug arm virtually parallel the control arms. You see the same extent of weight loss. You're not seeing a diminishment in the weight loss in these animals. The curves are not coalescing. So just take a look at that. Actually, yeah. So again, I apologize for not having it up here, but I do want to sort of compare these two and get your perspectives. I know the stock is impacted today, but looking at the NodThera data, there it goes down. It actually does after day 10 also start to go up. And then with combination with or just with Sema, Sema goes down. And in yours. Taking a look at that, that one goes down and then kind of goes back up. And then this is the combo. This is Sema. That's combo. That's Sema. Sema. So again, that's very identical. And your point is people are saying it goes back up, but there's also kind of goes down. Yeah, exactly. So your point is that by day 10, you know, the diets of the mice are changing. So you don't read into the fact that rarely do we see weight going back up. And so people are like, wait a second, the drug only works for a short period of time and then doesn't work. And your answer is mice change after day 10? The drug works because we know in humans we've shown the fact there's no loss of signal on 14 days of dosing. We actually reach steady state in 3 days. From a PD parameter. From a PD parameter. Yeah, the markers don't change, but okay. We don't lose drug. We don't lose a biomarker. Talking to the mic there. We don't lose any of the biomarkers in a 14-day study. If you look at day 2, day 7, day 14, day 10, you see the same effect on inflammatory markers and the same effect on complete aggregation of IL-1 beta. So belief in the mechanism, shown human durability of the drug, and check the box of NLRP3 in an animal model controlling obesity, controlling feeding, and being additive on top of semaglutide in a safe, effective dosing paradigm, right? Just to clarify, an observer would say if it's going back up, maybe the drug does have initial weight loss benefits, you may continue to suppress the signal PD markers, but the clinical effect or the effect of eating less or whatever the actual mechanism is starts to wane even though you're keeping the signal. So there's an escape pathway or whatever someone might say. Look at that. Your point is there's preclinical mice, things after 10 days, there's changes. And then, you know, look at the combo arm. If that was the case, the combo arm would have started to swing right back up because the drug would have lost its signal after, right? The combo arm just keeps going down. I see. What I got from that study two. I thought that study too is particularly interesting. First of all, it's the first study of an NLRP3 inhibitor in combination with GLP-1. Got it. Yep. They didn't do that. The competitor hadn't run that. Right. That was the first time I've seen data on that. There's a monotherapy arm, a combination arm, and a Sema arm. You can see there's a much more consistency in those curves. It kind of contradicts some of what we're talking about from study one. Perfect. See, Kyle, we got to have the second chart there. There's a combination and that keeps going. I think what's really interesting there is you're seeing a drug with an orthogonal mechanism to GLP-1 with a very differentiated, you know, sort of through our phase I MAD, very well tolerated profile, and you're seeing incremental benefits on every biomarker, on every inflammatory marker, on weight loss. So it's pretty encouraging to us. Absolutely. Okay. So you believe that the two studies show strong preclinical proof of concept for the monotherapy on weight loss and metabolic markers. In combination, you're the first person to show combination preclinical data of an NLRP3 with Sema, GLP, and you're showing continued steady declines. So additive, synergistic weight loss benefits beyond just the GLP-1. With a low likelihood of agitating tolerability issues that exist with. Because you're using a fairly low dose. Also lean muscle was not as impacted or was protected. Can you clarify that? Yeah. So again, these are very small changes in these animals, but in the combo arm, there's a clear incremental benefit on protecting lean mass, as you can see. Again, the data are extremely tight. Even in the combo study, you see a 5% weight loss above semaglutide, 5% weight loss above semaglutide. It's tight, it's consistent, it's durable, and it's maintained. And again, on the lean mass, there's two measurements. One is the actual dissection and measuring. The other is looking at DEXA, which is this imaging component. They both align themselves. Not just one measure. It's two orthogonal measures. One is an imaging measure typically used for body composition, bone mass. Second is literally weighing them. Again, 20 animals per group. This is not a small number of animals. It's 20 per group. Really, really tight data. Absolutely. I mean, we hit every endpoint in those two studies. Again, we've always believed there's an inflammatory component in the glial in the hypothalamus. If you look at the data now, there's more and more data coming out. People always talk about gut-brain axis, right? People are now starting to flip it and talk about brain-gut axis. It's not just a one-way here. What happens in the hypothalamus then signals back into the hormones like ghrelin, like leptin, and has effects on feeding behavior. Now, let's get to clinical. So you, well, let me first start from a chronological perspective. The other company has started and is finishing, if you can go on ClinicalTrials.gov, that the NodThera NLRP3 phase I obesity study has completed. We're awaiting data. If that company was here today, they could be happy to present here, but they're not here. And they also hired a new CEO. But those are the developments of the other player. There is pending clinical data, I think 28-day data from an oral NLRP3, and they have a new CEO. What do you expect out of that? Because it will impact the perception of your drug because you're starting your study, but won't necessarily have data in the immediacy. So help us understand that so that we can digest that when we see that data. And then what is your timelines for your drug? Yeah. So again, mechanistically, I would expect in that 28-day study, again, the dose notwithstanding to see control of lipids, control of metabolic components, cholesterol, lipids, inflammation, systemic, peripheral, CSF. It remains to be seen whether in the short study you'll see significant weight loss. 28-day study. 28-day study. Not a GLP-1 mechanism. It's not a GLP-1 mechanism where even in GLP-1s you see a very small% weight loss. It's like 4% with an injectable. I think it's 1% to 2% in 28 days is what sema. Okay. 1% to 2%. 1% to 2%, right? But certainly you should see everything else align itself in terms of, again, cardiometabolic parameters, inflammatory parameters. And we have every expectation. We will do that based on what we've shown now with this pathway, with the peripheral compound, with the central compound in phase 1 studies. We have no doubt about NLRP3 blockage. The question is what happens to lipids, what happens to triglycerides, what's the magnitude. And remember, we're going to follow this up with a longer study, a three-month study we are planning towards the very early next year that will be a monotherapy study. We also plan to do a combo with semaglutide study. There's a number of ways to look at it. I just want you to start with one thing. If you look at this approach in a way that the mouse studies have been done, you can imagine a paradigm where you can actually have weight loss with an incretin of the GLP-1, whether it's oral or injectable, and perhaps maintenance therapy with an NLRP3 inhibitor, sort of a safe, effective, not have the GI effects, not have all the motility effects you see with this pathway. So there's a lot of opportunities here as monotherapy, as combo therapy, as maintenance therapy that, you know, we're going to exploit the full potential in our study starting with the 28-day study imminently. So repeat that. They have a 28-day study coming. We'll see what the results are. I agree because we have published previously some 1% to 3%, 1% to 2% net in a short study combined with the metabolic markers suggest a clear picture of benefit, and we need to see more. You are also starting a 28-day study. 28-day study. Going to do a 12-week study and a combo study with Sema. Correct. When do those studies start and when will we see data? So the first study will start very early, second half. So everything is on. 28-day study. 28-day study. So everything is on track. So, you know, the CRO is lined up. I mean, we have a beautifully behaved drug, and we showed in the phase 1 study. We have a single tablet. There's no food effects, 100% bioavailability relative to the suspension we did. Everything is all go for that. And then we're planning the longer study now. So it's a different shift. We want to power these studies well because, again, these are easy studies, but not in easy populations. You want to make, and this is not going to be an inpatient study. These folks are all going to be going home. So we have to power them well given the heterogeneity of sort of the behaviors here. And that study will start in early, very early 2025. We will have full tox coverage. So this is a three-month study, but with the option of potentially going longer if we choose. And certainly the combo arm is going to be very interesting. There's more and more oral GLP-1s coming. So you can imagine a scenario someday where you can have an NLRP3 oral with an oral G or a double G or a triple G. So, you know, super exciting pathways here, but, you know, we're going to start with the first study to really show monotherapy effects of the drug. When would you see your 28-day data? If you're starting second half, could be end of the year, early 2025? Yeah, I think early 2025 would be a conservative approach, but could be. Early 2025 could be conservative. Okay. Could be sooner. You know, these are not top studies. But again, we're powering them enough power so we can actually get meaningful data in the, especially in weight loss. Well, I mean, it means just from an investor standpoint, if we're sitting here listening, that by the end of this year, there could be some quick 28-day data for you. So like always, we'll let investors l et you know when we've initiated the trial, first patients in. From there, I think we'll be able to give you a pretty accurate assessment of when we expect to generate data. Okay. Now, one of the other angles here too, I think is important is you think that regardless of what we're seeing and what amount of magnitude, that there's different approaches with the drug that could be either as a monotherapy for people who don't love injectables or GLP-1. I mean, by the way, orforglipron does have side effects and tolerability issues. So another drug that offers weight loss benefits as a monotherapy pill. In addition, you could be a combination. So add on to further enhance the efficacy or maintenance because you don't want to be on the GLP-1s forever. And protection of lean mass, right? Protection of lean mass. I mean, that's sort of the myostatin angle there that you don't see weight loss in, say, but in a combo, you actually protect lean mass. So there's just incredible opportunities here, all of which coming out with these individual markers from this mouse study, right? So just take each of them as a real signal for what you could expect in a human. Don't try and, you know, sort of take the mice and expect them to behave exactly like humans. No disease has ever been one-to-one. It's each individual markers that recapitulate what you expect in a human. Take home message. Yep. Now, I would argue that initial proof of concept, not only with someone else, but certainly your own data is a huge value inflection point. Obviously, you have the capital to get there, safe to say, because remind us on the balance sheet where you are with that. You did a recent pipe to add on to that. So we certainly have the money to get through these, at least the 28-day data. And then you also have other things as well. You have, so there's many opportunities to shore up and use capital because ultimately these are pretty big markets and pretty big studies. So at some point, you would think about what you need to do in terms of partnering or whatever. Oh, without a doubt. I mean, the whole, just focusing on the obesity, it's getting crowded. This is a novel mechanism. It's going to be one of the first in class there. And this beyond phase II, this belongs with folks that can manage these trials. These are large, expensive trials in a competitive area. And you really want to get this thing to patients or subjects because it's going to be a very effective, potentially be a safe and effective add-on or replacement potentially for the GLP-1s. So yeah, I think in this case, I would say it's fair to say the crowded market, high cost of development belongs in. Looking forward to more data on NLRP3, both with your peer, but specifically your data. Thank you for clarifying and running through some of the preclinical things and what to put into context and consider.