Good afternoon, everyone, and welcome back to Oppenheimer's Healthcare Conference. I'm delighted to welcome from Ventyx Biosciences, Raju Mohan, the CEO and founder, and Mark Forman, Chief Medical Officer. Gentlemen, thank you for taking the time to join us this afternoon. Our pleasure, Jeff. Raju, why don't we have you set the stage for Ventyx? If you could speak to just introduce us to the company and speak to what your focus is and really the core expertise that really stood up the company. Yeah, you know, the core expertise, you know, is to the genesis of the company or companies. We started with three different companies, each of them with a unique target and compounds. S1P1 was a company by itself. It's called Oppilan. NLRP3 was a company called Zomogen. Ventyx was always a TYK2 company. You know, a couple of years back, more than a couple of years back, 2021, we combined them to one company. This company now, Ventyx, has, of course, a TYK2 program, the S1P1 program, but now as a showcase or forefront of the development programs here, we have the NLRP3 portfolio with two compounds there. The core expertise, you know, I hate to shortchange anything now because we are a late-stage company. We're a company in phase II studies. We're poised to do a phase III with the S1P1. If you want to talk about genesis as opposed to the core, it is a chemistry-based company. Our expertise is to design novel small molecule drugs targeting immune broadly, autoimmune diseases, innate immunity. We have expanded now into the CNS side. We would call it a sort of a CNS immunology company as well. That is the basis. You know, most of the work we did early on was in, I would call it a me-too space. Me-too is not a bad place to be, which was to look at drugs that were in phase II, where we could identify an area where we could have a compound that would have better efficacy, better safety, and in ideal conditions, both of them. Differentiated efficacy, differentiated safety. We would build this hypothesis at the non-clinical level, establishing our rationale for why this drug would differentiate. We would prove that in the clinic. We've actually done that with the early compounds. We've done it with the S1P1. We've done it with our TYK2 in Crohn's disease, which we'll be showing the data in a little more detail in the coming weeks. You know, the challenge there is even if you show that, the dynamics of the market, the commercials, the indications change. We're in a position where the IBD portfolio right now is in a place where we need a partner. We need to justify capital there, even though we believe that we have the best in class or best in therapy in some cases. That's the genesis of the company. The core expertise we have is really to take novel drugs and move them quickly through proof of concept. In some cases, the path is not really clear. We have to then chart our own way, as in the case of the NLRP3 portfolio. I think our core expertise right now is from literally, to use a cliché, from bench to clinic, with Mark coming on board and us having built a clean Ops team, the Reg. We have everything in-house here to execute, to choreograph, to orchestrate our plan with still a group of CROs and collaborators out there. I think that's the vision I had for the company. You know, it's coming into fruition now. 2025 is going to be a key year for us, especially the first three quarters, in now getting data readouts from the NLRP3 portfolio in areas where there really is little to no precedent, right? Other than, you know, RP trial with Rilonacept. We're literally charting our way through these indications. Some of them are obviously based on biology, like IL-1 beta, canakinumab, and the rare disease and the CAPS. There is certainly the cardiovascular angle that we are not pursuing actively, but it's wide open from the cancerous trials. More mechanistically, building this idea for Parkinson's, for example, where we're going into a biomarker, we're going to go into a late-stage trial, post this outcome, depending on, you know, what we see, while still building the biology for this, working internally, working with collaborators to understand the links between our compound and the early stages of trigger. I think we've come a long way from being a company chasing after a TYK2 or an S1P1 to now literally laying out the biology and then showcasing where NLRP3 can be a dominant player, not just in terms of a concept, but actually having a compound that we can then develop, you know, and take it to market with or without a partner. I think that really sets the stage for a discussion around your NLRP3 programs. As you pointed out, you've got two programs, the peripheral and the CNS penetrant program, and the indications that really make available to you. Maybe let's spend a little bit of time talking about NLRP3 and the inflammasome as a target across a number of indications. As you pointed out, there's probably more history there in cardiovascular. There's the CAPS data for the rare mutation. As you think about other indications here that are more interesting, one that's gotten a lot of attention, rightly or wrongly at this point, is obesity. Looking beyond that to recurrent pericarditis, looking to things like Parkinson's, as you mentioned, there's a lot to be explored here. Can you sort of set the stage on NLRP3 and sort of what gets you excited, enthusiastic here on both the peripheral side as well as the CNS or neuroinflammatory side? Yeah. NLRP3 as a target is, you know, it's been around for many, many years in the biology being done. There were sort of three or four domain sites where people were looking at it. It really came into forefront with the CANTOS trial, right? This recognition of the downstream effects of NLRP3, which is IL-1 beta, have been, you know, around a long time. Basically, the immune system, it's there, as you know, to defend against pathogen invasion and maintaining tissue homeostasis and promoting damaged tissue repair. That was the whole genesis of the interleukins, right? Now, if you have pathological conditions that lead to overactivation of this response, it will further exacerbate the disease, whether it's in cardiovascular, which is understood, whether it's in CAPS and the family, which is understood. In the CNS area, there still remains this whole link here. It is really a tissue damage that leads to activators. There is clearly a trigger with particulate, whether it is in the lysosomes, whether it is in cholesterol crystals in the macrophage. That is the trigger. NLRP3 now is recognized as a sensor or activator based on this trigger, again, independent of which tissue it is happening in, whether it is in the heart or the kidney or liver or the brain or in the lysosomes, which is where people think some of the genesis of Parkinson's is. That became a target for drug discovery because by targeting the NLRP3, you are specifically targeting the aberrant pathology that is dependent on NLRP3 activation through pathological damage in the tissue, where NLRP3 or IL-1 beta was evolved. The evolution was in the first place to defend and repair it, right? That is what is exciting about this. Now, for us, we have not only been able to find a peripheral compound, which is not only is it potent, it's effective, has really no issues that are either off and on target. I say because early compound, even MCC950, which is the first NLRP3 compound identified, had hepatotox. A number of early-stage compounds from Inflizome went to Roche, IFM went to Novartis. Other compounds have failed just because of issues that came out in early trials. We have not only set our basis with an established compound that we have shown now a proof of mechanism in CAPS patients with our peripheral compounds and, you know, I would say an excellent safety profile. We have also been successful in engineering a CNS penetrant compound, right, which has been really challenging because people are working off chemistries that were not amenable to crossing the blood-brain barrier, right? We have taken this compound, which is a little bit behind the peripheral, but we completed a phase I study. It was probably one of the most, not to say complicated, but complex studies where we looked at biomarkers in serum. We looked at biomarkers in the CSF, food effects, dose response, cytokines, of course, safety. What excites us is we now have not just the tools, I would say, we have the drugs here to understand the relevance of this pathway in a number of indications. You know, literally, the moment you look at another disease, it has an inflammatory component or a trigger. I am not saying all of them are NLRP3 dependent, but more and more there is an understanding that inflammation is a trigger for what people always recognize for cardiovascular. There was a trigger in the macrophage and the plaque, certainly in certain aspects of chronic kidney disease, in Parkinson's or neurodegenerative disease. I was talking to somebody else before and saying that, look, this is a concept put out about 20 years ago that neuroinflammation is a trigger for neurodegenerative, and people just laughed it off, right? Actually, Rusty Gage here at Salk had this concept. It is coming back now in the forefront where people are recognizing that perhaps there is a component that initiates this early on, right? Finally in the obesity situation, right? Yes, there is a lot of skepticism about new drugs in there. We were in the mix of this with our mouse study, and you and I have talked about this before. There is now an understanding that neuroinflammation in the microglia in the hypothalamus potentially is linked to feeding behavior and a feed-forward feedback loop with orexigenic and anti-orexigenic genes. What's exciting to me is, and it's not, you know, it's not for the faint-hearted, right? Because these are not a true, if you gave me an S1P1 drug, an R drug, I would bet you the drug would work, right? Now, how good would it be depends on what we can achieve. We did achieve the highest pharmacodynamic effects, and we had the results in terms of our response. Here's an area where a little bit of signal finding, a little bit of searching for where there is a dominant effect, not just an effect that you can say, aha, there's an effect, but it does become a therapy. It does become a disease-modifying therapy. It becomes a co-therapy, an adjunct therapy for some of these very, very debilitating diseases where there is an unmet need. To me, that's exciting. The fact that we're in the clinic, we have data readouts that will be, you know, that'll be consequential to determining the next steps and hopefully getting people excited, which is, you know, right now, as you know, it's a very sort of a period where we have a lot going on. We have the best compounds unable to generate the excitement in this general community about how promising this target is, perhaps not in every indication, but certainly in areas where there is clearly the biology now. We have the ability to prove this in the clinic with what we're doing today and what we plan to do post our readouts. You are on mute. I think that's a great setup to talk about the CNS penetrant molecule and looking at neuroinflammation mechanistically, maybe spend a little bit more time both for obesity and Parkinson's, where, you know, the target isn't as well validated. You're in the clinic for both. Obesity is obviously a clear signal here. Maybe set the stage for us, you know, a lot of investor focus on obesity. Let's definitely talk about that. Also really on Parkinson's, a little more, it's more challenging, as you were noting, in terms of the link between neuroinflammation and driving some of the early Parkinson's, what we should be looking at in terms of readouts and those biomarkers to give you confidence to move forward mechanistically. I know there was a lot wrapped up there. Maybe let's talk about obesity, the trial you're running, what you want to see, and what you think is supportive mechanistically of this neuroinflammatory mechanism. Yeah. Let me take the obesity, and then Mark will take the Parkinson's here. Obesity, really, there wasn't a lot of preclinical work. There was not a lot of papers coming out, unlike Parkinson's, which Mark will talk about. There were bits and pieces of neuroinflammatory signaling. There was a link to GLPs being anti-inflammatory. Certainly, cannabidiols have been looked at, but nothing with NLRP3, unlike Parkinson's, where a lot of work has been done non-clinically. This other company did take a leap of faith and ran a mouse model of obesity, this diet-induced mouse model, and showed weight loss in this model, both with and without and in creatinine with semaglutide also as a control or as a co-administration. We have done this model. We did three different models, monotherapy, combination, and a dose response with a combo with semaglutide. You will see consistent weight loss in these models to about 8%-9% as monotherapy and then clearly additive on top of Sema. If Sema is about 14%, you see a 22% weight loss in the combo arm. Very clear, right? It is not equivalent to semaglutide. You do not see the same weight loss as you see with Sema. We do not have any expectations or are setting any expectations that we are going to be a standalone monotherapy or mono indication for a subject with obesity. That is not the idea here. What we did see from the mouse study was, if you look at the study now with a microscope at all of the endpoints, it was not just a weight loss study. There was weight, of course. There was feeding. There were effects on parameters of feeding or exogenic genes. We also looked at lipids, glycemic, so lipids as in LDL, HDL, triglycerides. We looked at glycemic indices. We looked at the HOMA-IR, insulin, glucose, HbA1c, kidney, liver, staining, steatosis, whole spectrum of these, right? It is pretty clear that in many cases, you see an additive effect on Sema. In the monotherapy arms, you can see comparable effects. There are also effects there that one could argue are not coming just from weight loss, right? The argument is, yes, you have a weight loss drug in the mice, and therefore all the effects you are seeing now are as a consequence of weight loss. That is not bad by itself, right? What you can also see when you zoom in on these parameters are certain effects you are seeing that are direct effects of NLRP3 on that target, right? For example, in the liver, we're seeing certain effects that we truly believe are independent of weight loss. It's a direct target, right? If you look early enough in the study, before you see weight loss, you will see regulation of biomarkers that are going down pretty quickly, right? You know, the study we're doing right now is a follow-on to what we saw in the mouse with little to no other supporting data from other studies and, you know, adipocytes, nothing, to see whether this plays out in a human. What we've done is we have a monotherapy, well-powered. It's about 40 subjects per arm, participants. You have monotherapy with a placebo control with our 3232. Then we have a combination, which is Sema + 3232 and Sema + sugar, right? You know, our focus really is on two things. One is, what does this drug do in the setting of cardiovascular metabolic dysfunction in these folks, right? With the BMI bracketing that we have, these folks will have, of course, elevated CRP, but in addition, they're borderline on the edge of, for example, liver fat. So 6%-7% liver fat, elevated HbA1c. They are not type II diabetics, but they're all in that elevated state, right? What's happening there? We have a DEXA scan to look at whole body composition. We have an MRI PDFF to look at liver steatosis and whole body imaging. They have a very specific component of this called this corrected T1 scan to look at effects on liver fat, really sensitive effects. Obviously, we're not going to see fibrosis in this 12-week trial. That's the monotherapy arm and the combo arm. From a weight loss perspective, I think for us, what would be good to see is an incremental benefit over Sema, which is not the therapeutic dose. In this trial that we're doing, a 12-week trial, we're still not able to get to the maximal dose because of the way we have to titrate it, right? In some ways, it's a subtherapeutic dose of Sema. The question is, what kind of incremental benefit do we get on a combo, right? If that's meaningful, then that's a discussion that we need to have ourselves. I think it's going to excite people because if you see 20%-25% more over a subtherapeutic Sema, it offers a lot of opportunity in that space. Again, because there's so little linking mouse with humans, and there's really no preclinical studies being done in even human systems, that it's really no way to know if this is going to pan out, right? You know, realistically, if we don't see weight loss, you know, unfortunately, people are going to look at it as a weight loss study, but it's not really meant to be a primary or weight loss study. It's meant to actually do signal finding in these cardiovascular metabolically dysfunctional population with weight loss as one readout. If we see weight loss and it's meaningful and it makes sense as an eventual therapeutic end, that's great. If not, there's clearly other goals for us to take from this study that we can then use to develop our compound rapidly in those indications, right? Let me make sure, you know, give Mark time for the Parkinson's, and then certainly we can follow up on this as well. Yeah. Let's slide over to Parkinson's, Mark. And again, a lot to be learned from looking at a real CNS penetrant NLRP3 inhibitor. Absolutely. You know, as Raju had talked about a little bit, the idea of neuroinflammation playing an important role in neurodegenerative disease broadly has been around for a while. As a pathologist, you know, I've looked at the brains of these patients, and you see inflammation in whether in Parkinson's disease, Alzheimer's disease, ALS, neuroinflammation is a key driver. What we've been learning is the role of the innate immune system and specifically NLRP3 driving this neuroinflammatory process. The data set is really most robust in Parkinson's disease, which is why we started there. Certainly, it's sort of a gateway to potentially an array of different neurodegenerative conditions. In Parkinson's disease, there's human data where you look at, you can look at, you know, blood samples and CSF samples showing evidence of cytokines increased indicative of the NLRP3 pathway in neuroinflammatory indices. There's also a lot of preclinical data in various orthogonal models of Parkinson's disease showing that NLRP3 is activated and that if you inhibit NLRP3, you can rescue the phenotype in the animal models. What we're doing in our biomarker study is really seeing, okay, first and foremost, can we, with our CNS penetrant compound, really influence the neuroinflammation in these individuals? It is a small study with just 28 days of dosing in an open label format, but looking at objective biomarkers of neuroinflammation. In addition, we're looking at some downstream biomarkers, things like markers of neurodegenerative processes like NFL. In a 28-day study, our expectation, we probably aren't going to see those things change. What we want to see is, can we robustly influence the neuroinflammatory biomarkers? The next step, that would sort of set us up to do the more traditional proof of concept study in Parkinson's disease using clinical endpoints as our driver. Really, first and foremost, making sure that we've got really robust target engagement in this population and using that as a gateway into doing the more definitive clinical efficacy trials. Again, as we see this in Parkinson's disease, there's an opportunity to think about where does NLRP3, as the science evolves, what other neurological disorders does this play a key role? There's certainly a litany of things that we're continuing to evaluate and work through as to what else we should be thinking about, you know, in the neuro space as well. Maybe in the interest of time, I'll sort of stop there and let you follow up. And just, I guess, first, in terms of looking at biomarkers and neuroinflammation in these patients, what kinds of effects are you particularly interested in seeing? Obviously, you know, as you're learning about this molecule and its potency, you're going to look at a couple of doses. Dose effects and magnitude of effect are going to be important. What do you need to see to get excited about moving to that next stage? You know, what we want to see is that we're really normalizing these neuroinflammatory markers. Whether it's IL-6 or HSCRP or other downstream biomarkers, GFAP, are they in some of the Parkinson's disease isn't a monolithic disorder. Not everybody has elevated markers in each of these indices. Where they're elevated, are we pulling them back down to the normal range and really seeing that? In addition, we're looking at an exploratory marker. We're doing some imaging with a new microglial biomarker looking at TSPO-PET, which can actually see if we get microglial activation. Looking at, again, on an exploratory basis, because we don't know in a 28-day setting whether we're going to be able to normalize that microglial information. If we start seeing that microglial activation coming down, that's further validation that we're really hitting what we think are relevant pathways for the neuroinflammatory condition in Parkinson's disease. Remind us when you're going to be able to update on that story. The guidance we've been providing is the Parkinson's disease will have a readout in the second quarter. The first half of the year, as we're getting into mid-February, it's likely to be the second quarter. Yeah, before the first half of the year, we should have data from the Parkinson's disease. Getting to the next question, I mean, the recurrent pericarditis and the cardiometabolic story that Raju was talking about, those will all come out in the second half of the year. We're going to get to see a lot of data this year. I think to some of the things that Raju was talking about, given as we're learning, other companies are also studying other indications, I think we're going to learn a lot about the NLRP3 mechanism and its potential. I think what I think, you know, Raju, as I've dug into this over the past six months with some what we think are some of the best-in-class compounds, you know, we're going to be poised to really, you know, run with this field and be leaders in this field as the year evolves based on, you know, as the data readouts come from across a range of different mechanisms, both our data and other people's data. Yeah. Just staying on the neuro side of this, and as you mentioned, you know, seeing broad activity across a range of neuroinflammatory biomarkers, how then, or I guess, what indications are exciting to you guys as you think about Parkinson's and beyond here for applications for this class of molecules? I mean, just from a very selfish perspective, because I've been in the neurodegenerative space for 30 years now, the Alzheimer's world is a really exciting space to be in because the biomarker tools that are out there really enable us to run more efficient trials. You have now with the anti-amyloid therapies, the opportunity to come in with some orthogonal approaches and really hope, you know, the goal, I think you could, you know, you're not curing the disease with the anti-amyloid approaches, but if you can come in with an orthogonal approach, you may be able to really drive that disease progression down, you know, and I think that's the goal here is using combination approaches in neurodegenerative disease. Alzheimer's disease is a nice opportunity. Just because the tools have been built up and are so robust, I think there's also opportunities in other spaces. I think it's a little bit more challenging in ALS because of the rapid nature of the progression and how do you find the patients early enough to treat them. I think if you can, if those tools evolve, there's an opportunity in other neurological indications as well. Obviously, MS is a prototypic neuroinflammatory condition, very crowded market, but there are some areas of a clear unmet medical need in MS as well. I think there's a number of things that we can explore, and we're just going to have to be very tactical as our data evolves to really where do we want to go. Yeah. Jeff, I think the excitement for us there is going to be equally important. Again, other folks excited, right? The big guy is excited because, as Mark said, it's only the beginning of the link here, right? If we go a stepwise link across all of these, it's going to take a long time. There is an opportunity for us to convince folks, us and other people that, hey, there's a great opportunity with the best compounds in the right indications and really lead the space, right? Now, just in terms of guiding expectations for data here, we will have the studies reading out for Parkinson's towards the end of the second quarter. A lot of data analysis to be done. Then deciding the next steps forward as to, you know, the plan forward, whether it's a, you know, a trial we do ourselves. We need to be thoughtful about what we do and put out because we're not going to necessarily put out something that has no link to the next steps as well, right? To have a real story, right? All that will play itself out in the second to third quarter as we start to get more data from the cardiovascular trial and from the RP trial, right? That story will play itself out. All right. Guys, it looks like we are up on time here. Obviously, you guys have a lot going on and some really meaningful data to prove some of these mechanisms and applications for the NLRP3 class here. Really excited about 2025 for you guys. I will send you guys on your way and hope you have some great meetings today and look forward to staying in touch as things progress. Likewise, Jeff. Always appreciate interactions with you. All right. Thanks, guys. Bye.