Again, everyone. I'm Alex Thompson, biotech analyst here at Stifel. It's my pleasure to introduce the Ventyx Biosciences team, Raju Mohan, CEO, and Mark Forman, CMO. So maybe I'll kick things over to you, Raju, to do a brief overview, and then we'll get into a bit of a Q&A. Yeah. So, you know, you're familiar with our story. We started out as an I&I company, small molecule I&I, disrupting the world of biologics with safe, oral-effective drugs, I&I space. I think we've now added a CNS to our I&I, so think of it as an I&I plus a CNS-I company as well. We continue to have the strongest quality compounds in the space. And, you know, we've got a new portfolio, not new, but newer clinical. Refocus. Yeah, well, yeah, focus, refocus, pivot, lots of words to be used, but a super exciting portfolio of NLRP3 compounds, unmatched, I think, across any compounds out there. We've rebuilt a team here since we were talking about the rest with Mark who's joined us as a CMO. Happy to have him here. First time with us and with you. We've got Thomas who's taken over the IR function. We've got, you know, so the team is a great team. They're laser-focused on execution and well-capitalized. And next to. Yeah, let's get into it. Yeah, let's get into it. NLRP3, right, the biology here is, you know, super complicated and far-reaching. You know, I guess maybe we could start off with just sort of the broader role of NLRP3 in chronic inflammation and why it's an interesting target to start with. Yeah, so NLRP3 has been around a long time. It's a member of the inflammasomes. It's the most well-known, although, you know, in coming years you'll see other NLRs, NLRC4, NLRP1, but this is the most well-characterized inflammasome, and the reason it is, is because early on it was linked, directly linked to helping catalyze the production of IL-1 beta from pro-IL-1 beta by turning on Caspase-1, and so once people recognize that in addition to the protective functions of IL-1 beta, which is the evolution of the cytokine, once there is an aberrant inflammatory state, it has an impact on a number of disease indications, right? And the CANTOS trial that Novartis did, in fact, the CEO of us was the PI on that trial, it highlighted a number of areas in the sort of broad population of patients, 1,000+, where IL-1 beta amelioration through an antibody would benefit these patients, right? So big, big broad trial. I'll come back to why there's a parallel in our cardiometabolic trial to that trial. And then there was, and so that was the interest that spurred a lot of folks to go into small molecule discoveries and prove that IL-1 beta really is upstream, is downstream of NLRP3, so evolution of the inhibitors, IFM Therapeutics, Inflazome, and then the CNS aspect, which is more recent, right? So I think there's a broad recognition, broad, that a number of these diseases actually are, they originate or the trigger for them is an inflammatory state, right? So that's the interest here broadly. Yeah. And you alluded to it again. I want to start with the CNS part of the story. And so you alluded to the neuroinflammatory component. I guess specifically, what do we understand about neuroinflammation and NLRP3? That's sort of the newer development here in the biology. It's a newer development in the biology, although if you go back now and look at some of the papers, you'll see primary assays that people have done in microglia, right? And what we did is we took human stem cells and differentiated them into primary microglia and showed that when you trigger inflammation in these cells, in this case LPS, you can actually block it, completely block the inflammation in these primary microglia as measured by downregulation of IL-1 beta, IL-18, IL-6, Caspase-1, right? So there's a direct link doing that. So that's just think of A, B, C, D, right? So A is sort of activation of NLRP3, B, microglia, right? B to C, a black box, and C, think of D as death of a neuron, right? Just think of A, B, C, D, right? No one's really connected A to B to C to D. So the first thing is A to B microglia, right? The C to D is also known, what happens when aberrant signaling, misfolding alpha-synuclein, neuronal death, tyrosine hydroxylase. So now the piece is who connects, who can connect, if you can, the B to the C? So now you have this A, B, C, D. I'm being very simplistic, but that's what, and so there've been a biology around it, and I think we truly believe that the microglia is a component. Is it a major component? Is it a really bad guy? One needs to figure out, but that's where it starts with NLRP3. Yeah. And so specifically, you know, obviously there's been a lot of work on small molecule targeting for NLRP3, particularly CNS penetrating NLRP3 inhibitors. Can you talk about the design of 3232 and the validation of your proposed target product profile with the Phase 1 data so far? Yeah. Good question. So, you know, in the past, in old days, we all did high-throughput screening as leads, right? Now it's a matter of everybody jumping onto other people's lead compounds, something comes out of literature. So for NLRP3, there was a compound called MCC950, right? MCC950 is an old Pfizer drug. It's a glyburide. It's a sulfonylurea. And that was shown to be an NLRP3 inhibitor. Now everyone jumped on it and said, okay, I'm going to take sulfonylurea, I'm going to start making analogs. And lo and behold, there was a dozen peripheral compounds, right? But sulfonylureas are sodium salts. They don't cross the blood-brain barrier. And people started to say, okay, I'm going to take this compound, I'm going to shove it in a human at multi-grams and hope milligrams cross over into the blood-brain barrier. And that's what it was, right? We, and I say we as in my team, decided to take another approach and said, okay, we're going to screen two things, we're going to screen a library of CNS molecules, privileged compound library, and we'll also start with CNS bioscaffolds like benzodiazepines, like imidazopyridines, the amidine scaffold, tricyclic, so let's take a CNS bioscaffold which has the MPO score, which has the polar surface area score, which has low P-gp, and now let's build in the NLRP3 motif, and we had a crystal structure of NLRP3 in the NACHT domain, so by doing so, we started with a bias towards CNS, and then once you have a lead, it's just classic lead-up towards your profile, and so we believe we are unique in a position of having the ideal CNS molecule, and I say it with the data, which is it's got optimal blood-brain barrier penetration. It's got exposure to CSF. It's got a good free fraction, and we have now shown it with our Phase 1 study where we, you know, where we hit all the biomarkers in the CSF at really low doses. For small molecules, how well correlated is CSF exposure to broader deep brain exposure? Very well correlated, right? It's not just a small molecule. The question is the drug in the CSF is a measure of free fraction in the brain, right? Now, very surprising, but people have actually done, I don't know exactly what the procedure is, Mark, but they put a small catheter in certain cases to actually correlate that. But in animal studies, in primates, in dogs, in rodents, very clear correlation of drug levels in the brain, free drug levels, with the CSF, which is the free drug level, right? So if you say I've got one micromolar in the CSF, that means you've got one micromolar of free drug available for its pharmacological activity. Yep. Okay. So for Phase 1, based on the Phase 1 data, can you talk about the level of target coverage that you can achieve? Yeah. Let me have Mark cover that. Sure. So, you know, in the Phase 1 study, what we actually did was just to sort of recap. Right after we did the traditional SAD and MAD where we looked at PK, we actually then did separate cohorts where we collected CSF at our low dose, which was 3 mg and 40 mg QD and QD. And what we did is we showed that at 3 mg we were getting modest target engagement. At 40 mg, we were getting robust target engagement greater than 90, well over 90, the IC90. And then we've modeled that data through the, both with the peripheral exposure and showed that a dose as low as 12 mg gives us, it gives us exposure over a 24-hour period at the IC90. So the doses that we're taking forward are 30 mg and 40 mg, which really, given the known human variability, should ensure that everybody's above the IC90 at the doses that we're testing. Okay. Yeah. So then moving forward, can you talk about Parkinson's as sort of the first, you know, neuroinflammatory indication? Mechanistic rationale there. Obviously, there's some competitor data offering proof of concepts. How are you thinking about, you know, that indication? Yeah. So again, we'll tag team, but mechanistically, the most well-studied disease indication is Parkinson's in the CNS space, right? A lot of work done in the microglia, a lot of work done looking at alpha-synuclein and its effects with NLRP3. And again, like I said, it's not a complete story, but it's very clear that blocking NLRP3 reduces the inflammatory state of the microglia, right? A lot of work been done. And even to the extent, and this is folks that have published in Cell, that NLRP3 could be a disease-modifying therapy for Parkinson's, right? That's a tall order, right? Everyone's claimed that, the MAO inhibitors and so on and so forth. But this is where it starts. There's obviously a set of diseases, I would say, so Parkinson's, Alzheimer's, Huntington, I would say the first three. And then if you go down, sorry, Parkinson's, Alzheimer's, MS. And then the second would be Huntington's, ALS, and some orphan indications, right? And for a lot of reasons, Parkinson's is the one, probably the hardest one in terms of diagnostics and biomarkers. We're looking at MS, obviously. MS is a much easier one to track. But clearly there's a belief. We believe that. Folks that we recently had a very light handshake with believe that. So there's a lot of evidence out there that at least you can start to affect the microglia and start to put this together. Now I'll let Mark talk about the trial, the design of this trial. Right. And just to sort of step back, I mean, a little bit, I mean, one of the things that we, the reason we're focused on the microglia is because if you look in the brains of all of these patients, both now you can do it in vivo with imaging, but in the past we did it at autopsy, we see across these range of diseases, huge activation of the microglia. And we believe in Alpha-synuclein, at least in vitro models, has shown that it's a direct activator. The initial study we're doing is a very small biomarker open label study, just looking to see, A, if in part, well, just to really translate the healthy volunteer data into patients, can we see at doses that are well tolerated and that give us really strong coverage, are we impacting the NLRP3 pathway looking at the downstream cytokines and CRP and also looking at, trying to look at microglia inflammation and then using imaging, PET imaging as well, and trying to see are we engaging the pathway as the first step to those series of, you know, of the A, B, C, D that Raju was talking about, are we at least getting the A and the B part and then would give us confidence to go in and then really test that mechanism in a larger powered study to assess efficacy. I guess specifically, you know, thinking about a 28-day study in Parkinson's, like that from a de-risking perspective, what do you need to see across some of these biomarkers like NfL, GFAP, or even thinking about imaging, you know, changes or impacts to feel like you're not just getting target engagement, but potentially impacting the biology here? Well, so I'll come back to what I think our first, you know, 28 days, you're right, is a short study. It was limited based on our tox coverage at the time that we got that. And so clearly some of these changes in inflammation are chronic processes and whether we will be able to see something in the course of 28 days or downstream markers like NfL, which is a marker of neurodegeneration, but we're focusing on the NLRP3 pathway. Are we seeing changes in CRP? Are we seeing changes in IL-6? If we see changes in things like GFAP and NfL and the TSPO PET imaging, that to us is like an upside. That's even more confidence. But in the short study, are we getting good target engagement, pathway engagement is the minimum bar that we need to move forward. If we see these other things, that gives us even further confidence that we're on the right track here. Yep. Okay. So then shifting gears, you know, the second indication for 3232, thinking about obesity, cardiovascular-related diseases there, you know, thinking about the mechanistic rationale for having a brain penetrant NLRP3 inhibitor necessary for treating some of these indications, how should we connect those two things? Don't think of it as a brain penetrant compound. Think of it as just an NLRP3 inhibitor, right? It goes everywhere. Yeah, it goes everywhere, and this is a lot of things. So it seems like the CNS penetrance is necessary for. We don't know that, right, Alex? So for obesity, if that really was a human relevant pathway, right? Big question, right? Yes, the belief is through a central action on the hypothalamus and controls because there is crosstalk between NLRP3, between GPR120, which has been implicated in feeding, between cannabidiol, as you've seen some of the Corbus work recently, Cardiol work, and GLP-1s, right? Surprisingly, GLP-1s are crossing into Parkinson's, right? Who would have thought? So the CNS compound, I mean, now I go back to my CANTOS analogy, which is the study we are running is a study in subjects with obesity, right? But also making sure that these subjects have elevated cardiovascular risk, elevated metabolic risk, elevated diabetes risks, most likely have fatty livers, most likely have elevated liver enzymes. And so can we go in with this drug in a beautifully constructed study? It's a placebo-controlled mono and a placebo-controlled combo, well-powered to detect not just body weight, but also see changes across in clinical chemistry, in biomarkers, and in imaging. So we're going to do an MRI-PDFF. We're doing DEXA, obviously, but MRI-PDFF is really to look at liver inflammation, liver steatosis, and then whole body imaging to see pancreatic cardiac inflammation, right? So think of it as a one step from the CANTOS where you've got all these tools now to look at where is this drug impacting inflammatory state? Where is the most dominant, right? And then go back because we know some of the, we know some of the story there. We know the IL-1 beta story. We know the IL-6 story, right? But really get a broad read that allows us with one molecule in one model, get these readouts for us to go through. Now, if obesity hits, great. Yeah, but I would not, I would not say there's any understanding of obesity as relates to human, much, much, much less so than in Parkinson's. Yeah. You talked about the CANTOS study. I guess, you know, there will be some IL-6 readouts next year in the broader cardiovascular space. How should we think about the relation between NLRP3 and IL-6 and potential like read-throughs to how you're thinking about clinical development? NLRP3 is a dominant driver of IL-6, right? There's no doubt about that. So when you block NLRP3, the levels of hsCRP, IL-6 track with NLRP3, right? If that IL-6 is in control of NLRP3, so if you stimulate and you have the cytokine storm and now you elevate the cytokines and you block them, everything tracks with IL-1 beta, IL-18, IL-6, and then finally hsCRP. IL-6 is just hard to measure. It's not the half-life. It's not, it's a tricky one to measure. But people look at hsCRP as a surrogate for IL-6, right? So we don't go around saying we are the oral IL-6 because again, you know, we've been, we've been burnt, but you know, people who made claims like TYK2 was the oral IL-23 is probably not, has not borne out, right? But this is a much, much more accepted pathway. To your question, when Novo reads out and when Tourmaline reads out, I think we are in a position to then understand the biology and be there as the oral safe driver of IL-6 in particular. Yep, and you'll have those sorts of biomarker data coming out of this phase too then, thinking about. We'll have biomarkers coming out of. Everywhere. Everywhere, right? I mean, the 28-day study in Parkinson's is with 3232, right? But we also have a three-month study with 3232, which is going to read out. So you'll have safety in now hundreds plus. We haven't exactly told the trial design, but trust me, it's going to be hundred plus subjects there, right? So you have safety in a three-month, in a hundred plus folks. You've got biomarkers in 28 days. And Mark is right. There's delayed biomarkers you may not see, but NodThera did show in a really sloppy study, and I mean it, you know, they've done great science there, but the study was sloppy in the sense it didn't quite show us exposure data, but they did show biomarker data. They did show suppression of neurofilament light chain in that 28-day study. You're talking about the Parkinson's study. The Parkinson's study, so if we can do that in a controlled study with a good compound, understand that where we know the PKPD, that's going to be a huge plus, and the other thing is Roche has completed a trial just like ours, 28-day trial, and when that data comes out, that's going to be another validation of this type of protocol as being the first step to, you know, the larger trials that Mark talked about. Yeah. Yeah. And so I think you alluded to it before, but I'm curious if you can add a little bit more color on the recent Sanofi investment and, you know, the terms of that deal. What does it sound like they're most interested in? Sanofi has historically been interested in, they've been interested in the CNS, neurodegenerative areas. They've been interested in MS with their BTK inhibitor, which just recently was a success, right? They have a strong interest in Alzheimer's. And obviously with us in this relationship, it's an interest in Parkinson's as well, right? And so I think the idea, and I truly believe these companies like Novartis, like Roche, who started early, Sanofi, they've built the machinery, the infrastructure to go into these programs and are waiting for the right compound to plug. Roche failed with Jecure. They thought they had the right compound. Didn't do great with Inflazome. But you know, that's not going to stop folks from either internally developing them or acquiring them to then fit into the pipeline, right? I think that's where we don't know exactly the whole intent of what, you know, we don't have a view of what they're doing internally, but I truly believe they're committed to a CNS pipeline, especially moving away from their Dupi franchise into more of an oral immunology play. And Paul has made it public now. Yeah. Makes sense. And then they have right of first negotiation. Negotiation, right? Which is very different from right of first refusal. It's a very. How does that sort of work from your perspective? It basically means that, you know, when we have the data, I mean, there's going to be two data points, the Parkinson's study and the cardiometabolic obesity study. If we have an offer on the table, right, anybody, they will have the first rights to, you know, to have the dibs on the offer, right? To say, hey, we want this. And so that's called the ROFN period. And once they opt in and say we want it, then there's the exclusivity period in which you negotiate the terms and so on, right? Again, we haven't talked about that, but the very favorable to us, we didn't want to be locked up for an indefinite period. It also means that if they don't opt in, then we have the option of, you know, going forward, going with any partner we think is fit. If we don't like the deal structure, we can say no, we don't accept it either, right? It's very different than other deals where you essentially have given up rights to one party for very little you can do in terms of the deal structure, right? Is this automatically triggered post the initial data set, or is it only triggered if someone else approaches you or if they decide they want to approach you? It's automatically triggered. It's triggered after the second data set, but it's also triggered, we're not going to go into the details of our program, but typical ROFN can be triggered at any time. Remember, it's only for 3232. It's not for the entire Ventyx portfolio. Yep. Yeah. So So for 2735, so for a peripheral restricted compound, you've done some work in CAPS. You know, can you talk a little about, you know, where you see that program progressing at this point? Mark, would you speak? Sure. So you know, the thing that, you know, the CAPS trial was, you know, just so one understands, CAPS is an ultra-rare disease with a gain of function mutation in NLRP3. So it's almost like a proof of principle, right? So by inhibiting NLRP3, we actually showed that we can not only reduce the cytokines, but actually improve function in patients. Again, it was seven patients. This is an ultra-rare disease. Where we're starting also by the end of the year is a study in recurrent pericarditis, once again leveraging that IL-1, IL-6 story where there's clear evidence with Rilonacept that inhibiting IL-1 plays a role. So we think we can come in with an oral molecule that really hits that pathway very well with a very rapid, you know, it's an orphan disease, a rapid-to-market approach where we can go over fairly lean and mean. But to your question earlier, it also with 2735, depending on what we learn from the obesity cardiometabolic study, we could say, you know what, for these indications, we don't need CNS exposure. And we could come in with 2735, which, you know, as an alternative so that we can really sort of separate out those indications where we need good brain exposure for efficacy and those that we don't because you really don't want a drug in the brain if it's not needed for efficacy. So this allows us to sort of, you know, we'll get, we're going to get a series of readouts next year and allow us to really decide how do we want to pursue each of those with the two different molecules that we have. So it's really nice to have these tools that we have to really sort of explore both of these, both peripheral and central indications. Yeah, so to just sort of add the tagline, 2735 has been groomed as the IL-6 oral. It's going to the finishing school, getting all of the things in, and be ready when it has to step out, right? So think of it that way. And then, you know, timeline to start a recurrent pericarditis trial is this year? This year, yeah. That's by the end of the year, we'll have that started, and then with the goal of having data by second half of the year. Okay. So for the rest of your pipeline, thinking of 002, you had your end of Phase 2 meeting. You know, key takeaways there, still only one more Phase 3 likely needed for approval? That's the guidance we have from the FDA. The FDA never tells you. Sure. They'll never produce anything. But the idea that we can do a single trial with a single dose, it bodes well for that approach. How would you characterize, you know, interest in partnership discussions for 002 at this point? I think, I think what I'll say is that the story is going to end up being a combination study when this all plays out. And I think that's going to drive the interest in this molecule because it's not this compound. I think people are tired of this suboptimal efficacy of 20%-25%. Now, you know, there's excitement about the TL1As, but Morphic was only, it's an oral entity really well understood, right? So I think the game changer is going to be if we can show 20 plus 20 is 35 or in that range, then you're starting to approach what you see with other drugs like PASI 75. Why are we stuck in this rut? And why do we accept 10%, you know, endoscopic remission? So that's our thought because I think from a commercial perspective, from the strategics, I think they're looking at a much longer haul as a monotherapy to get the same result that you're getting with these drugs. So I think that's where our interest is. We think S1P1 can be the backbone of combo therapy. I'll even go as far and say you could think of an S1P1 TYK2 combination, certainly an S1P1 biologic combination, S1P1 induction combo, maintenance with an S1P1. This all has to play out, right? So right now we're laser focused on the NLRP3 portfolio. But with the size, with the expertise that we have externally, internally in IBD space, we are going to look at this thoughtfully and see where can we actually prove that concept because that's when the excitement is going to come. Great. And then maybe, you know, last thing, last question here. Can you talk about, I guess, current cash runway and the embedded assumptions there in the context of, you know, what we've talked about today? Yeah. So what did we disclose the last $275 million that included the $27 million from Sanofi? And we've guided right now cash runway through 2026 minimally, right? I mean, these trials are really well-designed trials that you can get so much data without spending in the IBD space. You have multiple endoscopies, highly invasive, right? So we'll end up in a good position. I'm not going to go into details. When all the trials read out, we'll be in a good cash position. Obviously, if we start to think about potential Phase 2s and Phase 3s, that's a different story. But we'll have so many options at that point with the data coming out that we'll decide where to go with it. But right now it's a matter of just, you know, sitting back, not looking at your stock price, executing flawlessly, which the team has done in an amazing space with two of the best compounds I think out there. Great. Well, Raju, Mark, always a pleasure. Thank you for joining us. Thank you.