Good morning. Welcome to Ventyx Biosciences 2023 R&D day. For those of you who don't know me, I'm Martin Auster, CFO at Ventyx. It's great to see all you guys here in person. Again, thanks to everyone who's dialing in and on the webcast as well. Just to kick off, I'm gonna make a couple comments to kind of frame the day a little bit before handing it over to my colleagues. Here's the forward-looking statements. We'll be making such statements today that reflect our current beliefs and expectations for the business going forward. You can find additional details on our risk factors and disclosures in our most recent SEC filings, including our most recent Form 10-Q covering the third quarter, which was filed November 4th, 2022. Again, just some quick housekeeping on how the day is gonna work. We're gonna go straight through with presentations from 9:00 till about 10:45, give or take. We'll have a Q&A session at the end. We're not gonna have any breaks. We're just gonna kind of go right through the presentations and kind of keep a continuous flow. We'll have microphones available for Q&A from the crowd. For folks that are on the webcast, you can submit questions through a chat box, and I'll be able to see those and then read those out to the management team during the Q&A session. At the conclusion of the event, materials from the presentation will be posted in the investor section of our website at www.ventyxbio.com, and the slides will be shown live on the webcast now and then live in person as well. There's a press release issued summarizing the R&D day and some top-line highlights that was issued at 8:00 A.M. this morning that hopefully you've all seen. I'll be joined today by several of my colleagues who you see here. Before introducing those folks, I do also wanna give a big thank you to everybody in the clinical and research groups back home in Encinitas who, you know, put all the materials together, did a great job just supporting the team in general, making all these products and working on the clinical trials and making the whole company work. I also wanna thank Thomas Deal, who's our head of investor relations internally, who sort of quarterbacked the whole day, and our colleagues at Westwicke, Patti Bank and Josh Flax, for helping us out. The folks you see here will be speaking, our CEO, Raju Mohan, our founder as well, Dr. Bill Sandborn, our President, Chief Medical Officer, and Dr. John Nuss, our Chief Scientific Officer. We'll be joined during the Q&A session by Dr. Jim Krueger, who's a Professor in Clinical Dermatology Investigation at Rockefeller University. Jim has been a member of our clinical advisory board for several years and is a highly skilled and respected dermatologist. His group at Rockefeller was the first to conduct clinical trials with specific targeted immune antagonists in psoriasis, his recent work is focused on defining new inflammatory pathways in psoriasis. You can see Jim's disclosures and consulting arrangements listed at the bottom of the slide. Finally, onto the agenda. As you can see, we're going to be discussing the entirety of our both our clinical as well as our preclinical and discovery pipeline today. We'll be focusing a lot on our clinical stage, more advanced clinical stage programs, VTX958, our TYK2 inhibitor in phase II in a number of indications, and VTX002, our S1P1 modulator, in ulcerative colitis in a phase II there. With that, I'd like to hand the meeting over to our CEO, Dr. Raju Mohan. Raju? Yeah. Thanks, Marty. Thank you. Thanks, Marty. Again, welcome everybody here. It's humbling to see so many folks here. Again, thank you to the team here, thank you to the team back home, because without them, we would not have much to talk about today. Let me just move to the first slide here. This is not, this is not a biology lecture. This is not a chemistry lecture here. What, the point I wanted to make here is at the core, and we've said this before, Ventyx now has been around for two years, and from the beginning, we've said this, that we are at our core a chemistry-driven company. We build molecules from ground up. We own our pipeline. We own all IP rights, we own all commercial rights to our compounds. What's the approach that we take? We go after validated targets. We go after targets where there's some rationale, either from a biologic or from a small molecule. In the case of TYK2, we have the IL-23s, we have Sotyktu. In case of S1P1, we have the two front runners, ozanimod and etrasimod. In case of NLRP3, we have tremendous biology in the IL-1β's backing up the potential for these indications. Validated targets. Unmet need. There's reason that we believe that this market is still under-penetrated. The compounds are efficacious, but there is some room for improvement, certainly vis-à-vis the biologics. In the case of NLRP3, the biology has been compelling, but no molecules have been able to surmount some of the issues that have prevented compounds from getting into the clinic. Validated targets, unmet need. We then build a thesis on differentiation, and this is built from ground up. How do we differentiate on efficacy? How do we differentiate on safety? How do we build that model in the in vitro non-clinical setting? And finally, most importantly, how do we actually prove that in the clinic? That is the thesis, the core, the foundation of what Ventyx does. This wholly owned clinical portfolio is now targeting the cycle of chronic inflammation that's shown here. I'll let you look at this at your leisure. That showcases our targets here today, which is our TYK2 inhibitor, our S1P1 modulator, VTX002, our 2 NLRP3 compounds, VTX2735 and VTX3232, and the newest member of the Ventyx family, the IL-4Rα antagonist program. So the vision for Ventyx has been very clear from the start when we started the company, when we founded the company. One, to drive value for the company, to drive value for the shareholders, and most importantly, drive value for the patients, okay. Each of these programs, every single one of these programs, TYK2, S1P1, NLRP3, is a pipeline in a program, right. If you look at these molecules, you look at these targets, there are multiple indications that you can go for with the same mechanism. For TYK2, there's clinical validation in psoriasis, PSA, and SLE. This is from work that's been done with Dukoral. TYK2 and the IL-23 pathway has been validated in ulcerative colitis and Crohn's disease, opening up the avenue for a appropriate TYK2 inhibitor like VTX958. S1P1, both with ozanimod and etrasimod and years of work done in MS, the only safe and effective oral medications, and certainly for moderate to severe UC patients. Finally, NLRP3, as we talked about, there is strong biologic rationale. A number of years of work's been done, certainly by IL-1β biologics. This area is now waiting for a small molecule to then drive the biology into meaningful clinical therapies. Differentiated molecules. We've talked about this a little bit last year when we showed our phase I, when William Sandborn showed the phase I data for this molecule. We'll reemphasize that today in terms of the potency of the compound and the class leading coverage, the biologic-like coverage that we have shown in our phase I study in the both SAD and MAD portion of the trial. VTX002, Bill will talk about how we're targeting a best in class profile, both in terms of the PD efficacy of this molecule and potentially how this will translate into improved efficacy, significantly, meaningfully improved efficacy in ulcerative colitis. We're bringing it back home with the NLRP3 molecules, both the peripheral compound and the CNS applications. I don't need to tell this group here, in terms of the total accessible markets here, these are large markets totaling over $50 billion in worldwide sales. We've seen the projection for... TYK2, guidance given by both analysts as well as by Bristol. Clearly, where we feel where we can make a difference, that these markets have been historically dominated by biologic, injectable biologics, and perhaps in some cases, suboptimal small molecules. There's a clear demand for safe and effective oral agents. That takes me to the next slide. Just get a little glass of water here. Where our goal is to disrupt these large markets that have been dominated by biologics. Why is that the case? In many cases, the target indications remain under-penetrated. This is not just for the IL-1β story, it's across the board. We've seen how the shift has already happened with oral agents for MS, moving from biologics to the oral agents. Now, these are chronic disease populations. The patients commonly recycle through most of these therapies, whether they're anti-TNFs or biologics. In many cases, you have these immunogenicity with these drugs. All of this really suggests the fact that there is a room for a safe and effective oral agent. We are positioned with all our molecules, entire portfolio, to be able to disrupt this market. We've seen even with the success of JAK inhibitors, where there is a line of use restriction, they've been immensely successful. The same thing goes for some of the other compounds in this class. We feel a safe and effective compound is gonna be a major disruptor in this market that's dominated by biologics. That then takes me to my final slide before I hand it over to Bill. Now if you stand here and look at what's happened in the last couple of years, where we are with this portfolio, and we don't have our discovery program here, which is the IL-4. This is our clinical stage programs. We have VTX002, which is undergoing a phase II trial in ulcerative colitis. This trial will read out in the second half of 2023. We will have top-line data for this in a phase II study. With our TYK2 inhibitor, and this is what I was talking about when I said pipeline in a program. You can see here for 958, we have three phase II trials that have been initiated. We have dosed patients in psoriasis. We announced that last year. We have dosed patients in Crohn's disease. Bill, shout out to Bill and the team. We are screening now for patients in psoriatic arthritis and dosing will be imminent. Three phase III trials started this year. The first of those will read out in, again, in the latter part of this year, in Q4. This is the psoriasis trial followed by readout for Crohn's and PSA in 2024. First half of 2024 for PSA and then followed by Crohn's disease there. For our NLRP3 inhibitor, we have completed the phase I trial. This is a phase II-ready molecule. We will talk a little bit more about this towards the end of the discussion, but we are initiating a small proof of mechanism trial in CAPS patients in Q1 of this year, and Bill will provide some more color on that. Finally, in our second NLRP3 molecule, which is VTX3232. This is a truly brain penetrant CNS molecule. One of the indications that we are looking at is Parkinson's disease. There's a opportunity in a number of neuroinflammatory diseases here. This compound is finished all of the IND-enabling work. We will be initiating phase I in the first half of 2023 with this compound. Four phase II trials ongoing. One phase II-ready compound in NLRP3 peripheral, and one phase I to start in the beginning of this year. It's an amazing portfolio. Large markets, unmet need, disruption of biologics. With that, I think we should we'll move on to our first program, which is the TYK2 program. What I'll do is I'll introduce the program briefly before I hand it over to Bill to talk about the clinical stage programs here. It's a little bit of a history lesson, and you've seen these before. You've seen these slides before, just bring it back in context before I hand it over to Bill. VTX958 is an allosteric TYK2 inhibitor, so it belongs in the same class as some of the molecules you've seen and heard now, which is molecule from BMS or TYK2, the Nimbus compound, ours, and a few others out there. This idea of going after the allosteric domain really allowed folks to derive selective TYK2 molecules without crossing over into the JAK family. This was something that started a couple of years ago. There's been a huge amount of success in getting to selective compounds. Where there is a difference is how selective the compounds are. While you may have a very selective compound, if you do have residual crossover into other JAK families, that crossover will then show up in undesired activity or signaling through that particular JAK pathway. Before we go into the molecule itself, it really is important to talk about what happened in the latter part of 2022, which is the first TYK2 clinical compound, the deucravacitinib or Sotyktu, came out with a clean label. I know with every single one of you, I think Marty and I and Bill, there wasn't a meeting without having the discussion of where do you think the label is gonna come out. We all had our own bets, and Bill and I were somewhere between, you know, a second sort of a benign label and perhaps a clean label. I remember coming back from the Wells Fargo conference on the plane with Bill. It was 7:00 P.M. in the evening. We were flying over somewhere over Denver. That's when the news came out, and both of us are looking at the label. Where is the label? Let's look at the package insert back and forth, and there was no label. That, that event, the idea that one could differentiate TYK2 from the JAK class, not just on a molecular basis, but convince the FDA that this is a unique class of compounds, was a game changer for the field. It truly took the TYK2 space away from the JAK inhibitors, put it in its own playing field, and gave us the ability to play this game now better than most people out there, right? What you've seen now for Sotyktu, there's been analyst reports. There's been BMS projections with a clear trajectory up. I'm not gonna go into the numbers. You can read those are. A clear market share capture from Otezla starting in 2023 with a very high trajectory. What does that do? That's for derm alone, right? Think of the market that's under-penetrated for other TYK2 molecules like ours, where we're going after not just psoriasis but indications like Crohn's disease with a compound like this. There's plenty of precedents from IL-23 inhibitors here of how this has taken market share from the first compounds to more differentiated IL-23s even more recently. That's what happened to the class, and now we come back to our compound very briefly. Again, we've talked about this before. I'm not gonna belabor this too much. Here it goes back to the fact that everything starts with how selective you are in your affinity, in your binding to the pocket, the allosteric pocket, the regulatory domain of these two isoforms and how we differentiate from, in this case, from the deucravacitinib. We've talked about this before. We have a 4,000 fold higher selectivity for TYK2 versus JAK1. There's folks that talk about 10,000 fold and. I can tell you, in these assays, you're sort of at the bottom of the assay. Any small changes can amplify this. It's a pretty conservative number. We have 4,000 fold selective. We have no meaningful interaction with the JAK1 allosteric domain. In fact, we have no interaction with any of the other JAK families, not in the catalytic domain, not in the allosteric domain. This binding affinity translates into meaningful functional selectivity. If you look at the left-hand side, and again, we've talked about this before, I think it's important in this forum to just re-emphasize these data. If you look at the left-hand side panel here, because of its high affinity for TYK2, as does the upaca, both compounds bind and have functional effect on blocking the three cytokine of interest. IL-12, IL-23, and IL-23 in particular because of the indications that we've just talked about, and then type 1 Interferon alphas. They're all potent, all competent in blocking these cytokines. Where the difference really comes out and is striking is in the second table here, where across the board, across this panel, and remember, every single one of these cytokines, 22, 10, gamma, four, and six, they all signal through JAK1. It's not just one readout. It's five different readouts that tell us that we have no signaling through the JAK path. We have no inhibition of these cytokines, and we have no inhibition of these cytokines at any meaningful concentrations that we would achieve any concentration that we would achieve under the clinical settings, and we have shown that with our phase I trial. Deucravacitinib, while it may have some differences across the cytokines, it still hits a number of these cytokines, in particular IL-10 and IL-6. Those numbers then now show up in a manner where it limits the therapeutic window as you start to dose up. We know what happened with the phase II and phase III trials. Bristol, rightfully so, stayed within the threshold where they would have no effect on the JAK1 pathways, which was a 6 mg phase III dose. The takeaways from here are pretty straight. We have a potent activity against IL-23. This is a cytokine of interest to us in both psoriasis and in other indications that Bill will talk about. Really this selectivity of this compound, coupled with a broad therapeutic window, which is safety from all the non-clinical work we've done. Let me remind you, we've completed 28-day studies for the IND, four-month studies to support the phase II trial, and now the final chronic dosing, which is six and nine months dosing, which will support all our phase III and phase III trials and beyond. The entire tox package, the safety pharmacology is complete. This therapeutic window that we've seen now from our, from our selectivity and from the non-clinical safety and from the phase I data really allows us to have biologic-like target coverage that we'll show you, and that allows Bill to move into these trials, phase II and phase III trials. This advantage, the selectivity advantage that we have over Sotyktu really is expected to derive not just a differentiated profile, but the opportunity to go into diseases where Sotyktu cannot, like Crohn's disease. This is a recap from our phase I data. This is a table showing you that all five cohorts that we took. There was a mix of BID and QD cohorts here. We had three BID cohorts, 50, 175, and 350. We had two QD cohorts, 250 and 500 here. We can certainly come back to the Q&A session if folks have any questions about, you know, where is the curve or what. This is a curve here. When I show you 24-hour coverage of 350 BID, think of a curve as an X and Y-axis. Your X-axis is your concentration, your Y-axis is your time. When I'm saying I'm covering IC50 for 24 hours and the IC50 value is 865 ng/mL, well, think of that as the line in the curve, and that's what you're covering, right? The take-home message here is at the 175 BID dose, we're covering IC90 for 16 hours and more. At the 350 BID dose, we are covering IC90 for 24 hours. Historically, we've talked about this before, just worth mentioning here that the deucravacitinib Sotyktu covers IC50 for about nine hours and does not reach IC90 at any of the doses. In fact, even the higher doses that it took forward in phase III don't have IC90 coverage, right? It's pretty obvious when you look at this data that these exposures are biologic-like exposures. They have biologic-like potential and biologic-like suppression of the IL-23 pathways. Now a little lesson here in molecular pharmacology, which is we talk a lot about IL-12, 23. You see data for IL-12, and the reason you see data for IL-12 is because IL-23 whole blood assays are not feasible, but they both signal through a similar pathway. They share a common heterodimer, and you saw the PBMC data. When we say we cover IL-12, we're very comfortable we cover IL-23 as well, and including Interferon alpha, right? Class-leading target coverage with this compound. Then the last piece of data here that we talked about, but I think it's still worth emphasizing here. This is the phase I. We showed coverage. We showed safety. We don't bring back the safety tables here. They were shown in their entirety. We were pretty good about showing every single AE, both pre-interferon alpha and post-interferon alpha in the phase I data. Let's briefly talk about PD markers from this study, both in vivo and ex vivo. If you focus on the right-hand side first, this is an in vivo proof of concept. Interferon alpha is a pathway that TYK2 is involved in the phosphorylation of STAT proteins, TYK2 driven. The inhibition of TYK2 results in responsive genes shown here. There are three. These are three interferon alpha responsive genes. As you can see across the board, this very potent response on each of these three genes that are TYK2 mediated. Just something to point out here is that each of these measurements here have their own kinetics. There's kinetics of your compound, there's kinetics of Interferon alpha, and there's kinetics of each gene. What's really compelling is the ex vivo data shown on the left-hand side here, which is a direct inhibition of IL-12, 18 stimulated readout on Interferon-gamma. This is a direct measure for the fact that you are hitting IL-12, and I said before, IL-12 is a surrogate for IL-23. You're directly suppressing IL-23 signaling with this compound in this MAD study, both at the 175 BID dose and at the 350 BID dose. In both cases, you can see even at the terminal point of 24 hours, there's greater than 90% inhibition of the Interferon-gamma signaling, which then reads out to the blockage of IL-23. Okay? Before I hand it over to Bill, the take-home messages were target-leading coverage, excellent safety profile, direct effect on PD markers both in vivo and ex vivo, and that's what's now led us to move these compounds into the phase II trials that Bill is gonna talk about. Bill? All right. Good morning. Thank you Raju for setting things up. Let's start with TYK2 inhibition in psoriasis, and begin by looking at the landscape. The worldwide psoriasis market is forecasted to surpass about $31 billion in annual sales by 2028. You can see that growth in the graph at the bottom of the figure. We know that Otezla, with safety but quite modest efficacy, has been able to surpass $2 billion in annual sales. There's the strong sense that a more effective and well-tolerated oral drug could go a lot further than that. Raju's talked about the clean label for Sotyktu due to the favorable risk-benefit profile. You know, we're hearing and seeing signs that 25% or 30% of the new world prescriptions are Sotyktu, that a number of the prescriptions are in Sotyktu naive patients, that something like a third of dermatologists have now prescribed this. All of those things bode well for a robust uptake of this new class of drugs, distinct from JAK inhibitors that Raju has discussed. Then we have, you know, what has historically dominated the market, the biologics, and you see these oral agents that could be more effective really creeping up on the biologics and creating that new pre-biologic space. That's the rationale. How are we approaching that? Our phase II trial is a 16-week trial. We allowed for 16 weeks to really be able to see not just the primary endpoint of PASI 75 scores, which you can see easily by 12 weeks, but to see a more fulsome effect of what will happen with PASI 90 and 100 scores because that's. You wanna be into the anti-IL-23 antibody-like coverage with something where you're covering the target well, and a longer period of time optimizes for that. The trial's set up for success in that arena. As Raju said, we're already dosing patients. We're not disclosing the exact doses. That's pretty common for competitive reasons. I do wanna give you a little bit of a feel of the range of things. You can see we have three BID doses and one QD dose. At the high end, the. Dose D, and we'll use the same nomenclature in the Crohn's and psoriatic arthritis trials. Think about this for those trials as well. At the high dose, we are aiming to have 24 hours of IC90 coverage for IL-12 and 23 signaling. At the QD dose in the psoriasis patient setting, we expect to meet and exceed a bit the coverage that is provided by the marketed dose of Sotyktu. Obviously, we have an intermediate BID dose and a low dose. That gives you a feel for the clinical trial design. We've sort of talked to this, but if you rolled up the efficacy of what you expect to see with IL-17 and anti-IL-23 biologics, if you're looking at PASI 75 scores, you really expect to see them in the 85%-90% range. The placebo rates are relatively low and just contribute a small amount to that overall efficacy. Otezla is more like a third of that. Sotyktu at the approved dose of 6 mg once a day is nearly twice as good as Otezla, but you can see that it just lacks by 30% or more what's possible with full coverage of the target. I'm gonna walk you back through the phase II data from the biologics in a moment to show that this difference really has to do with the completeness of the coverage of the IL-23 target. You can see our aspirational target product profile on the right, where the target coverage that Raju just shared with you translates to target coverage that looks more like a biologic. This just walks you through a little bit some of the history of dose finding with one of the approved biologics, Skyrizi or risankizumab monoclonal antibody to IL-23. Let's look at PASI 75, and you can see there were three different doses, 18 mg, 90 mg, and 180 mg that were tested in this phase II study published in New England, I think. What you can see is with 18 mg, you have 63% PASI 75 scores as compared to the 80%-90% that you expect as you get up in the dosing. Recall that the final commercial dose of Skyrizi is 150 mg. Look over to the left. Here's the two psoriasis phase III trials with Sotyktu. For all the reasons that Raju showed, we expect about eight hours of IC50 coverage and zero hours of IC90 coverage for IL-23 with that dose of Sotyktu. You have efficacy that looks very much like 18 mg of risankizumab. Submaximal target coverage will give a really meaningful efficacy in psoriasis, but it doesn't give maximal efficacy. You can walk across and see how this story plays out. It's very similar. Again, 18 mg of risankizumab looks a lot like Sotyktu for PASI 90 and PASI 100 and PGA. Let's switch gears now from psoriasis to Crohn's disease. Currently, Crohn's disease is a sort of $13 billion-$15 billion annual market. There's a complete dearth of safe and effective oral agents at the present time. Many of us, including myself in my previous life as a key opinion leader in the space, had considered the IL-23 inhibition mechanism to probably be the most effective mechanism at present for treating Crohn's disease, particularly advanced therapy failure, Crohn's disease. An oral agent that can take on IL-23 inhibition becomes a very attractive agent for treating Crohn's disease. On the left, you can see there's off-label use of aminosalicylates, not safe but not effective, not approved. Still some use of corticosteroids. There's just this huge gap, and patients go sort of straight into biologics. The phase III studies with RINVOQ, so a JAK1 inhibitor for Crohn's disease have been completed. The results are robust, I would anticipate that will get approved, but it's going to have the line of use restrictions and the black box labels that come with JAK inhibitors. Being able to come in with a class that has a clean label and would have efficacy that looks like an anti-IL-23 becomes a very compelling opportunity. You can see that in the projected growth projections on the graph on the bottom. Our clinical trial here we call the HARMONY trial. This is an earlier phase study. It will have about 42 patients per arm. It's meant to be able to be fast and nimble and get to the bottom of this pretty quickly so that we can understand, you know, triggering a really large investment. It's a 12-week trial, which is the standard in the space for induction trials. We are taking the two highest doses from what you saw in the psoriasis program and carrying those forward into Crohn's and comparing to placebo. At the highest dose, we'll expect, you know, trough coverage or about 24 hours of coverage for IL-12 and 23 signaling at the IC90 level. We're optimistic that that degree of coverage will approach anti-IL-23 biologic-like efficacy. We have two co-primary endpoints. One is the change in from baseline in the mean CDAI score. This gives some examples of what that looks like, and we think the best predicate example is the phase II study of guselkumab or Tremfya. In my previous life, I had a role in that study, this was just a really good outcome measure for a phase II study to measure the clinical benefit. We have a second co-primary endpoint of endoscopic response based on the simple endoscopic 4 score for Crohn's disease. The reason we selected this is look at the placebo rate here. It's just rock solid around 10% or 12%. You have video of colonoscopy and review by a blinded central reading team according to an adjudication algorithm. The drugs that are effective are, you know, 20%-30% better than that. You know, we sometimes will see variations in the placebo rate if you look at a binary outcome measure of clinical remission in Crohn's disease. We've selected these outcome measures to be measures that we can really power to and are robust, and then we'll have exploratory outcomes for the other measures. Another thing that's worth thinking about is Raju hinted that it's unlikely that Sotyktu would to have a substantial success in ulcerative colitis or Crohn's disease because of the low target coverage. This is just to give you a feel with some of the anti-IL-23 or 12/23 antibodies, the differences in the drug that's required for psoriasis versus Crohn's disease. You can see in each case that it's double or more the amount of drug that's required to see optimized efficacy in IBD. Really, we think it's necessary to be at that full IC90 coverage to anticipate efficacy in IBD, and the trials with other TYK2 inhibitors that are achieving target coverage less than 24 hours of IC90 coverage are, I would predict, are not headed for success. Switching gears to psoriatic arthritis. This is also a growing market. As you can see on the bottom, something like 30% of patients who have psoriasis will end up with psoriatic arthritis, and in a proportion of those patients, the arthritis becomes the tail that wags the dog. There are a number of therapies that are approved, but many of them, like JAK inhibitors, have risk and black box warnings. Again, we think there's a opportunity for a safe, oral and substantially effective medication. The clinical trial design, in many ways looks like the Crohn's trial, so we've taken the two highest doses, with the top dose, aiming for 24 hours of IC90 coverage for IL-23 inhibition. It's a 16-week trial. Could have been a 12-week trial, if you're looking at ACR20, but we really want to fully characterize the ACR50 and 70 response, and we thought that a 16-week trial will more fulsomely characterize what's possible with the medication. Pretty straightforward trial. Just to remind us what was seen with Sotyktu in their phase II trial with psoriatic arthritis. Here you can see this nice dose response between the 6 mg QD and the 12 mg QD across the outcome measures of ACR20 and 50 and 70. I'll remind you that for IL-23 inhibition, the 6 mg dose should have about eight hours of IC50 coverage and zero hours of IC90 coverage. The 12 mg once-a-day dose should have about 16 hours of IC50 coverage and zero hours of IC90 coverage. Even in that sort of limited dynamic range for how they cover the target, you could see dose response, and we believe it'll be possible to go a bit further as you get up into 16 -24 hours of IC90 coverage for the target. I showed you examples of how biologics to IL-23 with dose finding that you might be able to tell that story about incomplete target coverage and what it looks like. We've done that a bit here with Tildrakizumab and psoriatic arthritis dose-finding trial, and then laid next to it, the Sotyktu, 21 and or 6 mg and 12 mg doses. What you can see is that the 12 mg dose of Sotyktu compares very favorably to a biologic at the high end of the dosing range that was studied, and this gives us some comfort that we're on the right track to maximizing the IL-23 coverage and that the idea that more fulsome coverage of the IL-23 target will lead to differentiated efficacy in this class of drugs. If you wanted to look at the Sotyktu responses compared to other orals, here you can see XELJANZ, RINVOQ, Cosela, look over in the green at the right side of these. You've got ACR20 on the left and ACR50 on the right. If you look at the 12 mg QD dose, and again, our target coverage will for sure exceed the 12 mg QD dose of Sotyktu, you can see that 12 mg QD dose is achieving ACR20 and ACR50 responses that look very much like RINVOQ and numerically or perhaps somewhat better than XELJANZ and certainly than Cosela. We're optimistic for this indication that we could have, you know, best-in-class differentiated oral efficacy. That's what the clinical trial program looks like for this class. I'm pretty sure you'll have some questions, and we'll look forward to those. One of the things we wanna do is to, of course, our final target product profile is once-a-day dosing. Raju and John and our CMC team have been working really hard to achieve that, and Raju's gonna tell you a little bit about how that's going. Thanks Bill. Let me briefly walk you through where we are today with our efforts to develop a QD tablet, extended release QD tablet that would be ready for phase III, and certainly have more discussions on the Q&A session, give you more color on exactly what some of the stuff is in here. Focusing on the right panel here, the target product profile. It's a single tablet, the QD dosing, and it's done by modifying the immediate release tablet into an extended release, a modified release tablet. The other TPP is to maintain class-leading target coverage observed in phase I. In simple words, to be able to simulate what Bill is using as his top dose in the phase II studies to cover trough levels of IC90 with the single tablets, essentially spread the dose across 24 hours, maintain trough IC90 coverage, do it with a single tablet for QD dosing. What we've done is utilized two technologies here. First, the take-home message is right on the top there, which is we have developed now proto-prototype tablets from these technologies that are imminently going into the human PK study. get real-time data in where we are with this TPP. On the right-hand side, two technologies in brief. We're not gonna go into some of the more details. We can certainly talk in the Q&A session. The first technology is a proprietary in vitro dissolution technology. This is sort of a two-dimensional look at a release profile of the molecule, which is the key to getting any kind of release, extended release, immediate release. What amount of drug is released over time, and the time being the dissolution absorption time in the GI tract. That's technology 1. Technology 2 is what is a dynamic GI model. Rather than being a in vitro assay in two dimensions, this now looks at the drug as it transverses through a built-in simulation of a GI model and then looks at dissolution profile both independently, also from what we've seen in technology 1 for these tablets, and understand exactly sort of the convergence of these two technologies. How do we look in a dissolution profile, which is where it starts? How does it look in a real GI model? Both technologies have been used successfully. There's a lot of precedent for historical precedent for success for each of those. We have used them. We have the tablets ready. As you go down to the summary slides, these tablets have been designed and engineered to have the desired TPP as shown above, and certainly bears out in the non-clinical testing here. The first cycle of human data is going to begin imminently in Q1 of 2023. We'll give you guys an update in mid 2023 as we approach the TPP. Towards the end of the year, we'll start manufacturing tablets for phase III. All the work that goes into CMC and stability and all the housekeeping that the CMC folks do to then bridge with the phase III start in the second half of 2024. Just some data. We talked about those two technologies and just to show you what tablets look like in these assays. John and I can certainly take a question and give some more color, right? The key is the tablets are ready. The in-human testing is gonna start in Q1, so in the next month or so. Again, as I mentioned before, the in vitro dissolution assays. These are assays that basically simulate the pH as you see the pH gradients that you change as you move through the GI tract. The in vitro dissolution assays and this dynamic GI model, it's a pretty acute model or a clever model of how you actually build this whole GI tract. Both of these assays drive and afford the tablets we talked about that we believe now have the ideal release kinetics per the TPP. Amount of drug per hour is released. What we see here is a longer T-max, so it's shifted, and a significant increase in bioaccessible drug release. With this technology, not only have we moved the T-max to the right, which is the essence of modified extended release, we're also getting much higher drug release, bioaccessible drug release, and I'll show you some data on that. Again, first formulations for testing have been selected, and we'll begin in Q1 2023. On the first graph here is a few things. If you focus on the line in that color. What color is that? Crimson. That's the IR tablet. IR tablet releases almost in minutes, and the T-max for an IR tablet is about one hour and change, 1.6 hours. Let's call the relative accessibility of this as one, right? What you're seeing now with these tablets, you've got a range. If you look at sort of this triangle in the middle, that's a range in which we have built the tablets, and somewhere in this range is the perfect TPP, and we're going in with tablet B that we believe is the closest one that we have to the desired profile. There might be slight tweaks on either end to get to the optimal TPP in this rapid iteration model. Here, tablet B in this assay, this is a human bio-relevant in vitro dissolution assay, has an ideal profile in terms of kinetics of release, drug release per hour, and that is shown in here. We then take these tablets and put them into this dynamic GI model. Again, if you could look in here. The two different assays, just try and understand this, just bear with me here. What you see in the right-hand side here is what is both the absorption kinetics as well as the bioaccessible drug release. If you look at the IR tablets shown in the crimson in here, the Tmax is now approximately the one hour and chain 1.6 hours closer to two hours. You have the relative absorbed per hour is shown here, and the total absorbed drug is now being normalized to one unit. If you look at the tablet B, which was the ideal profile from the in vitro assay, in this particular assay, you're seeing almost a perfect profile in terms of number one, the Tmax. The Tmax has now shifted, is greater than three hours, and we're also seeing a 1.5-fold greater exposure here, which means the drug released per hour is now cumulatively adding up to 1.5x of these tablets. These tablets built with these two assays in this range here will now go into human testing. Depending on how close we are to the TPP, maybe a couple more iterations to get to the final prototype, and then manufacturing will start in the second half of this year. To wrap up the VTX958 program here, I'll skip the first bullet, and we've talked about the second one. We've got three phase II trials. We've dosed patients in both Crohn's and psoriasis, and we will dose the PSA patient imminently in the next day or so. Bill talked about the trials that have been designed or the dose range that he's selected are designed to do what phase II trials do, to explore a broad range depending on the particular indication. The key take home message is the top dose, which is common to all three trials, will cover IC90 for 24 hours, the trough coverage of IC nine. That's the key take home message here. Phase II readouts will begin in Q4, we're looking forward to that and sharing those with you for psoriasis. Then we'll follow with Crohn's and CD in 2024. Finally, we've developed ER tablets now from the non-clinical work, a human-relevant non-clinical work, and we're on track with the human testing we've talked about. We talked about manufacturing, we'll give you an update in mid-2023. If you look down in the Gantt chart here and focus on the ER tablet work, we'll complete the prototype work hopefully by the middle of the second half with all of the late-stage optimization. Gives us plenty of time to scale up and manufacture for start of the phase III trials, which is gonna be in the latter half of 2024. All good there, and we look forward to sharing the data with you sometime middle of the year, and certainly take questions in the Q&A session. Thank you Bill it's all yours. All right, let's switch gears to S1P modulation. I know many of you are veterans in this space, having probably followed Receptos, Celgene, and BMS with ozanimod, and then Arena and Pfizer with etrasimod. I hope to have you leave today with a little bit different view of what's possible in ulcerative colitis. This field goes back actually to the early 2000s with Gilenya or fingolimod, a non-selective S1P receptor modulator that was studied in the 2000s for renal transplant. It turned out to not be much better than mycophenolate in that indication. Then along the way, it was tested in multiple sclerosis, and it got approved in multiple sclerosis for disease-modifying oral therapy. There's approaching sort of 1 million years or more of patient exposure with this. It's been very well tolerated from an infection and malignancy standpoint and has been a bedrock of treatment in multiple sclerosis. The non-selectivity, because it's not selective across the receptor subtypes one, two, three, four, five, ended up having a number of, let's call it on target, given the lack of selectivity, but off target in the sense that what you're really trying to do in treating an autoimmune disease is just block a subset of the lymphocyte trafficking and retain those lymphocytes in the nodes. Everything else that happens is, you know, not desirable. A more selective molecule that gets the benefits of Gilenya that was really fully dosed and highly effective in MS is sort of the holy grail, and that's what we're seeking. How does that look, and what does a really highly selective molecule look like, and how do some of the molecules that have come to the clinic for ulcerative colitis fall short of that? Well, one of the issues that plagues this class is that you see a first dose heart rate reduction, which in a few cases can lead to bradycardia. Separately, there can be AV block, but that's more S1, P2 and three receptor subtypes. It's the S1P1 receptor that really contributes to the heart rate block, and that's the same thing that drops the lymphocyte count. You must maintain that selectivity. How do you deal with it? Etrasimod found a couple of doses that it was tolerable, so they definitely had some bradycardia. They had some dropouts in the first week without titrating. It was a sort of tolerable dose, and that seems to be headed to approval. The rest of the next-generation drugs, ozanimod and ponesimod and siponimod, all took a titration strategy. The titration strategy has worked beautifully and largely or nearly completely abrogates the effect of the bradycardia by titrating over the course of a week. There's a little bit of secret sauce to just how you do the titration, and then there could be variation from molecule to molecule about how hard you can push the dosing with the titration. Of course, Gilenya doesn't titrate, and they have six hours of in-clinic monitoring. The titration regimen that we have for VTX002 really took care of the titration problem. What you'll see with the dosing is we're able to push up to multiple doses that have substantial lymphocyte reduction. We think we were able to more fulsomely dose find than the other drugs that have been taken forward in ulcerative colitis. Another area is speed of onset and half-life, and this has two components. What is the half-life of the parent compound? Etrasimod is about 30 hours. VTX002 is about 20 hours. More similar than different, but VTX002 is a bit shorter. Really importantly is their long-acting phosphorylated metabolites, which has plagued ozanimod. It turns out the long-acting phosphorylated metabolites account for about 90%, 95% of the active drug substance, and they have half-lives of 10 days or something like 280 hours. It just takes forever to achieve a steady state of the active metabolite, and the lymphocyte reduction is a long, slow plateau over four or five weeks. If you're doing an induction trial in ulcerative colitis and you're looking at an outcome at eight weeks or 10 weeks, which is what we did in my previous life in the ulcerative colitis studies, they're really only four or six-week trials by the time you have the maximum pharmacokinetic output. You would expect that they're missing what's possible in terms of efficacy. As I'll show you in a moment, that's kind of true. Finally, VTX002 is peripherally restricted, so it doesn't penetrate the brain to a meaningful degree. One rare but important complication of S1P modulation is macular edema. Now, if you remember your neuroanatomy, the retina in the back of the eye, it's part of the CNS. Being peripherally restricted in principle should prevent the complication of macular edema. On the right, you can see the dose-dependent lymphocyte reductions that we achieved with the liquid formulation in phase I, and we did not see elevated LFTs, which have been common with other products like ozanimod and Gilenya. It was quite well-tolerated in phase I. Just to go a little bit further in the pharmacology. On the left is the lymphocyte reduction as a function of dose with an oral suspension, and you can see that, you know, the top few doses are sort of plateauing in terms of lymphocyte reduction. On the right was converting to an immediate-release tablet. You can see the oral bioavailability, which was about 86% for the 20 mg tablet. That defined our dosing. We ended up taking 30 mg and 60 mg into the clinic in the phase II trial with the anticipation that the 60 mg tablet dose would achieve 70% or greater in absolute lymphocyte reduction from baseline, which, as I will show you, looks like where you get the best results in multiple sclerosis. What does the lymphocyte reduction look like across the landscape of multiple sclerosis and ulcerative colitis? You can see Gilenya, the first-generation Novartis drug, and Mayzent, the second-generation Novartis drug. Interesting as they did a second generation, they obviously recognized the value of a deep lymphocyte reduction, so they replicated it with their second-generation product. Then you have our aspirational data for VTX002, and I will show you some data in a moment about this. Then the Actelion Janssen drug, ponesimod, about 65% reduction. Zeposia is about 50%-55% reduction, and etrasimod in phase III is about 50% reduction. The two ulcerative colitis drugs that are either approved or have completed development and are under regulatory review have lymphocyte reduction right around 50%, and the best drugs in MS is probably in the 70s. What does that mean for efficacy? We'll look at that. Starting with ulcerative colitis, we can first look at the ozanimod trials, and what you can see on the left is there's just a consistent, you know, 10%-12% difference between drug and placebo for the highest studied dose of 1 mg, which gives you about 50% lymphocyte reduction. As I mentioned earlier, this probably underestimates what would be possible with ozanimod to a certain extent, because with that long-acting metabolite, the eight-week trial probably feels like a four-week trial, and the 10-week trial probably feels like a six-week trial, and those are a bit short compared to what we usually do these days, which would be a 12-week trial. We go to etrasimod. The phase II study had a 25% delta. This was about 50 patients in arm. The trial had been terminated early for slow recruitment, it's perhaps not a perfectly accurate point estimate of the efficacy. Clearly, the higher dose of 2 mg was effective. In phase III, there were two trials. One was a 52-week treat straight through trial with co-primary endpoints at week 12 and 52. At the 12-week endpoint, and again, they didn't dose titrate, and it's 12 weeks, so this is a full 12 weeks at the 50% reduction in lymphocyte count pharmacodynamic target. You can see that the delta's just right at 20%. Then there's a second 12-week trial pivotal study in phase III, where there was the higher placebo rate, and the delta's about 10%. If you blend these. The largest trial was the 52-week trial. If you know, blended and took the average of these, the efficacy is probably in the sort of 16%, 17%, 18% range over placebo, more effective than ozanimod, but, you know, not in that 20%+ efficacy range on a, you know, consistent basis that would be best in class for oral or parenteral therapy in ulcerative colitis. We think there's room to move a bit above these deltas. Let's look at their data a little bit differently. Here on the left, we've plotted the phase II and III data for the drugs as a function of dose, lymphocyte reduction from baseline, and the delta, meaning the remission rate minus the placebo rate. What you can see is a relatively linear relationship for clinical remission, and on the right, for the outcome measure of endoscopic improvement. You can also see that, you know, you have data points populating all the way over to 80%, and that's just white space in ulcerative colitis. The dose finding has not been done, because none of the drugs were really well suited to do it. In the case of etrasimod, without titration, they really couldn't do that. In the case of ozanimod, even with titration, The 1 mg was about the most that could be well tolerated. Just to get the feel for this, relative to multiple sclerosis, we did some similar work plotting clinical, the reduction in clinical outcome measures on the y-axis and change from baseline in lymphocyte counts on the x-axis. We've done it looking at clinical measures, so the annualized relapse rate, as well as MRI measures, gadolinium enhancing T1 lesion reduction on MRI. Some of the phase III trials have active comparators. Other phase II and III are placebo-controlled, so it's a little complex to show, and we have other slides we could share sometime, but for simplicity, not today. The slide on the left really captures it. This is phase III MRI data. Phase III, you can read that as just large datasets, so this is pretty robust. You can see this nice linear relationship from about 50%, and that's Zeposia in MS now instead of ulcerative colitis, going up to a 79% reduction with Gilenia at a 1.25 mg dose. You see this linear relationship and reduction in brain lesions. If you look over at the right, just to take a structural thing, we're looking at ulcerative colitis endoscopic improvement, across the range of 20% to, you know, low 50s, you can again see a relationship that looks relatively linear, you see highlighted the unexplored PD range in ulcerative colitis. We decided to plot ozanimod and etrasimod separately because we know that during the sort of relevant period of 8-12 weeks, that you have this slow onset of action with ozanimod due to the slow accumulation of the phosphorylated metabolites. This is illustrated nicely here that the dose response curves are more flat for ozanimod because they're just having a short period of time where they're at the target pharmacodynamic effect, and it's a bit more linear for etrasimod. You could imagine what it would be if you could take the etrasimod dose higher, had they dose titrated, and Gotten into a deeper level of lymphocyte remission, and you can sort of see where the line goes into the 20%+ delta over placebo, and very few things do better than that in ulcerative colitis. What's our clinical trial design then? We're comparing 60 mg or 30 mg versus placebo. We have a one-week titration period to mitigate first dose heart rate effects. A full 12 weeks at the target dose, so a total of a 13-week induction trial. It's randomized one-to-one-to-one. The trial has had an evolution. In the first portion of the trial, we didn't have the extension stuff to the right that I'll talk about in a moment. Everybody who completed the first 13 weeks of therapy, whether they were responders or non-responders, went into an open label extension trial at the high dose of 60 mg, aimed to continue for two years. After a period of time, we modified the trial so that patients who complete 13 weeks of blinded therapy, if they have had a clinical response, then they will stay on their blinded therapy for up to one year. The goal of this is to give us a sense of the maintenance effects of these drugs, you know, beyond the first 13 weeks to better formulate our phase III trial design. We'll have this interesting situation where roughly a third of the patients were enrolled under the protocol version 1, and everybody at 13 weeks will go to open label extension. About two-thirds of the trial, where the responding patients at week 13 will continue in blinded therapy, and you'll get a sense for maintenance. Just to think about blinding, during the placebo-controlled portions of the trial, we blind the clinical team at the company, and we blind all the investigators to the lymphocyte counts because showing them the lymphocytes would unblind. We have a blinded physician at the CRO that's a safety physician that does the unblinded monitoring, but the rest of us don't see it. After patients complete the blinded therapy, and particularly in the first version of the protocol, where patients then went on to the open label extension, at some point, it's okay to look at the lymphocyte counts, but you need to give some time to make sure that any carryover effects from the first 13 weeks of therapy are obliterated by the second period of time. We waited another 13 weeks before looking at the lymphocyte counts, but we're now accumulating patients where they've had 13 weeks of blinded therapy, 13 weeks of 60 mg, and then we can look at the 60 mg lymphocyte reduction doses, and I'll share that with you in a moment. Here's kind of what this looks like. I showed you earlier what the oral bioavailability of the immediate release tablet was at a 5 mg and 20 mg dose. Now we have observed data with a number of patients with the 60 mg tablet, and the mean lymphocyte reduction is 74%. It's just exactly where we aimed to be with that high dose, and we've hit it. You can walk back and extrapolate what we're likely to see with the 30 mg dose, which is probably in the upper 50s or low 60s. You can see on the right, where we had laid out previously what the lymphocyte reduction is for all the other products. Now instead of an aspirational number, you can see our real number of 74%. We think we've nailed exactly what we intended to do on the dosing. The other interesting thing is that the lower dose is actually right in the zone of ozanimod and etrasimod in terms of lymphocyte reduction. It will have the advantage that etrasimod had of a full 12 weeks at the target dose, so we should get the full pharmacodynamic effect and full chance to see efficacy over 12 weeks with that lymphocyte reduction. I anticipate that both of the arms in the study should be positive, and we'll have one that will look like the competitors or perhaps a little bit better, and one that will be significantly differentiated in the pharmacodynamic effect, and our intention is that it will be significantly differentiated for efficacy. How does this all fit into the bigger world? You know, in ulcerative colitis, mild to moderate patients get aminosalicylates, which are largely generic today. There's a little bit of use of corticosteroids, pretty much patients have gone to biologics. There's use of JAK inhibitors in biologic failure patients because of the line of use restriction. The place that's really interesting is sort of after aminosalicylates and a course of steroids, you know, what could you do to spare escalating to biologics? If JAK inhibitors were safe, they would go there, but that's not the world they live in. S1P modulators, we think fit really well in that space. This is obviously what led to the acquisition of Arena by Pfizer for the etrasimod product. I hope you'll agree with us that we really have the chance to build on that story and give a best-in-class S1P modulator that can break that 20% delta efficacy barrier and would be a big deal. I think we've really made all of these points. We think that both of our doses are likely to be effective. We anticipate seeing some dose response between them. We anticipate seeing differentiated efficacy at the high dose. We'll complete enrollment by mid-year, and that would allow us to read out sort of late third quarter, early fourth quarter for top-line data. That's absolutely how we're tracking. We have a team that's really working on all the phase III readiness preparations so that this can finish with a turnkey readiness to initiate phase III next year. That's it for that. I think we will now transition to a short segment on NLRP3 and then wrap up. Just to remind you, NLRP3, when it's activated, fundamentally drives excess of IL-1 beta and IL-18. There's somewhat less known about IL-18 as it plays out in the pathogenesis of specific human diseases, so that's an opportunity for future discovery. IL-1 beta is pretty well understood, and there's a number of diseases that are characterized by an excess of IL-1 beta that respond to IL-1 beta biologic inhibition with receptor antagonists or monoclonal antibodies. Those diseases are really very logical targets for small molecule inhibition with an NLRP3 inhibitor. What are some of those diseases where you have the biologic efficacy predicate? For cardiovascular disease, the well-known CANTOS trial studied about 10,000 patients with a history of MACE and an elevated C-reactive protein and showed that you could prevent secondary cardiovascular disease or MACE events with IL-1 beta antibody therapy. Dermatology, Jim Krueger could speak to this during the Q&A period, but he's done a lot of work looking to see what genes are upregulated and have hidradenitis suppurativa, and there's a marked upregulation as high as anything of IL-1 beta and HS, so that's a potentially interesting target. In the rheumatology space, there's acute gout, likely prevention of recurrent gout. There's juvenile arthritis and adult-onset Still's disease. There's recurrent chronic pericarditis. In the rare disease space, there's the Cryopyrin-associated periodic syndrome, or CAPS, which is a gain-of-function mutation in the NLRP3 gene. There are others, but these are a good list. On the CNS side, there are associations with an excess of NLRP3 and IL-1 beta, and then some CNS-specific biomarkers with Alzheimer's, Parkinson's disease, and to some degree ALS and multiple sclerosis, and John will talk about that in just a few minutes as it relates to our CNS penetrant compound. I'm gonna start by just talking a little bit about VTX2735. We released a high-level press release at the end of June, indicating that we'd completed the phase I trial, but this is the first time we've actually shown the data. This trading card slide, as Raju likes to call it, looks a lot like what he showed you for some of the other molecules. It's highly potent in human monocytes for on-target inhibition of IL-1β and highly selective for not hitting off-target things. You can see robust effects in a dose-dependent fashion in a mouse pharmacodynamic study. In green, you have the MCC950, which is sort of a tool compound NLRP3 inhibitor that is robust, but limited by hepatotoxicity. We've completed a phase I study, which I will share the high points of with you now, and then I'll talk about phase II. The phase I study, pretty typical study, eight subjects per arm, six active, two placebo. The pharmacodynamic aspect of this was to do whole blood draws on day one and day 10 after dosing in the MAD portion, and then do stimulation of that whole blood with LPS and ATP and have the readout of IL-1 beta secretion. Think of how useful measuring the whole blood assay was with TYK2 for seeing the target coverage of IL-23 inhibition. This is the IL-1 beta equivalent of that for NLRP3 inhibition. Then in MAD, we studied four doses up to a total daily dose of 200 mg. The drug was very well tolerated. We saw no evidence of liver enzyme abnormalities, which has been a problem with other drugs in the class, and a robust dose-dependent inhibition of IL-1 beta. Here it shows that you've gotten used to seeing the heat map, and what you can see is that as you get up to 100 and 200 mg of drug, that you have good target coverage over sort of 12 hrs. We did a relative bioavailability study, adjusted for the bioavailability, and then modeled what 100 mg and 200 mg or 100 mg and 150 mg BID would look like. Here you can see that at 150 BID, you have 24 hrs of IC90 coverage Or 22 hrs and at 100 mg, 20 hrs of IC90 coverage. It would be straightforward using the process that Raju talked about for going to a once-a-day formulation with VTX958 to do something like that with this compound. We're very pleased that, you know, we were able to identify doses that are safe and have really class-leading target coverage for 24 hours. On the left here, you see the relationship between drug concentration on the x-axis and IL-1β inhibition from baseline on the y-axis and just this dose- or concentration dependent, which is really dose-dependent, abrogation of 1 beta expression. On the right, we measured high-sensitivity CRP in these patients. Remember, these are sort of young, healthy patients that, in principle, don't have any comorbidities. Even young, healthy patients have the broad population risk of cardiovascular disease. Some of you are sitting here today with an elevated high-sensitivity CRP that puts you at intermediate or high risk for cardiovascular disease. Some of our volunteers had the average risk or high risk, and what you can see here is that with under treatment, the placebo patients, the mean actually went up. It went down for all the drug-treated patients. What's really interesting is to see that each of the patients who had a high cardiovascular risk level of high-sensitivity CRP or the average risk all dropped down into the low-risk range. This is an in vivo measure of efficacy along with the ex vivo stimulation test for IL-1β. You know, these were the outcome measures for the pilot studies in the cardiovascular risk prevention trials. For instance, in the CANTOS trial, they did a pilot study to show that you could knock down high-sensitivity CRP. They took those doses forward into a large cardiovascular outcome study to show that you could change the rate of MACE events. How would we take this forward into a disease setting? We've decided to go for the gain-of-function mutation, CAPS, we collaborated with a colleague at University of California San Diego, Hal Hoffman, who actually discovered the gene mutation that causes CAPS. We were able to study some patients with different CAPS mutations. What you can see is if you take whole blood monocytes from those patients, stimulate them with LPS and ATP, and then look to see if you can inhibit with VTX2735, that there's robust inhibition across multiple subgroups within CAPS. Some of the common mutations, the FCAS mutation, Muckle-Wells, and the most severe, the NOMID. If you use the MCC950 tool compound, you can see it worked for one of the FCAS variants, but actually didn't work very well for a number of the other CAPS molecules, suggesting that our compound is a more ubiquitous NLRP3 inhibitor than that tool compound does. The clinical trial design that we have is to take 10 patients with CAPS. Remember, this is an ultra-rare disease, so not easy to do. We'll be looking at symptom scores that led to the approval of three different biologics directed to IL-1β for CAPS and using that to measure outcomes. We're gonna treat five patients with 100 mg, twice a day for a couple of weeks, withdraw therapy, and if they relapse, re-challenge them just to show that it's reproducible. Then the second cohort will go up to 150 mg BID. Remember that these respectively give 20 hours and 22 hours of IC90 coverage for IL-1β inhibition. That's what the trial looks like. I think I've covered all of this. John, I'm gonna turn over to you to talk about the CNS penetrant compound. Thank you. All right good morning I'm gonna tell you about a couple of our newer programs. Bill mentioned earlier that we have, if you will, a portfolio of NLRP3 inhibitors, and this is the slide showing VTX3232, which is our CNS penetrant compound. Again, I've arranged it on a trading card format here, giving you the highlights of the compound, and I'll tell you a little bit about why we moved from VTX2735 to this particular area of VTX3232 and the attributes of the compound. We're really enthused about it, I will kind of give you some details about the discovery, et cetera. Then I'll move to a new discovery program we have that also we're very excited by. VTX3232 is an extremely potent brain penetrant inhibitor of NLRP3. The on-target effects are quite potent. You can see in our human whole blood assay, it's about 13 nanomolar, which is, you know, pretty astounding. It's a very potent compound in our hands. No off-target effects with other inflammasomes, we don't see any effects on NF-κB signaling. What we really designed this compound and engineered it to be was a compound that showed concentrations in the brain and its surrogate tissue, CSF, that gave us confidence that we could be able to get the compound inside the CNS and have a therapeutic effect. You can see in the rat PK and the dog PK studies that we show here in the middle and the right, that we do, in fact, in the rat, we can actually look at brain, of course. In the dog, we look at the surrogate CSF, which shows us how much free compound, free fraction we have in CSF. You can see that in both species, we see at a very moderate dose, we see therapeutic concentrations of the compound in the brain, which is very exciting for us. The reason we went to a CNS penetrant compound is that NLRP3, as most of you are highly aware that it's a, there's a real opportunity to address neural inflammation and their associated diseases arising from that using such an inhibitor. For example Alzheimer's disease, Parkinson's disease, have been, you know, in animal models, looked at with NLRP3 inhibitors and shown efficacy. You can also see that in a variety. Unlike simple macrophage NLRP3 canonical activation, you see the same thing in activated microglia. There's a second aspect of NLRP3 in the CNS, and that is to say, activation of NLRP3 takes place in neurons as well, and there's also activating macrophages that infiltrate, et cetera. This leads to neurodegeneration. We believe that such a compound will have a really high potential to be a disease-modifying drug. At a higher level, looking away from the biology and just sort of looking at neuroinflammatory diseases in general, you can see that by having such a compound, you could address a number of really clinically very important conditions with a single drug. For example, Parkinson's and Alzheimer's, there's fairly good evidence that an NLRP3 inhibitor could have a disease-modifying effect. Also, in Huntington's and ALS, as Bill mentioned earlier, we really believe that such a drug could be used to treat a variety of these important conditions. How did we get from VTX2735 to VTX3232? It was a lot of good chemistry by our team. VTX2735 and most of the first generation inhibitors of NLRP3 are sulfonylureas or very related compounds, which don't really have the physicochemical properties associated with high membrane, CNS penetration, if you will. We basically turned our back on that series and began to design compounds in a different chemical space. The idea being that we would sort of run a dual optimization program looking both at potency of inhibition of NLRP3, but also the associated brain penetration in preclinical species that we would use to bring a compound forward. The net result of these efforts was the discovery of VTX3232, which I've put a chart in here showing that, in fact, in all of our preclinical species, VTX3232 moves freely both forward and backwards across the blood-brain barrier. You don't have to achieve high plasma concentrations like you do in some of the earlier, quote-unquote, "brain-penetrant compounds" to be able to reach therapeutically relevant concentrations inside the CNS. This was, I think, the real advance here in this whole discovery process. We were able to kind of avoid the restrictions of the sulfonylureas and the very polar compounds that were the first generation compounds, now we have something which is, as Raju mentioned earlier, a truly brain-penetrant compound. VTX3232, we've been able to do an X-ray crystallographic study with VTX3232. It's got a very interesting mechanism of action. It sort of functions as molecular glue. It keeps the NACHT of the NLRP3 NACHT domains together. There's an essential ATPase activity which has to occur for NLRP3 activation. This compound sits in this particular cleft and holds that all in place and prevents nucleotide exchange and ATPase activity. It's actually quite a very interesting mechanism of action. We were able to get from this some important molecular interactions which drove our lead optimization efforts. As well as, you know, all of this, potency in human whole blood, et cetera, et cetera, you know, looking at the X-ray structure, this compound has extremely potent activity in a variety of neuroinflammation models that we've looked at. For example, on the left, you can see that in LPS-primed human microglia that were derived from iPSCs, we see potent inhibition of both IL-1β and IL-18 with no effects on TNF which confirms our earlier study in macrophages. In addition, in a, in a simple sort of, mouse neuroinflammation model where we dose LPS and look at neuroinflammation and its readouts, in the brain, we see a significant inhibition of caspase-1 formation. In other words, that key event where the inflammasome turns pro-caspase into caspase, and then caspase turns pro-IL-1β into IL-1β and gasdermin and the other components for as the end products of inflammasome in a activation, you see a considerable decrease in caspase-1 production, which we were very. This model is a little touchy, we were able to see what we wanted to, it looks very, very good. As Raju mentioned earlier, we are planning a phase I trial in the first half of this year. We've completed all of our IND-enabling studies. The obviously, the design of the phase I trial has to be worked out with the regulatory authorities. The good thing about this particular compound is it's very easy to see compound in the CSF, and we can get a read from both the plasma concentrations and the CSF concentrations, what the concentration in the brain per se is. We will also be doing the same sort of ex vivo whole blood LPS ATP stimulation study that we had done for VTX2735. Then, of course, that leads into the potential for using a cohort of Parkinson's disease patients to look at some markers from either plasma or CSF. So we're really excited to initiate these studies in this first half of the year. This is where VTX3232 is. Raju mentioned it earlier. We're, you know, putting the finishing touches on the IND submission, and the trial will start in first half of this year. In the last few minutes of this presentation, I'd like to show you an update of one of our discovery programs. As Raju also mentioned earlier, we have discovered all of our compounds. You know, our. If you look at this cycle of chronic inflammation, one of the places where we haven't really looked at was Th2 biology. Throughout most of my career, I've lived inside the cell. We've looked at enzymes inside the cell, kinases, et cetera, et cetera. We began to think about how we could affect Th2 biology from a small molecule perspective. We began to think a little bit about could we affect IL-4 signaling using a small molecule antagonist? It seems to be quite a big ask when you think about it. I mean, just the cartoon shows you that, you know, you have this large surface area between IL-4, the receptor alpha chain, and IL-4. It's quite potent, obviously quite a strong interaction, about 100 picomolar. The question becomes: Can we get a small molecule to disrupt that interaction? If we can do that, can we replicate the phenotype seen by Dupilumab? In other words, can we see IL-4 and IL-13 blockage? Can we get a robust and prolonged effect to be able to see this as a potential therapeutic? I hope to show you our beginning data, which I believe answers that question in a, in the affirmative. To this point, we see no oral small molecule IL-4 alpha-targeted antagonists in the clinic. There's, you know, this is something we've thought about for a while. I mean, what you're essentially doing is looking at disrupting STAT6 signaling. Now, you could do that with kinase inhibitors, but it's a little sloppy. There's, you know, you're gonna affect IL-6 and IL-4 and other things that, as Raju showed on our earlier slide for VTX958. This is a way, in principle, to almost laser-like hit IL-4 signaling very specifically and STAT6 very selectively without having to find a STAT6 and blocker inside the cell. What we have now is we've been working on this program for a while, and we're in a very, I think, very good position. We have selective submicromolar inhibitors of IL-4 signaling, excuse me, that also knock down IL-13 signaling. You can see that they have full antagonist efficacy here in the graph on this. They're not peptidic, they're not big. They're actually fairly small molecules, gives us a lot of room to optimize the potency further. They're non-covalent reversible binders. They're not peptides. They're true small molecules which disrupt IL-4 and IL-13 signaling by interacting with the IL-4 receptor alpha chain. We know that that's happening. We've looked at biophysical methods to affirm that hypothesis. We've looked at five, I think, different binding methods, and all of them show that these compounds are binding the IL-4 receptor alpha chain. We're currently trying to get a little bit more structural information. This is a bit of a challenge. Obviously, it's a membrane-bound protein, a little bit more difficult to do crystallography. We're looking at some structure-based NMR to help us understand exactly the nature of the binding on a molecular basis. The next steps are, as we further enhance the potency of these compounds, we will move towards looking at more of functional efficacy in some ex vivo models we have, and then look at in vivo proof of concept studies later this year. I think we need a little bit more potency. You know, sub-micromolar is really good. I'd like to be down, you know, below 100 nanomolar or so in the next several months, and we'll be able to start digging into this biology a little bit more, thoroughly. This is the end of that particular. Thanks John just to wrap up, John's summary in here. It's a big ask. He's being a little modest about this because we've made a lot of progress in this molecule. They're the true bona fide, pharmaceutical compound. There's excellent PK on these molecules. They're well-behaved. There's no flags in here. I have a lot of faith in the track record of John Nuss here. Just stay tuned as to how we progress this molecule, and we'll be happy to share some more stuff towards the end of the year as well. Let's just bring it back home now and before we open up to Q&A. I think we've talked about each of these in detail, certainly with Bill guiding you through the VTX002 story here, which is pretty exciting for us in terms of what we're seeing on the PD marker and the calibration that he gave with success on efficacy in both MS and particularly in UC. On VTX958, you know, we're at the cusp of the phase II trials. We've stayed on track. I'm so proud of this team on how they execute. We guided folks that we'd start all three trials last year, and we did. VTX2735, we're going into a proof of mechanism. There's no compound from any of the earlier molecules or deals that has really shown biological relevance, so we have to do that. Then, as John pointed out, that with the VTX3232, we truly have a balanced CNS molecule, and we'll gather some really meaningful data from the phase I study and get it phase II ready at the end of this year. Right? The catalysts are shown there. I think it was pretty self-explanatory. We're looking forward to the phase II data for VTX002, slightly ahead of the phase II for psoriasis, and then a nice cadence of news and data coming out to the end of 2023 into 2024. Right? Okay. With that, I'm gonna hand it over to Marty here. Thanks Raju. Yeah. Yeah, I'd like to invite the management team to come up and pull up those stools and join us for Q&A. For those folks who are at home on the webcast, there's a button that says Question at the bottom of the slideshow. Feel free to submit those questions in there, or you can send them to my email, ir@ventyxbio.com. Either way, we will kind of pull questions there. For those folks who are here in the back of the room, you'll see Patti Bank from Westwicke with a microphone and Josh Flax over in the back corner over there with a microphone. They'll be circulating to answer questions, and we'll sort of alternate between. Mike, he's gonna get the first question 'cause he had the first hand up. We'll cycle through live, and I'll read out questions as well that are coming in here. Thanks good morning I won't hog all the questions. I'll ask just two. In psoriasis, you know, obviously there's been a lot of news there from both an acquisition and whatnot, and people are trying to figure out how much you can push efficacy in psoriasis. Just from your expectations, is your view that you can get a little bit higher than deucravacitinib, but you could go way higher to IL-12 23? I think that's somewhat what the charts are. Just talk about where you think the range is there for psoriasis and what you could show. In ulcerative colitis, there's been a lot of developments there. I thought you gave a great presentation about how we could push remission rates there. Looking at some of these other ulcerative colitis companies, there's been a lot of discussion about the types of patient enrollment, what is driving placebo rates there. You're obviously an expert in enrolling UC studies, so could you talk about the different dynamics going on there and how much confidence you have that you could get high-end efficacy there? Because I heard that part of it is just trial designs. Thank you. Just take them both? Yeah. That was for S1P1. Yeah. starting with the TYK2 question, I think it's clear that compared to any. For the TYK2 inhibitor question, I think it's clear from our phase I data relative to the phase I data for both Sotyktu and for the Nimbus compound, that we have best in class target coverage and unmatched tolerability with that. We're the drug that's best suited to explore full target coverage, which with monoclonal antibodies has given you know, 90% PASI 75 scores in psoriasis, and enabled demonstration of efficacy in Crohn's disease. You know, we look forward to others presenting their data in IBD and psoriasis, but it's I anticipate that there may be dose response between Sotyktu and Nimbus. We saw in phase I that they did have some IC90 coverage, but it's more in the six-hour range. In fact, if there is dose response there, that bodes really well for us. You know, we're looking forward to seeing those data. Maybe some of you know when it comes out. We don't know for sure yet. We have ideas, but we'll see. For S1P, ulcerative colitis, the, you know, what impacts placebo rates, which can vary to some extent, my view is that trials that take forever to recruit tend to have higher placebo rates. You know, we're recruiting our trial quickly, and I think we'll be good on that front. You know, patients that have had more biologic exposure probably have lower placebo rates, although that doesn't have to be true. Higher baseline Mayo Endoscopic Score and all those things interact. The other part of the equation is what is the depth of the remission as you're going along. You know, for the endoscopy component of remission, at the back end, is it zero or is it one? Most UC drugs that have shown clinical remission where you have the endoscopy component, the endoscopy component is one rather than zero. As you're monitoring the trial, you can monitor what proportion of your remissions are zero versus one and things like that, which also give you a feel of. The patients who get to zero, it's very unlikely that remission with endoscopy zero as part of it is a placebo effect. There's things you can do for the entry criteria that you can monitor, and there's things that you can do, you know, looking at blinded data for just how the robust that's being seen, and all of that can guide your thinking. I feel confident with where we sit in the recruitment and, you know, the goal is to bring in an interpretable placebo effect. If you look at other drugs in the class, Humira had just a bit less than 10% difference of drug versus placebo. Entyvio, you know, people touted as a wonderful drug, but for induction, it was only 10% better than placebo. You know, ustekinumab, Stelara, 10% better than placebo. Many of the best-selling drugs in ulcerative colitis are only 10% better than placebo. Recently, Rinvoq sort of broke that bar and it's in the low 20s. They are relegated to, you know, sort of late line therapy because of their adverse event profile. You know, we've seen a couple of TL1A antibody studies hit in phase II in that 20% range. They're biologics and I think the small molecule that doesn't have the safety restrictions that gets to the very high teens or breaks that 20% delta barrier, that's gonna be a major breakthrough. That's what we're aiming for. Just ahead of the next question, I just wanted to reintroduce Dr. Jim Kruger, who's on my far left, a clinical dermatologist from Rockefeller, and one of our clinical advisors. Also immediately to my right is Christopher Krueger, not related, who's our Chief Business Officer. I just realized now I need to say not related. Yeah Jim if you have anything to add to the psoriasis studies or IL-23s for sure. All right. I think there will be a dose response that will be seen. You even see that dose response at higher levels of Sotyktu. 'Cause they've taken it into psoriatic arthritis and other. The skin efficacy actually goes up. They have not. The approved dose is not what one can maximize. Yeah Yasmeen Rahimi. Maybe a good place to start is you did a great job, like really a phenomenal outline of the data, new data update, really thank you for doing that. I guess the first question to ask is, I just want a clarification. When you talk about the doses with your TYK2 dose, the high doses, are they identical between the psoriasis versus the Crohn's studies, so it's just the nomenclature is consistent? They're the same. Okay. Same dose. That was dose D. That's the same dose across-. Okay. Psoriasis, Crohn's, PSA. Perfect. I guess the second question that will come up is since you're pushing doses higher, you know, a lot of questions from clients come in, like what type of, you know, skin lesions or rash or could pop up that could be on target versus off target. If you could just maybe help us understand, you know, from a safety perspective, When we get that data set, how we distinguish that. On S1P1, I really appreciated your beautiful new data showing lymphocyte reduction, but also this correlation to improvement. I just wanna make sure that those data points that you pulled were from only induction or was it a mix of induction and maintenance looking at lymphocyte reduction and response? Do you think it matters having, you know, your effect in maintenance versus induction? I'll let Bill address the S1P1 and the induction questions. In terms of on-target derm effects, we didn't put the table back into this discussion, but we had a table early on that basically lists, and you can go back to the IL-23s and what we did was show across a number of IL-23s, right? Not just one drug. The safety profile for IL-23s. That's a mechanism that the TYK2 has in common. This idea that effects you're seeing, the derm effects you're seeing with a couple of compounds out there are on target is just fallacious. It just has no basis in data out there, given the safety of the IL-23 drug and the safety of our compound all the way to 350 mg BID in an equivalent dosing paradigm, the 14 days where these derm effects were apparent and significant across those two other drugs out there, right? That's an established data-driven set that we have here. In terms of our high dose and how we are monitoring, I think, Bill, you wanna just talk about the phase II studies and, you know, the concern with derm effects or not? Yeah, I mean, recall in phase I, we didn't get into it in detail today, but we saw really no dermatologic effects up until the 350 BID dose. If you had 16 hours of IC90 coverage, nothing or below. You know, if you have 24 hours of IC90 coverage at 350 and you have 16 hours at 175, you can imagine there are doses less than 350 that will give you 20 - 22 - 24 hours of coverage. The derm that we saw at 350 BID was transient, and this is somewhat different than has been seen with the competing drugs in the class. One of the facial papular lesions completely resolved under continued therapy with no anti-acne medicine administered, and the other case was improving under continued therapy. We think we were just getting to the edge of it at 350 BID, and, you know, I'm not gonna get into the details of exactly where we've landed, but you see the logic. I feel confident that some of our intensive dosing will likely not have derm adverse events. If we start to get at the top, we'll see, and that's why we're studying several doses. We have an integrated safety monitoring program for adverse events across all three programs that we're looking at so that we can keep track of this over the course of this year and a half of as we run these trials and you get the sample size from three programs instead of one for those. We're watching very carefully. For S1P, the... If you'd sort of ask about like what's likely to be the durability of remission. For everything but S1P modulators and ulcerative colitis, the longer you treat, the worse patients do, and they regress to the mean. Every single biologic, whether it's a treat straight through design or a re-randomized responder design, you know, there's less patients in remission at post-induction at week, you know, eight or 12 than there is at a year. If you look at JAK inhibitors, where we, in that trial, we re-randomized responding patients. You definitely lost patients over the course of the year. It's the same thing with RINVOQ. Of course, the induction dose with RINVOQ is not safe or tolerable for chronic use. They use 45 mg, and then they drop down to 15 or 30 because you just can't continue it. With the S1P modulators, this experiment has been done twice in ulcerative colitis, first with ozanimod and our executive chair who's here today, Sheila Gujrathi, was the chief medical officer in those days, and I was the KOL, and we designed a straight through trial in phase II, and what we found is that the remission rates went up between week eight and week 30. You know, part of that we didn't appreciate at the time the long-acting phosphorylated metabolite, you could write that off to the metabolite. It happened again with etrasimod. The delta at week 12 with etrasimod in the 52 week ELEVATE trial was 20%, and at week 52, it was 25%. It got better. That S1P is the only place that that happens. There's something about the lymphocyte reduction in UC that just gets better with time, not worse. I, I think that's really appealing for where this could all land. Certainly with MS, you know, the bar is to go out for two years and show, you know, prevention of disability and things. The long-term effects there are certainly seen. Sam. Hey thanks for the questions a couple for me I guess first, with the modifications made on the extended release formulation of VTX958, how translatable is that data historically from preclinical studies to humans? Very high confidence. The reason we went through these two technologies, each independently and collectively, they complement each other and very high success rate. The reason is you're spending a lot of time building a relevant in vitro model, and then you're also spending time looking at a relevant dynamic model, which has all of the fluids and motility and everything else that you would expect, right? That's as close as you can get to a human situation with these two. The fact that they both complement each other but also individually show you the desired profile, very high confidence. Obviously, we have to show that, and that's why we're ready to start the human dosing. Then depending on how close we are, right? How close we hit the TPP in the first pass, and if not, we've got ample cycles. Each cycle is about two weeks, 2-3 weeks to then fine-tune. I showed you the bar, right? There might be a little here and there, but very confident based on what we've seen with both technologies and the data that we've spent a lot of time doing that. Gotcha. As you look at deucravacitinib's label, what aspects of the safety language, if any, do you think you could improve on with next gen TYK2s like the 958? Bill, you wanna take that? I think, you know, black box warnings around infection and malignancy and MACE events, for starters. We're, you know, none of that is in the boxed warning. TYK2, and that's what we aim to replicate. I guess things like, triglyceride monitoring, CK elevations, is that stuff? Yeah. You're monitoring. We saw nothing for those things in phase I. It, you know, it is phase I. We just need to see how it plays out. We'll have a rock solid sense of that a year, you know, at the end of the year as the psoriasis data reads out. Our starting place is that we have the potential to differentiate 'cause we didn't see anything with lipids, and we didn't see CK elevation, CPK elevation. you know, it's two-week trials and is a little short to be absolutely certain about that. We'll see. Our anticipation is we have the potential to be differentiated. Then a really clean non-clinical profile, right? We've now dosed up to nine months in the primates and everything we saw or didn't see in the first two non-clinical now bears out in this chronic safety as well. Raj you know Raju showed you just the exquisite selectivity where we just have absolutely no JAK1 signaling, a fourth whole, thousandfold difference in selectivity, and then you saw the readouts to the 5 JAK1 related cytokines. We think of the lipids and the CPK as being JAK1 driven. With the absence of JAK inhibition with VTX958, it's reasonable to speculate that you won't have those changes, but we gotta prove it. Yeah. The metabolites are clean, so we have minimal metabolites. Even those compounds don't cross over into the JAK family and have no off-target effects as well. That's the key. People forget that it's not just the parent, not just S1P1 story, but even in TYK2, there can be metabolites that cross over into the kinases, that can cross over into other targets and that's where you start to see issues here. I have a question that came in over the webcast, I think it's directed at Bill, asking if you could expand upon sort of how you see the S1P class ultimately being positioned in ulcerative colitis. Is there anything in your preliminary phase III thinking about sort of what to do to help position this class either sort of in a pre-biologic or post-biologic environment, and how that trial might sort of support those opportunities? That's a tough anonymous question. Yeah, I, you know, I am continuing to see reports, some written by people in this room, I think, looking at, you know, really querying physicians about their thinking as to where S1P fits. There, you know, is an evolving group of, you know, well-known key opinion leaders that believe that S1P modulation fits nicely as first line advanced therapy, so before biologics, and by regulation, it's clearly ahead of JAK inhibitors. I think as a second product comes to market and a product that has a, you know, with a company that has a history of an oral therapy, Xeljanz in the space and knows this therapeutic area for marketing, it'll be their second oral product which actually fit nicely together. It's got the short, half-life, so faster onset of action. I think that the market will be enhanced in the next few years as a second product comes to market and is robustly marketed, and physicians seem like they're increasingly ready for that. You know, a third robustly best-in-class molecule I think would just build on that story. I think this really has legs. This is my view. Phase III, so, you know, as you think about psoriasis, every program that has done phase III has had an active comparator, and of course, we have to think a lot about that and what to do in the world ahead. The inflammatory bowel disease companies have not done that for IBD up to this moment. The first programs to include active comparators were the Roche Genentech study with etrolizumab. That didn't turn out well, in part because of the focus on active comparators as opposed to adequately powering the primary comparisons to placebo. Janssen has an active comparator in their phase III study of Tremfya in Crohn's disease. We will see how that plays out. It's really early days for active comparator. We are at the point, I think, to think about it, but this will require some careful consideration with commercial colleagues over the next six months as we finalize our thinking about that. I don't think I'm ready to commit today. Hi thanks again for hosting the event. I'm curious on the CAP study. Since it's so small, how quickly do you think that you could enroll it? Is there any potential for us to see data in 2023 from that study? Just curious on how you're thinking about if you plan to commercialize it as a quick-to-market opportunity, or is it more just to demonstrate proof of concept? I'll take the first part and give Raju the easy second part. I do think we'll get data in 2023. We have, you know, given that it's not a blinded study, I think the ability to see data in pieces is there and stuff as well. Our anticipation is that we, and the CRO we're working with, we anticipate completing enrollment in the trial this year. Yes you know, the CAPS trial. Look, there's no one has shown any biological relevance of an NLRP3. It's been a real disservice to this field. Compounds have started and stalled, and we have a compound that is phase II ready. We're being really practical about this. We have relationship with Hal Hoffman. We know we can access patients, as Bill said, you know, up to 10. It doesn't have to be 10. Be real practical about how we design and enroll this trial and complete it and get data out there, right? I think beyond that, whether there's an opportunity in CAPS for a faster approval regulatory, I think we just wait for the data to make that decision. I'll comment on VTX2735 by itself, which is a phase II ready compound. I think Bill laid out in brief the opportunities there are for this mechanism, the IL-1β, the IL-18 in a number of indications, cardiovascular indications, cardiometabolic indications. We saw the interest from Novo in a compound from Dicerna. We truly believe, and I... People use best-in-class, I think our data bears out. We have a compound that's truly phase II ready, has an impeccable safety profile, hits the biomarkers. Our plate is full, right? We've got four phase II trials right now. Talked about phase III planning. We're discussing active comparatives here. We need to be thoughtful about VTX2735 as we have to be thoughtful about VTX3232, right? We're gonna position them as phase II ready compounds and then find the right avenue, the right studies to get the maximum potential for those compounds at the right time, at the right place, with the right, potentially a right partner as well, right? CAPS is a way for us to be the first ones to show biological relevance, biological target engagement and efficacy in a true model where there's a gain of function of NLRP3. We'll just take it from there once we get that data. Great thanks just last question. On the extended release tablets, do you think there's any potential for, like, a safety benefit versus BID dosing? Well, first of all, there's no safety concerns with the BID dosing. As Bill pointed out, you know, we're carefully using doses. Even the maximal dose that we used in the phase I study was extremely well-tolerated. We talked about this one or two incidences of these mild papules. That's a key point to take home. Our phase II doses, the top dose in particular, has all been selected with safety that we've seen or any lack of safety signals. That's a take-home as the BID doses are gonna be based on a safety profile that we've seen here. In terms of QD dose, look, by nature, the ER tablet is gonna have a much lower dose loading, right? You're basically taking this large drug load. This drug has The benefit of VTX958 is it's absorbed well. There's no dose saturation all the way up to 350 BID. There's no limitation on how much drug gets in. By nature, you're gonna take this drug load and efficiently spread it out into an extended release formulation. By doing so, you are gonna lower the drug roll. The tablets you have, and we don't exactly know where they'll end up, but they'll be significantly south of what the drug load is going to be. Lower Cmax, for example, which is exactly how you do it, and then a shifted Tmax. Think of the Cmax coming down and this hump being spread out. It all bears to a matching profile. Again, remembering the BID dose is going to be a very safe dose as well. Yes. Thank you Chris Shibutani from Goldman Sachs. A question on the TYK2 mechanism, on your strategy and how we should think about potentially reading across results as they unfold over the next 12-18 months. You know, your strategy, you're going after Crohn's. Maybe could you talk to the potential for going after ulcerative colitis and why not in the same prioritization. As the phase II data unfolds, I think we're gonna see psoriasis first, and there's a natural tendency, whether it's just sort of human instinct to sort of want to read across. When you think about mechanistically inhibiting TYK2, these indications, and the way you're designing these studies, is it fair for us to sort of imply either success will beget more success or not otherwise? Maybe Jim? Both. I'll start. Jim can add to it. Why Crohn's disease over ulcerative colitis? There are four anti-IL-23 biologics that have done phase II, and one that's done phase III in Crohn's disease. You have bimekizumab, mirikizumab, guselkumab, and risankizumab that have all been evaluated in Crohn's, and they've all shown a robust effect. They've shown an effect that is about as good in biologic failure patients as naive patients, and that's unusual. The magnitude of benefit at the optimal dose is differences in remission rates of 20%-30%. It's a large benefit. By contrast, in ulcerative colitis, we have less data, but what we have is a smaller delta. Anti-IL-23 clearly works in ulcerative colitis, but the Lilly compound mirikizumab has a 10% delta relative to placebo for reduction of remission. There was some less efficacy in the failure patients as opposed to the naive patients. Not as robust of a signal. For guselkumab, the phase II study in ulcerative colitis showed a 15% difference versus placebo. Let's say the delta's 10%-15% in ulcerative colitis and 20%-30% in Crohn's disease. We just think that Crohn's is a more sensitive disease to IL-23 inhibition, and it makes it a lot easier from a sample size perspective to nail it down in a phase II trial. That was the logic for going for Crohn's. I'm gonna sort of set Jim up. Jim Krueger has really set the mark, so to speak, in translational medicine studies in dermatology with the biopsy sub-studies in phase II and looking at the molecular effects of the drug and across doses. My read of the literature, and Jim Krueger can talk to this, is that he did such a study with risankizumab, so he knows what a range of doses and presumed target inhibition will do to gene signatures with full IL-23 inhibition. He did a similar study with Sotyktu, and he knows across the range of doses that were studied what happens to the signature. We are collaborating with Jim Krueger in our phase II study with the biopsy sub-study. We have that wide range of exposures that we showed you in the schematic. As a non-dermatologist, my aspiration is that Jim will guide us to being able to show that at low doses, at lower doses, that we look something like Sotyktu in terms of molecular expression, and at high doses, we look more like an anti-IL-23 inhibitor. Jim, am I smoking dope, or is that realistic? No. I think you're very close to where it's likely to turn out. You know, psoriasis is almost a monolithic disease of the 23/17 axis. We'll have the opportunity to potentially have response rates clinically, in the 90% range for PASI 75. There's a very good correlation between molecular expression of molecules on this pathway that are either IL-17 as the direct PD measure of 23 inhibition or things that are amplified in skin by IL-17 stimulation. There's a very large dynamic range of effects where, you know, some genes are amplified by hundreds of fold in the skin in this inflammatory state. That gives us the dynamic range to be able to dial in to varying degrees of inhibition that we can very readily measure through studies that have been frankly carried out over two decades with the evolving series of molecules that have gone into psoriasis. I do think that the data that come out in psoriasis will have, you know, important implications for Crohn's or maybe UC, in that, you know, certainly Crohn's is linked by genetics and cellular function of inflammation in a slightly different target tissue structure, right? I fully expect that the underlying immunology will be parallel. On S1P, if I could just ask a follow-up, regulatory and payer expectations. When the Sotyktu label was awaited, it was against a backdrop where there was a lot of concern whether or not it would resemble that of JAK inhibitors, it therefore, with a clean label, was quite momentous for optimism amongst many. The market, the stock reflected it on the TYK2 opportunity here. You shared that anecdote about being on the airplane. When we think about etrasimod's label, there's some issues in terms of the heart rate monitoring, the bradycardia, et cetera. How impactful do you currently think of the label and the regulatory perspective for S1Ps when etrasimod's comes out in terms of thinking about how that reflects upon the class? From the payer perspective, obviously, the clinicians you reference talk about putting it in the first line. We're going to be probably thinking about commercializing your S1P at a time when we'll be post biologics available for some of the most ubiquitous TNFs. Is it going to be enough to be on par with the efficacy in oral to go into a first-line setting in a post biosimilar world? The last part, first, as I pointed out, virtually all of the drugs that are approved are 10% better than placebo for induction. If we end up at 20%+ better, it's flat out superior to the standard of care biologics that people may or may not have had. If we achieve that aspiration, I think the ability to make a robust pricing argument should be there. Obviously, we've got to put a lot of work into that, but, you know, twice as good efficacy usually means something. For etrasimod, I would say that among the four companies at the time that were developing second-generation S1P1, they took a unique risk. Sheila guided Zeposia through a label that's very friendly. You know, there's no cardiovascular monitoring, and Novartis was able to do that and differentiate from their first-generation drug, Gilenya, with Mayzent. Actelion Janssen successfully did it, too. All three products that did dose titration have a really favorable label. We are following that path, we think that our dose titration strategy is highly de-risk for needing to have in-clinic cardiovascular monitoring. Of course, the final answer will come from our ultra data and our observed phase II and phase III clinical trial data. Everything we've seen so far with phase I and monitoring the ongoing study, I feel like we're headed to a good place for a label. You know, I'll leave it to Pfizer to speak about their data. That decision was made very early in the etrasimod development program. The people making the decision concluded that they were not confident that dose titration was going to get away from monitoring. They went a different path, which is to select a dose that was tolerable without monitoring. As you know, there were reported some bradycardia events in the first week of therapy without titration. You know, in the big picture, it looks like it was pretty well tolerated and clearly effective. How that will read out in the label, I think we're all looking to see. I'm not gonna predict. I think to the extent that they went a different path, they have a unique risk, around that, you know, the only other drug that didn't titrate was Gilenya, and they have monitoring. We'll go to Alex over there, and then to Dave. Great thanks Alex Thompson from Stifel maybe on VTX002 again, and your lymphocyte data that you showed across all the prior studies, looks like there's sort of some placebo effect there. I guess I'm curious, is that just due to normal variation? Any, any thoughts there? Then maybe with that, you know, how many patients are in that open label extension so far? A few comments. Yeah. To the former, we didn't really adjust for placebo there. For all practical purposes, there, with one weird exception, there is little placebo effect of on lymphocyte reduction. It usually bounces around between, you know, minus 2% or 3% or 4% or + 2% or 3% or 4%, but it's more or less zero. You don't really need to placebo correct. For some weird reason, in the phase II etrasimod trial, the placebo went up, like, 17%. The drug went down, like 34%. It looked like there was a huge disconnect between their phase I data and their phase II data, in terms of how much lymphocyte reduction you would have from a given dose. There became this idea that maybe there was something unique about ulcerative colitis that you took a haircut on the pharmacodynamic effect in the UC setting. In phase III, that evened out, and, you know, placebo didn't change much, and they had 50% reduction. The delta between, you know, +17 and -34 is sort of 50-ish. They saw the same delta in phase II and phase III, but that was the one case where placebo went up. I think placebo doesn't change much. Can you comment on how many patients have been followed at this point? Yeah. We're not gonna comment at this point. It's enough for us to show the data with some confidence. Remember, when you're looking at, you know, mean changes, you know, that's pretty powerful, right? We likely will disclose some more results out of that open label extension as the data become more fulsome in the coming months. I'm not setting an exact timeline to that. We are, you know, looking and analyzing that population of patients. I'm not gonna give an exact number today. I don't want people to back calculate and try and figure out when our last patient's out is gonna be and stuff. You know, as we approach completion of the trial and that, first, you know, third of the patients that were in the first version of the protocol becomes more mature, we can talk more about that. One quick IL-4 question. Just based on what we know about Dupixent, what kind of target coverage are you hoping to achieve? John? Yeah, I think our objective has to be high. The bar is high. You know, we'll be trying for, you know, 90% coverage for, you know, the appropriate, you know, daily dose, right? Yeah. Other CL? Yeah. Come up front. Thanks. Two for me. Just on extended release, what... I assume that's the only formulation you'll be taking into phase III. What are the risks that, you know, it's just not ready or when will you know if that's not the case? If you could just comment on that. Second on brain penetrant and NLRP3, at the bottom of one of the slides, I think you talked about potentially a Parkinson's cohort and looking at a wide range of pretty interesting biomarkers. What's the possibility we see that data this year? How important do you think those biomarkers could be? Yeah. Both good questions Matt timing-wise, we've, you know, given ourselves enough buffer to make sure that it's not the execution or CRO sloppiness or anything like that, right? That we have enough drug substance, drug API, it's all been done. Waiting to understand exactly what fine-tuning we have to do to the prototypes to get the phase III ready, right? We start thinking phase III, we're thinking commercial now. There's no backing down on the curve. What are the chances... Look, I mean, going back to what I said before, credibility of the, of the technologies, right? How they've translated into previous success with this type of approach. I think it's the profile of a compound that we've shown the target coverage, we've shown there's so much focus on an ER tablet, right? This is typical to what we've done with every program. We go from suspension to fit for purpose, in this case it's the IR, to an extended release, right? I don't see any sort of a mystery in here. We've done everything we can on the non-clinical side, and it's not looking at dogs or monkeys. It's actual human simulation, right? Which is exactly what's happening in the GI tract in both a static model and a dynamic model. You know, we'll just wait for the human data. My thought from the human is how close do we hit it on the first PK based on all the extensive work that John and the team have done in that space I showed you, right? We've got about, what? 15 that we've looked at. We've got 15 tablets ready, and the question is, how close are we with the first couple? We default back to a few on either side to hit that profile. We're not gonna compromise on the profile. Given the safety of this drug, given our ability to go into all of the indications, especially into the Crohn's disease, right? Enough time to then get to the final prototype, and then enough time between the second half of the year and early part of 2024 to get all the housekeeping done in terms of all the CMC, COAs, packaging, labeling, shipping. Just to understand how this works. You work with the integrated place that's a phase I unit, plus they are doing the early phase formulation. Then you get an ethics committee approval that allows you to have a spectrum of product for, you know, multiple different coatings, and you're allowed to take any mixture within all those specifications. You do all the stuff that John described to get the first tablet. You do the PK. From that, you can see I should add a little bit more of this and a little bit more less of that. You can do it tomorrow, go right back into the clinic, that each cycle time is about three weeks. If let's say you do five cycle times over four months, you can take five bites at the apple, and you're just increasingly tightening it up. What their experience is at this particular place is you usually get it right after, you know, it's almost always a solvable problem. Typically you get it right at about three ratchets, but you allow for five or so. That's the process we're just going into. You can see how quickly in a few months you've taken a good prototype that went through that, you know, artificial GI tract and just tightened it down in people. There's a question on NLRP3 CNS. Yes. Yeah. I think the first part of the trial is pretty straightforward. It's gonna be standard cohort, five or six in the SAD and similar, maybe one short in the MAD trial, right? Difference would be that in addition to looking at blood biomarkers and blood exposure, we'll also look at CSF levels of the drug, which then correlate into what we think are free fraction in the brain. That's the first part of it. The second part is, this is something we're still talking to folks about, the KOLs about, the addition of a cohort of patients, and let's just pick Parkinson's patients in the 1C part of it, right? I think there the consideration discussion that's key is if we do it, of course, we can measure blood levels in the CSF. That's gonna be the same as there is in the healthies. What biomarkers can we reliably understand, right? Is it alpha-synuclein or neurofilaments or other markers that consistently move as consistent as you can in a heterogeneous population that will give us relevant modulation of NLRP3 and IL-1β with our drug, right? If there's a lot of discordance amongst the biomarkers and what people have seen, then we have to be thoughtful about what data we will get out of that. I mean, Jim always talks about, you know, transcriptomics and small studies and 1B or 1C in psoriasis patients. We saw data that came out with MorphoSys in the 1C trial, and it was all over the place. Nothing on the drug. It's just these small studies and very hard to look at biomarkers or transcriptomics in these studies. That is the plan. We're talking to folks and very thoughtful about whether we add this cohort, and we'll do it if we think there's meaningful biology there that says these markers are elevated or suppressed. With the drug we have that we know will get there, can we show meaningful changes that will then guide us to other indications as well? Okay. Are there any further questions? We have time for maybe one more from the audience here. All right. Thank you very much to everybody for joining us today, and as well as all the folks on the webcast. Raju, do you want to... Any last comments? I think it's just thank you all for all the interest and, you know, just remotely and showing up today. Pleasure to meet you all in person. We are around, right? We'll be lingering. Yeah. Right Yeah. Thank you all.