Good afternoon, ladies and gentlemen, welcome to the Ventyx Biosciences fourth quarter and full year 2022 earnings conference call. At this time, all participants have been placed on a listen-only mode, the floor will be open for your questions following the presentation. If you would like to ask a question at that time, please press star one on your telephone keypad. If at any point your question has been answered, you may remove yourself from the queue by pressing star two. So others can hear your questions clearly, we ask that you pick up your handset for best sound quality. Lastly, if you should require operator assistance, please press star zero. As a reminder, this conference call is being recorded. I would now like to turn the call over to Dr. Marty Auster, Ventyx Chief Financial Officer. You may begin. Thank you, Chelsea. Good afternoon, everyone, and thanks for joining us today. Welcome to Ventyx Biosciences conference call and webcast, where we will be discussing our fourth quarter and full year 2022 financial results and providing a business update. As a reminder, the company's most recent investor presentation can be found on our website at www.ventyxbio.com under the Investors tab in the News & Events section. Before we begin today, I'd like to remind everybody that this conference call and webcast will contain forward-looking statements about the company, including, without limitation, statements about the anticipated timing of commencement, enrollment, and completion of clinical trials, the anticipated timing of release of clinical trial data, the market opportunity for our product candidates, and the expected timeframe for funding operations with our current cash equivalents, and marketable securities. These statements are subject to risks and uncertainties that could cause actual results to differ. Factors that could cause actual results or outcomes to differ materially from those expressed and/or implied by such forward-looking statements are discussed in greater detail in our most recent reports filed with the SEC, including our Form 10-K for the year ended December 31, 2022, which we anticipate will be filed this afternoon. Please note that these forward-looking statements reflect our opinions only as of the date of this call, and we undertake no obligation to revise or publicly release the results of any revisions to these forward-looking statements, unless of new information or future events, except as required by law. With that said, I'll hand the call now over to Dr. Raju Mohan, Ventyx's Founder and CEO. Raju, please go ahead. Thanks, Marty, and thanks everyone for joining the call this afternoon. Here's today's agenda. I'm gonna provide a high-level business update, and then I'm gonna hand the call over to Bill Sandborn, our President and Chief Medical Officer, and Bill will provide a little more color across all our pipeline programs. Finally, Marty will wrap up with a brief overview of our full year 2022 financial results before we open the call up for Q&A. Let me start with reiterating that 2022 was a year of outstanding progress and execution for Ventyx. I could not be prouder of our accomplishments as we continue to build an amazing team, strengthen our financial position, and successfully advance our unique portfolio of internally discovered, wholly owned small molecules that target large markets with high unmet medical need. Recapping now, in the third quarter of 2022, we reported positive top-line results from the phase I trial of our novel allosteric TYK2 inhibitor, VTX958. We believe these data demonstrate a potential best-in-class profile, including class- leading IC90 coverage of IL-23 and other TYK2-mediated cytokines. An excellent safety profile across all doses tested in the multiple ascending dose portion of the phase I trial. As we had previously guided, we initiated three phase II programs with VTX958, beginning with the SERENITY trial in moderate to severe plaque psoriasis, the HARMONY trial in moderately to severe active Crohn's disease, and the TRANQUILITY trial in active psoriatic arthritis. As I said before, Bill is gonna provide additional color on these trials. In June of 2022, we reported positive phase I data for our peripheral NLRP3 inhibitor, VTX2735. With the completion of requisite CMC and toxicology studies, VTX2735 is now a phase II-ready program. To that end, we today announced that we have initiated a phase II proof of mechanism trial for VTX2735 in CAPS patients. Meanwhile, our novel CNS penetrant NLRP3 inhibitor, VTX3232, has completed IND- enabling studies, and we look forward to initiating a phase I trial later in the first half of this year. We've achieved all of this while continuing to execute on the global phase II trial of our potential best-in-class S1P1 receptor modulator, VTX002, in ulcerative colitis. We are pleased to report that this trial remains on track to complete enrollment by mid-year, and we remain excited about the potential for VTX002 to differentiate from other S1P1 modulators in ulcerative colitis. With 2022 behind us, we held our R&D Day in New York in January and laid out our vision for what we believe will be a truly transformative year in 2023 for Ventyx. With a number of key clinical catalysts in the near-term horizon. The cadence of data will start with top line phase II data for VTX002, our S1P1 modulator in ulcerative colitis, which is expected in the second half of the year, likely late Q3 or early Q4. We expect to report top line data from the phase II SERENITY trial of VTX958 in plaque psoriasis later in Q4. Finally, we expect the phase II data readouts for VTX958 in psoriatic arthritis and Crohn's disease in 2024. As you can see from my brief summary, there's tremendous amount of activity across our entire pipeline. As always, we remain committed to our mission, which is to bring safe and effective oral medicines to large immunology markets currently dominated by biologics. We look forward to sharing more updates with you as we progress throughout this year. With that, I'm gonna hand the call over to Bill for a more in-depth update on our pipeline programs. Bill? Thank you, Raju, and good afternoon, everyone. I'm excited to provide a brief pipeline update today as we look forward to a very important year for Ventyx. I'll begin with VTX958. As we've mentioned, enrollment is underway in three phase II trials of VTX958. This includes the SERENITY trial in moderate-to-severe plaque psoriasis, the HARMONY trial in moderately to severely active Crohn's disease, and the TRANQUILITY trial in active psoriatic arthritis. We presented key aspects of these three phase II trials at our R&D Day in January. I won't repeat all of those details here, but it's important to reiterate that across the three phase II trials, we will explore a range of doses, including a high dose that is expected to approximate trough coverage of IL-23 IC90. We believe that VTX958 is unique among TYK2 inhibitors in development and may be the first to explore the therapeutic impact of near full inhibition of TYK2 pathways across relevant indications, resulting in potential biologic-like suppression of IL-23 activity. We believe that this level of inhibition of IL-23 will be important for maximizing efficacy in psoriasis and psoriatic arthritis. This high level of target coverage will also likely be essential for exploring the opportunity in Crohn's disease, where there is a particularly high unmet need for a safe and effective oral therapy, and where we believe relatively higher exposures with biologic-like target coverage will be required to achieve efficacy. Our team is laser-focused on the execution of these trials, and we look forward to reporting top-line data from the phase II SERENITY trial in plaque psoriasis during the fourth quarter of this year. We also continue to make progress on the development of an extended-release tablet formulation for VTX958 for a once-a-day or QD dosing regimen in phase III, which is expected to simulate our class-leading exposures in our phase II trials. At our R&D Day, we also showed early data from our prototype extended-release formulations that exhibit the desired release profile, both in in- vitro dissolution assays and in dynamic in- vitro GI modeling studies. These data give us great confidence in our ability to achieve our target product profile for the QD regimen. We look forward to updating you on these efforts in the middle part of the year after we have completed our initial in-human testing of these promising prototypes. In the second half of 2023, we will initiate CMC activities on the extended-release tablets to be phase III-ready with the start of phase III for psoriasis in 2024. We have also initiated broader phase III planning and will provide more details on this in the latter part of the year. Moving on to VTX002, I would now like to update you on the phase II program for our potential best-in-class S1P1 receptor modulator for ulcerative colitis. At our R&D Day, we laid out our strategic vision for this program and shared some very encouraging preliminary pharmacodynamic data from the open label extension of the ongoing phase II trial. Among patients completing week 26, which includes 13 weeks of blinded therapy, followed by 13 weeks of open label therapy with VTX002 60 mg. As of January 15th, we had observed a mean reduction from baseline in the absolute lymphocyte count of 74%, which we believe is clinically optimized at, in terms of pharmacodynamic response compared to the more limited absolute lymphocyte reduction achieved by etrasimod and ozanimod, which is in the 50% range. As we look across the landscape of S1P modulators in multiple sclerosis and ulcerative colitis, we believe that there is a clear and consistent positive correlation between the pharmacodynamic effect as measured by the absolute lymphocyte count and clinical efficacy. With S1P modulators in multiple sclerosis establishing both the efficacy benefits as well as an extensively characterized safety profile of ALC reductions in the 70%-80% range. Although extensively studied in these multiple sclerosis trials, exploration of the upper part of the safe, achievable ALC reduction has to date not been adequately explored in ulcerative colitis. Our phase II trial is designed to explore this hypothesis in UC with our 30-mg dose expected to achieve a pharmacodynamic effect similar to or somewhat higher than etrasimod and ozanimod, whereas our 60-mg dose is expected to achieve best-in-class absolute lymphocyte reductions in the 70%-80% range. With an early look at our open label extension data showing a 74% mean reduction from baseline in the ALC with the 60- mg dose, we believe we are tracking right on target, and we are optimistic that our dosing strategy targeting this magnitude of ALC reduction may translate to best-in-class efficacy profile in ulcerative colitis. We are very excited about the potential of VTX002, and we continue to make great progress in enrolling this trial. We're well on track to wrap up enrollment by mid-year in line with our prior guidance, and we look forward to reporting top line results in the second half of the year. Similar to the planning with VTX958, we have begun a wide range of other phase III- enabling studies for VTX002. Next, I'll briefly discuss our NLRP3 inhibitor portfolio. As Raju mentioned, we're pleased to announce today that we've initiated a phase II proof- of- mechanism trial of our peripheral NLRP3 inhibitor, VTX2735, in cryopyrin-associated periodic syndromes or CAPS, a group of rare autoinflammatory conditions caused by a gain of function mutations in the NLRP3 gene. Specifically, we're targeting patients with the familial cold autoinflammatory syndrome or FACS, which is the most common subpopulation of CAPS. This trial represents an opportunity for us to efficiently demonstrate clinical proof of mechanism for VTX2735 in a defined patient population with mutations in NLRP3 gene, where we know that IL-1 beta antibodies have already been proven effective. Longer term, we continue to see great potential for systemic NLRP3 inhibition in a range of chronic inflammatory conditions that are characterized by NLRP3-induced excess production of interleukin-1 beta, including various dermatologic, rheumatologic, and cardiovascular diseases. We remain on track to initiate a phase I trial of our novel CNS-penetrant NLRP3 inhibitor, VTX3232, during the first half of this year. We expect this trial will characterize the safety, target engagement, and CNS bioavailability of VTX3232 in healthy volunteers. As we highlighted at our R&D Day, we believe that the profile of VTX3232 may define it as a class-leading therapeutic for a range of neuroinflammatory conditions with a high unmet medical need. These could include Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, among others. We're very excited about this program, we look forward to advancing VTX3232 into the clinic in the upcoming months. This concludes our pipeline date for today. In summary, we continue to make great progress across the pipeline with five phase II trials now underway. We look forward to generating very meaningful phase II clinical data for VTX002 and VTX958 beginning later this year. None of this happens without a great deal of dedication and diligence for our team. I want to echo Raju's sentiments and thank the whole Ventyx team for their ongoing efforts. Before we move to Q&A, I'd like to hand the call back to Marty Auster for a brief discussion of our financial results. Marty? Yeah. Thanks, Bill. You'll find our financial results for the fourth quarter and full year, in our press release, and I'll summarize just the full year results here now. R&D expenses were $87.7 million for the year ended December 31, 2022, compared to $58.5 million for the year ending in 2021. This increase reflects the advancement of our pipeline into later stages of clinical testing, including execution of the ongoing phase II trial of VTX002 in ulcerative colitis, as well as phase II preparation and startup activities for VTX958 in psoriasis, Crohn's disease, and psoriatic arthritis. G&A expenses grew to $25.4 million in 2022, compared to $8.7 million in 2021, reflecting the buildup of our corporate infrastructure. Net loss was $108.4 million for the year ended December 31st, 2022, compared to $83.7 million for the year ending in 2021. Cash, cash equivalents, and marketable securities were $356.6 million as of December 31st, 2022. Subsequent to the end of the year, in early 2023, we raised $48.4 million in net proceeds through our at-the-market or ATM program, resulting in adjusted total cash and cash equivalents balance of $405 million. As we spoke on our last quarterly call, we expect our operating expenses to continue to increase throughout 2023 as a function of increased clinical costs associated with our five ongoing phase II trials with VTX958, VTX002, and VTX2735, as well as CMC activities, which we'll be undertaking to prepare the company for future phase III trials for VTX002, VTX958, and the rest of the pipeline. While we may experience some quarter-to-quarter variability in our operating results, the general trend will likely be higher over the course of the year. We continue to believe our current cash equivalent to marketable securities are sufficient to plan support planned operations into 2025. This concludes our prepared remarks for the afternoon's call, and I'll now turn the call back to the operator to begin the Q&A session, and I'll be joined there by Raju and Bill. Operator? Thank you, sir. The floor is now open for questions. At this time, if you have a question or comment, please press star one on your telephone keypad. If at any point your question is answered, you may remove yourself from the queue by pressing star two. Again, we ask that you pick up your handset when posing your question to provide optimal sound quality. Our first question will come from Michael Yee with Jefferies. Your line is open. Hello. Thanks for the question. I had a question, two-part question for Bill, maybe. I guess, recently we saw some data from a second generation TYK2, had some better positive data in psoriasis, but I'm, you know, interested in your views about how much better that was than the first generation TYK2 and what the implication is for what you could show with your psoriasis data as a second generation. Maybe talk about what your expectations are for your psoriasis data compared to what we just saw. Secondly, based on that, agree to that first global use in a higher dose in Crohn's disease, and therefore what you would expect out of that and what that would mean for you as well. Thank you. Yeah. Bill. Beginning with the next generation TYK2 inhibitor where data was reported, I think what we saw was that the higher doses that there were greater rates of PASI 75, 90, and 100 than what was seen in the phase III studies of deucravacitinib at the 6 mg once a day dose. We believe that the IC sort of 70 coverage is generally more robust with the next generation product, so that to our way of thinking, it really fits with our premise for VTX958, that more intensive target coverage will lead to greater efficacy. I think it's encouraging that you saw the greatest level of PASI 100 with the dose of that product that got a little bit of IC 90 coverage in the five- or six-hour range. You know, just to reiterate, the higher doses that we've taken forward will have substantial or complete IC 90 coverage over 24 hours. For Crohn's disease, what we know from the relationship between TYK2 inhibition and IL-23 antibodies is that the doses that are required to see efficacy in Crohn's disease, and the same would be true of ulcerative colitis, is that you need doses of antibody that are at least as great as what gave maximal PASI 75, 90, and 100 rates in psoriasis. So far, the doses studied with deucravacitinib, even investigational doses of six twice a day or 12 once a day, would not generate any level of IC 90 coverage. I would expect that it'll be harder to demonstrate efficacy in Crohn's disease, but we'll see. Thank you. Thank you. Our next question will come from Yasmeen Rahimi with Piper Sandler. Your line is open. Good afternoon, team, and congrats on all of the great updates. I guess, following on to the question that Mike had, in regards to the competitor data. One of the questions that a lot of clients are asking us is in regards to a plateauing effect that was observed with their programs. As you recall, at the 15-mg and 30- mg dose group, the PASI reductions were very identical. The question being raised is there just a function of just, you know, something in the molecule or why was it that you're reaching the plateau, given that there must have been differences in IC90 coverage between 15 mg and 30 mg? How do we know moving forward with the doses you are going with that there's not really a plateau? Greatly appreciate any of your comments there. In regards to, for Dr. Sandborn, if you could just give us a little bit more color in terms of how enrollment is progressing into SERENITY, and maybe to the extent you could comment on whether it's gonna be maybe early in the 4Q or later in 4Q for data. I'll jump back right into the queue for maybe for follow-up things. This is Raju. Just following up on Bill's answer to Mike, there's a lot of focus on this plateauing effect, you know, last week discussions with folks. You know, specific to the 15 mg and 30 mg dose, these are small trials. There's a lot of exposure variability amongst these doses, and that's one aspect of it. I think the real focus should be on the more sensitive endpoints where you clearly see a benefit for higher coverage. You see it for Deucrava, you see it for the Nimbus Takeda drug, and we expect that for our compound as well, right? I think the totality of this, as we should take home, is that from all the trials in psoriasis, IL-23 biologics give you about 80% of PASI 75, about 70% of PASI 90, and about 33%-50% of PASI 100. That's the overall efficacy profile we are targeting. We can show that we can achieve biologic-like coverage of IL-23 in our phase I data, and we're targeting biologic-like efficacy in our phase II trials, not only for psoriasis, but for Crohn's disease and psoriatic arthritis. Really focus on the more sensitive endpoints and cross-trial comparisons are difficult. Really, as you get to the higher efficacy endpoints, like PASI 90 and 100, you will see differentiation with drugs that have higher coverage IL-23. That's what we're targeting. Bill, why don't you update on the enrollment? Yeah, I mean, you know, I think we're circumspect about providing too much details on enrollment except to say that I'm very comfortable committing to top-line data in the fourth quarter of this year. You know, whether it's early in the fourth quarter or mid or, you know, we'll see. I'm confident we'll have data in the fourth quarter. Thank you so much, and keep up the amazing work. Thanks, Yasmeen. Thank you. Our next question will come from Matthew Harrison with Morgan Stanley. Your line is open. Hi, this is Steve for Matthew. Thanks for taking my question. I wanna ask about the VTX2735, the phase II trial is just started on CAPS. How should we think about the proof of concept, and what should we expect to see in the data? Thank you. Yeah. Bill? As you know, with CAPS, they have a variety of symptoms which can include rash, fever, arthralgias. There are validated scoring systems that measure those. The patients will not be on a biologic, so they will have stopped a biologic. They'll be symptomatic. We're treating them in the context of the trial and expecting to see improvement in the validated symptom measures, which should allow, you know, relatively direct comparisons to prior phase II and phase III data with the various biologic agents, which include anakinra, rilonacept, and canakinumab. Got you. Thank you. Thank you. Our next question will come from Jeff Jones with Oppenheimer. Your line is open. Good afternoon, guys. Thanks for taking the question. I guess I'll slide over to the 002 program. With the etrasimod data now published, and of course, Bill, you as first author, any thoughts on how that study data impacts your positioning of the 002 program? Obviously, that study's well underway. How does that help you in your thinking about positioning of the program and getting ready for phase III? Yeah. What you see with both ozanimod and etrasimod from their phase II programs is they had a lower dose that achieved roughly 30% reduction in ALC from baseline and a higher dose that resulted in 50% to sort of 54%, 55% reduction in the ALC. With each drug, you saw a linear dose response from the 30% reduction to the 50%-55% reduction. If you look analogously in multiple sclerosis, in phase II trials, they explored. There's four different drugs approved for S1P. In phase II, they explored, you know, across a range from 20% or 30% ALC reduction all the way to 79% ALC reduction. In phase III, a range across sort of 55% with ozanimod on the low side of multiple sclerosis, up to 73%-79% with different doses of Gilenya on the higher side of ALC reduction. Across all of these, whether you look at clinical remission and endoscopy across low to mid lymphocyte reduction in ulcerative colitis or annualized relapse rate, a clinical measure of multiple sclerosis or reduction in T1 gadolinium- enhancing brain lesion reduction on MRI with multiple sclerosis, you see linear relationships between the degree of lymphocyte reduction and clinical outcome measures on one hand, or sort of structural outcome measures on the other. At least in multiple sclerosis, you don't really plateau those effects until you get up to at least 65% ALC reduction and probably low 70s. What we believe is that the range above 55% reduction is unexplored in ulcerative colitis. Given what's been seen with multiple sclerosis, we think it's very logical that what's been seen with multiple sclerosis going to 70-something percent and the linear relationship between low to intermediate lymphocyte reduction in ulcerative colitis, that it's very logical to think that you could add to the magnitude of efficacy that was seen with etrasimod. We're really looking for 20%+ efficacy across the important outcome measures, but the primary endpoint will be clinical remission. You know, if you, if you think about most of the existing drugs, the difference between drug and placebo is about 10%. A 20%+ delta becomes, you know, really clinically meaningful, especially for a safe oral therapy. Great. No, appreciate that color and sounds fairly analogous to the way you're thinking about the TYK2 scenario. I'll jump back into the queue. Thanks, guys. Thanks, Jeff. Thank you. Our next question will come from Chris Shibutani with Goldman Sachs. Your line is open. Thank you very much. Good afternoon. If I could return to 958 and some of the context with competitor data that we saw at the AAD meeting, maybe approach it more from the question of not efficacy, on the overall tolerability profile as well. Looking to see how you view some of the relative information that we learned, in particular in terms of any potential that you might see something in the way of CPK elevation, how you're thinking about that potential with the ongoing phase II studies. Related to that, now that we have sort of a new visibility on the competitive data set and what's happening, I believe theoretically there's still potential for you to make modifications to your phase II programs across the different indications. How are you thinking about that? Is there potential for tweaks to any of the program designs? Thank you. Yeah, I'll take the latter question, and then I'll have Bill talk about some of the safety endpoints that have been disclosed with the latest Takeda Nimbus data. No, we have a very strong belief in our design of the phase II trials across all three trials, very carefully targeted, approached the way we've done the dose regimens, and we've or the dose cohorts. We've shared the broad strategy across all three programs with psoriasis and then with Crohn's disease and with psoriatic arthritis. Really at the top dose we're targeting, as we said, biologic-like coverage, trough levels, IC90 coverage for all three indications there. None of the data that you've seen come out, whether it's the TYK2 data or now recently the Nimbus Takeda data, has any impact on our strategy. We have a clear line of sight to, as I said before, and Bill's articulated this in previous discussions as well, Chris, that, you know, our belief in our target coverage with biologic-like coverage, we are really aiming for biologic-like efficacy across these trials. Nothing here needs to be adjusted or tuned, you know, and we're laser-focused on execution of these trials. Let me get back to Bill on your question about CPK and tolerability. Yeah, I mean, for CPK, if you walk back to deucravacitinib and, you know, like the between the prescribing information, what's available from the summary basis of approval at the FDA website, about 1% of patients with deucravacitinib at the 6-mg dose had CPK elevations that were grade 4 and about 1.5% had grade 3. It's a, you know, relatively similar low percentage, I think that was seen with the Nimbus Takeda data. All of these are very different from what you see, with, you know, either pan-JAK inhibitors like tofacitinib or JAK1 selective inhibitors like upadacitinib. To our way of thinking, these are just low rates of events that we've already seen the willingness of regulators to give a clean safety label. It's that those low rates are labeled, but they're not black box warnings. I think the data really are just consistent. The additional emerging data from my point of view are still consistent with allosteric TYK2 inhibitors being, you know, highly selective, different from JAK inhibitors and consistent with clean labels, and we believe our product will be right in that zone for tolerability. Thank you. Thanks, Chris. Thank you. As a reminder, that is star one to ask a question. Our next question will come from Sam Slutsky with LifeSci Capital. Your line is open. Hey, guys. This is Rami on for Sam. Thanks for taking our questions. First, I guess with the NLRP3 inhibitors, can you remind us what level of IL-1 beta and IL-18 reductions you're looking for in order to see clinical benefit across the range of indications you could go after? Secondly, what level of detail do you anticipate providing for the mid-year update regarding the extended- release formulation of 958? Is it primarily safety and PK data, or is there anything else we should look out for? Yeah. Let me take, let me take the extended release, and I'll have Bill talk about the level of coverage we expect for the cytokines for NLRP3. On the ER tablet, Rami, we'll provide a pretty meaningful data update at the mid-year or, you know, somewhere in the mid-year timeframe that we've talked about. We've showed data for the prototypes that we've already completed. We've showed relevant in- vitro, human- relevant in- vitro data, which is both, as Bill said, dissolution across different bio-relevant or GI relevant changes. We've also showed data from a dynamic GI model, which again is very relevant to what happens in the absorption distribution phase. I mean, safety, these are short studies. We've done longer studies, obviously, in the MID phase, so don't expect any really safety issues. We'll show you a comprehensive profile that says we can achieve IC90 coverage with a QD regimen. That's what you will see in the immediate timeframe. Related to the NLRP3 inhibitors, if you recall the translational medicine phase I data that we shared at R&D Day with the 2735 NLRP3 inhibitors, so the peripheral compound during the multiple ascending dose portion of the trial, we did a whole blood ex vivo stimulation assay at day 10, where you give LPS and ATP and then look at the ability to block IL-1beta production. At the higher doses, the higher doses in MAD were 100 mg and then 200 mg, we were really able to completely abrogate IL-1beta production. You know, what we're looking for is read-throughs to clinical efficacy where you have clinical diseases that are, you have a, an alteration in NLRP3 that leads to an excess in IL-1beta, where you can see, you know, effects of monoclonal antibodies against IL-1beta, treating that excess and resulting in disease improvement. as I mentioned earlier, we are, for instance, treating the NLRP3 gain-of-function mutation, CAPS, with this. We know that's characterized by very high levels of IL-1beta and it's currently treated with antibodies. you'll, you know, we will need to abrogate the IL-1beta production to see those patients get better. you know, the point of that trial is to show that the complete abrogation that we saw with those higher doses in MAD in phase I translates into the clinic. Having shown that, then you could have some confidence that, you know, you could think a variety of other diseases where randomized controlled trials have shown that IL-1beta antibodies are effective. This would be things like recurrent pericarditis, juvenile arthritis, adult-onset Still's disease. There were definitely studies that showed that acute gout achieved that. You've seen it for secondary prevention of MACE events in patients with a prior history of MI. We know that there's translational medicine studies have shown high rates of expression of IL-1beta in biopsies of patients with hidradenitis suppurativa. There's a variety of places that one could logically go once you've shown that your small molecule NLRP3 inhibitor treats an IL-1beta-driven disease. Got it. Thanks so much. Thank you. Our next question will come from Emily Bodnar with H.C. Wainwright & Co. Your line is open. Hi there. Thanks for taking the questions. I guess going back to safety for VTX958. We saw with the Nimbus molecule there were some signals of acne and viral infections. Could you maybe talk about if you expect to see this in your phase II study? I know you didn't really see it in phase I, but it was noted with Deucra as well. Interested to hear your thoughts there. Maybe if you could just give your perspective on the oral psoriasis market in general now that we're getting a lot of new mechanisms showing positive data like the recent oral IL-23 agent and also an oral IL-17. Curious how you think the TYK2 can fit in that. Yeah. A number of great questions, Emily. Let's just take them one by one here and I'll have Bill jump in if needed here. First on the dermatologic side effects that you've seen now with the Nimbus compound and it's been seen with Deucrava. And we made this very categorically clear that we do not believe these are on target. There is no reason mechanistically that TYK2 should manifest or an IL-23 pathway that TYK2 is targeting should manifest these dermatological effects, the acne and the folliculitis and other effects. As you pointed out, you know, this kind of magnitude of effects, and we ran trials in a similar timeframe that folks have done before, the sort of 14-day phase I studies where these effects were elicited very early in these trials. We think these are off target for both the Nimbus compound and for the deucravacitinib. We have speculations, ideas about potentially what may be happening, hitting some other targets that are involved in these side effects. From our perspective, we don't expect to see these. They are not TYK2-driven, and so they're off target. I think that's the most relevant conclusion for our compound, VTX958. I think the other question was about. Viral. About the— Go ahead. Yeah. The viral infection was specifically COVID, and there did seem to be a treatment an imbalance between placebo and the treatment groups, although it wasn't very dose-dependent, as I recall. We don't really see that with the anti-interferon alpha antibody anifrolumab in lupus patients. I'm not quite sure what to make of that. As the presenter at AAD noted, the study was run at the height of the COVID pandemic and so it's sort of a unique circumstance. None of the patients died or were seriously ill, as I understood it, from the infection. I'm not too sure what to... I think it's a little premature to know what to make of that, except to say that, you know, when you look at anti-interferon alpha antibody with really complete target coverage with lupus, this is not an important issue. There's no such signal with IL-12/23 inhibition with STELARA or with IL-23 inhibition at, you know, very high antibody doses with either, you know, TREMFYA, SKYRIZI, et cetera. I think it's likely to be sort of a fluke of the pandemic and not go further, but time will tell. Also to note that this really, you know, hasn't been seen to any meaningful degree in the way that COVID was seen in the Takeda phase II study. That really wasn't seen in the phase II and phase III trials across multiple indications with deucravacitinib at doses that are getting up to overlapping with some of the Nimbus Takeda doses. I in terms of I see, you know, 50 and 70 coverage for the TYK2 target. I'm gonna guess in the fullness of time that that safety issue won't be replicated, time will tell. Back to the newer oral IL-17s and oral IL-23s. Let's just dig the oral IL-17 first. Look, we had a discussion about PASI 75. We're discussing PASI 90. We're talking about PASI 100 possibilities with drugs that can achieve the coverage that we do in biologic-like coverage. To talk about a drug where there was absolutely no PASI 75, I just don't think is relevant to this discussion today, and we can have more discussion subsequently if and when we see better effects with an oral IL-17. I'll put that to rest there. In terms of an oral IL-23, and I'm assuming you're referring to some of the Protagonist Janssen PR that has come out. It's really hard to speculate on data that we haven't seen. We expect to see this data in the latter half of the year, and we can have a discussion just like we're having today with a competitor compound. It's certainly very hard to speculate on a PR, generic PR that came out. I think more in context of the opportunities that we have with our approach with 958 across a broad range of autoimmune indications and perhaps the lack of opportunity for some of these newer oral IL-23. I'd love to hear Bill's perspective on that because I think that's more important to us broadly. Today we can discuss and talk about data that we haven't seen. Bill? Yeah. We'll need to see, as Raju said, what the data look like in psoriasis. As I mentioned earlier, you really— To unlock the inflammatory bowel disease market, you really need to have doses that, you know, mimic an optimally- dosed IL-23 antibody in psoriasis. Doses that would give you PASI 75s of up to 85% or 90% and 60%-70% PASI 90s and, you know, sort of 33%-40% or 50% PASI 100s, and the IBD doses are often a bit higher than that. Part of that is a couple of reasons. The, you know, antibodies, and I think peptide antagonists are gonna be the same. You're basically binding already secreted cytokine, and different disease settings can give different amounts of cytokine, and you can have differences in target-mediated clearance. You can also excrete parenterally administered drug in the gut. This is well described that REMICADE, for instance, given intravenously, is lost in the stool in severe colitis and Crohn's disease. You know, those are reasons why you need more antibody for IBD than you need for the optimal dose of psoriasis. Even if with the peptide antagonist, you show that you can start to get into the zone of IL-23 parenteral agents for efficacy, I would expect that like antibodies, you'll need to go further than that to have efficacy in IBD. By contrast with TYK2 inhibitors, they're really intracellular- acting, and you're eliminating the secretion of the cytokines to begin with. You wouldn't expect to have that same target-mediated clearance. I think as you get to IC90 coverage, you should be able to effectively treat Crohn's disease and ulcerative colitis. That's what we're, you know, planning to demonstrate in our ongoing phase II trial in Crohn's disease. Thank you. Our last question will come from Alex Thompson with Stifel. Your line is open. Hey, guys. This is Pat for Alex. Just a quick question on IL-4 receptor alpha program. If you guys could just talk about biological proof- of- mechanism there and what kind of benchmarks from Dupi maybe are out there that you guys are taking a look at. Thanks. Well, first, you know, truly excited about an oral agent that's, you know, similar pathway as DUPIXENT. You saw this morning the data from the COPD trial. You know, it's super exciting for us to be in that pathway. We, you know, we showed early data at the R&D Day and when we felt comfortable, we're, you know, on our way to a, you know, really mechanistically exciting approach to how to target the IL-4RA antagonist. I think beyond that, you know, we just wait to stay tuned for. We'll share some more data perhaps end of the year with, you know, progressing towards our candidates, including showing proof of— relevant proof of concept in animal studies. And the benchmarks against Dupi have been all pretty validated. Initially it's a mechanistic approach targeting four and thirteen, and then certainly showing some proof- of- mechanism data and then, you know, similar track to what we've done with all our drugs. In this case, you know, differentiation is clear. I think more importantly, targeting DUPIXENT-like efficacy is gonna be the goal for this molecule. Thank you. Thank you. There are no further questions at this time. I would like to turn the floor back over to Dr. Raju Mohan for additional or closing remarks. Yeah, thank you. Thank you all. Thank you for participating. Thank you. Some great questions. Thank you for listening to us. You know, it almost seems like we need another R&D Day here because, you know, obviously we are very passionate about the programs. We understand our molecules, we understand differentiation, and, we love to discuss the dialogue with you. Thank you all again, and I'll look forward to the next discussion. Thank you, ladies and gentlemen. This concludes today's Ventyx Biosciences fourth quarter and full year 2022 earnings conference call. Please disconnect your line at this time and have a wonderful day.