Jefferies, thanks for tuning in. It is my pleasure to have Raju Mohan, CEO of Ventyx, joining me. Welcome, Raju. Yeah, thank you. Thank you, Andrew. For those in the audience less familiar with the story, maybe spend a couple of minutes talking about Ventyx, what you're working on, what you're trying to achieve, and then milestones over the next 6 months- 12 months would be very helpful. All right, sure. Ventyx has been around for about four years now. We started in 2021. Our initial focus was on, I would say, immunology, very narrow. It's now, I would say, expanded to neuro, immunology, cardiovascular, metabolic. First compounds were S1P1 and TYK2 inhibitors. We took S1P1 into the UC and TYK2 into psoriasis and Crohn's. While we met the endpoints, it just wasn't competitive enough. At least the Crohn's, the psoriasis data weren't competitive enough. We moved the youngest member of our portfolio, which was NLRP3, into the forefront and Lally pivoted to be a company that's focusing on inflammasome. I started this effort in about 2017, which is where IFM and Inflazome had done deals with Novartis and Roche, respectively. Very few players, a couple of pharmas, not much happening. Compounds had stalled. We have stayed true to it. Obviously, companies have now pivoted to that space. A number of companies had a focus on a different angle but have seen the opportunity in this space. We're thrilled to have a portfolio. I think that's one of the best in class. Hopefully to show clinical relevance with these molecules. Great. There are a whole bunch, like you alluded, NLRP3 players out there. What makes you most differentiated from others out there? I think any time a target becomes a target of interest, people will jump into the field, right? I always tell people, I think every grandmother in India and China is probably making NLRP3 inhibitors right now. It's good. It's good for the field. We've seen a lot of peripheral compounds now develop. Companies, some of them are here, have pivoted to NLRP3. For us, the initial focus was on peripheral compounds. We've built a portfolio of peripheral compounds. The concern was toxicity. People believed a lot of the tox issues were on-target effects. We've shown now with our peripheral compounds that we can dose, for example, in the RP study, ongoing RP study. We've done a CAPS study. There's just no signals that are associated with anything to do with the structure of the compound. On the CNS side, it's been a challenge for people. People have taken these old scaffolds that were, God, they go back to the Pfizer days, right, and shoved them in the brain and called them brain penetrant. That is not how you get a drug. You can get minuscule amounts to cross the blood-brain barrier. We have engineered our molecules to basically be brain-biased and then turn them into NLRP3 compounds. That is a difference. I think clinically we are further ahead. Many other companies that were sort of in the space have dropped out. There are a lot of new compounds that are showing promise, I think. I think that is good for the field. Good. Maybe let's dive into 3232, your CNS- penetrant compound. You recently shared some initial data in cardiometabolic obesity patients. Ultimately, you show a whole swath of biomarker changes, very strong across the board. What's the take-home message and how are you positioning this asset going forward? The trial was designed to actually take advantage of two different populations. One was a central effect on obesity. 3232 is a compound that has really good brain penetration, real balanced levels. We see in the doses we tested, we are about three times above the IC90 for covering blockage of NLRP3 as measured by IL-6, hsCRP, IL-1β in the CSF, right? We have got good coverage. Therefore the question was, do you have any CNS-mediated control of obesity, control of feeding behavior? There is no peripheral effects of NLRP3 on weight loss. It is not a GLP. There is no effect on motility. The idea was, is a human like the mouse where you see effects on feeding behavior? We could answer that question with a brain penetrant compound. The positive aspect of this is there is also peripheral exposure, right? We had 3x above the whole blood IC90s, right? Here the relevant measure is human whole blood. We thought, let's take this drug. Let's enrich the population with folks that are obese. We had 30 BMI-42 BMI, fine folks with elevated CRP and with cardiovascular risk factors. No overt diabetes, but A1cs that were in the borderline, fatty liver, elevated lipids. Very comprehensive trial, but one simple endpoint, weight loss. Then this real comprehensive look at everything from liver, the kidney, the heart, effects on lipids, effect on glycemic indices, effects on plaque stabilization, PAI-1, the whole gamut, right? Plus we had MRI PDFF. We had a CT1 correction. The simple answer was there is no effect of NLRP3 on weight loss, right? Zero. There's complete disconnect of what happens in neuroinflammation in the hypothalamus and any effects on feeding behavior, contrary to what folks are out there saying, well, they didn't have brain exposure. How the hell? I mean, sorry, pardon my language. How do you know? You're still stuck in a mouse, right? There is no connection. Now, why mice have this effect? We don't know. Mouse have a very different feeding pattern than humans do. That was put to rest. Once you put that to rest, there's one side of the parameters, markers all sort of disappeared, right? There's no effect on lipids as mediated by weight loss. There's no effect on steatosis in the liver. Although we see effects on inflammation, it's decoupled from steatosis, right? The weight loss was put to rest. What we saw because of the peripheral effects of the compounds was very strong effects on NLRP3 markers like hsCRP, like IL-6, like fibrinogen, like SAA. There were orthogonal effects in the liver as in direct effects on Lp(a) little a. We talked about inflammation. We talked about very significant impact on inflammation, even though we did not focus on it in the data release. There was a clear unambiguous effect on dropping CRP, which is really a measure of upstream IL-1β and IL-6, right? We bring it down to levels as what I call these are immune homeostatic levels, right? Right by the time we were putting the data out, there was this whole guidance from ACC. Peter Libby had published an article where he really talks about the sweet spot of how you want to block these cytokines without going down into areas where you're not opening yourself up to opportunity infection because of the evolutionary role of these cytokines, IL-1β, IL-6, in prevention of infection and post-pathogen defense. How are you positioning this drug going forward? Is the concept, okay, we have an hsCRP drug, so we're going to pursue CV indications, run long-term outcome studies on top of that? What is the strategy going forward? I think you have to look at who's we, right? The opportunities are clearly for folks that have looked at it long and hard in neuroinflammation and neurodegenerative diseases, right? I think the early interest, even in our ROFN or relationship we had with Sanofi, was based on their interest in Parkinson's and Alzheimer's, MS, potentially even ALS, and down to Huntington's disease. That aspect is always of interest to people. Yes, difficult trials, a lot of unproven biology, but certainly the idea that neurodegeneration actually begins with neuroinflammation and what happens in the microglia and release of cytokines. That is one aspect of it. We'll come back to who we is, but that's an area where people are interested. Obviously, we've made it very clear that we will not by ourselves pursue that area. These are difficult trials. There's no clear choice between Parkinson's or Alzheimer's. I think eventually it'll all play itself out, but the biology is pretty compelling in the Parkinson's space. Now, in terms of cardiovascular, obviously there was the CANTOS trial. Folks always ask, is there any proven IL-1β? And there is. Certainly in CAPS patients, canakinumab is approved in folks that have a gain of function mutation of NLRP3. Certainly in RP, also in heart failure. There is a clear efficacy proven approved drugs, which is not what you can say about IL-6, right? I don't think calling ourselves an oral IL-6 is accurate because I would say we are an oral immunology inflammatory mediator that is affecting all of the aberrant biology through the activation of inflammasome. In layman's terms, you're dealing with this systemic low-grade inflammation, right, which is now linked to not just neurodegeneration, but a whole bunch of cardiovascular, cardiometabolic indications and not treated by either lipid-lowering therapy like the statins or by the newer incretins and Gs and triple Gs that just don't address it, right? I think it's a beautiful add-on to, I think, the next generation of therapies that are evolving out, and especially the oral ones that you'll see. It sounds like Alzheimer's, cardiovascular are two areas. Now, Sanofi has a ROFN. Can you talk a little bit about the status there? When do we exactly hear the next update and what is this next update? The ROFN starts when they get the data package for the second trial, which was the obesity trial. We obviously had the data from the Parkinson's in June. The ROFN will extend to the ROFN period. I'm not going to go into what that is. Then post that, there is a negotiation period. Of course, if folks agree on that, there's a definitive signing period, right? That's what ROFN is happening. Certainly, there are other areas outside of 3232 that can attract people. As far as the ROFN is concerned, we have an obligation to have that play out with Sanofi. It's exclusively on 3232. It's not on an indication that's based on the compound. I see. The level of other strategic interest, any comments? No comments. Understood. Okay. We'll stay tuned, basically. Yeah. I mean, I think as you know, just as much as excited investors, I think for strategics that have, like I mentioned before, Novartis, Roche has always played in the field. I just don't think they've had compounds to really move into the kind of trials you want. I think now with what we've seen with obesity acquisitions, drugs, this fits in perfectly with that, where you can get a real benefit on top of what you're getting with these drugs as well. Yeah. Understood. Okay. Shifting gears then to the peripheral compound, 2735, you have an RP data readout in Q4. I would love to define what success is to you in that readout. What kind of pain score reduction ultimately do you want to see to move forward? Yeah. So folks not familiar with RP, so RP, recurrent pericarditis, it's loosely a cardiovascular indication, also a rheumatology indication, right? These are folks that have post-MI, they have inflammation in the pericardium, they have stabbing pain. These can be episodic. They can have recurrences. Right now, the only, well, there's a bunch of different ways that are treated besides corticosteroids and NSAIDs. There's colchicine, which is a kind of an NLRP3. It's actually a microtubule modulator. Then you have an approved drug called ARCALYST, which is from a company called Kiniksa. What we're doing is looking at a trial with 2735, which is our peripheral oral NLRP3. It's different from 3232. We've taken this compound into CAPS patients and shown the effect. In CAPS studies, we've done extensive phase I modeling, and now we're going into RP. Essentially, the trial is very similar to Kiniksa's phase II trial, where you treat X number of patients, and we're talking about 10 + to have a data cut, right? The 10+ doesn't mean that's the total extent of the trial. It just means that when we have 10 + folks, we'll have an interim cut. We'll now calibrate this with what's been shown in the phase II from Kiniksa, which is reduction in CRP and a reduction in pain score, right? You'll have a mix of patients in this trial that are either CRP positive, which means that they have CRP higher than 10 mg per L, and a pain score higher than four on a 0-1 0 NRS pain score. For folks that are CRP negative, there has to be evidence that they're on steroids, corticosteroids, and a previous history of an MRI to confirm evidence of pericardial disease. You do have a mix of folks in the CRP, but of course, you have to make sure that the CRP is suppressed because of the corticosteroids. They all have to have a pain score above four. What we look at is a six-week time point and look at reduction in CRP, but I would say equally or more important, reduction in the pain score. We do not walk around saying, "Oh, my CRP is high today or my CRP is low." If you're in pain, you certainly will notch that down, right? I mean, I think to be competitive, even though, look, it's an oral drug, there can be a certain amount of discount leeway for an oral compound, right? But I truly believe that you have to be in the range of Kiniksa on the pain score for being competitive, right? Just because for folks to be on a drug long-term, if you don't deal with your pain, you will not stay on the drug. Understood. The bar is high, but that's the way it sometimes goes. To make clear, Kiniksa is an injectable. Kiniksa is an injectable. It's doing $500 million right now. It's doing $500 million. It's not the greatest regimen it comes as of. We're not going to go into it. The second generation of Kiniksa actually is a better version of the first generation one. It's not a trap. It's actually a monoclonal. We expect to compete with the efficacy of these drugs with an oral NLRP3 blocker. Okay. I personally have looked at Kiniksa's phase II open label study. You're following a tried and true pathway. The baseline pain score was around 4.5. I think in my notes, they went down to 0.8, so. 0.7. Okay. So that's the. That basically means patients were between zero and one, right? The folks went down to one or zero. I think 1- 0 is fine. One and zero may be something that happens on week six. You may have a week four, it might be a zero, and week five, it might be a one. It goes back to zero, but it has to be in that range. Okay. If the baseline is four at least, to go to below one is at least a 75% reduction. Yeah. I really don't like this reduction in percentages because if you start at four and you go down to one, it's 75%, right? If you start at six and go down, it's a higher percentage. It's not where you start out with. It's where you end up, which means 0- 1. Because for Kiniksa, if you look at their starting CRP levels, right, so the geometric mean and median, they were much higher, right? There was no standard of care. There was no Kiniksa. There was no ARCALYST, right? Typically, their CRP level, even though the threshold is 10 mg per L, the Kiniksa levels were much higher, right? If you looked at us going down from, let's say, 10- 1 or 10 to whatever, their levels are starting out at 25 and 30. It's not where you start out with. It's where you come down to, which is levels where you've reduced. In the case of RP, it's less obvious than cardiovascular where you're saying, you know, bring it down below two, two being the threshold for risk factors, right? The drug will drop CRP. I mean, I think NLRP3 molecules, as you saw in our 3232 trial, we just dropped it right down. I wouldn't worry so much about percentages. I would worry about, are you starting at the threshold you said you would, which is 10 and above, right, for patients that were not on steroids? Now you're bringing it down to where you think you would be, which is what our drug will do. More importantly, are you bringing the pain scores down to between zero and one, no matter where you started out, right? It's four and above. They were, what you said, they were at 4.7 or something. 4.5. On the pain score, yeah. We might be higher on the pain score. It all depends on when you actually catch these patients, right? They will come in, they have a flare, and they will score themselves. Some of them might be a four. Some of them might be a five. I think six is sort of like people have told me it is like kidney stones. And seven is more like labor. I mean, these people will score themselves. It is really where they end up that is important. Is it fair that pain scores is primary, CRP reductions is a secondary, like a bonus cherry on top type of thing? I think both, right? For a drug to work, I'm going to show you both aspects of it. Obviously, the CRP negative folks won't drop as much as the CRP positive will. I think they both go together. Now, the pains, again, don't look at it at week six, right? Look at it at week one, two, three, four, five, six. These folks go on to week 13, right? Some folks will continue on to week 24, potentially once we have the QD drug regimen going. It's not just what happens in week six. Got it. You'll see if it bounces around seven, eight, and there's a reflare. It's really the totality of, given their small numbers, the way to look at it is not just moment in time, look at it across the duration, right? That will give you comfort in the absence of large numbers in a trial like this. I see. I see. Bottom line, this interim, at least 10 patients, give or take a BID dose out to week six. Although the trial is much bigger, actually, it sounds like you're valuing a QD dose on top of that. And then the. The initial, yeah, the initial trial, yeah, was more like a, it was a compressed trial. It was phase II. We had set up upwards up to about 30 patients, BID dosing only. The folks that have followed our, I mean, some of the investors get into the clinical trials. We've changed the protocols to allow, first of all, extending it to 24 weeks, to adding a QD drug to the end of the open label period, to be able to bring the QD drug back to the beginning of the trial for the folks, right? All of this is in preparation for phase III, where we can now do a little bit of dose ranging with the QD drugs much earlier than we had planned, right? Because really, after a certain point, wasting patients on a BID drug just slows you down. The idea is we cut the data at a certain point. I'll see it. We'll show it to the investors. We keep moving with the QD drug. We expand into other jurisdictions, prepare for the end of phase II or type C meeting. These are low revenue spend, low risk activities that can really help you. Once you see the data, you proceed ahead with it and start to think about phase III. Yep. The QD cohort, when do we get that data? Hopefully, when we show you the 10 week, 10 patient data, we'll try to give you a forward-looking picture as well. Oh, in the same press release? Yeah. Yeah. Hopefully. I mean, the goal is to convince you the drug works with the six-week time point. No reason to turn it into a slightly expanded presentation. Okay. Bottom line, though, we're not necessarily just going to receive a week six data. You're going to share the curves to help us from week one to week six, especially on hsCRP. Is that correct? Yeah. I believe so. I hope so. Yeah. I wouldn't call them curves. It'll be numbers, right? Oh, okay. Yeah. How should we think about safety of this compound? You want a safe compound. I think safety, if you're going to have an oral, if you want someone to transition from a biologic to an oral, especially for chronic dosing, especially in these indications, safety is paramount. Look, we've dosed this drug now for many, many weeks. We've done it in CAPS patients. We've done it in the RP study. Within what we've tested for both compounds, 3232 had gone into a 12-week study in folks, about 80 people that took the drug, 12 weeks. As we showed, no real safety signals, no risk, no infections. Both very safe drugs, biotherapeutic window, good therapeutic margins. Understood. Let's just say this succeeded. You decide, "Oh, let's move to phase III." When do you start that actually? And then do you expand to other indications? Right now, the focus is on RP. Typical time between phase II and phase III is between 6 months-9 months. In this case, we have kind of a coalescing, right? Like I said, initially, it was a phase II is done. We'll keep the phase II running. We'll expand to other countries. Then we'll start to plan for phase III. At some point, of course, phase II will finish. So yeah, hopefully sometime in the second half of the year. Understood. Certainly in the second half of the year, but hopefully more towards the third quarter. Okay. I think that's all the time we had unless we have 20 seconds left if you want to say one last. Look, it's a great time to be in this space, right? That's why having camaraderie of folks. I was in the inflammasome meeting. It was a good discussion with other folks in there. It's great to have this target, which I got excited almost a decade ago to see folks excited about that. Plenty of room for a number of drugs, right? We just happen to be in the forefront of a lot of unknown biology, right? There's no proven path here other than canakinumab. It's a fun, exciting time to be here. Great. Thank you so much. Thanks everyone. My pleasure. Yeah. Thank you guys.