Ventyx Biosciences at Wells Fargo Conference: Inflammasome Leadership

On Friday, 05 September 2025, Ventyx Biosciences (NASDAQ:VTYX) presented at the Wells Fargo 20th Annual Healthcare Conference 2025. The company highlighted its strategic focus on the NLRP3 inhibitor program, showcasing optimism about its compounds’ potential. However, challenges in the competitive inflammasome space were also acknowledged.

Key Takeaways

• Ventyx Biosciences positions itself as a leader in the inflammasome space, focusing on NLRP3 inhibitors.
• Successful trial completion for VTX2735 in early Parkinson’s patients, with further trials in Recurrent Pericarditis expected to yield results in Q4.
• VTX3232 is being explored for obesity and cardiometabolic indications, with positive outcomes in Parkinson’s disease trials.
• The company is optimistic about overcoming historical challenges with NLRP3 targets.

Operational Updates

• Inflammasome Space Leadership:

- Ventyx emphasizes its leadership in targeting NLRP3 with two main compounds: VTX2735 and VTX3232.

- VTX2735 has completed trials in early Parkinson’s patients, showing promising biomarker exposure results. It is also undergoing trials for Recurrent Pericarditis with readouts expected in the fourth quarter.

- VTX3232 is being assessed for its impact on obesity and cardiometabolic health, utilizing comprehensive methods like DEXA and MRI.

• Clinical Trial Developments:

- VTX2735 aims to demonstrate efficacy similar to Arcalyst in Recurrent Pericarditis, with trial designs mirroring successful precedents.

- VTX3232’s Parkinson’s program has shown complete target engagement, with potential for partnership to advance its development.

Future Outlook

• Recurrent Pericarditis (RP):

- VTX2735 is focused on achieving outcomes comparable to established treatments, with potential expansion into myocarditis.

• Parkinson’s Disease (PD):

- Ventyx is seeking partners for VTX3232 to explore combination therapies and enhance its development as a disease-modifying treatment.

• Cardiometabolic Indications:

- The company is targeting meaningful endpoints in cardiometabolic studies, considering partnerships for combination therapies with FGF-21 orthologs or GLP-1 therapies.

• Additional Indications:

- Exploration into osteoarthritis and rheumatoid arthritis is on the horizon, leveraging insights from other trials.

Q&A Highlights

• VTX2735 Differentiation:

- Designed to address liver effects seen in prior compounds, focusing on efficacy and safety.

• RP Trial Benchmarking:

- Aims for outcomes in line with Arcalyst, targeting reductions in pain and CRP levels.

• VTX3232 Strategy:

- Likely to be partnered for further development, with an emphasis on combination approaches and larger trials.

For more details, readers are encouraged to refer to the full transcript below.

Full transcript - Wells Fargo 20th Annual Healthcare Conference 2025:

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: All right, everyone, I think we’ll get started here with our next fireside discussion. My name is Derek Barcila. I’m one of the Wells Fargo biotech analysts. I’m very excited to have Ventyx Biosciences here from the company. We have Raju Mohan, who’s the CEO, founder, and director. We also have Matthew Moore from the company, the Chief Operating Officer. Gentlemen, thank you so much for joining us.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Yeah, thank you, as always.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Excellent. Maybe, Raju, if you want to start, just kind of give a high-level view of Ventyx Biosciences, and then we can drill down into the specific program.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Sure, yeah. I’ve been doing this with you now for a few years. I think the high-level view today is a little different than the high-level view a few years ago. Essentially, we are now a company that owns the inflammasome space, and within that, I would say NLRP3 is the main target. While we still have our two earlier drugs, the S1P1 molecule and the TYK2 compound, hopefully find a home for them, we really are with the leaders in the inflammasome company. We have two compounds that are in clinical development. One is the peripheral molecule. This is VTX2735. We’re going after RP. It’s sort of a mixed cardiorheumatic indication. We just completed a trial in early Parkinson’s patients with biomarker exposure readouts, a very successful trial, which now moves towards a much longer phase two efficacy. We have this final trial or two trials reading up.

One is the recurrent pericarditis, which we just talked about. That’ll read out sometime in the fourth quarter. We have a large placebo-controlled and a combo arm with our brain-penetrating compound in, I would say, two aspects. One is obesity, looking strictly at weight loss and then consequences of weight loss as one. The other is a much broader look at the effects of NLRP3, IL-1β, IL-6, on cardiometabolic factors, be it the liver, the heart, the kidney, really a whole body scan. When I say scan, I mean there’s DEXA, there’s MRI, there’s MRI PDFF. I think in terms of high-level picture, we have one readout completed in Parkinson’s. We have two readouts coming in in RP. I think with these readouts, even though they may seem like they’re sort of monolithic, if you look at what we’re doing with these compounds, it’s not just one quadrant.

You’re almost like scanning the entire 360-degree space to say, this is where the inflammasome or NLRP3 plays a dominant role, and doing it with two compounds to sort of expand. When the data comes out, I think it’ll be clear in some places. In some places, it’ll be another to put pieces together. I think the NLRP3 space is going to be a dominant player in decades to come. We happen to be at the position where we have the two of the best compounds out there.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: That’s great. Maybe starting with VTX2735, how is this kind of compared to some of the other paths and also current NLRP3 inhibitors in the systemic field? Ultimately, where do you kind of feel like this molecule could be differentiated?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Right. Just on the chemistry-wise, we built this compound to a peripheral compound knowing a lot of baggage with earlier compounds. There was a lot of anecdotal real data saying they had liver chalks, the compounds had failed, and they had failed. You had the earlier deals with IFM and Novartis. You had a deal with Inflammasome and Roche. There was a JAK cure deal. All these compounds have just lagged, right? They haven’t seen any meaningful data come out, which means the target is still alive. We’re still talking about this. Every day you see another NLRP3 review. The compounds failed. That sort of put a damper on people. What’s wrong with this target? I think there’s been a resurgence of new compounds coming in.

Because we built our compounds from scratch and making sure that we met all these, you know, the efficacy, the safety, even the liver effects people have talked about, even early stages. We have the best peripheral compound out there, 2735. There’s obviously a lot of competition there. There should be, because that tells you that the field is now heating up. With this molecule, we’re not looking at RP, right? Certainly you can position this comp. We finished a study in CAPS patients. We talked about it last year, which is a gain of function mutation. We’re looking at the RP. Like I said, once this data set reads out, there’s a potential to take this peripheral compound or a second-generation peripheral compound into that space as well.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Got it. Maybe just walk through some of the data that you’ve generated with VTX2735 and, you know, some of the PKPD that you’ve looked at from the, you know, normal healthy volunteer study, but also, you know, some of the safety events that you’ve seen in that trial and from this compound.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Right. VTX2735 has gone into a phase one study. It went into a study in CAPS patients. This is a small trial, but there’s only 200 patients in here. We had seven patients in there. It’s now in the RP. It’s in the RP study. We also have, for folks that follow this, the doses we had in the CAPS study and the doses we’re taking into the RP study are all BID doses. We now have a QD drug that’s been dose titrated and dose equivalents to the BID studies. We’ve done studies with that drug as well in normal healthy volunteers, right? Without exception, what you see with an NLRP3 inhibitor, the caliber of the quality of what we have, is a rapid drop in IL-1β. IL-1β is not exactly the, even though that is the first target, it’s not exactly easy to measure.

We look at downstream markers. There’s IL-6. IL-6 has an effect on acute phase reactants like HSCRP. HSCRP is now accepted as the most stable. In every instance, our compounds will drop HSCRP. There will be a dose-dependent drop. You will see this drop maintained over the course of your dosing and potentially even beyond the drug withdrawal, right? I think that’s the genesis of the biology. That’s where we are. If you have a bona fide compound, you will block IL-1β and IL-6, which are the pathological damage inducers. You can then measure it with something like HSCRP, which is when we go to the doctor, they look at HSCRP, an easy measure of the mechanism of this compound.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Got it. I guess what are the key learnings from that CAPS trial that you ran? I guess in terms of not only validating the mechanism, but ultimately, you know, better understanding, you know, for de-risking, you know, RP.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Yeah, I mean, that’s an interesting one because initially in CAPS, we want to, you know, we would have been grateful to get one patient or two patients, right? There’s anecdotal reference. I know Roche said they had tried a patient. My good friend Neil Walker said he had tried a patient with his MK2 compound, but nobody published anything, right? We were able to get seven patients, of which five completed. We dosed them for two weeks. We had a washout for two weeks, dosed them again. Without exception, if you look at these patients, they all come in with different baseline levels. They all come, depending on the biologic they’re on, on the CRP, the autoimmune pain score. Without exception, we dropped all of these patients down to basal levels, whether it’s in the key symptom score, whether it’s HSCRP, whether it’s IL-6, every patient was brought down.

The lessons were that this drug works as it should. If you want to see a dramatic drop in HSCRP, you have to start with an elevated CRP. Otherwise, you’re not going to see that drop in here. More importantly, you can maintain that effect through the course of the washout because we didn’t see a lot of re-flare going on with this drug here, right? The first real proof-of-mechanism for biological relevance, right? I mean, CRP is CRP. Actually showing these folks felt better. The CAPS patients, it runs in families. They have, unless you treat them, they have severe fevers, they have colds, they have joint pains, right? Crazy headaches. Once these folks start feeling better, they are more apt to stay on the drug. They’re more apt to tell others, it’s a very tight community of this thing.

It was really rewarding to see the effect of this drug in patients that have been suffering. I can tell you, even with good biologics, people will still prefer an oral drug.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: For the two patients that dropped out, what was the issue there?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Family issues. Remember, we had to bring them all in and keep them here for months. One patient felt good after the first two weeks and decided he felt fine and went home and flared. There was nothing to do with the drug. It’s just, you know, they’re kids, they’re mom and kids that come, they leave family behind. They had to be in-house for two weeks, for six weeks, and then a follow-up. It’s just a lot of burden on these folks, right? Yeah. They eventually have a pill, they go home, they can take it. For this trial, we were lucky to keep five.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. The core message is that, you know, basically using CAPS, we can see this reduction in CRP, the inflammatory markers that will translate to RP.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: That’s a pretty broad extension because the mechanism is dropping HSCRP, dropping IL-1β. RP is a disease where you have, or we believe there’s an aberrant effect of NLRP3, overexpression of NLRP3 in the pericardium. That’s what’s causing the inflammation, the pain, and you’re blocking it. It’s a little different in CAPS patients, a gain of function mutation. It’s genetically higher. Yes, the outcome is the same. Having done this a long time, don’t ever take for granted one trial over the other. Yes, we’re pretty bullish about RP. We think we have the best chance of actually showing efficacy with an oral drug.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Maybe you could talk about your proof-of-concept study there, the design. I guess, you know, how do you feel about the output of that trial relative to, like, you know, comparable drugs, like again, like Arcalyst. How are we going to kind of benchmark those?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Matt’s really taken ownership of this program and sort of understanding, you know, competitive landscape positioning. You want to just take that?

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: Yeah, I think, I mean, Arcalyst did us a favor. They have a pretty good blueprint for how they got the drug approved. We’re sort of following a similar development pathway. Our phase two study is designed very much like their phase two study. We’re looking at patients who are flaring in spite of being on the best available oral therapy. They can be on NSAIDs, colchicine, steroids. The only exclusion is they cannot have been on prior biologics. We’re looking for patients that are actively flaring. The goal is over the six-week primary measurement period to reduce pain and CRP to, you know, to normal levels.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. I mean, is there like, what do you expect in terms of kind of like onset? Do you expect faster onset or about, you know, relative to Arcalyst? Is that an area where you can win or do you think that’s unlikely?

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: Arcalyst is a, you know, it’s a good drug. I think that, you know, reducing, I mean, if you take too long to reduce the pain, patients will drop out of the study. We need something that’s competitive, right? With ours, a little bit, you know, a little bit sooner, a little bit later.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: I think a biologic is, we’ve been equivalent between days here, right? Is it three days for us, two days for them? A biologic is always going to be a much faster onset. I’m talking about a day here or a day there, right? I wouldn’t worry about it.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: From a differentiation standpoint, I guess there’s this kind of view of maybe targeting, you know, one beta by itself versus one alpha and one beta together. Where do you guys kind of feel in terms of the biology and, you know, ultimately, will we determine who wins out of the proof of concept or will we need kind of the pivotal trial?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: No, I mean, I think this trial, what we’re doing, is as definitive as their trial that they did. The clinics are dead. The months are from the other companies. Yes, you need alpha there. Our argument is alpha is there. It’s potentially a waste product. What we think is that any alpha that’s produced in the consequence of NLRP3 activation, which it is, it’s going to be blocked by an inhibitor. We believe we’ll see efficacy comparable to what you see with the other drug out there, right? We believe in that. We’re doing a different experiment. Obviously, I have not seen the data, but I think a lot of this alpha story is, it’s there. It doesn’t always bear out. I think beta is the dominant player. More importantly, NLRP3 is the dominant perpetrator of this process.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Have you been able to look at that in the lab or preclinically to kind of confirm that? What gets you confident that?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: We haven’t looked specifically at the pericardium per se, right? We know when we activate NLRP3 with a number of agents, LPS or an agent like Nigericin or anything else, you will see the alpha as a product of that, right? You have gasdermin D blockage, pro IL-1β, IL-1β, IL-18, and there is alpha as well. You completely block that alpha. That’s fair that you block it up. Now, do you need to block it for efficacy? You’re blocking it. You can’t selectively not block the product in there, right? Again, we’re doing the definitive experiment, right? We will see the results. Conceptually, from what I’ve read and what we’ve seen in these patients in the expression, I don’t think that is a definitive argument to say we have alpha.

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: The other point I would underscore is if you look at the three biologics that are the IL-1 biologics, canakinumab, anakinra, and Arcalyst, I think a lot of the statements about IL-1 alpha are sort of pertained to canakinumab, which is a pure IL-1β blocker. Our drug works differently. NLRP3 inhibition is not an IL-1β blocker. I think that you can’t necessarily transfer those conclusions to an NLRP3 mechanism.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. I guess going back to the question on benchmarking, we want to see something in kind of line with Arcalyst. What is that? What do we need to see from your data set? On which specific endpoints are we focused on when you guys report the data?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: I think the phase two data had two endpoints. One was in that set of patients. The first set, it’s HSCRP dropping concurrent with the NRS pain score dropping, right? I think that’s something we’d have to show. Starting with your basal levels of the pain score, which this is a published protocol, has to be 4 on a scale of 0 to 10, an 11-point scale. The CRP is going to be greater than 10 mg/L, right? We need to show we’re competitive with dropping the pain score and the CRP. If we’re not, then I think we’ll have to rethink what this drug can be competitive, right?

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: What does that mean in terms of magnitude? Are you looking for like a 50% drop or?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: I think the Clinix pain score was about one in that score. I think you have to be in that. It’s a short range and it’s a subjective score, right? It’s a question of how quickly do you drop it? It’s a six-week trial, another seven weeks follow-up, right? It’s not just how quickly you drop it. What’s the magnitude of the drop? How does it stay over the course of six weeks and seven weeks? Because it’s subjective, right? My understanding from talking to KOLs and I was just at this conference in Europe, the way the report may bounce around, right? It can’t go to four again, certainly higher. That’s just got to be in that range.

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: I think about it on a percentage basis. You just want to think these patients should be pain-free or close to pain-free on your drug, zeros or ones.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. If we get a good signal in this trial, how quickly can you move into kind of the next phase? Obviously, as you said, there’s a nice blueprint here from Arcalyst in terms of the pivotal trial. Is there any other sort of changes you would want to modify?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: No, I mean, a typical phase two to phase three in my experience is about six to nine months. We have a QD drug I mentioned. The QD arm is going to start to go in here. Certainly, discussion with the agency, even though there’s a blueprint, you know, Arcalyst had been around and approved. This is again, I have to put out some rationale for this molecule, but we don’t see any hurdles.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Would you have like two dosing arms in the pivotal, or would you go back and do a smaller trial like that you’re doing now?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: We haven’t quite gotten there, but we have the option of either studying a second dose in the ongoing trial here or a 2D dose or having an adaptive design in phase three. None of it is consequential to the timing or getting where we want to be. It will all be done as part of the trial. Obviously, you want the least efficacious dose that you can also see in the trial, right? Especially for an oral drug. We have all that in place. It’s just a matter of getting this trial done, getting ready for the agency, and then moving forward.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. Yeah. In terms of the opportunity there, how do you think about, you know, obviously with a couple of agents there, some on-label, some off-label, and then kind of the emergence of an oral, there’s also some more longer-acting things I think in development as well. You know, again, how does this market evolve and particularly where does an oral take share?

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: I think there’s just a great opportunity in this market, this indication for an oral period. I think we need to see the data to really determine sort of where to take this. I think there’s a version of this where you go head-to-head with Arcalyst. There are some patients that might prefer to be on an oral to an IV. I think there’s a pre-Arcalyst patient population. Remember, to get into our study, you have to basically fail on everything but Arcalyst. It feels to me like there’s a space between colchicine and steroids and Arcalyst where one could play. These might be first recurrence patients or second recurrence. I think there’s also an opportunity to migrate patients off of Arcalyst at some point. I can’t remember if the average is 18 months or something or longer, the average duration, but Arcalyst is an expensive drug.

It’s close to $300,000 a year. It’s once weekly injections. Once you’re stable, if you have a very severe patient, you can think about a scenario where you rotate off of Arcalyst onto an oral to prevent the further flares. I think there’s multiple places.

Oh yeah, of course.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Ex-U.S. markets, right?

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: Yeah, exactly. I think XUS is a big opportunity. I mean, just in Madrid at the ESC meeting, there’s a group of KOLs there that are desperate for something other than colchicine and anakinra. Anakinra is a daily injection, right? It’s tough.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Yeah, okay, gotcha. I guess, in terms of RP, what other kind of potential expansion opportunities does confirming and basically showing proof of concept in RP, what other indications could that open up?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: I think in that family, if you were to look at, I think Roche is running an osteoarthritis trial, right? RA comes up, you know, people always kind of a visceral response to an RA drug. What I think about it is if you had a drug that was as good as Rinvoq without any of the real or perceived baggage, you know, that could be, so that would fit right in, right? That whole mechanism of rheumatic cardio extension, right? We’ve considered, we’ve seen where Roche’s trial ends up, but that’s an obvious one. Don’t forget, there’s a whole biology from the Cantho’s trial on the IL-1β story, right? From which now you have the Novos and the Tourmalines looking at the next downstream, which is IL-6.

Look, we can’t do it all, but we can certainly take data and reads from what folks are doing and start to position this as an oral alternative to those studies, right? I think that’s the way we look at it.

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: I think low-hanging fruit as well for VTX2735 could be myocarditis. Same docs, same, I mean, new European guidelines just came out for pericarditis, and they lumped the two, myocarditis and pericarditis, in the same sort of category. I think that’s a logical place to go.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Interesting, okay. Maybe shifting gears to VTX3232. Obviously, this is your CNS-penetrant NLRP3. You got a couple of strategies here. Maybe let’s start with Parkinson’s and just kind of highlight the data that you guys have already generated and then ultimately kind of the development path there.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Right. For VTX3232, this is our brain-penetrant compound. Probably the best compound I’ve seen and worked on in, you know, over two decades of doing this in this particular field. Hits the target. We know that from phase one. We had exposures in CSF that completely blocked IL-1β at 10 to 15 milligrams. The Parkinson’s study, in all fairness, was an extension of the phase one study. These patients are really not that different from phase one patients. They’re slightly elderly, so you see baseline levels a little bit higher. They’re not severely inflamed. They have symptoms. They are UPDRS scores. In terms of the look we wanted to take, it wasn’t that different. There was no way we were going to position a phase two or phase three trial without actually looking at the patients to make sure the exposure was relevant.

There was no compromise in the blood-brain barrier in these folks that you were getting higher exposure or lower exposure. The study basically was set up to prove in these patients that you are hitting the NLRP3 target in the CSF. Of course, safety, but getting the appropriate exposure at the doses and the QD doses, and again, the same cascade. It’s not just one cytokine. The whole picture has to line up. I’m hitting IL-1β. I’m hitting IL-6. I’m hitting HSCRP. I’m hitting Cinnamomatoid A. I’m hitting fibrinogen. All of this consistent in CSF and plasma where you can measure it. That was the success factor that we defined for ourselves. We had no expectations on changing downstream markers of neurodegeneration in a 28-day study. Certainly no expectations on motor function, although there were surprisingly changes in the UPDRS score that we saw.

All that will play itself out in a future study. The goal here was to position the compound as the best NLRP3 inhibitor that hits the target that you believe eventually is going to be the effect in the motor neuron disease or Alzheimer’s or any other downstream neurodegeneration where you believe the trigger is neuroinflammation.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. I guess maybe a step back in terms of what you’re seeing in terms of the ratio between the plasma and the CSF, and what gets you confidence that again, you’re getting enough drug exposure for actual activity.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: We saw that early. We as chemists deal with things like it’s not just brain to plasma ratio. It’s something called KPUU. It’s a partitioning factor. Certainly, we look at, you know, efflux proteins like MDCK to make sure that all that is done. We settled on KPUU. We saw a really good distribution in what I call the zoo panel. The zoo is the mouse, rat, dog, and monkey. In the zoo, we had really good CSF exposure. In humans, when we look at the CSF exposure, it essentially proves what we saw in the other species, sort of an equal partitioning of the drug between the peripheral and the CNS. Obviously, we’re not sampling the brain, but a drug in the CSF is a validated surrogate for free fraction in the brain, so actual drug levels. We also have microglia inhibition numbers.

We know if we reach our IC50 in the microglia was one nanomolar, right? CSF is pretty much a cell-free system, so if you reach one nanomolar levels in the CSF, you know you’re there. Our trough levels at 10 milligrams were completely blocked IC90 for IL-1β, right? Everything checks out. The exposure, the microglia numbers, the cytokines all line up to the fact that you’re completely covering the target, right?

Matthew Moore, Chief Operating Officer, Ventyx Biosciences: Remember, our doses were 40 milligrams in Parkinson’s, 30 milligrams in the cardiometabolic study. It’s 10, 24-hour blockade. We’re multiples of where we need to be. We’re saturating.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. You think about kind of phase two trial design in Parkinson’s. I guess, obviously, these will be probably harder endpoints in terms of just more disease-specific. I guess, how do you think about that trial design? Ultimately, when could we actually see data from that trial? Is there more enthusiasm for some of the early things from both you and Notera to generate excitement around the enrollment?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: I don’t think there’s any other trial that’s going to give you any more confidence than going into an efficacy trial, right? You have to start to do these long trials, placebo-controlled, potentially dose-ranging with, at least for now, MDR and UPDRS as an endpoint. Look, to be very clear, from the beginning, we have a loose relationship with Sanofi in the sense of a ROFIN. They have been interested in this program from the time they signed on. It’s a ROFIN, which I mean, we don’t have any obligations to them in terms of following their directive on what we do, but they have a right to the compound. I do think with the data we’ve generated, the data that will come out of our much broader study, the safety database, that this is going to attract folks that want an actually much bigger playing field.

There is a lot of discussion about Parkinson’s versus Alzheimer’s. MS is sort of put aside just because of some of the space itself, but people agree that both Alzheimer’s and Parkinson’s is a need there. There’s this reaction, right? The graveyard out there. This comment belongs in the hands of a partner. There have been no bones about it, right? For this thing to make, if we really believe this is going to be a disease-modifying therapy, which is the belief, pretty bullish belief out there, right? It really does belong in the hands of somebody who can look at combination approaches and move perhaps even in parallel. I’m not saying it’s one partner or the other, but you know, what’s the field of dreams? If you build it, they will come. I think I truly believe.

We could be cavaliers and say we’ll run a phase two here, and then what, right? I think you have to have the muscle, and folks have shown their ability to stand that, right? We have companies that have taken a BTK inhibitor very successfully. They’ve shown interest in TREM2 and other folks have shown it. I think for now, we’ve met our success factor. We’ve built the molecules. The CMC plan is in place. We still are building, we’re building a plan, don’t get me wrong, right? We’re not sitting around and not looking at those fields, but I think it could be, to be clear, something like this does belong in the hands of a partner.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. Maybe to segue to the cardiometabolic, you’ve kind of called this readout data-rich. You guys are looking at a lot of different biomarkers. Maybe explain what we should take from the output here in terms of de-risking and some of these indications, and ultimately what doors this really opens up for you or potentially a partner in the future?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Yeah, great question. To look at this trial as kind of two outcomes, right? One is the weight loss outcome. We had no intention of going on a weight loss trial. If you talked to me two years ago, weight loss was not on our mind. We would have taken this compound for Parkinson’s neurodegeneration, and that would be there. We would go with it, right? The mouse model, we talked about this before, there was weight loss in the mouse. We consistently saw about 8 to 9% in three studies we did. Other folks have touted much more weight loss, which I don’t think is credible. This study had to be done, right? We have a placebo-controlled study. It’s in 160 plus subjects, and there’s a combo arm with semaglutide, well-powered. What’s the outcome?

Once in a while, you’ll see if there’s a meaningful weight loss, particularly in the combo arm on top of sema, right? Meaningful meaning 25, 30% above what you would expect to see with sema in the 12-week period, right? The consequences of that on other functions, so lean mass, other parameters that move in a positive manner. We have this other piece of it, which is essentially exploiting a brain-penetrant compound, but that has peripheral exposure, excellent exposure, to look at all the other aspects of liver, heart, kidney, glycemic indices, lipids, to really see where the IL-1β story or the IL-6 story is going to play out, right? In terms of, again, meaningful endpoints, not just little blips that you don’t explain, right? You don’t want to say this is interesting. That’s not the output.

It’s to say this is where one could position an NLRP3 inhibitor with or without another drug, with an FGF-21 ortholog, with another GLP-1 to get this benefit in there, right? No one has done it before. It’s not an easy story to tell. Once the data come out, the way we’ve designed it, it’ll start to become obvious where it’s sort of irrelevant, but where this biology will actually be relevant and dominant and potentially an adjunct to a number of diseases where there’s still unmet need.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: Gotcha. I guess with the remaining time here, as you kind of think about the story and the narrative, like as you said in the opening remarks, you know that Ventyx has kind of evolved over time with some of these assets and now, you know, firmly kind of a leader in NLRP3 biology. What do you feel is underappreciated maybe among kind of the investor community around this target? As you said, it hasn’t had just a massively clean record in terms of efficacy and safety, but obviously your molecules have already kind of passed some of the initial sniff tests here. Where do you think parts of the story should?

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Yeah, so I think NLRP3, all the baggage is on the target. I don’t think it’s there anymore. Look, every day you see new companies talking about NLRP3, some form of NLRP3. I think that bias is gone. I think where investors miss the story, and I understand it because like I’m telling you, the story is a very dense story. It’s a very complex story. By design, it’s not a simple A to B, not a DPP-4 inhibitor. It’s not, it’s really this massive probe, and someone had to do it. We are the ones to do it. I think patience will pay off. RP, straight shock, right? Either we have a drug that’s competitive or it’s not. Weight loss, a little more nuanced depending on what it is.

The other one is, I think, something that’s going to be really, really, I hate to say cool, not a word I want to use usually, but you will see effects that you will say, aha, right? This is where NLRP3 or inhibitor is going to be an add-on to another drug just to push the efficacy a little bit higher as going in there. That’s hard. I think it’s up to us to educate the people, to talk about NLRP3, to bring the discussion we had today. Eventually, the data will speak for itself.

Derek Barcila, Wells Fargo Biotech Analyst, Wells Fargo: All right. Raju, we’ll leave it there. Thank you so much, Matt.

Raju Mohan, CEO, Founder, and Director, Ventyx Biosciences: Yeah, our pleasure. Thank you, Derek.

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