All right, thank you, so we'll get started with our next fireside discussion here. My name is Derek Archilla. I'm one of the senior biotech analysts here at Wells. With us, we have Ventyx Biosciences. From the company, we have CEO and Founder, Raju Mohan, as well as the Chief Medical Officer, Mark Forman. Gentlemen, thanks so much for joining us. Yep, thank you. So maybe, to just lead the discussion, Raju, if you don't mind just kind of giving a high-level view of the company, what you guys are working on, and then we can kind of dig into the Q&A. Okay. Sure, yeah. So I think at the top level, we're sort of a bifunctional company, if you want to call it. You know, on one side, we have the IBD portfolio. We have the S1P1 agonist. We talked about the phase II results last year, late in December timeframe. We also have the Crohn's molecule we talked about, a month back on the phase II study in Crohn's disease. On the other side, we are an NLRP3 company. We've got two compounds that are in phase II trials, imminently in phase II trials, phase II, phase II-A trials. One is a peripheral molecule, VTX2735, and the other is a CNS penetrant molecule, VTX3232. So again, you know, we can talk about the IBD drugs at some point, but really focus on expanding the portfolio in the inflammasome space. You know, when we started NLRP3 about five years ago, it really was. People didn't know what the inflammasome was, certainly not NLRP3. It's become sort of a central player now in biology, a number of indications, cardiovascular, metabolic, potentially obesity, certainly neurodegenerative diseases, and a number of other risk factors. You know, we believe we have the best compounds to literally explore the role of a small molecule that directly targets IL-1, IL-1 beta in particular, and sort of coalesce with the spectrum of diseases that have been looked at, or are pathologically impacted by IL-1 beta. Think of us as a company. It's almost a sort of evolution from an immunology company to more of an immunology plus a CNS immunology, if you may. With Mark Forman, who joined us as our Chief Medical Officer, you know, we have now the ability to explore in areas where, you know, people have had failures but have been afraid to go in, especially the neurodegenerative. We think, again, we have the best molecules to explore areas where these debilitating diseases that have really, you know, no neurotherapy. Mm-hmm. Yeah, so maybe start with the NLRP3 portfolio, and in particular, VTX3232, the CNS penetrant. So I guess, you know, this is an area we haven't seen very many CNS penetrant molecules. Like, what's kind of some of the challenges that you kind of overcame in designing that molecule? And I guess, you know, what gets you confident that you're seeing- Mm-hmm ... good penetration, but also the ability to, you know, the preclinical models, like, what are you seeing in terms of level of activity, you know, in the CSF or in the brain? Yeah, yeah. So kudos to the team. So a little chemistry lesson here for you folks, which is most of the NLRP3 compounds. In fact, most of them in the last, I would say, five years, came from a scaffold called MCC950. It's a glipizide, a sulfonylurea. It was a Pfizer molecule, and had been used in glycemic control, as glipizides are. And folks found that this was a NLRP3 inhibitor, and they tweaked around with it, made it more specific for NLRP3, and that became the genesis for a number of companies. So Inflazome, IFM Therapeutics, NodThera, Ventus Therapeutics, Ventyx, us. And these are all compounds that had minimal brain penetration. A sulfonylurea, for those you know, is a charged compound, a sodium salt, and charged molecules don't cross the blood-brain barrier. You know, well, I'm a chemist by training, but you know, sort of been out of the lab. My charge to the team was: Don't, you know, bang your head against the wall trying to push a sulfonylurea literally into the brain, because you're not gonna have success. Think of a brain-penetrant scaffold. Think of a benzodiazepine, think of a tricyclic molecule, think of imidazopyridines, think of an Ambien, and start with a scaffold that you know has the bias towards brain penetration, the polar surface area, the PSA score, the Kp,uu, everything that you do in vitro, in vivo, to see. Forget about NLRP3. Start with a scaffold that you know gets in the brain, that you can now build in the NLRP3 motif. The crystal structure is known. You can solve the NACHT, the NACHT domain, and that's exactly what we did. We started with a brain-penetrant scaffold, privileged scaffold. As you know, scaffolds that are attached to different proteins, built NLRP3, came up with some lead compounds, and then lead optimization in a classic sense to then optimize this compound to be, what I would say in my thirty years of doing it, probably the best molecule overall in the CNS, balance between peripheral and CSF and brain penetration, and to your question, Derek, about what the profile is, and we've published it, it's on our website as well. In human studies, in phase I studies, we see a nice dose-dependent exposure both in plasma and the CSF. The CSF, as you guys know, is a surrogate for free fraction of the drug in the brain. So when you look at levels of a compound in CSF, you are now directly estimating what it would take to reach the free drug levels in the brain. Obviously, in humans, you don't do sampling as you would do in an animal. So the compound has good brain penetration, almost near-equivalent partitioning between the central and peripheral compartments. It has, like I said, dose dependence, and about 10-15 milligrams QD, we can completely suppress IL-1 beta levels in the CSF, and IL-1 beta is the target for NLRP3. IL-1 beta is the target that drives NLRP3, IL-1 beta, IL-6, hsCRP. That's the cascades. So we've got a PK, we've got a PD estimation in the CSF, so we know what we need to target in the brain. A good safety profile and ability to dose and with Mark now looking at the phase II-A trials, we can explore, when needed, a wide dose range for various phase II studies. Got it. Y eah, maybe if you can elaborate on the mechanistic rationale and one of those indications that you're looking for proof of concept in, in obesity. So obviously, we've seen some data from a competitor, we've seen some of the animal data as well. But, I mean, what's kind of the biological rationale, you know, targeting NLRP3 for that indication? Yeah. Let me have Mark add to it, but like I'll start out by saying, you know, I think the same question is asked about Parkinson's, right? And there is no human evidence yet of NLRP3 affecting eventual endpoints in motor function. Mm-hmm. But folks have tied together different links between NLRP3 assembly, activation, IL-1 beta release, microglia, astrocytes, neuronal death, right? And that experiment has to now be proven in humans. I think in obesity, the excitement came from the mouse model. People have looked at NLRP3 in obesity over a large number of years, sort of crosstalk between inflammasome and feeding and leptin and ghrelin and so on. Mm-hmm. This animal model that NodThera published showed weight loss in an animal when dosed with an inhibitor, with a placebo control. Folks got excited because potentially now you had the ability to have weight loss in humans and mechanistically or orthogonally have a benefit in humans. Unfortunately, the story got muddled by claims from this other company that we can get semaglutide-like efficacy. Mm-hmm. Which in reality is not true. So the maximum you will get in a mouse is about 8-9%. Now, we've done three experiments in these studies with a dose ranging NLRP3, and we max out at about 8-9%, which is not... You see about 14%-15% with Sema. Yeah. It's not meant to be a Sema competitor. It's meant to be a compound that's orthogonal or synergistic. But in terms of the biology, maybe Mark can comment on, you know, where some of the science is right now. Yes. So, I mean, I think the other thing to, just to sort of start building on what Raju was talking about, is the animal data that we've generated, that we talked about, a few months ago. It's not just the obesity effects, it's the overall effect on cardiometabolic health in the animals. So there's effects, additive effects on weight loss and some... But also, you get on top of that, when you get the weight loss, you get more preservation of lean body mass, which is the ultimate goal. And then on top of that, we see improvements in lipid profiles, improvements in biomarkers of lipids, of liver fat, improvements in biomarkers of renal biomarkers. So we're viewing this as less, you know, a focus on obesity, but more on cardiometabolic health and the metabolic and all the metabolic processes associated with it. There's evidence that there's both central and systemic inflammation, and you see that in individuals with obesity. You see evidence of inflammation in those individuals. When you look in the animal models, in some of these DIO models, you also see inflammation in the brain, particularly in the hypothalamus, which is regulating some of the metabolic pathways. The idea is that by having a centrally active molecule, we can both tamp down the peripheral inflammation and some of the central inflammation and give us a chance to test that hypothesis on the role of this NLRP3 inhibition activation, and then inhibition with our molecule in a variety of conditions, focusing on not just obesity and weight loss, but also these other factors, cardiometabolic health and other and long-term risk factors. We know that there's evidence that they're starting to emerge, that if you inhibit some of these downstream inflammatory processes, you can have benefit as well on cardiometabolic health and outcomes in the... That's sort of the science that we're really trying to explore with these programs. Right. And is that, like, largely kind of... Obviously, some of that science based on, like, CANTOS and kind of understanding, like, cardiometabolic health and outcomes, you know- Yeah -relative to the inflammatory? Yeah. That's the sort of science that we're sort of, you know, trying to build on, and we're upstream of there so we can have, a very, very targeted. It's not just sort of... It's a very- Yeah IL-1 beta and the downstream effects, rather than sort of a global inhibition of some of these inhibitory processes with a small molecule-based approach. Yep, got it. And so for the phase II- A that you guys are running in obesity, can you maybe just give us a little background about, like, what type of patients you're trying to enroll? And ultimately, as you were saying, like, this is not probably going to be a standalone weight loss drug. So like, what's the goal of the trial in terms of understanding the weight loss as a monotherapy, but also as a combination? Yeah. So I'll, again, have Mark add to it. So to be very clear, right, this is an opportunity for us to sort of really construct a model in a human, where you can now look at, as Mark said, effects on cardiometabolic parameters. So whether it's lipids, whether it's glycemic control, you can look at liver effects of obesity, so fatty liver and consequences of that inflammation in the liver. You can look at certain kidney markers, again, in obese subjects with obesity, that affects on renal function in GFR. And certainly, you can look at weight loss by itself, both in a monotherapy mode, in a combo, combination with an incretin, some of the type. But in terms of... I don't think we've really talked about specific trial design at this point, so, you know, I don't think we're going to go into it. You'll see that we'll get more granular as we get closer to the trial. So, yeah, so let me actually just wrap it up by, it's gonna be a pretty standard. If you look at some of the recent trials folks have done, and of course, they call them obesity trials, they're pretty much, you know, focused on oral intact incretins or different Gs or triple Gs or myostatin in some cases. So a population very similar, so folks within a broad range of BMIs, let's say thirty to forty. And with that sort of a range comes, you know, all of the metabolic dysfunctions we've talked about, and we can then systematically look at them both in terms of biomarkers, in terms of body composition. We've talked about DEXA imaging, potentially MRIs, to look at liver fat. There's very sensitive techniques right now doing that. So just stay tuned. I think that's gonna be the trial, and I think Mark was very articulate by saying, "Let's not simply focus on obesity, because that's not the only place- Yeah. - in an NLRP3 impact. This morning, there was a note on some of the links to hsCRP being the major, a major player, a negative player in MACE this morning, and there's a link to some of the companies that are doing trials with IL-6. So I think that's where the trial design is set to be, and then, you know, we'll have Mark get more granular as we start to talk about the actual trial start itself. I mean, is there any way to enrich... Like, again, obviously, obesity is so broad, right? Like, could you look, given the fact that you're gonna work more mechanistically on, you know, inflammation, neuroinflammation, systemic inflammation, to target patients that are more, you know, inflamed? Yes. Obviously, there's a lot of biomarkers for inflammation, so, like, which one would you choose or which one... You know, again, is there even an enrichment strategy that you could look at? I mean, I think there's some very simple things. I mean, it's a complicated question, but there's some very simple approaches. So one, I mean, so again, we know that a large proportion of obese patients have evidence of systemic inflammation. And so there are things like CRP that we can look at, and we can enrich for populations that have not just, you know, the high body BMI, but also these evidences of inflammation like CRP. So those are the things that we're gonna take forward, because those, to your, I think, where your point, your question is getting at, those are the patients likely to benefit. If you just take somebody who doesn't have that evidence of an activated inflammatory state, you're unlikely to see benefit. In fact, in our animal studies, in lean mice, we didn't see any effect of our drug. It was only in the obese animals. We didn't see any effect on a lot of these parameters in sort of healthy mice. So I think the idea is that by going into a population that's both obese and has evidence of inflammation, we're more likely to see with our drug, that's the population that our drug is most likely to have benefit in. Yep. Okay. Now, I know you're not supposed to cross-trial compare, and you're certainly probably not supposed to cross-trial compare, like, mouse studies, but, you know, there's always, the look of, like, what NodThera had generated relative to the data that you generated. So I don't know. Again, are these different models? Maybe just set up, set it up with what we saw and- Yeah, and it's a good question, right? Because raised a lot of questions, and honestly, and you know me, Derek, I'm not defensive in this at all. Very sort of improper conclusions were made from the study. So first, and I'll say this, and then Ellen and I have talked about it, the NodThera CSO. That compound, it was dosed three times a day in mice, hundred plus milligrams, three times a day, right? I can guarantee you, with or without weight effects, I mean, obese mice, these mice will lose weight. If you dose an animal with this amount of mass sitting in the stomach three times a day, oral gavage in them, they will lose weight. These guys are stressed out. So again, as I said before, we believe, the maximal mechanistic weight in the animal, forget about the humans- Yeah ... is about 9%-10%, right? Anything on top of that, that NodThera showed in different studies, they went anywhere from 9%-10% to claiming they were as good as some of the type, is- has to do with something else, whether it's toxicity or something else, I cannot, you know, point to it, but it's not an NLRP3. And they know that. That's what they got. That's the drug they have, and they did a great job in showing mechan- beautiful paper, right? Yeah. That weight loss beyond 9% is specious, it's coming from something else, right? The weight is the weight. Secondly, we have run three studies. These are different. It's the same mice strain, these are animals that are put on a high-fat diet, but depending on the age of the animals and the extent of obesity, you will see a different trajectory of placebo versus your compound, right? Some of the older animals will sort of gain, stop gaining weight, and then suddenly move on. Initially, they will not, they'll sort of stabilize, and then they start to gain weight. And you'll see this trajectory of the placebo, and then your drug arm doesn't drop as rapidly by itself, but it's always relative to placebo, right? The way I would think of each of these animal studies, let's talk about what's your favorite. Let's deconstruct a dish. When you see deconstructed something, right? They've taken a dish, maybe a pastry, and they've blown it apart, and now you're seeing components of your cream and your cake and your raspberries, and just deconstruct it. Forget about what the shape of this pastry looks like from different bakeries. It's the actual components of this. As Mark pointed out, in the animal studies, if you took each animal and just looked at lipid effects, PCSK9, HbA1c, liver fat, markers of inflammation, hypothalamic markers, crown-like features, all are consistent within the experimental, from study to study to study, right, for us. That's what you take now, and you hope to deconstruct or construct in a human to say, "Aha, this is what I saw in the mice consistently." Other than being mice, the mechanism is still inflammation, hypothalamus, feeding, ghrelin, leptin, GPR120, you name it, right? Mm-hmm. So we did exactly what the mouse experiment did. Nothing changed. NodThera's human study was not a weight loss study because both cohorts in that study were calorically restricted. So both had two thousand calories when these folks are used to eating five thousand calories a day. So I have mind-boggling sort of analysis of why they even called it a weight loss trial, right? Because you're not. You're keeping these folks in a clinic, you're restricting their food. The most you're gonna get is very hangry people, right? Mm-hmm. Because they are now not getting to eat. We had a really good experiment. Yes, it begs the question, is there a role of NLRP3 in directly affecting body weight? And if it's not a significant body weight... The best you do with an oral right now is what? About 5%-6%, what they've shown within 12 weeks. Then to Mark's point, what is the real benefit for our compound above, over, and above an incretin, right? In terms of preserving muscle mass, in terms of liver effects, in terms of other biomarkers. And eventually, can you actually use an NLRP3 with a more tolerable dose of a GLP agonist? Once we see this trial play out, once we see all the endpoints, I think everything else can be laid out. So yes, the mouse studies were very consistent. We've done three of them. Monotherapy, the first one, combo, the second one, dose ranging, the third one, and nothing has changed. Nothing, the excitement or lack of it that existed when mouse studies came out is still what it is, right? And we're gonna play out the human experiment now with our compound. Got it. And just lastly on the phase II, so I know you talked about maybe doing the 28 study, now moving maybe to a traditional 12-week study. I guess, you know, what additional, other than just longer follow-up, like, what other biomarkers would we be able to, like, really capture that helps de-risk it? Yeah. And Mark hadn't joined us when that decision was made. So two things: One, we didn't have the tox coverage to do longer studies, right? Yes. We had finished one-month tox. We were sort of doing, we were in the middle of our four-month tox studies, and typically, as you know, you do one-month tox, and you do a three-month tox, three to four. And then you have the chronic tox, six- to nine-month tox that you do, and that's sort of the complete tox package. And we decided that, look, three months gets us nowhere at this point. Let's just flip the three-month study to a nine-month study to be done once and for all. Allows us to dose folks for three months, maybe even longer. Mm-hmm. And that pushed the study out towards the fourth quarter, end of the fourth quarter. And by doing so, we realized that, look, given all of this, cloud around metabolic output of the result, obesity, it behooves us to play it out to twelve weeks. And so once and for all, not just test this hypothesis in a cardiometabolic, where we are pretty comfortable that this drug affects CRP. And to the CANTOS trial, the rescue trial, with CV effects magnitude to be determined, let's play it out so there's no sort of a lingering question. We should have run it longer. Maybe we're teasing the weight loss. Let's just play it out. Let's play the study out, similar to what's been shown with Viking and Structure and Scholar Rock. 12 weeks is a good calibration for meaningful effects- Mm-hmm ... right? right? Whether it be weight loss or other metabolic. And that was the reason, and we said: You know what? No harm, no foul. Study, study gets pushed out a little bit, but in the end, we'll have a definitive answer with both monotherapy and a combo therapy. Yeah. And then hand it over to, Got it. And is there any reason to think in the combo that there could be, again, mechanistically, any sort of like lean muscle preservation using the combo? Or is that really not something that you would see with NLRP3 specifically? I mean, and in fact, that's what in the animal models that we talked about, we saw more preservation. So that's one of the questions that we need to get at in the clinic. Yeah. Do we see an additional benefit on top, not just the weight loss? Right ... but the quality of the weight loss, the character of that weight loss will be important. I mean, I just want to the extent, you know, the trial, I mean- The other thing that we get from a twelve-week trial that you don't get from a one-month trial is you're gonna get a much better understanding of the safety and tolerability picture in its early days in our compound. And you're gonna see, you know, a lot of these. You can also gonna see some durability of effect. So you often, in these trials, in short duration, you'll see an acute, a sub-acute effect, and then they, you know, and then it goes away. And we're gonna get a chance to see, is that, any effects that we're seeing sustained for a meaningful period of time, that really gives us a sense of how to go, what are our next steps after this trial? Yeah. And so there's really a lot of good reasons to go after a longer duration trial to really inform how we're gonna prosecute the program beyond this initial phase II-A. It's a really sort of an exploratory trial. Sure. to really get at a number of different pathways. Got it. I wanna shift gears to Parkinson's also, just to kind of talk about that. So you know, we've seen some data where you have some from NodThera in that early trial, and you're kind of looking to replicate that potentially. I mean, is there any differentiating features in your trial, you know, relative to theirs? And again, should we just get a clear picture of just like how both of these work and you know how the early efficacy. I mean, these are not traditional like approvable endpoints, but you know could be informative. So just again, how de-risk do you think this trial can you know can- Yeah. So Let me just talk again. Typically, don't talk about competitor, but since the, you know, that is the benchmark here. We have a well-calibrated compound. So again, as I talked about in the mice, we believe effects we'll see or not see, hopefully, we'll see are direct effects of the compound because we've shown the exposure. It's linear exposure. There's no. You don't have to use hundreds of grams of our drug to get about 3%-4% of the active drug through the, through the periphery. That's the whole premise of that competitive compound, right? It's, it's very rapidly metabolized in blood, so it's a matter of how much. It's a race against how much compound survives plasma esterases and manages to cross the blood-brain barrier and get into the CNS, right? That, that is their mechanism. Dump a bunch of molecule in, and you pray that, you know. No, no, so literally, you have to dump it twice a day because it's gonna be rapidly metabolized, and whatever it doesn't, obviously, partitions in there, right? And so what they showed in phase II-A study was an effect on, of course, effect on some inflammatory markers, not described, but we assume it's hsCRP and IL-1 beta and so on. And they talked about a neurofilament light chain, but there was no real numbers. They showed the data in the phase I study for four subjects. They had four subjects with the phase I study, where you saw three of them, there was some directional movement, one of them, nothing happened. This was a bigger study, but there was no PK, there was no PD, there was no exposure, there was no... As a private company, again, they're, you know, not obliged to show much data. So yes, it was a positive study from their PR, no data. So I'm not saying we're left sort of alone because we believe in the mechanism. Sure. But we'll have to sort of calibrate this ourselves, again, given the fact that we don't have much data from them. But, you know, our compound is so well-designed. We've done it in phase I studies. We've looked at CSF, looked at biomarkers, so we're just gonna be adding more biomarkers in the PD patients that are more PD-specific. So you've got NLRP3 biomarkers, general inflammatory biomarkers, and you've got now Parkinson's degenerative. Mark, anything to add to that? No, I mean, I think, you know, this is a trial that, again, we're sort of dipping our toe into the water here, right? It's a small trial. It's 10 patients that we're really doing a biomarker study in, and so we're gonna get someone's insights into, in the target patient population, how is the drug tolerated? What's the exposure look like in the patient population? And then what are we modulating the systemic and central inflammatory biomarkers? We're putting some exploratory things, some imaging biomarkers. Can we modulate microglial activity in a short trial, given the half-life of microglia? You know, it's not clear. You know, we don't know what to really expect, but we're certainly just really trying to get a feeling for that. If we're modulating inflammation in the PD population, that sort of provides us, you know, the impetus for the next step. The next step is the challenge in PD because efficacy trials are long and complicated in Parkinson's disease. I would also say we should also think about what's happened in the Alzheimer's disease space, and the world has changed with our ability to use biomarkers to inform our understanding of biology. If we again use the Alzheimer's disease world as a marker, there's twenty years ago, all Alzheimer's disease had these big, massive, very challenging trials to run, and now we have a way of doing much more targeted approaches. I think Parkinson's disease is coming along in that way, and there's a lot of pre-competitive work to really enable us to do to develop tools that are then linked, you know, biomarkers that are then linked to downstream clinical outcomes. So trying to figure out what the next step is, the traditional efficacy trial versus something in between that, is something that we need to sort of struggle with over the coming months while this trial is playing out. When you talk about biomarkers, does that include imaging? Like, or is this, like, absent of- Yeah. I mean, I use the term biomarkers very broadly. Uh. It could be imaging- Okay. It could be fluid biomarkers. Okay. It could be functional biomarkers. You know, I mean, in the Alzheimer's space, it's a lot of the amyloid tools targeting amyloid and tau. Yeah And looking at those. And are those tools coming along with alpha-synuclein? In Parkinson's disease, can we use those tools to really inform our decision-making and how to prosecute these programs? I mean, if you start to see proof of concept and more success in Parkinson's, like, does that open up, you know, other neuro, like, more traditional neuroinflammatory, so sans obesity, but like, you know, again, MS or other indications that you could pursue? Like, does that help de-risk that, or are they kind of very, very distinct? I think if we—so MS is. We'll put in one bucket, which is really a pure inflammatory disease, and then there's the neurodegenerative disease bucket. Got it. In the neurodegenerative disease space, there's this common theme of these aggregated proteins that are actually leading to the inflammatory process, and there's more and more data that the inflammasome is meeting that inflammation. So these aggregated alpha-synuclein or Aβ in Alzheimer's disease are aggregating, are leading to this inflammasome activation, and it provides a very distinct pathway. MS is a very different story because it's a very, you know, it's an autoimmune disease, and it's also a very competitive landscape. And so, I mean, I think there's not only, you know, large molecule, there's small molecule, there's very effective treatments out there already. So I think how we go, if we have success and we show these biological activities, is really gonna be, you know, we're going through this exercise. What is the unmet medical need? What is the scientific rationale? What's the commercial opportunity? And what indications we go after, assuming this PD trial yields the kind of data we're hoping to see, will really be a combination of looking at all three of those factors. Got it. And I wanna hit the peripheral, but just lastly, on the Parkinson's. So, like, what's kind of like the go, no-go kind of criteria based on that 28-day study? Like, what do you need to see to kind of move it forward? I mean, we need to see an impact on the inflammatory process. I mean, that's... I mean, in a short duration trial, that's what we're really expecting. We should see, you know, CRPs dropping. We should see IL-6 dropping. I mean, if we're not seeing that, the drug isn't doing what it needs to be doing to be effective. So it's really that's the bar that we're setting. I mean, if we see, in addition, evidence of neurofilament, you know, I mean, neurofilament doesn't change that quickly, or GFAP is another biomarker of neurodegenerative disease, and inflammation doesn't change that fast. So in a short duration study, which is all we could do based on the tox coverage that we had at the time that we're starting it, you know, we started the trial. It's yeah, we enrolled our first patient, you know, but but we're, you know, we haven't, you know, we're just recruiting. We're actively recruiting and recruit the trial. We could only dose up to 28 days, so we're a little bit limited what we could do. Gotcha. Yeah, and then wanted to touch on VTX2735, the peripheral NLRP3. So you sound pretty excited about the recurrent pericarditis opportunity. So maybe just frame out, you know, kind of how you're thinking about the opportunity and the development plan there. Yeah. So, you know, we've been talking about positioning our inflammasome space, I guess, probably last couple of years, right? While we were maturing our IBD pipeline and, you know, end of last year, the time had come for us to, you know, put a stake in the ground and establish a path forward. And so we, you know, CNS molecules, as Mark said, they are sort of a space where we can. We have the ability to explore broadly the areas we're going into. And twenty-seven thirty-five, it's a peripheral compound, has benefits of being peripheral, so you don't need to have the compound in the brain, because the question always comes, why don't you just take three two, three two across a broad swath of diseases? It's also about peripheral exposure. I think it's both a commercial positioning understanding, and the fact that twenty-seven thirty-five is well suited for secondary prevention in MACE cardiovascular indication, that again, it's upstream of IL-6. And RP is an area that's we have precedent from the Kiniksa trial, from rilonacept. It was a short trial that led to a phase III that was registrational, right? We believe NLRP3 is ideally an oral, essentially an oral IL-1. IL-1, it has IL-1 beta, but also it also impacts IL-1 alpha that's produced by NLRP3. So NLRP3, aberrant NLRP3 is indeed the driver of this disease, then an oral compound is gonna be positioned as is rilonacept. We don't have to beat rilonacept. It could be as good as rilonacept in an oral drug. Colchicine is not a great compound, so there's a great opportunity for us to, in this case, literally look down further on and, you know, and determine what we're gonna do in a phase III. Unlike the other areas where there are large, large trials, and we have to potentially find a partner, whether it's Parkinson's or any, you know, Alzheimer's, here, there's a clear path on successful phase II- A. You can actually look further down on your own, and also have the optionality of partnering at that stage. So yeah, it's a pretty exciting area, and again, we hope to talk more about this towards the end of the year as we start to get into the human. Got it. Maybe just last question, just in terms of timelines and, and kind of upcoming milestones, maybe just, remind us of what's coming in the next 12 or so months? Yeah. So the first trial that we'll announce is gonna be phase II-A. this is the early Parkinson's biomarker trial, and so expect that, you know, shortly. And then the second and the third, which is phase II-A in cardiovascular, obesity, cardiometabolic safety, as well as the RP trial, are both gonna be towards the end of the year. And I would expect data sometime in the second half, early second half of next year. Gotcha. You know, typically two, two-plus quarters for these trials to- Right ... to complete and read out. Okay. Well, I think we'll leave it there. Gentlemen, thank you so much. Derek, always a pleasure.