Citi often involves doing everything that Marty can't figure out, right? Something like that. What is [audio distortion]? Yeah. Good to be here, Chris. Okay. Excellent. So we've had quite a journey for this company. You and I have known each other for a couple of years now, and actually you're familiar with the trials, tribulations, travails, the opportunities, the grit, the necessity of being in the drug hunting, drug developing part of the business. So how are you feeling at this moment in time, this chapter in the trajectory of Dr. Mohan's career? Yeah. Honestly, I feel great. We signed up for this. We signed up for this 20+ years ago. As you go into a small biotech and you build a company and you build a portfolio, it's exciting. You know you're going to have ups and downs. I would say in the last couple of years, our drugs have been very successful. I'll just give you an example of the S1P1. We've got an amazing drug that has unmatched endoscopic remission. We showed the phase II data. We'll have open label extension data. We'll have long-term data here. Our TYK2 compound met all the clinical endpoints, just wasn't where we thought it would be competitive with other drugs, right? That's part of the deal. So as we turned this year into showcasing our newer portfolio, which is the NLRP3 set of compounds, this is a really exciting time for us. And I'll tell you why. Because unlike S1P1 and TYK2, where if you know you have a drug that hits the biomarker, you know you're going to get efficacy. The question is, how much efficacy? What's the safety look like? How does it compare with other drugs? Here's an area where there is a lot of excitement on the biology, a lot of link to biologics in disease indications like IL-1 betas, like canakinumab, but very little in terms of human proof of concept, proof of mechanism in a large number of indications. And we started out with our peripheral compound and showing proof of mechanism in CAPS patients, right? And we're now poised to show proof of mechanism or efficacy in subject obesity. We're going into a biomarker trial for Parkinson's. And there's a whole, so yes, you have ups and downs. But if you look past the downs, you look at what we have built and what this drug can do for patients going forward. So yes, I mean, you have to take the ups with the downs. And when you're down, you get up and you understand how things have been different. And when you're up, you stay modest and you nose to the ground and you execute. So that's how I feel. And we've got a great team. And the team has learned. And they're all coming from similar backgrounds. They're all resilient. Okay. Yeah. No, you've managed to—if I think about the TYK2 story, it was a couple of years ago, you were sort of well-positioned to capture a lot of momentum that was happening there, whether it was with the Bristol approval, with the opportunity that was done strategically, competitively. And so that enhanced. And here you again find yourself kind of at the right afterparty, so to speak, with an opportunity here. So maybe just level set us, talk a little bit about, give us a maybe elevator ride, quick NLRP3 biology lesson. Yeah. So NLRP3 is the most well-known inflammasome. So it's an inflammasome. It's a complex that sits in an apex where it controls IL-1 beta and IL-18 signaling, as well as pyroptosis. But let's focus on these two cytokines, IL-1 beta and IL-18. And initially, these proteins have evolved as host defense mechanisms against pathogens. But when this mechanism goes aberrant, you then end up having impact on multiple diseases. You have rampant inflammation leading to, for example, in the case of Parkinson's, potentially glial activation, astrocytes, neuronal death. So IL-1 beta is really a defense mechanism. But when it goes aberrant, it can have severe effects on multiple of these disease indications. Now, on one side, you've got NLRP3 controlling IL-1 beta. On the other side, you've got biologics like secukinumab, canakinumab that have shown in the large CANTOS trial effects on cardiovascular parameters, effects on chronic kidney disease, effects on certain aspects of inflammatory signaling in glycemic control. So there's a bridge between NLRP3 and what can be done with IL-1 biologics. And we think NLRP3 is going to be, if you have a drug which is safe and effective, a good oral mechanism for neurodegenerative diseases, cardiovascular disease, and obviously now this interest now in controlling obesity. Tell us where this compound, VTX3232, comes from. I don't believe that back of the shop that there are people running around with goggles and mask specs, but there's more of a focus on gathering assets from a business development standpoint, bringing new barrier insights, et cetera. Yeah. So the genesis of our compounds, and this goes back many, many years, it's all ingrown. So my background is a chemist. I've worked for many years for Exelixis and most recently for a small startup in San Diego, and then got on my own and built a team. So all our compounds are designed and built internally. Yes, we don't run around with goggles anymore. Those goggles are worn by chemists in India and China and San Francisco. But we do design them. And we design them with two aspects in mind. Can we get better efficacy? Can we get better safety? Or can we get both with these drugs? So we own all IP to our drugs. We own all commercial rights. And VTX3232 is a very unique compound. It was designed to be a brain penetrant NLRP3 inhibitor right off the bat. We didn't take sulfonylurea, which was the first generation drugs, and start to sort of put massive amounts in the loaded animal or a human up with massive amounts of drug, hoping small amounts would penetrate. This is a well-designed molecule. It has almost near-perfect CNS attributes. We've shown that in phase I. We'll come to that in a bit. Let's talk about the starting points in terms of data and what our understanding is preclinical data, which you've recently shared there. So we have preclinical mouse data for VTX3232 monotherapy and in combination with some semaglutide. Just run through some of the key takeaways in your view. Yeah. So first, the key takeaway is this is a mouse experiment. We didn't design this drug for the mouse. So just for a second, if you go to the human data, what we have shown in humans is we can dose up to 40 mg per day QD. And in doing so, we get exposures not just in the blood, but in the CSF. CSF is a surrogate for free fraction in the brain. And in the CSF, we completely abrogate IL-1 beta, hsCRP, IL-6, all the biomarkers that you would associate with NLRP3 signaling and potentially with disease indications, wipe them out. So this drug, starting at 10 mg, has the maximal therapeutic efficacy against the target, NLRP3. And we go all the way to 40 mg per day safely and effectively. So you can imagine efficacy in the human starting at about 10 mg, somewhere between 10 mg and 30 mg. So that's the human. So now what the mouse study does and what an animal study does is understand link to biology and disease. So this is a mouse model of obesity. This compound was not designed for the mouse. This compound has very short half-life in the mouse, irrelevant because it has a wonderful 17-hour half-life in humans. Short half-life in the mouse, its potency is tenfold weaker in the mouse than in the human IL-1 beta. But this is a compound we're developing. And we're glad it has mouse activity. So we dosed it in the mouse to see what effects it would have in a diet-induced obese mouse. So as monotherapy and as a combination therapy with an incretin, in this case, semaglutide. In both studies, so both studies were slightly different. In the first study, the animals, and this is getting into minutiae, the animals are older. They are more obese. And that's something you just get off the shelf. And we showed both effects of monotherapy on this compound versus control. And we showed that semaglutide in this model is active. Semaglutide is a positive control for this model. The intent was not to claim that we would be as good as semaglutide. It's an experiment to see does our compound, which is a most effective NLRP3 inhibitor in the humans, does this compound have any weight loss in this diet-induced obese mouse? The answer was yes. We then did a second model where we actually controlled the mice a little bit in the sense of having mice that were on a diet for 15 weeks. So they were not just overly obese. They weren't aged mice. So mice on a diet for 15 weeks, normal mice, 15 weeks of diet. So now they're diet-induced obese mice. Now we had an experiment where we did the monotherapy with VTX3232. We had semaglutide as a control. We also had a combination arm with 20 mg/kg BID of VTX3232 with semaglutide. And again, in the study, we showed weight loss as a monotherapy, about 8% weight loss, about 4 grams in the study as monotherapy. And then combined with semaglutide, there was an additive effect of the drug in a total of 22% weight loss on the combination arm relative to the placebo mouse here. Questions about, well, what is the trajectory of this weight loss and so on? It really is. I hate to use the word irrelevant. I would say it's not relevant to the human experiment. Because we know what we covered in NLRP3 in the humans. We know we max out on the enzyme inhibition. And we're getting weight loss in the mice. And therefore, in the humans, as we do this dose ranging experiment, we'll need to see how much weight loss we get each of the doses that we try. So this was not an experiment to say, hey, you've got to get X percentage weight loss for you to do this human experiment. The experiment was to see, do you see weight loss in mice with your drug? And do you see effects on a combination on top of semaglutide? Comparison with a competitor is, again, not relevant because their doses were 100 mg three times a day, combination of mechanism-based effects, combination of animals being stressed out for three days. Again, they had weight loss with their drug. Now, if both these drugs were equivalent in the mouse in terms of exposure and potency, you would expect similar weight loss because that's what mechanisms do. It doesn't matter what kind of a statin inhibitor you have. If you dose one statin and a second statin, you're going to get the same efficacy. You may have to dose one at one milligrams, the other maybe 10 mg. But again, you're blocking the enzyme, in this case, NLRP3, the protein, you will get similar efficacy. The mouse experiment, just to make it clear, was a proof of mechanism in the mouse for this compound, knowing that we now have a human phase I study showing us where we need to be in terms of dosing and target coverage. Returning to the biology lesson, talk a little bit about the rationale for combining NLRP3 with GLP-1. Yeah, it's interesting because, again, this is uncharted territory. So we know so much about GLP-1 biology in terms of not just weight loss, but effects on overall metabolic parameters. We didn't know so much about GLP-1s in, for example, Parkinson's disease. And there was a paper published in the New England Journal of Medicine showing effects of a GLP-1 agonist in a 12-month study in Parkinson's patients. So there you start to see this convergence of neuroinflammation, neurodegeneration, obesity. Similarly, with NLRP3, what we have to date is a mouse model showing that you get weight loss. There's no human. But as you start to now understand the biology of NLRP3, you start to see a link between NLRP3 activation in the glial cells, in the microglia, in the hypothalamus, and potentially a link to feeding behavior through ghrelin, through GPR-120, through leptin signaling. So this idea that we talk about of a gut-brain axis now has to be taught in the opposite way, which is the brain-gut axis. So there's a cross-talk between NLRP3. There's a cross-talk between NLRP3 and the cannabinoid pathways. This seems to be now linked between NLRP3 and the GLP-1s. And now there's going to be more and more data showing that this effect here could be orthogonal, so affecting different parts of the arcuate nucleus in the brain, different activation of proteins leading to a combination of feeding behavior and satiety that may actually end up being a safe and effective mechanism. Whether it's monotherapy with NLRP3, whether it's a combination therapy, whether it's an add-on therapy where you have weight loss with an incretin and maintenance will all have to be teased out in human studies. And I think we have the best compound to do that. Efficacy metrics, ultimately, typically percentage weight loss. More granular within that is this question of body composition that factored in. Mechanistically, talk to that in terms of what you observed. And again, just to recenter, we're still on the preclinical data here. We're on preclinical data. And again, these preclinical studies in the mouse, for example, are really meant to take each piece of the data and recapitulate sort of the human pathology. You don't take the whole model as a human model. So in this case, we look for, in this study that Chris was talking about, in both studies, we look for preservation of lean mass. And we do it by two methods. We have a DEXA method, which is an imaging method. And we also do it a good old-fashioned dissect and weigh the muscles that we did. And again, in the study, and we showed this for the second study, we also have the first. Mirror each other. You actually see, in the combo arm, it becomes statistically significant. So independently, semaglutide and VTX3232 didn't reach statistical significance. But in a combo, there was an incremental increase in lean mass or preservation of lean mass relative to weight loss in these animals. So there's a hint from this experiment that a mechanism such as NLRP3 should have a positive effect on weight loss and a positive effect on preservation of lean mass, which is a big, big part of managing safe, effective management of weight control or weight loss. And then finally, the dimension that's extremely relevant when we talk about end game and making this a commercialized product for a vast number of people potentially, tolerability. What can we reasonably glean from the preclinical data in terms of biomarker signals on the tolerability front that will clue you into what we need to really be paying attention to on the clinical side? Absolutely. So again, we have the luxury of having finished the human phase I study, dose ranging study, a SAD/MAD study, dosing all the way to 40 mg where we are way above what we need to cover the target, and established that as a bona fide stage to move into phase II. And let me just talk about that. I'll come back to it in a second. So I'll plan for phase II studies at the end of the year. And let's focus on the main study. It's going to be a three-month study. This is going to be a study as a monotherapy, dose ranging study with VTX3232. And we can go as high as 40 mg in this study. Or we will go as high as 40 mg, knowing that we can completely cover the target starting at 12 mg. So dose ranging study, VTX3232, obviously placebo-controlled with all the appropriate biomarkers that we talked about, including imaging and looking at lean mass, weight loss, all the cardiometabolic parameters, glycemic control, cholesterols, triglycerides, effect on liver fat, and also a study in parallel that would be a combination study with semaglutide, obviously, again, placebo-controlled. The details to be exactly what doses we'd look for semaglutide. Do we look at lower dose? All that will work out. So that's the goal for us in this phase II study, which will then read out sometime in 2025. In terms of preclinical studies, we've shown this compound is extremely well tolerated. We're almost done with our chronic tox, which is six months in dog, sorry, six months in rat and nine months in dog. So this is all complete in the coming months. So we'll have full tox coverage. We've shown a very high therapeutic window for this molecule. In phase I study, we've seen virtually no AEs that were other than mild, nothing where the drug had to be stopped. Anything that happened was recovered. So an extremely safe drug, extremely well tolerated. And we hope to see the mechanism prove out in humans in terms of seeing safe and effective weight loss in the three-month study. Talk about that journey from 12 up to what you describe as the upper limit currently in your planning of 40 mg dose response. What are we seeing? So in the phase one study, we had two cohorts. We had a cohort we just measured drug in the plasma. Of course, we look at safety, all the clinical parameters. We look at biomarkers in the blood. So we look at NLRP3 biomarkers, which is essentially IL-1 beta in the downstream hsCRP, IL-6, fibrinogen, SAA, serum amyloid A. We also had a cohort where we looked at sampling in the CSF. So we had a group of folks that we actually had a catheter. We sampled the cerebrospinal fluid. And here again, we look for drug exposure, which tells you what you expect to see in the brain. Obviously, you're not sampling the brain. You have the CSF. And then in the CSF, we look for biomarker suppression of biomarkers. And as we showed in our phase one, starting at about 10, 12 mg, we get complete coverage. So I see 90% for IL-1 beta in the CSF. We also see blockage of IL-6, fibrinogen equivalent to what's been shown with canakinumab. So essentially, the take-home message is that starting at 12 mg, we have full complete inhibition of NLRP3 in the target tissue where CSF is a surrogate for the brain. And so beyond 12 mg is the dose ranging study to see how far we can go. And even at 40 mg, we will be well below the no adverse effect level of this drug. So we've got a wide safety margin. And if we hadn't seen complete coverage of the target at 10 mg, probably would have gone higher. But we don't need to. We're going to bracket this study somewhere between 10 mg and 40 mg. Give us a nice safety window and look at, again, the end points that we want to see, which is essentially weight loss, cardiometabolic control, preservation of lean mass, and a combination study where you can look at the effects of the compound with GLP-1s. Again, it is not meant to be a replacement for the GLPs. It's meant to be a safe therapy for weight loss without some of the baggage of the incretins, which is effect on gut motility and nausea and potential pancreatic effects people have seen. Because this mechanism sort of passes all of the peripheral effects and deals with the central effect of feeding control. So to be clear, as we think forward for the next six to 12 months, actually, through the first half of 2025, so perhaps we'll be sitting on the stage here with a little bit more data, phase IIA study, 70 patients, I believe. phase II study is a biomarker study in these patients. 28-day measuring point. 28-day study. study. Measuring points would be, of course, weight loss. But we don't necessarily have any benchmark for weight loss in shorter studies. But we would see how the kinetics of dropping hsCRP, which is the driving mechanism for what we think is hypothalamic inflammation. So kinetics of hsCRP, obviously safety in the 28-day trial, again, cardiometabolic parameters that we've seen now in the animal studies. And really, in parallel, we're going to start to initiate the three-month study as well. In parallel. In parallel. Our tox coverage is going to be done sometime in the fourth quarter. So we can have longer dosing, three months or longer. So look at the pivotal study for this being the three-month dose ranging and a combo study. There isn't anything in particular that you're watching from the phase II-a that will inform the design of the phase II with. No, these are early days. We think the three-month study is the key study where you can now calibrate weight loss versus other drugs that have shown anywhere from 5% weight loss for an oral drug, as you saw recently, or a competitor compound, different mechanism, upwards to double-digit teens for incretins. I think it's a good place to be in terms of weight loss calibration. The 28-day studies are a good place to be for biomarker work and understanding kinetics of inflammatory control, which also guides us for other indications. How rapidly do you actually drop CRP? Because eventually, that's going to be how it's competitive with other drugs, especially the biologics. hsCRP is not one of the metrics that I am familiar with. What's a good amount to be dropping by on a 28-day study? So we showed with our peripheral compound in CAPS patients where these folks, and CAPS for folks that are unfamiliar with it, is a gain of function mutation in these patients for NLRP3. So a very direct study with this mechanism. And so we had patients that came in with different levels of hsCRP depending on what biologic they were on and how much the washout was. So anywhere from, let's say, three to 100 units of hsCRP coming in. And after 14 days of dosing, completely flatlined the hsCRP. So we dropped it down virtually to normal levels. And then once you take them off the drug, allow them to flare again. If they flare on the second part of the study, we drop it down completely. So we know in seven to 14 days, we can completely drop hsCRP. Now, this now tease out the kinetics. That's in an abnormal pathophysiologic backdrop. So in normal healthy is what we should be. In the normal healthy is, again, it's interesting. In the phase one study with the peripheral and now phase one study with VTX3232, we again saw a consistent drop in hsCRP, albeit within the normal range. So folks, we all have different levels of inflammatory load in us. And so even in the healthy volunteers, those that had elevated hsCRP still above the upper limit of normal, we dropped every single one of those down virtually to baseline in those subjects. Concomitantly, similar effects were seen on downstream pathways like IL-6, as I talked about, serum amyloid A, fibrinogen. All of them go down in concert with IL-1 beta and hsCRP. And that's a driver. That is the driver of inflammatory pathways, as you know. And so that's the main target. In our phase II studies, we're going to be looking at not just BMI as a criteria, also folks that have elevated hsCRP, because that is the mechanism we're looking for. Again, I think just beyond phase II next year, these are big studies, the GLP space, not just GLPs, but the Gs, the double Gs, the triple Gs, the oral compounds coming in. It's such a crowded area. There's so much to be done. I think this really does belong in the hands of somebody that can blow this one out in terms of all of the opportunities. I talked about safe and effective monotherapy, combo therapies, maintenance therapies. But our goal is to prove the best-in-class weight loss drug, if that's what the mechanism takes us. And don't forget, what we started out with this drug was really a focus on neurodegeneration. We have a Parkinson's study starting in the second half of this year as a biomarker study, again, to lead into a longer phase II study. Okay. A bit of a Wall Street question. Is there a gating factor? I know the guidance is for the 28-day data in the first half of next year. Is there any chance that we can get data sooner than that, before the end of this year? Post Labor Day, we're all going to be thinking about catalysts. What's the possibility of sharing that data from the 28-day study? These studies in obese subjects are easier to recruit. At the same time, we want to have a large enough trial. We talked about 70 subjects. Studies will start to enroll towards the second half of the year. So we're not making any promises for this year. We expect data in early first half of next year. And again, really focus on the three-month study, 12-week study, because that's where we actually would there's a good calibration for weight loss in that study as well. And that's a study where if you're going to get any weight loss, meaningful weight loss, you should be able to see it in that study along with, of course, the biomarkers, which we expect to move even in the 28-day study. The question in the room is going to be, do you see effective weight loss with this drug, as we have shown in mice? We are covering the target. Like I said, we've got a full coverage of this target. So if there is a drug or somebody that can show weight loss if this mechanism is valid, it's going to be this drug. So we want to make sure we give it its full day in the sun, 12-week study, calibration with other drugs, and prove out the mechanism for obesity. Thomas, I'll just pull you in here as you've been sitting here. Obviously, in the last week or so, you've been engaging with investors across different events, a little bit of controversy and volatility for the stock, which is not uncharacteristic in this category, in this therapeutic area across the small mid-cap spectrum. Did Raju address the issues that were perhaps being brought up, whether they were bullish or bearish? Is there anything that you would point to that you want to use this platform as an opportunity to address? No, I think he really covered all the details of our obesity thesis. I think, as you said, not surprising necessarily that there's volatility and kind of a myopic focus on every little detail right now around the obesity story. I think for us, it's just incumbent upon us to not be overly reactive to those stock moves. Obviously, we listen to the market. Is there anything in particular on the bearish side? The magnitude of the move last week in the stock suggested that there was cognitive dissonance that you would address. No, I think as Raju said, it's just we view this study as a study that is additive to the body of evidence that there is an impact of the NLRP3 mechanism in obesity. It's not a study that we want to comp to competitors. It's not a study that we're using necessarily to calibrate to an exact human dose. I think the message for us is, look, we're really excited about this mechanism. We think pharma is excited about this mechanism. Obesity is obviously a thesis that we're going to prosecute. There's other things as well. It's Parkinson's. We've talked a little bit about cardiovascular disease and indications like recurrent pericarditis. Regardless of the stock move, we find ourselves in a position where, fortunately, we're financed to begin to generate a number of hopefully value-inflecting data points across each of those opportunities in the next couple of years. As we've said, we ended Q1 with about $302 million. We expect that'll take us into the back half of 2026 with our current operating plan. Yeah. And to me, I had one thing to this, Chris, is it's not about being defensive because we weren't there to defend the mouse or defend our data. One of the comments I heard was, well, this dose they took here is going to translate into much higher doses in the humans. Well, we already have the human data. Most companies start with mouse animal data. Then we do a dose modeling, human dose projections. We have human clinical phase I data that says we cover the target in a 14-day dosing, both in the blood and the CSF. We know what the human dose is going to be. If this target works, we have to block it completely. We block it completely with 12 mg to 14 mg, 15 mg. The human dose is established, whether it's 15 mg or 20 mg or 25 mg, somewhere in that range. So taking a mouse study and projecting human dose just showed a lack of understanding of what the study was about because that would require knowing the clearance, the half-life of the compound, the mouse IL-1 beta. All those numbers were irrelevant. This was a mouse study. So anybody who does that has to take all that dose modeling, which is a waste of time because we've already shown human dose. So those are the kind of things that unfortunately got lost in the, or some people got lost in the message. But as Thomas said, obviously, we react to the markets, but then we move on with what our goal is, which is to conduct and execute. And one thing the team has done amazingly well is execution. So stay focused and execute on this molecule and the other compounds we have. Then remind us, when you were focused on the IBD indications, you had Bill Sandborn, who is broadly acknowledged as quite an expert and a familiar face to most of the investment community. Do you have someone who is essentially the skipper of this opportunity to take it into this opportunity? Yeah, absolutely. So we have an active search for a CMO and hopefully will announce one in the coming weeks, months. But we have an amazing clinical development team. We built it even pre-CMO and before we went public. The team executes. They have executed on a number of indications: psoriasis, IBD, now cardiovascular, now obesity. But it needs a skipper, and the skipper will be joining soon. Okay. Well, terrific. Welcome to the jungle. We'll be here where it is. Thank you so much, Chris. Pleasure. Thank you very much.