Okay, excellent. Well, last but not least, we're going to talk obesity and much more beyond that, but I'll turn it over to you, Tien, to kick things off. Great. Hi, yeah, I'm glad to be here. I'm Tien from Aardvark Therapeutics, and the CEO of—was that Fireside or? I think just folks are still learning some more about the company. So why don't you perhaps give us a lay of the land, the way you see it, and some basics of the technology, and we'll jump right in. Sure, great, great and a little quick intro from our CSO. Yeah, Tim Kieffer, Chief Scientific Officer. Fantastic. So, Aardvark, we have an oral small molecule drug that actually has some unique properties. It's gut-restricted, so there's very little systemic absorption, but our drug is actually activating gut-brain signaling through the vagus nerve, and it basically is engaging GPCR on enteroendocrine cells and inducing the localized release of a spectrum of gut peptide hormones to regulate hunger, and we think it has a lot of relevance for the rare disease part of well, at least for a number of mechanistic reasons, but also for general obesity as well. Great, fantastic. So maybe just the underlying, I know you have a later-stage trial in an orphan indication, and you're doing obesity as well. Is it, first of all, is it the same drug? It, there's the same component in both drugs. There's the single agent is for the rare disease, and then a combination with sitagliptin is for general obesity, and there's mechanistic rationale for both. Okay, got it. But I want to get into exactly what the product is, but just ahead of that, if you-if I could just get a sense, because pricing is so different between the two, can you price segment those two different products? We believe so, because, when we do Because of the combo? Do the combo, yeah, yeah, the sitagliptin component is fairly innocuous to most individuals, but it does increase the risk of gastroparesis, which is a known mortality risk in Prader-Willi. So although it's a more effective combination for weight loss, it's probably contraindicated for Prader-Willi. Okay, got it. So maybe let's get a little more specific. What exactly is the single agent, and what's the combo agent? So the single agent is, the ARD-101 is a small molecule. It's engaging bitter taste receptors in the gut, and bitter taste exists in your mouth, but also highly expressed in your gut, and it's inducing your enteroendocrine cells to release a spectrum of gut peptide hormones. Those convey their effect through engaging vagal afferent signaling to your brain to shut down hunger. Okay, got it. And then in the combo setting, it's ARD-101 plus? Plus sitagliptin or Merck Januvia, and that will be generic soon, and the idea behind this is that our drug induces a release of a spectrum of gut peptide hormones. CCK, that is, we think, abrogates hunger, and that's actually one of the key features of our drug, but it also amplifies the endogenous secretion of GLP-1, GLP-2, GIP, other relevant gut peptide hormones, which are substrates of DPP-4, which degrade them naturally. So by co-administering them with a DPP-4 inhibitor, it prolongs the residence time of the induced secretion of those hormones, and those have relevance for anti-appetite, which augments the weight loss effect of the drug. Got it. Got it. But I guess the question would be, I totally agree, DPP-4, GLP-1. I totally understand the axis, but DPP-4 has never showed standalone weight loss. So whatever they did, they never showed standalone weight. They clearly have helped on A1C, but none on standalone weight loss. So how does that tie into whether DPP-4 may certainly deliver some of the mechanistic and certainly on the A1C side as well, but do you think it will add on weight loss? That's actually, thank you for bringing that up. Actually, maybe Tim is best to describe this, because there's actually a very, you know, cogent. Yeah, so you're absolutely right. They are weight neutral. They've been in millions of patients, as you said, very good drugs for lowering blood sugar, treating diabetes, but weight neutral. The difference here is we have two components. One is the luminal side activation to release the hormones in the gut, that full spectrum that Tien was talking about, including GIP and GLP-1. They're normally, their half-life is like one and a half to two minutes before DPP-4 cuts them. So we have two kind of levers we're pulling. So one is to stimulate the secretion, and then the DPP-4 inhibitor to prolong their biological activity. So on its own, each component. You're promoting GLP-1. We're promoting it, and then we're protecting it in the gut so that it can activate the gut hormones. I guess the direction I'm going with that is, is it possible that your monotherapy delivers the same thing without needing the DPP-4 in there? Yeah, we demonstrated that, that data, and we actually do think that there's weight loss. We recently shared the data from our randomized placebo-controlled phase II study we did some time ago in general obesity patients. We did see weight loss, but we think the relative strength of the combination is far exceeding the single agent alone for weight loss, which is something that's not as needed for Prader-Willi subjects, but we think, and we actually showed comparative data on single agent versus the combination as well recently. Okay, great. So then, as I start to think about the, actually, maybe remind us the monotherapy and then the combo, what amount of clinical data do you have right now? Sure, and maybe Tim can go. We don't have clinical data on the combination, just to be clear. We have preclinical data in the gold standard model, which is a high-fat-fed mouse, and just to put some specific numbers on it, the combo led to 19% body weight loss in that model within 30 days. To compare that, tirzepatide, the gold standard, you know, benchmark was 20.5% in 30 days. With a fully oral combination, we're almost on par with a high dose of tirzepatide. Makes sense. The POWER trial will address this. What about the mono, the clinical data? So the study that Tien was talking about, we saw at the end of study a 1.3 kilogram. That was a Prader-Willi study or. No, this is in obese. Okay. So that was a phase II obesity study? Yes, 28-day dosing period, no diet, no exercise, and there was a randomized placebo-controlled trial in 20 subjects. The placebo difference was 1.3 kilograms at the end of the study. This is in patients who weren't encouraged on diet and exercise, like most of the GLP receptor agonist studies. To benchmark that, 2.4 milligram semaglutide 28 days is around 1.6 kilograms. Okay, got it, and these were obese patients coming into the trial, right? Yes, and you know, we fully expect this signal to be further enhanced with sitagliptin. Also, that study was done at a low dose of ARD-101 as well. Again, without diet and exercise. I think one of the key contributions for weight loss for our drug is it makes fasting easier, because we're addressing hunger as a kind of one of the intrinsic properties of the drug, so there's an intentionality to diet. It makes it easier. Got it. Is there taste issues with this drug? No, it's actually formulated to be coated so that you don't have inadvertent taste perception in your mouth. If you were to leave the tablet in your mouth for minutes, it should still remain intact and render itself undetectable. So it's meant to release its contents in the gut. So the idea is to avoid subjective awareness of the bitterness. Okay, got it. Okay, that makes a lot of sense. Could you remind us what trial-where's the status now with the clinical development and where you guys stand? Sure, the potentially registrational phase III trial, the HERO trial, which stands for Hunger Elimination or Reduction Objective in Prader-Willi subjects, that we had first patient dose in the second quarter of this year. And we have the cadence and expectation that we will have top line data Q3 2026. 3 Q 2026, wow. So this is fairly late stage. And, what's the primary endpoint? Is it weight loss? No, it's HQ-CT. So one of the things that's key in Prader-Willi is that these patients have this unabating, unrelenting hunger that they feel, you know, perpetually, and it's very easy to conceptually conflate obesity and hyperphagia, but they're not always related. You can actually have, you know, even skinny Prader-Willi subjects that have extreme hyperphagia, because their food access is often 100% controlled by their caregiver, so they only eat what they're given. So their BMI or their weight is not necessarily correlated with their hyperphagia. So as a result, the primary endpoint is a hyperphagia score called HQ-CT9. It's a nine-question questionnaire for the primary caregiver, usually a parent, and you have a zero to four points for each of those nine questions with a maximum score of six. Got it, and that's a regulatory endpoint? Yes, that is our primary endpoint. It's similar to others that are in the space. Okay, is this trial under SPA or you don't need, I don't even know if SPA works in FDA anymore? Yeah, yeah, yeah. Well, I mean, well, we have an orphan drug. We have, we're PWS qualified and, yeah. Okay, will weight loss be tracked as well? Yeah, we will track that, but although we don't think that's actually the primary driver of measuring effect, but we do actually expect body composition to improve. We think mechanistically, invoking this gut-brain afferent signal is actually helpful for encouraging lean body mass. One of the things that's notable in Prader-Willi individuals is that even in the circumstance where you restrict calories, they often have a high body fat percentage, and we believe that's because of insufficient gut-brain signaling. In our phase II study, we actually shared DEXA data where we saw a reduction of body fat percentage of 1.5% and lean body mass gain of 2% in that 28-day treatment period. Got it. So, for this to be competitive, there's VYKAT in the market as well. Maybe first of all, remind us, compare what that offering is versus what this will be. Sure, sure. So VYKAT is diazoxide choline, and it's recently approved at the end of March of this year. And it's again trying to address hyperphagia, but you know, there's a the exclusion for patients with renal insufficiency, and also there's all you know, the hyperglycemia is something that needs to be monitored in the case of that drug. And in our circumstance, we actually think that the degree of benefit is actually quite dramatic and within a short period of time based on our observations of our open label phase II. And we also don't have exclusions for renal insufficiency, and we actually think we help with hyperglycemia because we're increasing insulin sensitivity based on our glucose tolerance data in a clinic and also pre-clinically. The endpoint they used, HQ-CT, was identical to what you guys used? It is identical. Identical. Because you said HQ-CT9, I don't know if they were using the nine. No, yeah, it is a nine, yeah. It's, it's. They're using the same. The same one, yeah. The treatment difference that's on label at week 16 is five points. Do you think you are tracking comparable or better? I think the five-point delta was based on a withdrawal study, and I think that the five-point delta wasn't what was seen in the first prospective pivotal trial. So what's the right comp then? I mean, we think the clinically meaningful reduction HQ-CT is something that there's not a defined endpoint. I mean, I think even one-point reduction, as long as there's no like a compensatory liability with adverse events, would be thought of as clinically meaningful for a number of KOLs, and patients. So you don't need, I guess, why did they run withdrawal and why wouldn't you run the same? We actually have implied optionality to run a withdrawal trial should we need that, but we actually think we'll see the delta manifest in the traditional prospective study. So you think the delta manifests in the traditional. Did they report out the drug versus placebo in the initial part before they did the withdrawal? Yes, yes, yes. What was the delta there? I don't recall offhand, but I remember that I think at the 28 days, it was about approximately -2 for placebo and their drug. At the end of 13 weeks, I think it was placebo was about -3, four and something, and then I think their drug was, you know, yeah. I guess when you speak to clinicians on being in the marketplace along with VYKAT, how do they see the differentiation? This is definitely not combo therapy, is it? Or could it be? No, it's not mutually exclusive at all. We don't think of that as, Is that right? Mutually exclusive, yeah. And there are also—we perceive there be a number of subjects that may not be able to initiate or may have apprehension about initiating VYKAT or for a number of reasons, if they've tried VYKAT, they would, you know, discontinue. But I don't think we need to necessarily be superior in terms of effect size, because there's a number of patients that actually will not be able to sustainably be on VYKAT. But even looking at anecdotal the data that we have, we're actually very convinced that our drug has pretty robust benefits. And very importantly, one of the reasons we chose Prader-Willi as an indication was that beyond hyperphagia, Prader-Willi patients actually have hyperanxiety, systemic inflammation, and very extreme constipation with gut transit times often five days. And we think mechanistically with this gut-brain signaling, it has a capability of actually addressing those other features as well. And anecdotally, we've seen really good, encouraging signs of effect in those parameters. And that's like one of our key exploratory endpoints is PADQ for anxiety, as well as inflammatory bowel markers and also stool assessment for inference of gut transit. Fantastic. Any questions in the audience on any points we didn't touch upon? Anything we should have brought up which you get asked more and we haven't touched upon? I think I'm very excited also that you know the obesity data we have with the combination almost recapitulates our contention about what the mechanism of our drug is, because the fact that the sitagliptin combination has elucidated so much more additional effect on the gold standard model gives us assurance that we're invoking more than just a single gut peptide hormone release, right? Then actually that we're recapitulating normal biology with this. I think that both reads back into the prospective therapeutic benefit on the single agent alone, as well as the possibilities with the combination. Outstanding. Sounds great. Well, thank you so much for joining us. Looking forward to being in touch and good luck into the phase III readout. Thank you very much. Appreciate it. Thank you. Thank you.