All right. Great. Good afternoon, everyone, and welcome to TD Cowen's Obesity Summit. Here, we have a fireside chat with Aardvark Therapeutics. My name is Tyler Van Buren, a senior biotech analyst at TD Cowen. From Aardvark, we have Tien Lee, the CEO, and Tim Kieffer, the Chief Scientific Officer. Thank you very much for joining me, Tien and Tim. It's a pleasure to have you both here. Thank you very much. Thank you. For those in the audience, if you have questions, you can go ahead and submit them via the web portal, and I'll do my best to get them asked over the course of our fireside chat. Tien, maybe I thought you could start with a brief intro or quick overview of Aardvark Therapeutics and the company for those who are less familiar. Sure. Yeah. Aardvark is a San Diego-based company, publicly traded, and we started the company in 2017. The program is focused on gut-brain signaling drugs, oral small molecule drugs to reduce hunger. Our lead program is in Prader-Willi syndrome. We're in a phase III with expectation of a Q3 2026 readout. We also have very exciting general obesity programs with a couple of phase II programs in planning, one of which will start at the end of this year. Great. Thanks for that. We'll get to Prader-Willi's towards the end, for sure, but I want to focus on obesity since it's the essence of the summit. Again, for those who are less familiar with the platform, probably not super well informed with respect to beta taste receptors in the gut and the mechanism of action. Maybe you all could start by walking through the biology of beta taste receptors and how it can positively influence hunger-associated conditions like obesity and Prader-Willi's. That's great. I think this is a great question for Tim, our Chief Scientific Officer. Sure. I think everybody's familiar with beta taste receptors in the oral cavity and the tongue. Those same taste receptors are concentrated on what are called enteroendocrine cells lining the small intestine. These are very specialized cells scattered throughout the entire length of the intestine that secrete a number of hormones to regulate food intake and appetite and hunger. ARD-101 is a molecule that is taken orally. It's coated so that you don't taste or perceive bitter in the oral cavity. When it gets into the intestine, it releases ARD-101. 99% of it stays in the gut. It binds to the TAS2R on the enteroendocrine cells and triggers the release of hormones, importantly in their natural location within the intestine. By design, those hormones then bind to sensory afferents, which through the vagus nerve convey the feeling of suppressing appetite and hunger through that gut-brain signaling. That is something that is really unique to Aardvark, triggering that natural physiological pathway to give us the feeling of fullness and dampen hunger. That's great. Maybe you could elaborate on the distinction between hunger and appetite. Sure, sure. Appetite is more like a reward-based drive. You love cheesecake or ice cream. Thanksgiving's coming up, and all these delicious foods are driving your brain to want to eat something based on the expectation of reward. That's what appetite is. Hunger is the stick to the carrot. It's the negative feeling you get when you fast for a prolonged period of time. When it really bothers you, you feel like you want to eat anything. If you're trapped in a room with nothing else to eat but dog food, eventually this hunger would compel you to eat anything, and the food quality matters less. Both appetite and hunger are simultaneously drivers for your eating behavior. Gut peptide hormones regulate both appetite and hunger simultaneously. Got it. Okay. I guess as you think about the unmet need with obesity and Prader-Willi's, how do you think this mechanism will differentiate versus the current standards of care? Importantly, we think this is an orthogonal approach to GLP-1s. GLP-1s, we believe, and other approaches are more anti-appetite, so they diminish the perceived quality of food. You are less inclined to want to eat that food item. Just to be a little facetious, it is like turning a delicious food, dog food, to your brain, so you are less inclined to want to eat it. That is what GLP-1s do, but they also have a concordance of nausea. Some of the main liabilities of just that approach in isolation is that there is associated nausea. There is a weight rebound that happens when you discontinue. We think that is actually because of the compensatory increase of hunger that is there when you decrease appetite externally. You have a compensatory increase of hunger, so you can simultaneously feel hungry but have food be less appetizing at the same time. When you stop taking the anti-appetite drug, you have a rebound rate regain that's now driven by hunger more than it started with. There's also lean body mass loss with weight loss as well, too, that we believe this mechanism of gut-brain signaling will be helpful in terms of preserving lean body mass. In all three parameters, we think our drug has a very good paradigm to either be used as an alternative or as a complementary treatment. Got it. From your approach to beta taste receptors and the data to date, you have not observed any of these same safety issues. What does the safety look like so far? Yeah. Before even the initiation of phase III, we had over 70 patients between phase I and phase II programs. We have not seen more than a grade two transient AE. There has been nothing really in terms of a repeatable pattern, with some incidental transient grade one diarrhea, for instance. We had some only grade two, I recall right now, some itching that was addressable with immune therapy and other transient effects that we have seen. It has been a very tolerable safety profile. Even our chosen dose that we are proceeding with for phase III actually represents a dose that is far below what we think the toxic limit of our drug is because of the fact that it is gut-restricted. Also, the molecule has properties that render it well tolerated. Okay. Great. Let's dig into your obesity program a bit more, starting with ARD-201. It is a combination of 101 that you're exploring in Prader-Willi's with acetagliptin DPP-4 inhibitor. Maybe you could just talk through the rationale of this combination for obesity and weight loss. Sure. I think Tim, again, is probably better suited for this. Yeah. Sure. The ARD-101 we were just discussing, again, triggers the release of the gut hormones. A number of the gut hormones are, after their release, very quickly cleaved by this enzyme dipeptidyl peptidase 4, which clips two amino acids off the amino terminus and renders them biologically inactive. That half-life is about one and a half to two minutes, for example, in vivo for GIP and GLP-1. The synergy here is we have this oral compound to trigger the release. We then add the DPP-4 inhibitor to prolong the biological activity of the gut hormones, namely GIP and GLP-1, to extend their biological half-life. That's kind of the rationale. Very interesting. What did you see preclinically that supported this combination and ultimately your decision to go into the clinic? Yeah. We shared that at Obesity Week, some very, I think, compelling data in the high-fat fed or diet-induced obese mouse model. This is kind of the gold standard in the field. It is highly translatable, particularly for the incretin field. The animals were put on a high-fat diet to establish obesity and also glucose intolerance. We then treated the animals with various combinations, including ARD-201, but also with semaglutide/tirzepatide, kind of the approved drugs. Just to highlight a couple of the key aspects of the data. First of all, with ARD-201 as that oral combination of the 101 and the DPP-4 inhibitor, within 30 days, we got 19% body weight loss. Just to put that into perspective, high-dose tirzepatide in a cohort of those animals gave 20.5%. We are almost on par with high-dose tirzepatide in this model with this oral combination ARD-201. As I just want to emphasize, Tien was talking earlier about the safety profile. We don't expect nausea or vomiting, those GI side effects that plague GLP-1 receptor agonists because it's more physiological and it's gut-brain signaling. To see something comparable to the injectable in this model was really exciting. Another unmet need in this field is looking for an off-ramp. As Tien talked about, when patients stop taking GLP-1 receptor agonists, there's a quick rebound in weight. There's data from Blue Cross Blue Shield showing in the real world. In their study, approximately half the patients have already ceased taking a GLP-1 receptor agonist within three months. It's a real problem. We wondered, could we have an off or offer an off-ramp with ARD-201? We had a two-phase study, again, preclinical in the same mouse model. We achieved that 20% weight loss with tirzepatide. We then transitioned some animals to that oral ARD-201, and they had equivalent weight maintenance to animals that stayed on the high-dose tirzepatide. That was really encouraging. Lastly, we wondered if there could be some synergy with ARD-201 and a low dose or micro-dose of tirzepatide. We reduced the dose tenfold, which would be lower than a clinical starting dose, should be free of nausea, added on ARD-201. Now there was further weight loss. We got 30% within 30 days, which, again, really remarkable and encouraging to see with this oral combination and a very low dose of tirzepatide. Those studies will all be replicated in the clinical setting with our POWER and STRENGTH clinical trials. Yeah. 30% in 30 days would not be too bad in humans. Maybe you could talk about the phase II data from 101 in Prader-Willi's and to what extent that has provided proof of concept for your efforts in obesity. Yeah, happy to do so. We're very, very encouraged with this. We did this phase II study at a time when the company was less well capitalized, and we only had the GLP tox data to allow for 28 days of dosing. We selected a treatment period of 28 days because at the time, that was all we were permitted to dose continuously for. We had 18 patients that had completed dosing. Twelve patients had a dose of 200, and then we had six patients that had a higher dose. In totality, we saw really encouraging reductions on the hyperphagia score, that's the approval endpoint Hyperphagia Questionnaire for Clinical Trials. We saw really substantial reductions. Really, the degree and consistency of HQCT reductions was very encouraging for us with patients that were anecdotally leaving food on plates or even forgetting about mealtimes. Some things that are really remarkable in the context of Prader-Willi, just to give proper context. In Prader-Willi individual households, oftentimes families are told not to even have toothpaste or mouthwash around because those could be potentially eaten, that's so significant as the drive for hunger. Having food left on plate and things like that were really very encouraging to us and gave us confidence to proceed into the phase III. We actually expect that even our phase III data could potentially have underrepresented what the potential is because across clinical trials in this space, the data at three months generally looks more robust than one month because usually time is needed for really maximizing the potency of the agent used for reducing hunger. A number of other parameters and controls give us encouragement that we should see robust signals in our phase III as well. This is kind of our expectation. Great. I promise, again, we'll get to Prader-Willi's in a second. Just staying on obesity, the planned designs of the two Phase twos, the STRENGTH and the POWER trials, maybe you could walk through the designs of both of those and the follow-up periods and what will be the comparators in those trials. Sure. The POWER trial, the acronym stands for prevention of weight regain. We are trying to address a particular problem. By the way, we are not restricting the potential commercial application to just any one of these, but we want to look at each of these problems separately in context. The POWER trial will recruit patients that have already lost weight on GLP-1. 15% or more is what we are aiming for. These are patients that have successfully lost weight, but they want an off-ramp. They want to discontinue using these injectables, but the expectation is rapid weight regain once you are off of GLP-1. We are going to bridge them over to ARD-201. Our expectation is if we recapitulate what we saw in our preclinical studies in the DIO mouse, that we should be able to sustain their weight loss and potentially help with even their lean body mass composition, potentially maybe for some patients, perhaps continue more weight loss if needed. We believe that we want to demonstrate this ability to retain the weight loss without having to use the injectable. That study should start before the end of this year with expectation of readout second half of 2026. Based on the trajectory of weight regain, we think that we can see very meaningful data even as little as 12 weeks after discontinuation. Just to note, in the previous experience with GLP-1s, patients that have lost weight generally regained about 70% of the weight loss within the first year, with about half or a little more than half of that occurring within the first three months. If we look at three-month or 12-week data, we should be able to see some substantial change if there is change to be seen or at least preservation of the weight loss. The STRENGTH trial is a prospective weight loss trial looking at 201 versus 201 plus GLP-1. We haven't noted when the expectation of readout will be, but that study should initiate first half of 2026. Great. I guess as you think about the STRENGTH trial, how do you anticipate that the treatments might synergize with GLP-1s? Will it be an additional impact mechanistically, or do you expect it to be a true synergy? We think our drug is additive in a very unique way with GLP-1s. Maybe the best way to think of this is that when your body is trying to naturally coordinate satiety, there is actually a panel of gut peptide hormones that are released contemporaneously. It is the coordination of these multiple gut peptide hormones and vagal afferent signaling that really tamp down your hunger and appetite. We think that unilaterally, just looking at a systemic GLP-1 is kind of missing a lot of the potential synergies of all these other gut peptide hormones. This is the reason why we think even a small, modest dose of GLP-1 receptor agonist, along with our drug, which helps potentiate the endogenous release of these other relevant agents, will kind of be complementary to their approach. That is why we have seen this synergy. If you'll note that in our data disclosure in Obesity Week, we were showing one-tenth of the dose of tirzepatide, which corresponds to a dose less than the starting dose clinically, which by itself would not be expected to convey benefit, but also with much benefit, but wouldn't be expected to also cause nausea. That one-tenth dose with 201 gave a weight loss in that DIO mouse model that supersedes what we're aware of in terms of even the other GLP-1 receptor agonists in development. We think it's just, in a way, recapitulating normal biology with amplification of what the effects could be conveyed by a GLP-1 receptor agonist. That's great. You have talked about the POWER trial starting by the end of the year and STRENGTH starting in the first half of next year. When could we expect potential updates or data from these two trials or an interim look? Data will start to be becoming available for second half of 2026 for the POWER trial. And STRENGTH trial, we haven't given guidance yet, but hopefully we'll be able to give some updates relatively soon on that. But the POWER will be the first one to readout for general obesity. And this will probably be a little bit after the HERO trial readout, which is in phase III right now. Got it. Are you prioritizing one versus the other, or they're running in parallel and you're just waiting to see what data from both look like and how to move forward? We think the POWER data readout will happen first. It is because the trajectory of weight regain is so well established and so remarkable generally that bending the curve on that should be something that is, we believe, very demonstrable with the data set that we anticipate. We think both are important, but procedurally and in terms of our expectation, we think the POWER trial is the first priority in terms of what we are trying to see for data. Okay. Before we go to 101 and Prader-Willi, I just wanted to ask one question on 868, which you kind of unveiled/discussed with the Obesity Week presentation. Maybe you could just touch very briefly on this program, the mechanism, and some of the early preclinical data and next steps. Happy to. This is an asset that we purchased while we were still a private company more than a year ago, at least around a year ago. It is a drug that was first developed as an oncology therapeutic. It is not a cytotoxic compound, but it was actually chemically derived from a soybean derivative. It impairs mitochondrial oxphos. It was meant to treat as a combination agent for different kinds of cancer. We think that the alternate application for this is as a potentially oral drug, not injectable. By impairing oxphos, you are forcing the cell to shunt energy production to glycolysis and lipolysis, which is more inefficient in a certain way. You are wasting glucose to create lesser ATP, but doing it in a way that does not produce hyperthermia, which is a liability of mitochondrial targeted drugs in the past. We demonstrated the weight loss. We looked at retrospectively the clinical data when this was applied in a phase B before. We saw really about over 10% weight loss in about three months in humans with taking this drug. Also in preclinical models, we saw pretty substantial dose-dependent weight loss in a way that also is muscle-preserving, which is another unique feature of this mechanism. This is something that's orthogonal to both GLP-1s and our other programs. It's a very exciting early-stage program that we're looking for partnering opportunities presently. Great. Very interesting. All right. 101 and Prader-Willi's. Maybe you could talk about, you've already touched on kind of the phase II data set. Maybe just talk about the phase III HERO trial, the status of enrollment there, and again, when we should expect top-line data and what you hope to see with that top-line data. Great. We have a target enrollment of 90 patients. It's a one-to-one randomization looking at treatment after 12 weeks and what their HQCT score is relative to the baseline. We have a number of very meaningful exploratory and secondary endpoints, including CGI score, anxiousness score, pro-inflammatory cytokines, metabolic biomarkers, DEXA scans. We expect that we dosed first patient in Q2 of this year. Enrollment's going very well and very strong with high engagement from the patient advocacy groups and prospective patient enrollment. We expect to deliver top-line results Q3 of 2026, and we're very enthusiastic about this. Great. Why did you all include a 28-day observation period in the phase II study? Just curious what the rationale was behind that. What do you mean for phase II? Yeah. Yeah. We were only permitted to dose for 28 days, so we would have done longer if we were able to. At that time, we only had data tox clearance to dose for 28 days. That is why we selected that. I think even our KOLs were advising us that it might be a little bit too ambitious because generally, even drugs that are thought to be effective need a longer period of time to demonstrate benefit. We were confident in the MOA and how it was relevant for PWS, and that is why we selected that dosing interval. Got it. Okay. I guess for the HERO trial, it is a minimum age cutoff of 13, but you have amended the protocol to go as young as 10. Just maybe, again, the rationale for this adjustment and the implications for a label if successful in Phase three and approved. Sure. Just for context, our phase II had only ages 17 and up because we have a first-in-class drug. There is generally a fairly higher role rate to push into younger patients. Through alignment with the FDA, we started with 13 plus for our phase III. We moved it down to 10 plus. We intend to move it as low as seven plus. We believe that is going to be a good representative sample. We hope to have a label of four plus eventually. The reason why we would not want to integrate patients younger than seven in our trials is because oftentimes the hyperphagia, patients are not born with it. They start manifesting the hyperphagia sometime between ages four to eight, sometimes four to eight. There is a natural history of increase of hyperphagia during that time before it levels out. Just to keep the data a little bit more interpretable, we wanted to keep our inclusion criteria to be seven plus eventually, but we hope to pursue a label of four plus. Okay. Great. We're up on time with the next session starting at 3:30 P.M., but just want to ask a final question on the Phase three HERO trial. Obviously, you need to achieve statistical significance on the primary endpoint of HQCT, but is there a specific reduction or minimum reduction that you're guiding to? What other endpoints, whether it be efficacy or safety, are you most focused on in terms of differentiating 101 when you get the readout? I think one of the key advantages is expectation of safety. I would note that renal insufficiency is not an exclusionary criteria for our trial. Neither is hyperglycemia, because we think our drug actually helps with glycemic control. I think there are many in the field that believe even an HQCT reduction at one point, if there was no adverse trade-off, that would be meaningful. We think the drug is complementary to existing therapy and is not mutually exclusive. That being said, based on our understanding of our own data, we think that the expectation of HQCT reduction, we think, is a minimum of six points better than placebo based on our experience with the phase II. Of course, that was based on a limited data set and some extrapolations, but we expect the HQCT reduction to be fairly robust. If we assume six points, that would imply only 23 patients per arm would be giving us 90% confidence with even assumption of a standard deviation of 6, which we think is pretty cautious. With 45 patients per arm, we think we're more than sufficiently conservative with our design. We have high optimism for the HERO trial. Okay. Wonderful. We're over time. With that, we'll go ahead and wrap. Tien and Tim, thank you very much. Thanks to everyone for logging in. I hope everyone has a great day. Thank you very much again. Thanks.