I'd like to get started this morning. Welcome everyone to the Piper Sandler Healthcare Conference, day two. We have with us Aardvark Therapeutics and their Chief Financial Officer, Nelson Sun, and Chief Medical Officer, Manasi Jaiman. Welcome both. Maybe if we could start, and you could tell us a little bit about Aardvark, you know, the focus of your pipeline and your research. Sure. You wanna go ahead? Yeah. So, Aardvark Therapeutics, started in 2017 by Dr. Tien Lee, with an idea to change the paradigm of how we treat medicine and patients, specifically in rare disease. And over from 2017 to where we are now, there has been a lot of development that's happened, specifically in the metabolic space. We started out in rare disease, Prader-Willi syndrome, and now currently are working in our obesity pipeline, and that we'll talk about today. Yes. I think we've got two main programs. One, as Montse mentioned, is in Prader-Willi syndrome, and that program, the lead compound is a drug called ARD-101. And then for obesity, we have ARD-201. So ARD-101 is a bitter taste receptor agonist, and the way it works is that it targets the bitter taste receptors in the lumen of the gut, which in turn release incretins, including GLP-1 and CCK. And those incretins in turn signal to the brain through vagal afferents to both dampen hunger as well as appetite. And then 201 is 101 combined with sitagliptin, which is also Januvia that's coming off patent next year. The theory behind combining the two is that ARD-101 elicits the release of endogenous incretins and sitagliptin. It works to prolong the half-life of certain incretins such as GLP-1 and GIP. Through the mechanism of action, we think for Prader-Willi syndrome, we think we are really targeting the hunger pathway, which we believe is the primary mechanistic dysfunction in patients with Prader-Willi. In obesity, we think we're piggybacking off of that, as well as dampening on the appetite side of the equation, through kind of increasing the half-life for the other incretins that are released such as GLP-1 in addition to the CCK. Maybe you know, at a high level, it seems like you're going after the brain axis. Correct. And it's clearly, you know, a unique approach to what I think, you know, a lot of development programs in obesity and metabolic syndrome are tackling, which is strictly, you know, providing GLP-1 agonists or coagonists. So what's, you know, the biological explanation in terms of the gut-brain axis? Why are you focused on that in terms of obesity and Prader-Willi? Let's start with Prader-Willi specifically, and then we can talk about kind of the obesity angle. Generally, what we know in Prader-Willi syndrome is that there's a hypothalamic axis deficiency. Most of these drugs, if you talk about GLP-1s which have been tried in Prader-Willi, they're not effective because it's really targeting the hypothalamic pathway. The idea behind targeting TAS2R specifically in the enteroendocrine cell, the INL cells, was to bypass the hypothalamus and that specific pathway but have kind of a different alternate pathway, which is the gut-brain axis through the vagal afferents. Now, key important pieces behind PWS and this pathway is that it bypasses certain areas of the brain that also cause some of the side effects of certain of the GLP-1s, including nausea. The area of the hypothalamus specifically is noted to have severe nausea with some of the drugs that are out there. And because of the vagal afferent pathway, we actually don't hit that specific area in the brain. But as Nelson mentioned, it's not just CCK. It's GLP-1. We have other incretins that are involved in this, and more so through the CCK pathway in the bitter taste receptors on these I and L cells. And I think that's the uniqueness of the MOA, but also the safety profile that we've seen. And I know that people are curious about the phase two data, but that's really where we were so sure about what we've seen in order to move to phase three in Prader-Willi specifically. And so the phase three in Prader-Willi is ongoing? It is. When is the data expected? Right now, we have noted that top line is Q3 of 2026. Can you talk about the phase two data, and we'll give you confidence in moving to the phase three? Sure, sure. So within the phase two data, specifically, seeing, you know, I already mentioned the safety data, so that's unique to our MOA. Seeing as the potential safety and tolerability that we've seen allowed us to know that, okay, the patients tolerated it, but you wanna see efficacy as well. So early efficacy signals for us from the phase two showed that there was a reduction in hyperphagia almost the majority of the patients involved. And that was important. It's a 28-day study, which was open label. What we noted from that was very quickly these patients were able to decrease their hyperphagia specifically. Phase two used a hyperphagia questionnaire, the HQCT, and that is the primary endpoint for almost all PWS clinical trials that are assessing hyperphagia specifically. By noting the decrease in there, plus the safety signals that we didn't see, allowed us to know that we should move forward, but in a larger study, randomized placebo controls, and global. You talked about reducing hyperphagia, and I think you're measuring that through the HQCT score. Mm-hmm. Can you talk about what would be considered a clinically meaningful benefit in the trial? And would that translate or that should, I guess, translate to a statistically positive benefit as well? Correct, correct, and so what we have noted externally, and I will say this, that there's a clinical benefit, and then there is the clinical trial signals that you wanna be able to see. Clinical benefits, patients and families will tell you one-point difference depending on where in hyperphagia it's affected is meaningful, so the hyperphagia questionnaire assesses behavior, drive, and severity of hyperphagia. Those are kind of the three buckets, and if you have even one-point difference in any of those buckets, that's a drastic change for patients, and so one-point would be meaningful for patients, but from a statistical standpoint, and across the board, you know, there isn't specific guidance from the FDA, but what we've noted is a four- to five-point difference in hyperphagia is an important finding. Got it. And then on age, I believe that you now have patients 10 and above? We do, in the U.S. and Australia. So what was the rationale in 10 and above? I think previously it was 13 and above. Correct, correct. So our phase two was 17 and older. Phase three started with 13 and older with the idea that we always wanted to go into the younger population because hyperphagia itself sets in, probably around four to five years of age and peaks at around eight and continues. And so there's no deviation once you have peak hyperphagia; it kind of stays and sustained throughout your life with PWS. And so we knew that having earlier younger patients was important because those are the patients that dynamically can actually change the most. If you look at the data across the board in the competitive landscape, the hyperphagia level is most affected in the younger age group. And actually, some of the competitive landscape information also shows that in Salinas data, the drastic changes happen in that younger age group. So again, we wanted to make sure not only from a patient perspective because hyperphagia occurs so early, but we also know that dynamically these patients have the most effect. For HQCT, who assesses that? Is it the physician or? It is the physician. How, you know, from a site-to-site standpoint, how do you minimize site-to-site variability on scores? Because you know, I would assume that there's a risk of that. Absolutely. Because this is a qualitative questionnaire. And so you wanna keep certain things consistent. So one of those things is having caregivers be the same caregiver that brings the patient to the site, but it's also the same physician that assesses the HQCT with the families during those visits. So if they start to see the patient from day one, then they follow them through the journey of the clinical trial to keep that consistency and accuracy. From a company standpoint, how do you ensure for quality control of the assessments? Is there a blinded check, for example, that? There are blinded checks. There's also, I mean, there's operational details that are really important in studies that have a primary endpoint based on a qualitative score. We get this question all the time. So it's the training of the scientists, the training of the caregivers. It's the really careful allotment of time for these families, decreased burden of the number of times they have to come in that all affects how the trial's executed. And then again, QC checks from the background from the operation site. The trial has an unblinded analysis, an interim. I think that would be conducted by a third party. Can you talk a little bit about that? Because that's a unique feature of the study that you typically don't see with other studies. Correct, correct. So we're actually the interim analysis is not for futility or efficacy. It's actually just for sample size re-estimation, and that was important for us because, again, we wanna complete the trial. We understand it's 90 patients at this time, and we don't think we needed to know more about it because it's a short trial. It's three months, and then followed by an open label, and so wanted to continue through. One unique feature I think that we also, I think we've talked about before is how we're bringing patients in. So hyperphagia is a qualitative score, and people talk about placebo, specifically. And so all patients are allowed to be in the study, but they have a baseline score that they have, and they have a screening score. Everyone comes in at the screening score based on our requirements for inclusion, but they may have variability in that baseline. We actually assess and stratify based on where they were at baseline, not at screening. Everyone comes in. They have no reason to embellish or increase that score for any reason to be in the study. Their true score should be baseline, and that allows to minimize the placebo that may be there inherent too. The third party will conduct an analysis. Do they make a recommendation to the company on the sample size re-estimation? They do based on powering and conditional powering. Okay. And when do we get that, I guess, the information or update? We have not disclosed when that will happen, but I think what you can work around is we have top line in Q3, so. Okay. Perfect. And then the trials, are patients on antipsychotics allowed to be in the trial? They are. They are. What percentage of patients typically with Prader-Willi are on antipsychotics? There is the research group that often participates, and then there's the real-world population. So real-world population, about 30%, 20%-30% depending on which country you're in as well. So the U.S. is heavy in using antipsychotics compared to ex-U.S. and specific antipsychotics as well. But we wanted, this is a global clinical trial, so we wanted real-world representation. So we did, we actually included antipsychotics as allowed to be in the study, which was initially excluded, and realized that this was not representative. We did not want that to be included in the label. And obviously, end of the day, FDA will decide that. But for the real-world population, it was important to get those that were represented in the U.S. and ex-U.S. as well, so. From a site and standpoint, what's the split U.S. versus ex-U.S.? What do you anticipate in terms of lay patient enrollment in the trial? About a third are in the U.S., and the rest of the sites are ex-U.S., so in the United States, Canada, Australia, South Korea, E.U., and the U.K., and the few countries in the E.U., and so we've had a lot of engagement. We're open in the U.S. and Australia, and the rest of the world's about to go online, so you'll see that on ClinicalTrials.gov when that is updated, but a lot of engagement. That's very encouraging, and we've been really busy. Do you anticipate any geographic variability on HQCT? We'll see, we'll see. You know, right now, the data we have is U.S. and U.K., externally, right? And so we'll see if there is, I mean, ideally, if we do the training right and everyone performs the same version of HQCT9, or at least you are not gonna get a bias from the way this questionnaire is administered. But you know, Prader-Willi is, as a syndrome, the same across the board when it comes to the main issues, hyperphagia, growth hormone deficiency. And so hyperphagia is hyperphagia. And so I don't know how there's variability within hyperphagia, but I don't think it's gonna be variable based on demographics. Now, I do, you know, we've got a couple minutes. I do wanna touch on ARD-201 as well. Mm-hmm. You're, I think, initiating a phase two. Yes. ARD-201. Can you just talk about that? Yes, yes. Our phase two clinical trial, which Nelson touched upon as well, is really now to look at another way of looking at kind of one thing we talked about, GLP-1 receptor agonist. If you have our drug, which is ARD-101 plus sitagliptin, it's gonna enhance the features that we already talked about. Not only are we increasing the incretin pathway, but we're maintaining the longevity of that effect with the sitagliptin additive. Our preclinical data that we presented at ObesityWeek just recently, and it's available as well on our website, shows really promising work. We're excited about what there could be potential in terms of. We're on GLP-1. What happens after? You wanna come off of it? Is there weight maintenance? Can we prove that ARD-101 plus sitagliptin, which is called 201, has benefit in maintaining weight once you've lost it post-GLP-1 receptor agonist? So that's our next clinical trial, to look at weight maintenance. That's one of the pipeline that we've also talked about in terms of what comes after this. So looking at head-to-head comparison of GLP-1 receptor agonist with ARD-201, or based on the data we showed, is it synergistic? And we believe it is based on preclinical data. Great. And then, when do you anticipate data from the maintenance study? We are anticipating preliminary data end of next year. The patients would have come off of GLP-1. Correct. What's the time period that they need to be off GLP-1 before they go on the trial? Right now, what we've disclosed in terms of trial design, which will be available soon, is that there should be a very short period of time. Actually, we should ideally identify these patients before they've gone off the GLP-1 receptor agonist, and that's important just because then you have a little bit more control over the less time they're off, the more time you actually get to see that true weight maintenance. We're built those controls in the trial design. Got it. And then you're also doing a weight induction study as well in combination with. Correct. With GLP-1? Correct. What's objective there? Is it to drive greater weight loss by, you know, week 8 or week 12? Correct, correct. And so right now, for the next iteration of this study, we're really what we've disclosed at this time is that we wanna see similar effects that we found in preclinical data. So if you look at the preclinical data, the trial design will likely be similar to that where we're looking at a combination or head-to-head comparison to understand if we are non-inferior or if we are better. Great. I think we're about out of time, but really appreciate all the rapid-fire responses with you, Manasi, and Nelson. So, thanks, and looking forward to all the updates in 2026. Yeah, thank you so much. Thanks for having me.