Great. Thanks everyone for joining the first Stifel Cardiometabolic Day. We're excited to be here and start the discussion with a number of companies. First on my end I have Aardvark Therapeutics. Happy to be joined by CEO Tien Lee and CSO Tim Kieffer. Maybe Tien, we can just start with kind of a quick intro to Aardvark and then kind of ARD-101 and then we can jump into Q& A. Great. Thank you very much for the forum, James. Aardvark Therapeutics, San Diego-based biotech company. We're developing small molecule oral drugs to regulate eating behavior. We believe we have a very unique gut-brain signaling drug. It's orally given, gut-restricted, and it's invoking the release of a number of gut peptide hormones through signal through gut-brain to turn off hunger as opposed to appetite. We can get into that, but we think it's applicable for a number of different conditions, notably Prader-Willi syndrome for the hyperphagia, but has also applicability for general obesity as well. Awesome. Yeah, definitely want to dig in. As you mentioned, pretty interesting and unique mechanism of action here. Maybe it'd be great to dive into that in a little bit more detail and walk through some of the key highlights and key tenets of your therapeutic strategy and why it makes sense. Specifically, hyperphagia and Prader-Willi, since that's the first readout. Maybe we can start there because. I'll give the 30,000 ft view and then I'll defer to my colleague Tim to kind of give more details. Essentially, we think there are two different large heuristic drivers of eating behavior. One is a reward-based drive and that's your body's chasing towards something positive like a delicious food, for instance. Then hunger is the feeling you get when you've starved for a while and you fasted and that's driving you to eat. Food quality doesn't matter in that context. We think that our drug has releases gut peptide hormones that are relevant for both pathways. The unique aspect is that we're actually hitting these anti-hunger pathways as well. I'll just defer to Tim to convey further color on that. Yeah, sure, Tien. James, happy to add a little bit more to that. As Tien said, it's an oral drug, it's activating taste receptors but not in the tongue. It's coated so that it's not activating those receptors. The receptors for taste, interestingly, are highly concentrated on enteroendocrine cells lining the small intestine. These are cells that release hormones in response to meals. The taste receptor activation by this drug in the lumen, remember as Tim said, it's restricted to the gut. 99% of this drug stays in the gut, binds to those receptors on the apical side in the lumen, and triggers the release of these hormones. The hormones then activate sensory afferents carrying through the vagus to the satiety centers and dampen appetite and hunger. That's what really makes it unique. It's not high peripheral dose like we typically see with drugs in the obesity field trying to act centrally. We're activating the normal gut-brain axis in a more physiological manner. Yeah, it's really, it's an interesting idea, this kind of hunger versus appetite. Maybe it'd be good to understand how truly sort of delineated these two paths are and your confidence that in Prader-Willi it's really hunger and an impairment of the signaling of some of these hormones. Sure. I'll start off and then again defer to Tim for further detail. I think there's several hints that something's more hunger driven than not. I think one of the big hints is whether food quality abrogates the overeating. Right. I think even for general obesity, if we were always surrounded by unflavored celery, there would be lesser amounts of obesity because there'd be people who wouldn't want to be inclined to eat something if they were low food quality. In Prader-Willi, these patients are incredibly ravenous in terms of their hunger and they'll even eat non-food items, trash and so forth. The other hint is ghrelin. Ghrelin is a biomarker that really correlates well with your self-perceived hunger state. Even if it's slightly elevated, you feel if you skipped a meal 20%, 30%, 40% above normal and you feel very bad. In Prader-Willi, it's up to 4x higher than normal, which is really dramatic. I think it's probably the condition that's associated with the highest ghrelin. Paradoxically, GLP-1 receptor agonists are associated with a slow rise in ghrelin over time too. It's almost a compensation. You undoubtedly lose weight for most people when you're on GLP-1, but you have this compensatory upregulation of hunger. You look at hunger surveys, people with GLP-1s actually will note that they're paradoxically hungry, but they just still don't want to eat. The other hint, ghrelin does, ghrelin as a hint, low quality food is a hint. That's hunger. Also, the fact that GLP-1s haven't really been really successful in Prader-Willi is also reflective of the fact that it's like a carrot and stick analogy, that having a diminished carrot is not really what's problematic for Prader-Willi. It's really the stick. It's the hunger that's driving that overeating. I defer to Tim for further color. No, I think that's great, Tien. I think it speaks to the elegance of the approach that we're taking by activating these hunger pathways, the gut-brain axis, which is really unique to this approach. Yeah, it makes sense. You know, in the literature there's some interesting sort of data on, you know, CCK, you mentioned ghrelin, some of these other relevant hormones. At times it's sometimes conflicting. Curious how you think about the overall literature out there as it relates to CCK, some of these other hormones, and really what the key learnings are in terms of what we've seen in Prader-Willi patients or animal models, etc. Yeah, maybe I'll start and then Tim can jump in. You're right. There's a lot of literature supporting the role of elevated ghrelin and low CCK as driving hunger pathways. I think there's also a lot of literature showing complementary data that activation of bitter taste receptors can reduce hunger. I think that's reassuring. It's not just ourselves showing activation of these pathways. We've got compelling data on isolated enteroendocrine cells showing that ARD-101 will stimulate the release of these hormones. We've got clinical data showing the reduction in ghrelin, an increase, for example, of GLP-1. I think collectively there's good support for these pathways. I also want to add one more thing. You know, I think there's apparently like conflict of whether high or low CCK exists in Prader-Willi. What would be the utility of increasing that if there was already more imperviousness to signaling? I think a good analogy is with insulin resistance and diabetes. In that context, there's insulin resistance, but the therapeutic intervention is actually more insulin to overcome that resistance, and it still remains effective. The fact that even if you have a higher threshold for engagement doesn't preclude hitting that pathway harder. I think that's what we're doing. That's just one of the driving mechanisms of action of ARD-101. CCT is not the only thing that's driven, but it's still consistent with our thesis. Yeah, maybe I'll just add one more quick point that circulating levels don't necessarily reflect what's happening locally within the gut. That's, you know, that gut-brain axis is not through systemic levels, the levels within the gut activating those sensory afferents through the vagus. Periodic measurements of hormones that have a half-life of one to two minutes and act within the gut are not necessarily a good surrogate of that path. Yeah, no, that makes total sense. It kind of raises another interesting question here. You know, Jens, I know you've talked about this before in terms of it almost being like turning the switch back on, on this pathway. Kind of along those lines, how do we think about how much release of these hormones do we need? Is it like a certain threshold, or is it just about hitting it again? That's kind of the thought of turning it back on. Yeah, I think directionally, just even increasing the gain there is helpful. There are a lot of other therapeutic hints that Prader-Willi subjects have a deficiency of gut-brain signaling because beyond the hyperphagia, they have hyper anxiety, inflammation, and slow gut transit. All of those are correlated with this gut-brain afferent signaling. Tuning that up should be therapeutically helpful and consistent with their phenotype. Great. Okay. I think one of the other interesting and maybe sort of challenging biological questions here is just this whole idea of, in Prader-Willi patients, do we know that this system's still functioning and that even if you hit it, it kind of still works? Just curious, kind of, your thoughts there. Obviously, it's presumed that some level of hypothalamic damage is involved in Prader-Willi. Just curious how you think about the ability to get around that, and these overall hunger systems still kind of being able to be modulated and still drive an effect in these patients? Absolutely, I can answer that. I think Tim usually has a better answer, so I'll just refer to Tim. I would say, I don't know that damage of the hypothalamic satiety centers is the right word. I think they're probably developmentally impacted, but the circuits are still there. That's pretty clear. Keep in mind that again, we're not peripheral administration trying to get into the CNS. We're activating sensory afferents through the vagus, which actually go to the brain stem, and then from there it's neurons that feed into the paraventricular nucleus. The proof, I think, is in the pudding, so to speak, with the clinical efficacy showing acute dampening of hunger in patients with Prader-Willi. There's also anecdotal evidence of food left on plate, delay of feeding time. These, I think, are pretty strong evidence that the pathways are there, they're functional. We just need to turn up the gain, so to speak. Interesting. Makes sense. I guess maybe now we can jump to the data you've generated and maybe just kind of give a quick overview of the Phase II data, the highlights here, and how do you think they stack up relative to what else we've seen in Prader-Willi. Okay, great. Yeah, so information. We completed dosing in 18 subjects with Prader-Willi syndrome. We had a 28-day treatment period. At the time the company was less well capitalized. We only at the time had achieved GLP tox studies that would enable 28 days of dosing, which is why we did that shorter study. You would note that most studies, almost all studies in the competitive space, have at least three months or longer treatment periods because it's understood that because probably individuals often have a very pattern-oriented behavior, it takes a longer time to detect changes in behavior. Despite that, in 28 days we saw really remarkable benefits. We had two cohorts of patients, one at 200 mg BID and another six that had increasing doses of ARD-101. We saw consistently very encouraging reductions in HQ-CT. HQ-CT9 scores were almost 50% reduced relative to their initial starting baseline. I think the level of change in that short period of time is also very, very encouraging in the context of what others have seen in other studies as well too. As Tim pointed out, the anecdotes, some of the strong anecdotes were very, very encouraging. Multiple patients, families reporting food left on plate, which if, you know, you have experience looking at Prader-Willi individual behavior, it's very unusual to expect food to be left on the plate. They usually have very, very absolute control of their food access and then they usually eat everything they're given. Having food left on plate is a really very, very encouraging. Patients forgetting about their meal times because they're distracted, playing a video game and so forth, and just behavioral benefits. Also beyond just the hyperphagia, we saw anecdotes of reduced anxiety, improved gut habits, transit time, also reduction in inflammation. These are all formal assessments in our Phase III where we actually have those as key secondary endpoints. We didn't have those formally assessed, but the anecdotes were very consistent. We're very encouraged by the totality of data we got from our Phase II. Yeah, that's helpful. I guess maybe in terms of secondaries in the Phase II, was there any formal secondary assessments, and is there anything you can kind of share there? We had body composition data that we shared. In the 28-day period, we saw an average reduction of body fat percentage by 1.5% and an increase in lean body mass of 2%. Although we didn't measure CGI, we will do that for Phase III. I think the level of. Overall. Being in patients was actually more than reflective of what their HQ-CT reductions were. Just to give you a quick summary of some of the secondary endpoints in their Phase III, we have a CGI score, we have inflammatory biomarkers, we have gut peptide hormones, metabolic biomarkers, and also a body composition with DEXA scan. We actually are very hopeful seeing a positive change in many of those parameters. Yeah, makes sense. Okay, great. Obviously, naturally in Phase II, smaller kind of open-label studies, there's always a question of how real is it, and just kind of be curious what gives you confidence there beyond some of the data you walk through and how it stacks up relative to typical placebo responses we may see in this disease. Sure. If you look across the competitive space, I think the general expectation within 28 days is about two points of change within a 28-day period. I think that's also the typical placebo, around that magnitude as well. We saw in our HQ-CT9 assessments about - 8 or better average reductions, with some responders that really had much greater changes as well, I think as much as - 16. The quickness in which this occurred too, even though our first formal assessment was at 14 days, I think anecdotally patient families saw that there was benefit almost within the first day or two, and there wasn't any other suggestion or priming that that would have been an expectation for the patients as well. The fact that we consistently heard that the feeling of benefit was so quick after initial dosing was also very encouraging. The strength of the anecdotes too, like leaving the food on the plate and certain things, would be very hard to reconcile with placebo given the strength of signal that we saw based on that behavioral change. Yep, makes sense. Okay, great. I think one of the other sort of interesting clinical questions here is, obviously this drug's gut-restricted. There's no sort of formal PK/PD. I guess you studied kind of two different dosing regimens in Phase II, and you're taking the dose escalation up to 800 mg BID into the Phase III, I guess. Can you maybe just expand a little bit on kind of how you selected dosing here and your confidence that you're sufficiently engaging the target with this dosing regimen. Great, sure. I just want to let you know that motivation for increasing from 200- 800 was really to compensate for some observation that patients that were taking their drug between meals tended to do a little better than the ones that reported taking it along with meals. The thought was that perhaps there was a food dilution effect and then the higher dose could maybe compensate for that. The high dose is actually still low dose when you compare it to the toxic limit of the drug because it's gut-restricted. We didn't think we were introducing greater safety risk at 800 versus 200. We observed very innocuous and very well tolerated safety with our 800. I'll just defer to Tim to convey the rationale also. I think you covered it pretty well, Tien. Okay. Yeah, great. Makes sense. I know you've shown and talked about animal data that kind of shows higher efficacy and higher dosing and makes sense given also the clinical signal you saw in Phase II. I guess, talking about the Phase III, just in the last five minutes here or so, you've made some changes recently. Data are expected in three cases next year. Maybe just talk about some of the changes you made and some of the key design elements in here that you've implemented that you think kind of optimize the trial for success. Sure, sure. We pushed back the top line because we also wanted to expand the age for the inclusion criteria. Our Phase II only had patients age 17 and up. Our current Phase III has age 13 and up. We wanted to get ahead of any potential restriction on label based on age. We wanted to expand this current trial to accommodate patients younger than 13. We're looking to incrementally lower that age, you know, to 4+, 7+. We're trying to incorporate patients that are younger than 13 before we close out the study, which is kind of like our driver for doing that. The other element is that there's a kind of known confounder of placebo effect in other trials because, as you would imagine, mathematically it's easier to see a change. You have a higher baseline of HQ-CT, it's easier to see a - 4 or five or six score from mid- 20s than in the teens for your HQ-CT. Because of that, the inclusion criteria has a certain cutoff that you cut off, generally uses a score of 13 or higher. In order to, I mean, I'll just say that there is an incentive for some families to over report HQ-CT to make sure to be included in trials. Once in the trial, there's a natural drop in that HQ-CT which drives the placebo effect. We're trying to wash that out by having a second baseline assessment when patients are already qualified to be in the trial. Hopefully we help to wash out some of that reporting bias. I think that is one of the key elements of our study design to reconcile with that. As it currently stands with 45 patients per arm, we're powered to have a 90% confidence to see a delta of placebo-adjusted four points HQ-CT, even assuming a standard deviation of six. We think the true effect size is greater than placebo-adjusted of six, which we do believe, then that implies only 23 patients per arm will be required to get a 90% confidence. We think we're more than sufficiently powered in terms of the study size. You've also talked about how you have an interim here for a sample size re-estimation, which kind of gives you some flexibility on adding patients as you need, I guess. Can you maybe talk about that interim and some of the mechanics there, and maybe when we might hear more about that or you'll give an update on that if you are. Yeah, we have an interim assessment through an independent committee just for sample size re-estimation. I think in terms of the details of that, we're intending to either convey updates as early as, you know, Obesity Week, which is the first week of November, or maybe by the Q3 update on where we are. In terms of the outcome scenarios of that interim, is it basically, you know, this trial is still well powered or you need to add patients? Just curious what some of the outcome scenarios here are. Yeah, we have optionality to add more patients, I think up to 100. I think up to 130 patients, I believe, but I forgot the exact number. We don't expect it to need to really do that much, frankly. It's there in terms of the protocol for size resizing if needed. Okay, right, great. Maybe just so that all makes sense, maybe just in the last couple of minutes here, just to make sure we highlight it, it'd be great to just get a quick overview on your other program, ARD-201, and kind of for obesity in general. I know you've shared some animal data and you announced some development plans. It'd be great to just get the quick overview there. Great, we're very excited about this. 201 is our other program, which is really just a fixed dose combination of ARD-101/sitagliptin, which is Merck's Januvia, which will be generic in 2026. When we used it together, sitagliptin really potentiates a lot of the activity for ARD-101. As Tim had mentioned before, our drug induces the release of a number of gut peptide hormones, some of which are substrates for DPP-4, which rapidly degrades them. If you have a DPP-4 inhibitor, we can actually augment the hormones to exist longer. We looked at the gold standard model, the diet-induced obese mouse, which has been very translationally predictive of the efficacy in people. We saw 19% weight loss with that combination and that really supersedes what we actually previously thought because we optimized the PK of sitagliptin in our studies to reflect human biology and to give you a benchmark of what 19% weight loss in this model looks like in the same conditions for tirzepatide. Tirzepatide conveyed about 20.5% in that model. We're almost there in terms of comparison with injectable GLP-1 receptor agonists with a drug combination that we don't expect to induce nausea. Notably, the other part of the data that we released recently is the fact that when we optimize weight loss with tirzepatide, when we bridge them off into ARD-201, they have weight maintenance statistically similar than if they maintain on the injectable GLP-1RA. That was very encouraging. One of the really intriguing things that we shared recently is also when you combine a microdose of tirzepatide, 1/10 the dose, which corresponds to a clinical dose up, which corresponds to below the starting clinical dose that you wouldn't even expect nausea in most people. When you do the microdose of GLP-1 plus ARD-201, we see a 30% weight reduction in DIO mouse. It really supersedes what we think even the injectable GLP-1s achieve in the same model. We're very excited about that and our clinical studies are going to be reflective of that data. We're trying to recapitulate the observations in people with our power and strength studies upcoming. Awesome. Great. Definitely looking forward to more updates there, and we're up on time, but this was a super helpful discussion. Thanks, Tien and Tim, for joining, and thanks everyone for listening in. Thanks for having us, James Of course.