Good day, and thank you for standing by. Welcome to Aardvark Therapeutics Obesity Week Investor Webinar. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today. Nelson Sun, Chief Financial Officer of Aardvark Therapeutics. Please go ahead. Thank you. I want to Welcome everyone to our Obesity Week Investor Webinar. During this call, we will be making forward-looking statements related to our current expectations and plans for the company, as well as our clinical programs and ongoing preclinical work across our portfolio. Forward-looking statements are subject to risks, uncertainties, and other factors, including those outlined in the press release we issued yesterday and our recent filings with the Securities and Exchange Commission. These statements represent our views as of this date and should not be relied upon as representing our views of any subsequent date in the future. I'll turn the call over to our CEO, Tien Lee. Thank you, Nelson. Thanks to everybody for joining us today. In recognition of our data presentations at Obesity Week, we'll be spending the first part of today's agenda focused on our metabolic obesity programs, including ARD-201 and WE-868. ARD-201 is planned to be a fixed-dose combination of our TAS2R agonist and DPP-4 inhibitor, showing very promising results in preclinical studies and based on earlier clinical studies with ARD-101. WE-868 is a program that we in-licensed prior to our IPO. We are conducting preclinical studies to explore its novel mechanism for obesity. Our Chief Scientific Officer, Tim Kieffer, will discuss the data we presented this week at the Obesity Week Conference for our ARD-201 program, as well as a first look at preclinical data from our WE-868 program. We will then welcome two esteemed guests, Dr. Tony Lam of the University of Toronto, who will discuss nutrient sensing and the gut-brain axis, and Dr. Caroline Apovian, Co-Director of the Center for Weight Management and Wellness at Brigham and Women's Hospital, who will discuss trends in obesity clinical development. Finally, we'll turn to our most advanced program, ARD-101, which is currently in the HERO phase III study for the treatment of hyperphagia associated with Prader-Willi Syndrome. Our Chief Medical Officer, Dr. Manasi Jaiman, will provide an overview of that program, then lead a conversation with Stacy Ward, CEO, and Dorothea Lantz, Director of Community Engagement, Prader-Willi Syndrome Association USA. For those new to our story, I wanted to start with a few highlights. About how we're positioned for success in an important year ahead. Our most advanced programs are focused on targeting hunger to treat rare metabolic diseases and obesity. We expect to achieve multiple meaningful milestones in the next year, including a potentially pivotal phase III data readout for our lead product candidate, ARD-101, for the treatment of hyperphagia due to the rare disease Prader-Willi Syndrome. The program represents a validated, attractive market opportunity, as evidenced by the strong uptake for the first therapy approved for the treatment of hyperphagia due to Prader-Willi Syndrome. In addition, we are focused on advancing novel approaches that address the limitations of existing therapies for obesity, which are the focus of our presentations at Obesity Week. There are two drives for eating behavior: appetite and hunger. Appetite is a reward-focused drive, while hunger focuses on pain avoidance. Imagine a situation where your only food option is really low quality, like dog food. Initially, you'll have no desire to eat it. That's appetite. Given enough time, you'll eat it to alleviate the pain of hunger. These two drives are in balance, and when we eat food, gut- peptide hormones are released that regulate both appetite and hunger. We believe our proprietary compound, ARD-101, uniquely addresses hunger through gut-brain signaling, whereas GLP-1-based approaches rely primarily on appetite signaling. ARD-101 is a gut-restricted oral small molecule. About 99% of the drug is retained in the gut. We are targeting enteroendocrine cells in the gut, where ARD-101 induces secretion of peptide hormones that, in turn, activate vagus afferent signaling to the brain to shut down hunger. Importantly, for today's discussion, we are also developing ARD-201, which is planned to be a fixed-dose combination of ARD-101 with the DPP-4 inhibitor, sitagliptin, for both weight loss and weight maintenance post-GLP-1 withdrawal in metabolic obesity. We are advancing three clinical trials: the potentially pivotal HERO phase III study of ARD-101 for the treatment of hyperphagia due to Prader-Willi Syndrome, the POWER study of ARD-201 to prevent weight regain in patients with established weight loss on GLP-1s who want to bridge to an oral therapy to maintain weight, and the STRENGTH trial, which is assessing ARD-201 both as a monotherapy and in combination with GLP-1 drugs for induction of weight loss. We anticipate the top-line data for the HERO clinical trial to be available third quarter of 2026. The POWER trial will start later this year, with anticipated preliminary or interim data available second half of 2026. We will be initiating the STRENGTH study in the first half of 2026. With that very high-level introduction of Aardvark, I'd like to turn the webinar over to Tim Kieffer, our Chief Scientific Officer, who will first discuss the data we presented on ARD-201 and then the early data on WE-868. Tim? Thank you, Tien. I want to start with a discussion on the rationale for ARD-201. As Tien noted, ARD-201 is planned to be a fixed-dose combination of our proprietary TAS2R agonist, ARD-101, and the DPP-4 inhibitor, sitagliptin. Why do we think this combination has potential in metabolic obesity? ARD-101 stimulates the release of multiple gastrointestinal hormones like CCK, GIP, and GLP-1 via activation of gut-based TAS2Rs that are located on the luminal side of enteroendocrine cells. These hormones can then activate neural pathways originating in the gut and traveling to the brain to dampen appetite and hunger. However, gut hormones are rapidly broken down by the enzyme dipeptidyl peptidase-4. This is where sitagliptin comes in because, by inhibiting DPP-4, it extends the biological activity of gut-peptides, including GIP and GLP-1. This is the basis for its use in treating type 2 diabetes. Thus, with this uniquely fully oral combination, we are aiming to boost the release of a spectrum of gut hormones and extend their biological activity. Importantly, this approach allows the hormones to act at their native site within the gut without achieving chronic pharmacological systemic levels that can induce nausea. Our Obesity Week data is shown here. In the diet-induced or DIO mouse model, a gold standard in translational research in obesity, administration of ARD-201 resulted in 19% weight loss in 30 days. In comparing to the trajectory of weight loss for ARD-101 or sitagliptin as monotherapies, the combination demonstrated a synergistic effect that was almost on par with that achieved with a high dose of tirzepatide, which was 20.5% weight loss at 30 days. That experiment was assessing ARD-201's potential as a therapy to promote weight loss, but a significant challenge for GLP-1 therapies is weight rebound following withdrawal. We modeled discontinuation of a dual GLP-1/GIP receptor agonist. Mice were treated with high-dose tirzepatide and then randomized to several post-tirzepatide paradigms: vehicle, high, or microdose tirzepatide, ARD-201 alone, or ARD-201 combined with the microdose of tirzepatide. Please note two key findings here. The ARD-201 maintenance arm showed preservation of prior weight loss after stopping tirzepatide, equivalent to staying on high-dose tirzepatide, and ARD-201 combined with the tirzepatide microdose ultimately achieved approximately 30% weight loss. I want to now share additional data on body composition. It is widely known that patients who are on GLP-1 therapies for weight loss experience the loss of lean body mass. This can increase the risk of sarcopenia and may exacerbate the weight rebound problem. We wanted to understand how DIO mice would respond to ARD-201 with respect to body composition. You'll see in this slide that we present data for fat mass and lean mass in two ways. On the left, we present the body composition in terms of the percent of fat versus lean mass at the end of the study. On the right, we present the data as grams fat versus lean body mass. Note that while animals maintained on high-dose tirzepatide had significant loss of both fat and lean mass, animals transitioned to ARD-201 spared lean mass. Moreover, recipients of ARD-201 and the microdose of tirzepatide lost the greatest amount of fat. In addition to assessing body composition, we also dug into glucose homeostasis. Mice treated with ARD-201 demonstrated improvements in glucose tolerance compared to vehicle and similarly to the mice maintained on the higher dose of tirzepatide. Glucose tolerance was further enhanced in the recipients of ARD-201 microdose tirzepatide combo. These are significant findings given that diabetes or pre-diabetes often accompanies obesity. In addition to presenting our preclinical data for ARD-201 yesterday, we highlighted our clinical experience in metabolic obesity for ARD-101. A reminder that ARD-101 is our proprietary TAS2R agonist alone, and ARD-201 is a planned fixed-dose combination of ARD-101 and sitagliptin. These data were generated in a phase II placebo-controlled randomized blinded study in adults with obesity, and it showed encouraging trends with respect to percent body weight loss over the brief 28-day course of the study and in a follow-up, as shown in the left graph on this slide. By the end of study, there was a placebo-controlled differential of about 1.3 kg. For comparison, in the step one trial evaluating 2.4 milligrams of semaglutide, the placebo-corrected weight loss after four weeks was approximately 1.6 kg. It's important to note that participants in our clinical study received no diet or exercise counseling, as is typical in many obesity clinical studies. In addition, as part of this study, we assessed self-reported measures of hunger and food craving, and those participants in the ARD-101 arm had significantly lower hunger-related scores and food craving compared to those taking placebo. In the metabolic obesity indication, similar to our phase II clinical experience with patients in PWS, there were very few adverse events in phase II. We feel these findings with ARD-101 alone and the preclinical data for ARD-201 that I detailed earlier in this talk support our hypothesis that combining ARD-101 and a DPP-4 inhibitor may generate synergistic results. We are also hopeful that the combination of ARD-101 and sitagliptin will be highly tolerable, given our ARD-101 data and sitagliptin safety profile. Now that I've detailed our 201 data, I want to turn to a new program we're working on for metabolic obesity, WE-868, which we've not spoken about until now. WE-868 is a synthetic isoflavonoid that modulates cellular energy use via mitochondria but without mitochondrial uncoupling. The compound reduces oxidative phosphorylation, the metabolic pathway that generates the majority of a cell's energy. When oxidative phosphorylation is reduced, the cells turn to glycolysis and lipolysis pathways, thereby increasing energy expenditure. It's especially important to flag that the WE-868 mechanism of action is distinct from classic complex I inhibitors and has shown no evidence of mitochondrial uncoupling with WE-868. What piqued our interest in WE-868? Originally developed for its potential downregulation of mitochondrial activity in tumor tissue, in a phase I-b study combining WE-868 with bevacizumab in patients with colorectal cancer, subjects treated with WE-868 lost an unexpected amount of weight, a 10.3% average weight loss over a mean treatment of 92 days. 19% of subjects lost more than 15% of their initial weight. WE-868 was generally well tolerated in this study. I want to emphasize that while WE-868 was originally developed in oncology, it appears to be much better tolerated than most small molecule cancer drugs based on the one phase I-b data. Based upon these clinical observations, we assessed WE-868 for weight modulation in preclinical models. We first assessed if WE-868 can prevent weight gain in mice switched from standard low-fat chow to a 60% fat diet. We examined weight changes at two doses over 60 days, and both the low dose and high dose blunted weight gain. We also assessed body composition changes, and they indicate fat mass reduction with preservation of lean mass, as you can see in the graph on the left of this slide. While the data is not shown here, I wanted to point out that we also saw supportive changes in glycemia and liver stress markers consistent with improved metabolic health. Building on the data showing the potential for WE-868 to attenuate weight gain, we wanted to assess its ability in mice to induce weight loss. For this experiment, we again used the well-validated DIO mouse model. Here, the mice were obese at the start. In the 39-day course of the study, we saw dose-responsive weight loss for the mice given WE-868. Compared to semaglutide, both the low and high dose of 868 generated greater weight loss at the end of the study. We also observed favorable shifts in body composition for the mice dosed with 868 compared to vehicle and semaglutide. We also assessed glucose homeostasis via IP glucose tolerance testing, and those results demonstrated significantly improved glucose tolerance for the mice dosed with 868 compared to vehicle. The results of our work on 868 demonstrate potential for the compound to be further developed in metabolic obesity. We will continue to generate preclinical data on this program, but we remain focused on our lead programs, ARD-101 in Prader-Willi Syndrome and ARD-201 in metabolic obesity. With that, I'm happy to welcome my Canadian colleague, Dr. Tony Lam, professor at the University of Toronto and the associate director of the Banting and Best Diabetes Centre, to discuss nutrient sensing and gut-brain axis, a subject that Tony is a world-leading expert. Thank you so much for joining us today, Tony. Thank you, Tim. For the past 20 years, my lab at the University of Toronto, Toronto General Hospital, as well as the Banting and Best Diabetes Centre, has studied the gut-brain axis. In particular, we wanted to know how the gut-brain axis would regulate feeding, body weight, and glucose homeostasis. We were interested in this, along with all the other labs around the world are, is because there is clearly a huge unmet need with respect to lowering weight or to cure obesity, with all these complications that come along. Although we do have good options for lowering glucose for diabetes, yet losing weight becomes a priority. We were interested for the past 20 years in the gut-brain axis for the following reasons. There were now a large fold of studies that were done in both. Rodents, humans, monkeys, and other species you can think of that have looked at this gut-brain axis. In simple terms, we and others believe that this gut-brain axis in parallel could regulate how much you eat. Appetite, feeding, hunger, as well as, at the same time, glucose homeostasis. We believe this concurrent, rapid axis could take place because it all started with signals that are generated by nature, such as taking a meal. In this particular case, lipids. We and others demonstrated that when we simply put in a small amount of lipids that mimic a meal into the upper tract of the small intestine, before the lipids have a chance to enter the blood circulation while it's still in the upper small intestine, it could rapidly trigger a gut-brain afferent axis within minutes. This, within minutes, could impact how much we eat and how much glucose is regulated in the body. Because of that, we spent the past 20 years looking at what are the signals that could come from this. Nutrient-stimulated conditions that are engaged by lipids and more so glucose as well. As you can see in this busy diagram, I apologize for the busyness here, but I am attempting to take the reviews and the work that we have done from our own lab to give you the perspective that we have done in the past 20 years within the limited time that we have. Within this time frame, we were able to explore a few signals that could be generated with respect to lipids and glucose taken after a meal. These signals are generated originally within the enteric endocrine cells, as Tim has mentioned prior. Both lipids and glucose, when entering into these cells, would go through multiple biochemical pathways that would involve the mitochondria that was just mentioned earlier. These signals, without highlighting too much of the details, eventually, within seconds, would trigger the release of two key peptides that are made and secreted from the enteric endocrine cells. This has been demonstrated in both humans and rodents. They are CCK, as you can see in the middle of the diagram, as well as the world-famous GLP-1. It is important to note that the release of CCK and GLP-1 within minutes will activate hormonal-dependent receptors that are believed and has been demonstrated to be expressed and found on the vagal afferent nerves that innervate this part of the intestine. We believe, we and others believe, that the activation of the release of these hormones, all due to the. Nature-triggering signals such as lipid and glucose will bind to the receptor without needing the hormone to enter the circulation to exert its endocrine effect. This rapid effect will then transmit via the vagal afferent to tell the brain, as I would have coined earlier, remotely to regulate feeding and glucose, as shown in the previous diagram. Apart from understanding the signals that are generated within the intestine, one needs to understand the overall picture, how these gut-brain axis are regulated. This is a simplified diagram that was highlighted by our lab, of course, based on many years of studies from many laboratories around the world that have contributed to this. In short, I would like to put the focus on the vagal afferent nerves within this diagram, where the nodose ganglion is found. This is the site, this is the area within the vagal afferent where the signals are detected and relayed to the brain to facilitate the gut-brain axis that was just described to regulate feeding, food intake, as well as glucose homeostasis. Of note, these signals are generated not only from the small intestine, as we were referring to earlier, but as well as the stomach as well. It is not just a matter of a rise of nutrients, but it is also a lack of it that can have a bidirectional viewpoint in determining the signals, how it should be sent and relayed via the nodose ganglion to the brain. By looking at multiple mechanical-induced changes at these branch points, as well as at the level of the intestine. More or less, the overall idea is that this vagal afferent gut-brain axis can serve as a key mediator, as we believe for the past 20 years, that is relaying signals, particularly after a meal, that is, while it's still within the stomach and/or the intestine, that is enough to trigger this nodose ganglion-dependent vagal axis to regulate obesity and diabetes. It is important to understand the fundamental physiological signals that are generated from the intestine, how it communicates via the central nervous system in the brain to regulate weight and glucose. It is equally important to understand how these pathways could be disrupted in the context of obesity, leading to a rise of hyperphagia, feeding, as well as dysregulation of glucose. Part of the disruption is due to changes in microbiome, as we have found out from studies that are published by many others, as well as by our own as well, as we view in this review. Changes in microbiome, as incurred in both humans and rodents by high-fat diet, could change many, many things, including microbiota-derived metabolites such as bile acids. These bile acids, as shown, could trigger multiple receptors to affect this gut-brain axis that we began to describe. This disruption largely is disrupting the ability of lipids, glucose, or proteins, nutrients, to stimulate the release of GLP-1 and CCK. Hence, you can almost predict, based on the findings prior, this will lead to the inability to trigger this gut-brain axis to regulate feeding and weight. Many, many labs around the world are trying to understand, in a cell-specific manner, what are the mediators in this disrupting pathway that could have incurred by changes in microbiome. How we can restore these disruptions. I just want to highlight. It is important to look at the upper small intestine, as shown in the left, as abbreviated as USI, particularly where CCK and GLP-1 are secreted. We found recently, when it comes to protein sensing, such as casein, that is found exclusively in milk products, that these pathways that are triggered by proteins in the upper tract do share similarity but also major differences in the lower part of the intestine, such as the ileum. We found that although some molecules, as shown in this diagram on the left, could regulate feeding and glucose, the same molecules, such as PEPT 1, may not be able to regulate food intake in the lower tract. It all depends which site one is targeting. Although the same molecule could have completely different functional output on feeding and glucose regulation, thus making the case extremely important that when it comes to activating this gut-brain axis, we and others believe that the initial signal would have to come from cells within either the upper tract or the lower tract, such as the ileum, or maybe both at the same time. It all depends what one wants to trigger in terms of GLP-1. Did not talk too much on, which is the GIP, as well as PYY. It all depends what we would like to alter. Now, it is understood to, it is important, I guess, for many of us to view the gut-brain afferent axis in the context of the weight-lowering effect of GLP-1 receptor agonists that we now see worldwide. We recently wrote a commentary on a paper in Nature that looked at GLP-1 receptor agonists. I, again, took the advantage of focusing our own review such that we can give you the journey that we took, which made the case, in my view, that gut-brain afferent axis could be able to employ to bypass some of the nausea-dependent effect that is coming from the clinic in the direct effect of GLP-1 receptor agonists, as shown in this diagram on the right. Particularly in the area of the site where GLP-1 receptor agonist is acting directly in, such as shown in the bottom right. Rectangle there, there's an area in this area called the AP, which is referred, which is always known as the area postrema. Of note, this is where the GLP-1 receptor agonist is activating its receptor that is expressed in that nucleus to cause nausea-dependent effect. We and others believe that by triggering the release of GLP-1 from the gut, not reaching at a pharmacological level, which would have elucidated these nausea-dependent direct effects that one sees due to its endocrine effect, we believe that taking advantage of this remote gut-brain axis could remotely still achieve the same weight-lowering effect of GLP-1 receptor agonists, but without incurring the nausea-dependent effect that is only seen in a pharmacological dose. In summary. We also believe that the bitter taste receptors do play an important role in this gut-brain axis, remotely regulating feeding and glucose for various reasons, existing literature, of course, but particularly that the bitter taste receptors are expressed throughout the small intestine, be it the upper small intestine that we saw in the earlier figure, as well as in the ileum. As to what the receptor does within these cell-specific areas remains to be studied. All in all, if one, as published by a previous group, which I am not aware of the study earlier, but as I dug more into it, there are studies showing that if one administers a bitter taste receptor agonist in this particular case, it has been found to rapidly increase against the two peptides that we have focused on, CCK and GLP-1. Although they did not demonstrate directly this could have led to the drop in feeding, they did show in the same subject. In parallel to an increase in CCK and GLP-1 in response to the agonist administration, it did lower feeding. A lot more study needs to be done, from my point of view, at least from an academic point of view, in understanding the mechanistic contribution and the relative contribution of how the bitter taste receptor, together with lipid sensing or potentially other nutrient-sensing pathways, could take place under a physiological context or pharmacological context. All in all, we and others believe that the gut-brain axis could be employed, particularly targeting in a gut-restricted manner, to rapidly lower feeding, weight, and glucose levels to combat obesity and diabetes. Thank you. Thank you so much, Dr. Lam, for sharing with us. Next on our agenda is Dr. Caroline Apovian, co-director, Center for Weight Management and Wellness at Brigham and Women's Hospital, and professor of medicine at Harvard Medical School, who will discuss trends in obesity clinical development. Dr. Apovian? Thank you. I am going to be talking about what's been going on in the obesity field. I've been in the field for 35 years. I'm one of the co-founders of the field of obesity medicine. Now we have, through the fellowships that we've developed in obesity medicine all over the country, we started with five fellowships, and now we have 35. We're graduating doctors who know how to treat obesity. Now we have drugs that can safely and effectively treat it. This is where I work at the Brigham and Women's Hospital, and we are now merged with the Mass General Hospital. Both of our weight management centers combined see 24,000 patients per year. This is my team at the Brigham. We employ doctors, nurse practitioners, physician's assistants, dieticians, exercise physiologists, and psychologists to treat obesity in a multidisciplinary manner, including diet and exercise, medications, and bariatric surgery. Next slide. As you heard from Dr. Lam, there is circuitry that regulates your body weight within a very, very tight control. The hormones that come from the gut go to the brain. What they are doing, basically, especially leptin that comes from fat tissue, is protecting fat mass. The brain gets signals when you eat that are computated, and the brain figures out if you have eaten enough. If you have eaten enough, you get signals back saying you are full. If you have not eaten enough, you still get hungry. These are the hypothalamus neurons, POMC and. Neuropeptide Y neurons, that get activated by our gut hormones. We have developed treatments over the past 30 years - 50 years because the prevalence of obesity has been increasing in the United States and worldwide. Why has the prevalence of obesity been increasing? We believe it is the environment that has changed, not our genes. Our genes have not changed, but the environment, and specifically what in the environment, has not been proven yet. We have very good intel to suggest that it is the food supply. It could be ambient temperature. It could be an endocrine disruptor in the food supply or in the air. It has not been proven yet. The drugs that we have available—this is a paper a few years ago published in the New England Journal reviewing lifestyle versus pharmacotherapy. Pharmacotherapy certainly improves weight loss at one year. Since that time, we have developed better medications. The GLP-1, GIP era, we're now in it. In the future, we'll have triple. I heard the other day, penta agonists, five different agonists in one pen. What we're trying to do is to mimic the effects of bariatric surgery. Bariatric surgery changes the gut hormones of five and more hormones. What we're doing with our injectables now is trying to mimic the effects of bariatric surgery. Here's what the schematic looks like. The hypothalamus is in the middle there with the POMC and NPY neurons. There are afferents coming from the gut. Note that we've got insulin and leptin there. Insulin is an anabolic hormone. Leptin protects fat mass. There are CCK, PYY, GLP-1, GIP that signal to the brain. We think that there has been some kind of. Inflammation due to something in the environment that has caused these signals not to be able to get into the hypothalamus, and we're all defending a higher body weight. This is an old, this is a graph from a paper that Rudy Leibel published in the New England Journal of Medicine. One of the discoveries of leptin. When you gain weight, so he had people gaining weight. On the left there, 10% weight gain causes an increase in total energy expenditure of about, sorry, 500 calories per day. When you gain weight, you increase your total energy expenditure by about 300 calories-500 calories a day until you lose it. When you lose weight, 10% or 20% weight loss, he showed that your total energy expenditure drops by 300-500 calories a day until you regain that weight. That is the work of the hormones, including leptin, that signal to the brain. Where do they signal? They signal to muscle to make muscle more efficient at burning energy until you've regained that lost weight. This paper was translated sixteen years later. This paper by Proietto and colleagues showed that if you put men and women on diets and they lose 30 pounds over the course of 10 weeks, there will be weight regain after that. That is the next slide. This is what they did. They put patients on a very low-calorie diet for 10 weeks, and you see that 30-pound weight loss. Over the course of the year, people regained weight. Not only did they look at that, they looked at the hormones in the blood now. They looked at leptin, PYY, CCK, insulin, and amylin. Also the hormones that we know have something to do with hunger. Leptin, PYY, CCK, insulin, and amylin cause satiety in the brain. Ghrelin and these other hormones cause hunger. Leptin levels were reduced by 65% due to a 14% weight loss. That 30 pounds represented 14% total weight loss. Leptin levels dropped by 65%, which means you get really, really hungry because your body thinks it is starving. There is not enough fat tissue. Same with PYY, CCK, insulin, and amylin. Some of these hormones Dr. Lam talked about. The increase in ghrelin produces short-term hunger. Basically, after these patients were off this diet, they were preoccupied with food for the rest of the year, more preoccupied than before they lost the weight. The net result of all of this is weight gain. What are we trying to do with our new hormones? Again, we're trying to mimic the effects of bariatric surgery. This is the Roux-en-Y gastric bypass. This small pouch that's created right up there in the yellow, the small gastric pouch, and you bring up a piece of jejunum. That's the surgical operation. What that does is. The food goes down into that small gastric pouch, into the jejunum, and the jejunum produces some of these gut hormones: GLP-1, GIP, PYY, CCK. Smaller amounts of food are in contact with the cells that produce the satiety hormones earlier. These hormones are secreted, go to the brain, induce satiety with less food. The ghrelin-producing cells are in the stomach that is isolated now from the pathway, the food pathway. Those cells do not see food and are not activated, so you do not get hunger. That's why the gastric bypass works. That's what we're trying to mimic with the production of GLP-1 analogs. Okay. I think this is exactly what Dr. Lam was talking about, that these gut hormones are secreted by the gut. I'm talking about the vagus also gets the afferent vagus does see these hormones, but so does the bloodstream. Here is a schematic showing the efficacy of current and newer anti-obesity drugs as compared to bariatric surgery. How much weight loss can you get with bariatric surgery? You can get 25% from the sleeve gastrectomy, 35% from the Roux-en-Y gastric bypass. That's really tremendous weight loss. With these newer GLP-1s, semaglutide is giving us 16%-17% weight loss at one year. Tirzepatide is now giving us 20%-22% weight loss at one year. You see that we're approaching the kind of weight loss you can get with surgery. As I said before, surgery is adjusting the secretion of multiple hormones, not just one or two. In the future, we'll probably have triple agonists. Retatrutide is going to come out. Amylin agents that are co-formulated with semaglutide and tirzepatide, and even others. What we're going to see is that there will be a multidisciplinary approach to obesity that includes combination drugs. If those combination drugs give side effects or people do not lose weight on combination drugs, another approach would be, with patients who have a BMI over 40 or over 35, metabolic bariatric surgery. The mechanisms behind the weight-reducing effect of these GI peptides, they work in many different parts of the body. There are receptors in the brain, in the gut. In muscle, what they do is they uncouple. You You have uncoupling going on, and that is why GLP-1 seems to increase energy expenditure. If the uncoupling is too intense, we think that is why we are seeing GLP-1 cause fatigue. GLP-1 and GIP cause fatigue in patients taking these agents. We have to do more research on that to figure out what exactly is going on. That may be a limitation of the super physiologic doses that we are giving of GLP-1s that Dr. Lam was talking about. We may have to be more careful. These are super physiologic doses. They are not the physiologic doses that you see when food enters the GI tract. The advantages of targeting multiple agonists is that, again, we are mimicking the effects of gastric bypass surgery. Unlike bariatric surgery, bariatric surgery is still working because it is altering the gut hormone secretion when food enters the GI tract. We are giving injectables once a week now, having nothing to do with food intake. That is part of the problem. All right. What are our current unmet needs? I just mentioned a few of them. Others are the nausea that Dr. Lam talked about. The nausea can be significant, and that is why the makers of these drugs, liraglutide, which is Saxenda, semaglutide, and tirzepatide, have dosed them, have had multiple doses starting at a low dose and going up to mitigate the side effects of nausea and vomiting, diarrhea, and constipation. If you think about it, the reason why people have nausea and constipation is because. The super physiologic doses of these agents, if you eat too much, if you're at a dinner and you eat too much, what happens? You get nauseous. That's the action of GLP-1. To tell you you're full and you're too full. And what else does GLP-1 and GIP do? They delay gastric emptying. If you really delay it, you get constipated. That's another super physiologic effect of these GLP-1s. They're great, don't get me wrong, but there are these side effects. What is our new frontier to tackle? Yeah, we need to combine these agents to get, again, to where we are with metabolic bariatric surgery. Because after all, 35% weight loss is great. We don't really want to go beyond that. Beyond that will cause malnutrition and protein-calorie malnutrition. We want to get, with our injectable agents and the orals coming out, we want to get a little better weight loss. Wouldn't be bad. We do not want to cause it too rapidly, and we do not want to have nausea, vomiting, constipation. The next frontier is going to be to combine agents with what we call NuSH therapies, Nutrient-Stimulated Hormonal Therapies, which is GLP-1s, with agents that can mitigate that side effect profile. Okay. The other thing about this is that obesity is a chronic disease. When you stop GLP-1 therapy, you regain weight. We want to get to a point where we can have agents that patients can go on after they stop GLP-1s. What's happening now in Massachusetts is that in January, all the private insurers are going to stop covering GLP-1s. And now we're. Struggling to figure out what to do with these patients who can't afford $500 a month. What do we do? We need agents that can help maintain that weight loss. All right. We can talk about this later. Next. Body composition is another problem. The Obesity Week meetings are all about lean mass loss with GLP-1s. It is true. We are seeing lean mass loss. It is part of losing weight. You have to lose lean mass because of the Krebs cycle. What do we do when patients already have sarcopenia and are losing weight with GLP-1s, and they have lean mass loss, and then they are at higher risk for falls and osteoporosis? That is the other unmet need in these blockbuster drugs. All right. Thonese are the unmet needs. Dr. Apovian, really appreciate the insight you have shared today. Thank you for your time. We are now scheduled for a 15-minute Q&A session before we transition to our Prader-Willi Syndrome program. I encourage Q&A to focus on the obesity program. If we do not get to all of the questions, there will be additional Q&A at the end of the program. Maggie, will you open the floor for questions? Thank you very much. As a reminder, to ask a question, please press star one and one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. Please stand by as we compile the Q&A roster. Just a moment for our first question, please. First question comes from Josh Schimmer from Cantor. Please go ahead. Okay. Thanks for taking the question. Actually, a small world, Tony. My dad is Professor Emeritus at the University of Toronto and had his research lab at the Vest Institute, which I used to visit growing up. Thank you for the presentation and overview. Just curious about this lipid path through the vagal nerve and confirming that it is the exact same path that the TAS2R receptors are signaling through. Is there any preclinical data that suggests that these two signaling approaches down the same pathway may be synergistic? I know you identified that as an unknown, but curious if there's been any work done to date to suggest that attacking this pathway from the two mechanisms may be additive. Hi, Josh. This is Dr. Lam here. Thanks for your question. If I hear you correctly, you're asking whether there are evidences to suggest that the. TAS2R receptor pathway within the gut shares similarity with the lipid-sensing pathway that will eventually go to the gut-brain axis. Is that what you were asking? Correct. And whether there is any evidence to suggest that. A two-pronged approach combining these modalities may be synergistic or additive. I think it remains preliminary in nature, but it does suggest there could be some overlap because it does suggest that both CCK and GLP-1 are involved. Very similar to what we and others found when it comes to lipid-sensing. When it comes to the upstream pathways, I think there could be synergism that could have caused a further rise of CCK and GLP-1, perhaps, in various obese, diabetic, as well as healthy conditions. That remains to be seen. Okay. Got it. Maybe a quick question for Dr. Apovian. You mentioned that in Massachusetts, coverage of GLP-1 for Medicare. Will be expiring. Would there be any rationale for CMS to cover an alternative obesity drug? Just a little bit confused as to what you were trying to message in terms of an unmet need with lack of coverage and then why another compound might be covered. No. Yeah. I did not make myself clear. I'm sorry about that. In Massachusetts, come January, the private insurers, all private insurers in Massachusetts, so United, Harvard Pilgrim, Blue Cross, Blue Shield, Aetna, will stop coverage of GLP-1s because it is just too expensive for them. For any reason. They are still going to cover for type 2 diabetes, but not for obesity. Clinically, because we have so many patients on them right now, 24,000 patients just in the MGB system, we're going to, of course, those who can pay $500 a month through NovoCare or LillyDirect will be able to continue to. The $500 a month. Most of our patients are not going to be able to stay on those medications indefinitely. I'll argue that even our wealthier patients, they do not want to stay on these drugs indefinitely at $500 a month, even though we're trying to tell them, "Just consider it a car payment because you've lost 50 pounds." What we need to do is to figure out how to maintain the dramatic and healthy weight losses that these patients have incurred. Are those patients who are not going to be able to stay on GLP-1s. We have our older oral medications that, of course, we're going to use. Bupropion, naltrexone, phentermine, etc. But they're not going to be for everyone. These oral agents were certainly not as effective as our GLP-1s and have other side effects: blood pressure increases, insomnia, and other things. That is what I was talking about. Now, whatever is happening at the government level with Medicare is aside from this. Medicare in Massachusetts and in many other states do not cover GLP-1s, period. MassHealth, so Medicaid, is the only insurer right now that is still actively going to cover only Zepbound, and only after you try three months of phentermine. Does that answer your question? Sure. Thank you. Thank you. Just a moment for our next question, please. Next, we have James Condulis from Stifel. Please go ahead. Hey. Thanks for taking our question there. It's Mark on for James. I actually had two questions. One for ARD-201 in general obesity and then one for the isoflavonoid compound that you guys shared today. I guess for 201, the preclinical weight loss data totally look encouraging. We're wondering if you can maybe help contextualize the doses and exposures of the incretin compound in the mouse models as an active reference arm for 201 and how that potentially maps onto where things are being dosed in patients and how comparable that is. For WE-868, the phase IV open label, they'd also look interesting. Wanted to know if you could maybe explain how we could potentially decouple the weight loss effects of the isoflavonoid from maybe the other cancer drug being dosed concomitantly. Thank you. Hi, Tim Kieffer. I'll start with the 201 question, then we'll turn it over to Bryan to comment on the WE-868. Your question on 201 was about the GLP receptor agonist that we're using, the doses, and how that correlates to clinical use. Is that correct? Yeah. Exactly. Yeah. Yeah. Thanks for that question. It's very provocative to us that the combination of 201 with the GLP receptor agonist had such tremendous synergy. Specifically, the typical doses we've used, both of semaglutide and tirzepatide, are close to the maximal effective dose in the DIO model. We're using the same sort of doses of these agents that Novo and Lilly have used and others are using in this model to achieve kind of maximal levels of body weight loss. I will just point out that the dose we call the microdose of tirzepatide, one nanomole per kilogram, which was one-tenth of our high dose, 10 nanomoles per kilogram, would be probably. An order of magnitude lower than the starting dose used clinically for tirzepatide. That's really encouraging to us because we're trying to get away from the nausea that you heard about as a real limiting factor for taking GLP receptor agonists and is probably a key reason why a lot of patients drop it, don't get the long-term medical benefits, including the cardiovascular benefits, and therefore why I guess there's debate over medical coverage if patients aren't going to stay on them long enough. I hope that answered your question. Yeah. That's helpful. Thank you. And then for the isoflavonoid? Yeah. Bryan. Yeah. I'll address that. I mean, the original theory behind that compound was that your cancer cells require more energy. If you can inhibit mitochondrial function, you would preferentially inhibit cancer cell growth, right? That was the theory. What we've shown is actually, in mouse models which have no cancer, they actually do lose weight. In that way, you have decoupled from the cancer therapeutic. As far as the clinical data that was out there, the patients that were being treated were a type of cancer where they typically are not losing weight, and the therapy that they were being given was an antibody, so not a chemotherapy that causes the loss of weight. Really, we're pretty convinced that the isoflavonoid is directly impacting the weight loss. Thanks. Thank you. Just a moment for our next question, please. Next, we have Melanie Fong from Bank of America. Please go ahead. Hi. This is Melanie on for Tim Anderson. I have a more commercially oriented question. Given that the PARA trial is expected to initiate later this year, and marketing companies such as Lilly already have weight maintenance trials ongoing for their oral therapies, could you potentially elaborate on your current thinking around ARD-201's differentiation and potential marketing position or market positioning outside of maybe tolerability and weight maintenance when it may potentially be later to market? Thank you. Yeah. I think that's a good question. Yeah. I think there are a lot of unaddressed space for obesity management. Right now, the way we conceptualize how we could be positioned, prospectively because of the safety profile and unique metabolic changes that is inferred here, either as an alternative prospective weight loss agent, and this is what we're going to interrogate through the STRENGTH trial. Second issue is what Dr. Apovian had elucidated in terms of the need for a reliable means for maintaining weight loss achieved on GLP-1. Potentially used in synergy with GLP-1 for even a greater degree of weight loss for those that haven't achieved the target weight. We are actually exploring multiple avenues for which this could be complementary to existing therapy. I think there's still a lot of space. I also want to remind that in the U.S., I believe more than 50% of patients that receive a GLP-1 prescription actually withdraw within three months. A lot of it is largely due to intolerance due to the GI side effects. Given the fairly strong expectation that our drug is not inducing notable degrees of GI disturbance or nausea because of the selective engagement of vagal afferents, those patients that cannot tolerate a GLP-1 otherwise would be potentially candidates for this treatment. I hope that answers your question. Let me know if I— If I may add, this is Caroline Apovian. The orals that are coming out, orforglipron and oral semaglutide and some of the others later, they're still GLP-1s. They still have side effects of nausea, vomiting, and other GI effects like reflux. They have a lower efficacy, some of them, not all of them, than the injectables. The unmet need is still going to be there with side effect profile. Okay. Great. Okay. Great. Thank you. Helpful. Thank you. Next, we have Raghuram Selvaraju from H.C. Wainwright. Please go ahead. Hi. This is Jade on for Ram. Thanks for taking our questions. You touched on it briefly before, but really what would you consider the most significant unmet need in that mass market obesity? Is it that ability to prevent the weight regain that we're seeing, or is there anything else that you really would consider more at the forefront? It's the biggest unmet need. It's not about preventing weight regain. Really, the biggest unmet need, you put your hand on it, it's not understanding that obesity is a chronic disease and that any of these medications need to be taken long-term. Even though the GLP-1s and the incretin hormones, we are all prescribing them, they have changed. They have changed already the health of people who are taking them. They are blockbuster drugs. There is no doubt. However, the biggest unmet need is that people still do not understand obesity to be a disease. We need a longer-term strategy. We need more convenient dosing. We need oral agents. We need monthly agents. We need agents that have less side effects: nausea, vomiting, constipation. What I talked about before is we do not know what the effects on the muscle are. We need a multimodal approach. The market is so open for other agents to add to our GLP-1s to either mitigate the side effects or become synergistic to promote more weight loss. We need a maintenance strategy that is cost-effective. I absolutely agree. Back on what you were saying about private insurers no longer paying for GLP-1s for obesity. Really, this may be completely beyond you and beyond the scope of this session, but where do you really see how we could get legislators, payers to understand this? I think that there are many strategies that have been put forth. One is that someone needs to understand—I'm sure people do. They're just not seeing beyond one year. The insurance companies are not seeing beyond one year because they know that if they wait five years, the person they're insuring now is going to be with another insurance company. Of course, you can say, "Well, then you're going to get people from another insurance company, and you're going to reap the benefits of their paying for a GLP-1." It's all going to be a wash in the end. Everybody will end up reaping the benefits of putting people on anti-obesity medication, the 42% of Americans who are eligible for them, so that we can get a 10%-20% weight loss across the board and reap the health benefits that we've seen with the SELECT trial, which showed the 20% reduction in cardiovascular MACE events. In patients with obesity. Thank you so much. Thank you. Due to time, I will now pass back to Tien. We will come back to questions towards the end of the call. Okay. Thank you so much for the questions. For the rest of today's webinar, we will focus on our Prader-Willi Syndrome program. I will turn over the program to our Chief Medical Officer, Dr. Manasi Jaiman. Thank you, Tien. Hyperphagia remains one of the most challenging and life-altering symptoms for people living with Prader-Willi Syndrome. It consists of a constant hunger that places a tremendous burden on individuals and families, with few effective treatment options available today. ARD-101 takes a new approach, working through the gut-brain axis to naturally stimulate key hormones that help regulate appetite and satiety. This novel mechanism may offer a safer, more physiologic way to reduce hunger and restore balance. Following encouraging results and strong tolerability in phase II, we're now advancing ARD-101 into a global phase III program, taking the next important step towards bringing a much-needed therapy to the PWS community. Now, to understand how ARD-101 works, it's important to look at the biology driving hunger in PWS. Patients with Prader-Willi Syndrome have disruptions in their hormones that regulate hunger, particularly CCK, as mentioned, a key satiety signal that tells the brain when the body is full. When this system isn't functioning properly, it contributes to excessive hunger and even leads to anxiety around food. Other metabolic issues also include constipation, increased body fat, and inflammation. Now, ARD-101 locally triggers the release of CCK in the gut, reactivating this natural satiety pathway. It aims to restore one of the body's most natural hunger-relating and regulating mechanisms by targeting this fundamental gut-brain signaling problem. Now, to further assess this, ARD-101 was evaluated in a phase II clinical trial involving patients with Prader-Willi Syndrome, ages 17 and older, over a 20-day treatment period. Hunger levels were measured using the HQ-CT questionnaire, a validated tool for assessing hyperphagia in PWS. During treatment, participants showed a meaningful reduction in hunger and food-seeking behavior, with an average improvement of about nine points on the HQ-CT scale. In addition, early signs suggested a more favorable balance between fat and muscle mass. Together, these findings demonstrate that oral ARD-101 can meaningfully reduce hunger in PWS, supporting its potential as a novel therapy targeting appetite regulation. We've learned a lot about the potential of what ARD-101 could do from the phase II study. This led us to the phase III HERO trial in PWS, which is now enrolling. We're excited to announce the trial now welcomes participants aged 10 and older, thanks to a recent expansion of eligibility. In this trial, participants are randomly assigned to receive either ARD-101 or a placebo for 12 weeks. After that, everyone will have the chance to continue in an open-label extension. The main goal is to measure change in hunger and food-seeking behavior using the HQ-CT questionnaire. This study marks an exciting next step in our journey to bring new hope and meaningful relief to those affected by Prader-Willi Syndrome. The HERO trial was carefully designed with families in mind to make participation easier, more flexible, and more meaningful. The schedule is simple, with just four in-person clinic visits and three telehealth check-ins. There's no need to fast or skip meals, and travel and lodging costs are covered, making the study accessible to more families. Participants keep their regular routines with the same caregivers throughout, so there's minimal disruption to daily life. To ensure accuracy, all study teams receive standardized training so every assessment is consistent across sites. When the main trial ends, participants, as I mentioned before, can continue in an open-label extension where everyone has the opportunity to receive ARD-101. Every detail of the HERO trial was built to support families, simplify participation, and focus on outcomes that truly matter. Now, even with recent progress, there's still a strong need for new options to treat hyperphagia and Prader-Willi Syndrome. Current therapies can take up to six months to show meaningful benefit. They also carry limitations, not recommended for those patients with kidney or liver conditions, and sometimes causing difficult other side effects like excess hair growth or swelling. In some cases, there are also safety concerns such as elevated blood sugar or ketoacidosis, which are especially important since many people with PWS already face metabolic challenges. That is why innovation is so critical. We need treatments that work sooner, reach more patients safely, and offer a better overall experience with fewer side effects and greater day-to-day comfort. For individuals with PWS who live with the constant burden of hunger and its impact on their health and the impact on their families, we need therapies that truly ease that struggle, improving each and every single day of their lives. That concludes my formal remarks. Now it is my pleasure to introduce our guests today. I have had the privilege of working with both Stacy Ward, Chief Executive Officer of the PWSA Prader-Willi Syndrome Association, and Dorothea Lantz, the organization's Director of Community Engagement. They are both exceptional leaders within the advocacy community, and we're honored to have them join us to share their insights and experiences. Welcome, Stacy and Dorothea. Thank you, Manasi. Thank you so much for being here. Let's get started. I'll start with you, Stacy. Sure. You speak with families and caregivers quite often. Can you describe the day-to-day experiences and challenges faced by caregivers and families with children living with PWS? Sure. What that looks like really changes depending on the age of the child. When a child is born with Prader-Willi Syndrome, the things that parents are first dealing with is that failure to thrive diagnosis. The child is in the NICU. They're not latching onto a bottle or a nipple. They're not gaining weight. Then they get the diagnosis, and they feel like the floor has fallen out from underneath them. They do not know what it is. They do not know where to find resources. In some cases, the diagnosis is delivered in a very disrespectful, dismissive manner. Families come to us at that point looking for hope. What will life really look like for my child? How do we apply for Medicaid? How do we get early intervention services? What therapies does my child really need to have at this point? That is really kind of from birth until about two. That is a lot of what they are reaching out and asking about. It is all encompassing for those families during that time. Around three, when we get to early intervention in school, things change. We start to see parents having to educate everyone else about PWS. How is everyone else going to keep their child safe now? Hyperphagia does not really—the average age is about eight when we start seeing her. Really because of growth hormone. Yes. Growth hormone has made a huge, huge difference in this. Around three, when they are introduced to school, what we start seeing is a preoccupation around the food and a different ability to access their curriculum and engage the same way their peers do. Parents are wondering at that point, "When is the light switch happening? What is happening right now? Are they already in hyperphagia? Is this normal behavior?" They are still doing all of their therapies, whether it is at school or at home or in a lot of cases, both. In some cases, we start to see some challenging behavior around that age. For families then, it is really all-encompassing. It goes from being about. Getting their child to gain weight and be healthy to how do we make sure our child is safe in every other environment. Through school age, it varies. I mean, some of the things that parents are calling us about are legal issues. Their child has been arrested for stealing food in a store. They are trying to manage every aspect of their child's life, keeping them physically safe, making sure that they're seeing doctors who know what Prader-Willi Syndrome is. Finding money to travel to the doctors who know what Prader-Willi Syndrome is so their child can get the best treatment. Fighting insurance companies for their growth hormone. Managing the food safety in their house. For many of those families, this is the age where we start seeing them lock pantries, lock their kitchens up, make physical modifications to their homes, enclosing their full kitchen, or putting a lock in the refrigerator, talking about what family planning looks like. Do we still want to have other children if this is their first child with PWS? And if it's not, how balancing other siblings and making sure they meet all of those needs. Post-school. The discussions change, and the needs change a little bit. We are at full-blown hyperphagia for almost everybody at this point. It is managing, in some cases, obesity. I think it is important to recognize that you can have hyperphagia and not be obese. Correct. Correct. That is a misconception. Very much so. That is a huge misconception. It often results in families being dismissed because their child looks good. They don't need assistance. They look good because their parents are spending 24 hours a day managing that. The parents aren't sleeping. Siblings aren't sleeping. Yes. They raised their hands. Yes. Dorothea can speak from a parent's perspective about some of this. This is. is. Their challenges with relationships at this point. Between 84%-88% of the PWS population are single parents. The divorce rate is exceptionally high because the stress of the caregiver in managing somebody with PWS really takes a toll on those relationships. There is the day-to-day of just managing their child and the day-to-day of managing everything. It's interesting. You made the statement about it's all-encompassing. It truly is, right, from the minute that they're born until the rest of their life. Correct. You have talked about the day-to-day challenges. Dorothea, kind of what are the invisible costs that we do not know about when it comes to emotional, financial? Stacy, you spoke a little bit about the emotional, but in terms of deeper emotional, financial, the social costs. Just so everyone listening knows, I have an eight-year-old son who is living with Prader-Willi Syndrome. When Manasi says this is all-encompassing and Stacy says it is all-encompassing, it is literally a 24-hour-a-day, 7-day-a-week PWS journey that we are on in our house. The invisible cost of PWS, it is everything. Emotionally, it is just maintaining a high level of vigilance and making sure that every environment you are in, whether it is your home, whether it is the school, whether it is a therapy or a physician, everything has to be completely micromanaged. Setting expectations for the individual with PWS so that they have their day planned out. That gets very difficult, especially when you're dealing with things like clinical trials. And we're schooling our families and our loved ones with PWS as to what to expect when you're traveling to a site. What does anxiety look like on an airplane? What does an outburst look like for an 18-year-old traveling to a clinical trial site who is now, because of growth hormone as early intervention for PWS, now you have an 18-year-old who's 6 feet 2 and lean, okay, maybe not a traditional PWS obese individual, and they lose it and get angry and TSA comes. And they're arresting your loved one with PWS for an outburst that they can't control. Or tasing them. Or tasing them. Or tasing them. Stories that have happened. It is. Preventing access to food for some families that looks like locked kitchens. It looks like locked refrigerators. Stacy was talking about what it's like to send your child to school, and you're so excited, and you spend those first several years like, "My kid's going to walk. My kid's going to crawl. My kid's going to do everything that other kids do." You send them to school, and everything is, "Let's learn how to count by counting the pieces of pie on this plate. What color is this apple?" Everything incorporated into their learning environment from day one is around food. Even a child who's not hyperphagic yet has that food curiosity. I mean, it is a different world for a child that has PWS. It's making sure that the schools understand and that the teachers understand, "They're going to teach my child, 'Can you not do it with food?' And let me explain why." There's that cost of the training of schools. From a financial perspective, I mean, use your imagination. The costs are exponentially higher than raising a typical child. From day one, I'll give you a personal example. We spent 17 days in the NICU, and a couple of weeks later, I had a $250,000 bill sitting. That was my first experience with PWS. There are the eight specialists that my son required his first year of life. There are the therapies, the physical therapy, the occupational therapy that bill at $150 an hour, and you do that three hours a week for each therapy. You build in, you get to two, and you start speech therapy. Then you get to three, you start ABA therapy. Then you get to four, you start hippotherapy. Then you get to 18. And you have to figure out if you're going to be able to have your loved one live in your home or if you're going to have to move them to a group home type of situation, which is typically upwards of $150,000 a year. I mean, in addition to everything else that's going on. So the financial cost of making sure that we are creating a safe life and giving our loved ones everything that they need to thrive and be the best version of themselves, I mean. Pick a number. I mean, just hearing your anecdotes and your personal story, by the way, thank you for sharing that. I can't imagine the day-to-day burden. I can't imagine, and I don't think people who generally don't know the disease and don't know the space can understand the day-to-day burden. To be honest, I think even people who are in the space don't understand. We hear all the time from parents that they don't have a support system because there's nobody else who really understands it to leave their child with. Date nights, babysitters, family holidays. It becomes very isolating because the child with PWS or adult has so many needs around those things that some of it is the hyperphagia, but some of it is the anxiety and the routine and the emotional dysregulation. They just don't go. Right. This is what has become our norm in our home. I remember Hunter was probably two when COVID happened. I remember looking at my husband, and I said to him, we were three weeks in, and I kind of laughed. I said, "The rest of the world is now a PWS parent. I can't go to the grocery store. I can't go to the drugstore. I can't see my family. I can't see my friends. I can't go out to dinner. I can't go to parties. I can't celebrate holidays." This is the world that so many of our families live in constantly to this day. No is my favorite word now. You get to the point where your family, whether they love you or not, your friends, people you've known your entire life, you just get to a point where they stop even asking you if you want to be a part of things or if you want to go to things because it's the level of anxiety that it creates for your loved one. Imagine you're walking into a family party, and you know there's going to be a table of food there. You're going to be celebrating a birthday. There's going to be a cake. This is all of our loved ones. That's all they're thinking about. We go to a family party with my son, Hunter, and he knows immediately. He's like, "The food is there." Instead of us being able to enjoy each other as a family, we're tag teaming, trying to divert his attention from this table of food that he can't get away from. This is an eight-year-old now who's not hyperphagic. He doesn't look like what most people expect when they say your child has Prader-Willi Syndrome. Stacy was mentioning that most of our population, most of our population that's had access to growth hormone from infancy or at least that first year of life, are very lean. It's shocking to me when I take Hunter to his doctors in Miami, and they say, "Wow. He's doing great. Look at him." I was like, "What does PWS look like for these physicians who I know are treating other individuals with PWS?" It is this stigma of what an individual with PWS looks like and the difference between. Explaining to people that hyperphagia does not equal obesity. I mean, I have to explain that to physicians on a regular basis, and it is insane. Right. It is the part of education that still needs to happen, right? It will continue to be a struggle. I know that through you and the work that you do, you are really out there and informing people. I think that is what has really changed the dynamics of how people perceive PWS. There is a lot more work to do, but you have really moved the needle so much. When it comes to. What this implies, I mean, I think about it in terms of what therapeutic options are there, right, and how it implies to how people perceive what that change looks like. It's not based on weight. It's based on other factors from food-seeking behavior to anxiety. Stacy, what does it mean to you that there is now a therapeutic option for PWS? This community has waited 70 years to have a treatment. We are so incredibly lucky that we have one. 95% of our diseases do not have a treatment. We recognize that, and we are excited, and we celebrate it. The truth is, it's not enough. Imcivree is a wonderful drug, and it's helping many people, but it's not a drug that is going to be appropriate for everyone. There is no drug, any one drug, that's going to be appropriate for everyone in any case. There are more symptoms and characteristics of Prader-Willi Syndrome than just hyperphagia. What I would like to see, it's exciting, and it's moved the research forward, and it's gotten people paying attention to PWS. What I want to see us do is see this as a starting point rather than an endpoint. Let's start looking at other hyperphagia treatments, such as ARD-101, and then treatments for the other symptoms of PWS as well. To really target the full constellation of challenges for PWS, we're going to need combined therapies. Because of the way that our population metabolizes medication differently from typical individuals, there isn't ever going to be one medication that's going to be able to work for everyone. The work that you all are doing here at Aardvark is amazing. The fact that you have allowed our organization and our community, and you have brought us in to engage with you from the very, very beginning, I think, has really shaped the way that everybody is looking at not just PWS and treating PWS, but rare disease. You are setting an example for other companies as they are going into the rare space. Thank you for doing that. Just like you all were talking earlier about the fact that there are multiple GLP-1 medications, and there may not be one that works well for somebody. Maybe it is semaglutide, maybe it is tirzepatide. It is very similar, I think, in the PWS world because of the way we metabolize medication. The need for multiple treatments is absolutely there. I think it is important to recognize that not having treatments is catastrophic. It is deadly. It is deadly. In the last two months, we've lost six individuals with PWS under the age of 27 from either obesity-related complications or gastric complications. That's devastating. Yeah. It's unacceptable. For a community as small as ours, although it feels very large sometimes because we're so intimate, that ends up having a devastating effect, not just on parents, but individuals with PWS. I had a—she's now in her 20s, but when she was 19, and a friend of hers who had died at 19, she said to me, "Am I going to die now too?" That's the reality that we're faced with without treatments. We spend a lot of time in DC, and we were at a meeting last year. It was last year. We were at a meeting last year where a family was sharing their story, and another individual living with PWS, in the middle of the meeting, turned to her mom and said, "Am I going to die?" Part of the challenging work that we do as advocates and making sure that the folks on the Hill and policymakers in general understand what our community is going through, why we need multiple treatments, why we need to be able to engage with companies and the FDA. Is when we're teaching our loved ones living with this disease to become their own advocates, they're hearing some of the worst stories that they haven't been exposed to before. It's heartbreaking. I can tell you, my son, this last year, my son was actually participating in a clinical trial that failed. We got word in September that it wouldn't continue. It did not meet its primary or secondary endpoint. We have spent the last six weeks pulling him off drug. I ripped that Band-Aid off pretty quick when we found out the drug was not going to continue because I figured we better figure out what it is that we are going to deal with. I can tell you, it has been the most challenging six weeks that we have had in the PWS space as a family since we received his diagnosis and got through that first year. His levels of anxiety within 24 hours of being off this failed clinical trial drug went through the roof. I have never seen—he is a sweet, kind, loving boy. He is still sweet, kind, and loving, but his levels of anxiety have heightened to a point where I am beside myself as a parent trying to help him. We have talked about different issues that people with PWS have. He began to scratch his head and his scalp to the point where he had open scabs all over his scalp. We ended up fighting MRSA for a week, which put him on a heavy dose of a crazy antibiotic that triggered the anxiety and the PWS behaviors even more. The last six weeks, it has been watching him have to go through all of this just withdrawing. It has disrupted his sleep more than his sleep has already been disrupted as a result of excessive daytime sleepiness with PWS. It is just this mountain of worry. We are only eight years in. Sorry. No, I am left speechless only because that is, it is so hard to understand. I think. For everyone listening, it's probably something so foreign to them unless you are part of this community and you experience this. And each individual family experiences something different too, right? Dorothea, we were talking about this earlier, that. What you're going through—and you made this comment earlier about how. People have it worse. That perspective, to me, really resonated that we're dealing with such variability per family. Ultimately, what we know is that we don't have enough, and we need to continue the work. Last question for you both. When you speak directly to the scientists and even the investors listening in. Working on the PWS therapies or working in the space, what do you want them to know? I remind them that the work that they're doing—I mean, we're not just data points. We're family. Every piece of work that you do, every research that goes into PWS is going to land in a real family, in a real future. In a real home. As you're looking at PWS as a specific rare disease state, understand that you have the opportunity to save lives. At the end of the day, that is what this research does. It's saving lives. I'd like to first thank the people who are in the space, the investors, and the scientists. Being in the rare space is not always easy for scientists. It does require a lot of investment. The fact that people are doing it, we are so incredibly grateful. I think the other thing that I'd like them to understand is Dorothea tells the story of coming off a clinical trial that failed. Despite that, I'm going to speak for you for a second. Good luck. It was very difficult, and it's been very difficult, but she'd do it again. That is the case with all of our families. They would do it again because the potential benefit outweighs the risk by far. I think it's so important to remember that this community is desperate, but also willing to be part of the discussions and want to see more treatments. I just think that sometimes we forget about those families and what they're willing to do as well. Yeah. I can say this from my experience working with Tien as well, is that that's our north star, you guys and the patients, always. With that, I want to thank you so much. We're truly grateful that you were here to share your stories, your experiences, your insights. We're really lucky to have you here. Thank you again. Thank you. Thank you. Thank you so much. I think in the remaining time, we'll have more Q&A, and I'll just open that up. Thank you, Tien. Just a moment for our first question, please. First question comes from, pardon, Andy Hsieh from William Blair. Please go ahead. Okay. Thank you. Really appreciate hearing your personal stories about PWS. I'm curious, maybe from a patient standpoint, if you have a checklist and if you have a magic wand that basically highlights everything that you would wish for from a therapy, what would it be? Can you basically kind of list them maybe in the order of importance in terms of what you want from a clinical profile perspective? Thank you. I can give that a shot. From a clinical perspective, the first thing we want to make sure is that we have a safe drug. Okay? Everything that I want it to target in order, that may look different depending on a parent's experience with their loved one and what symptom of PWS is most prevalent. I think we can all agree that the first symptom that I would want to see treated would be hyperphagia. From there, if we can have something that overlaps with the anxiety, which, what we understand as parents is that when hyperphagia decreases, we see a significant decrease in anxiety overall because they're not starving. I mean, it's hard really for people who aren't living in this world to wrap their brain around. This is. Tien and Aardvark spent a lot of time talking about the difference between appetite and hunger. This is an insatiable hunger that is as relentless as breathing. There is no control. When you are starving all the time, you're feeling all the symptoms of hangry, as we refer to it. Multiply that by feeling like you haven't eaten in three days. Add in all those symptoms, you can begin to start to understand why these levels of anxiety. I would start with hyperphagia, roll that into anxiety, top it off with excessive daytime sleepiness, wrap it up into a nice little package, and eventually get to gene therapy where we can wave that magic wand that you're going to give us, and we're going to cure it. I would add in. Because I'm a behavior analyst, I'm going to throw in the behavior piece. I think. There are pieces of the anxiousness that will go away or be managed better when we have treatments for hyperphagia. But there are other pieces that we see more prevalent in those with [subtype PD], but true psychosis is another issue and some of those psychiatric issues. I would love to also see a treatment for that after hyperphagia and excessive daytime sleepiness. I agree. Great. Thank you so much. Just a moment for our next question. Next, we have Katherine Novak from Durant. Please go ahead. Hi. Thank you so much for taking my question. I. Sorry. I just have one about. Thoughts on what level of HQ-CT9 reduction might you consider to be clinically significant? Anecdotal evidence on what one point versus a few points versus seven or eight might look like in patients. Thanks. So this is Manasi. I can answer this, but I think that it would be interesting also to kind of talk to Donineothea and see her perspective. From a clinical trial perspective and what we've seen and heard, I'll speak to that first. From a clinical trial perspective, I think having a meaningful change of three to four points, depending on where in the hyperphagia scale you're changing, right? Because there's three components to the scale: behavior, drive, and severity. If you tell me that you're hitting each one of those pockets and overall changes the overall food-seeking behavior for a patient, I think that has meaningful outcomes for families. I will also say this: when we've heard from parents through our advocacy groups that even a one-point change, depending on where it is in the scale that changes, it could be meaningful for the families. I think that what we're looking at, yes, there could be a variability in the overall change on the scale. Not one person has the same score. They're based so much on the scale, right? Because there's 36 potential points, nine questions. It changes, and it's different for each family. With that, I'll ask Dorothea to kind of weigh in and see what that would be for you. I think you hit the nail on the head. Any decrease in hyperphagia and hyperphagic tendencies can make a significant difference for a family. I think that's the general consensus amongst our community and why our families are so willing to come back to the table repeatedly and participate in clinical trials because any reduction. In hyperphagia and behaviors and anxiety can be life-changing, not just for the person with PWS, but for everybody living around that person. I'll add that I spoke with a family who was in the phase II trial and had the opportunity to physically see the difference in somebody who was in it. And that individual's hyperphagia questionnaire only changed a few points, but their quality of life changed drastically. This was somebody who wasn't able to go to school and now could, was being, not actually arrested, but handcuffed. That went away. Was able to participate in things with their siblings. And that's only a couple of points, but for them, that was a drastic change in quality of life. Yeah. Twenty days of bliss, I think, is what Mom expressed it as. Yeah. Right. Right. That was our phase II 28-day trial. Yeah. Katherine, I hope that answers your question. That does. Do you mind if I ask one more? We've probably talked about this, but can you speak to COVID's impact on the phase III randomized controlled portion of the trial? How important is this change in routine or stress levels when it comes to hyperphagia-related behaviors? I guess that's not for me because that was not our trial. I don't know if you're asking Stacy or Dorothea if they have any anecdotes from that. Yes. What I can say is that, in general, COVID wreaked havoc on every rare disease clinical trial that was happening at the time. There was a PWS phase III clinical trial that was happening at the time. As a result of the change in routine and everything else that was going on in this country, it significantly skewed the data. Our community, that is really when you saw from an advocacy perspective. That's when I started working at PWSA. Actually, that's what brought me back into the world of advocacy. When we realized that we needed to get involved from a policy perspective, we needed to reengage with FDA. We put together an external patient-focused drug development meeting so that they could understand and hear directly from families and individuals living with this disease. How that affected them, why they needed to look at the data differently. COVID, in general, affected all of the rare disease community in a very negative way. I don't remember what the percentage of clinical trials that ended up failing as a result was, but it was quite a mess. Thanks. Thanks so much for sharing and for taking the time to answer my questions. Thank you. Next question comes from James Condulis from Stifel. Please go ahead. Hey, thanks for taking our question. It's Mark on for James again. I had two questions. One for the phase III, could you maybe just go through again sort of the dynamics and logistics for the interim analysis? I'm just curious if you could kind of clarify that. I also had a question for the advocacy group. I wanted to sort of gauge interest in this clinical trial sort of in the context of what's happening right now with Vykat on the market. Thank you I can take that apart. I talk to a lot of families on a regular basis, and there is a tremendous amount of interest in this trial specifically. I think that the safety protocol that we've seen and the decrease in side effects. Or that less side effects than what we're seeing with Vykat is appealing. I've talked to families who have said, "I would like to do a trial." It's really important to our community to get the trial filled and to then also have the open-label extension. Without that, I do honestly think people would not have enrolled in. Wouldn't without having that option. Without a doubt, having the open-label extension or not having it is a deal-breaker for our community. Yeah, that's huge. The recent decrease in age makes a huge difference for our families because Vykat can start as young as four. We have a lot of families who really want to wait and see and are looking to see what other options start to come these next few years. There's time, right? Because you do not really start to see the true hyperphagic tendencies until around the ages between eight and ten years old. Sometimes it can—I have seen it start as young as five and six. Really, you get to that critical state around ages like eight to ten. That age decrease is going to be—that is huge for our community. There is a tremendous amount of excitement around this drug. Yeah. One of the other things I have heard from families, and maybe you have too, Dorothea, is even though Vykat is available to them right now, filling this trial is important in that they know Vykat can be an option down the road should this not be successful. They are willing to delay that in order to fill this trial and see if this is successful for their child before going to Vykat. Absolutely. It is a really interesting dynamic that is happening. It is. We are seeing it. With regard to the interim analysis, we are going to perform interim analysis when 50% of the patients complete dosing. It will be a sample size re-estimation only. There will be an outside blinded statistician that will run a conditional powering analysis and let us know whether or not we should increase the in the study. Thank you. Thank you. Next, we have H.C. Wainwright. Please go ahead. Hi. It is Jade on for Ram. Earlier, you spoke about the necessity of multiple therapies, including ARD-101. How combinable might ARD-101 be with existing agents like Vykat and other agents like that melanotide? Yeah. We think that ARD-101 has some unique properties that really help with the safety profile in the fact that it is 99% gut-restricted. By consequence of that, it's not reliant on liver or renal processing. Mechanistically, there shouldn't be an overlay in terms of competing metabolism with other agents or AEs that should be of particular note to us. In theory, and also the mechanism of ARD-101 is very orthogonal to other approaches. In terms of a therapeutic intent, we think it's also potentially combinable. I think in the future, I don't think it's mutually exclusive to look at ARD-101 as mutually exclusive with any other treatment that we are aware of. You haven't run any preclinical trials or anything combining the two yet, or? No. A lot of the patients have a lot of different con meds. Just to help with the precision of this trial, we're not allowing concomitant use. We haven't explored preclinical. Frankly, there's really not reliable preclinical or translationally relevant models for Prader-Willi anyway. In the clinic, we haven't yet explored that. Okay. Thanks. That's fascinating. Just one more quickly. Do you think there would be any applicability in any hyperphagic syndromes beyond hypothalamic obesity and Prader-Willi Syndrome? Yes. In fact, our drug, ARD-101, we believe that one of the distinctive features is the anti-hunger effect through gut-brain signaling. We selected Prader-Willi Syndrome as our first clinical target only because we thought that the drivers of Prader-Willi Syndrome were very congruent to what our drug was doing. I think it was mentioned that right up there with hyperphagia is the hyperanxiety. There's also high inflammation. A lot of these patients also have rheumatic-like manifestations and elevated pro-inflammatory cytokines. There's also very extreme constipation for a number of patients with delayed gut transit time. There's also high body fat percentage in patients that even do have normal BMI. There's even early gallstones. All those features that I just listed are congruent with insufficient gut-brain signaling through vagal afferent conduction. Since our drug is amplifying that, we actually see potential for addressing the multitude of those conditions. I think that's one of the important things to highlight. As far as the applicability, we think the anti-appetite effects of ARD-101, it's amplified with combination with sitagliptin, which wouldn't be used in Prader-Willi because of the risk of gastroparesis. That's just another demonstration of the complementary potential for at least the ARD-101 contribution to other treatments, of which the 201 is actually a representation of one possible combination. We also released data this Obesity Week about the combination with GLP-1 and how that actually amplifies even a one-tenth dose of GLP-1 allowed for a substantially greater degree of weight loss in an obesity model that's the gold standard. In head-to-head with high-dose tirzepatide. High-dose tirzepatide was not as efficient as one-tenth dose tirzepatide plus 201. It is, again, underscoring the synergistic and complementary nature of our treatment. Thank you so much. Thank you. Next, we have Jeet Mukherjee from BTIG. Great. Thank you for taking the question. Just a quick one regarding the phase III and the age 10 that you had mentioned as the inclusion. I was just curious as to maybe why the age was not lower, and is that something you ultimately plan to do longer term? Thank you. Yeah. Our intent is to have the inclusion criteria ultimately age seven and up. The one thing is our drug is a first-in-class drug. By consequence of that, there's a higher hurdle to have allowance to dose in younger patients. We're in the process of completing requisite juvenile tox studies to allow for the expansion into age seven and up. We've gotten alignment for age 10 and up. I think one of the reasons why we're able to do so is because of the gut restriction. The normal concerns for pediatric dosing. I'll note that it's 800 milligrams no matter who you are. The reason why that is sensible is because it's not really a volume of distribution issue. It's a gut-restricted drug. It doesn't have the same type of proportional exposure you expect based on body weight. That is why we are also confident that the safety will persist as we explore younger ages with the same dosing paradigm. Great. Thank you. Maybe just a quick follow-up, perhaps one for our panelists, just in terms of the other medications Prader-Willi patients are on, anti-anxiety medications, antipsychotics. Do you see any of these other medications exacerbating hunger? Is that something you are kind of dealing with on a day-to-day basis? Thank you. Yes. Most of the psych meds we see exacerbating hunger. Unfortunately, there are not a lot of psychiatrists in the space who are familiar with PWS. They are throwing medications at people with PWS, just trying to manage symptoms, essentially. It is causing other issues like increase in hunger or increased anxiety, different sensory issues. In general, people with PWS have sensory deficits. Some of those meds will exacerbate those as well. Thank you very much. You're welcome. Thank you. Next, we have William Wood from B. Reilly Securities. Please go ahead. Hi. Thank you for taking our questions. Congratulations on your presentation. I actually just have one on, or maybe it's sort of a two-parter on WE-868. Just curious, you spent a lot of time discussing the gut-brain axis and sort of that regulation. This seems to be much more whole-body regulation, perhaps not specifically CNS, but in general, whole body. I'm just curious how you're thinking about using this as you take it forward, whether you're thinking combination or monotherapy. Sort of the part b, since you already have a phase I-b study where you've tested it, how quickly can you move this back into the clinic to pursue development? Thank you. Yeah. We're focused right now on proving that the WE-868 program works. We're not envisioning it as combination therapy. We're actually envisioning it more as a supplement, another alternative for patients that don't respond to GLP-1 therapies. As we advance the development of that, we can see where it fits into the obesity pharmacopia, if you will. As far as advancing back into the clinic, we're going as fast as we can, as always. The original trials were done by IV dosing, and we're converting that to an oral dosing formulation. That takes a while to get that work done. You have to repeat some tox studies before you can jump back into the clinic. We haven't given clear guidance on exactly when we'll be back in yet. Got it. That's very helpful. Thank you. Thank you. This concludes the Q&A session. I will now hand back to Tien Lee for closing remarks. Thank you very much, everyone. I really appreciate all our invited speakers. This allows us a really great perspective across a number of different perspectives. Dr. Apovian, Dr. Lam, Dr. Jaiman, Stacy, super grateful for all your time and contributions, and of course, to the rest of our team. Thank you very much for all the ones who dialed in to participate. Looking forward to the next steps and a very exciting year ahead. This concludes today's conference call. Thank you for participating. You may now disconnect.