Good day, and thank you for standing by. Welcome to the Aardvark Therapeutics update call. At this time, all participants are on listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will 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 will be recorded. With that, I will now turn the call over to Aardvark Therapeutics founder and Chief Executive Officer, Tien Lee. Dr. Lee, please go ahead.
Good morning, everyone, and thank you for joining us today to review the efficacy and safety data from HERO, our Phase 3 trial of ARD-101 for the treatment of hyperphagia in patients with Prader-Willi syndrome and from its open-label extension. We will also share an update on the lift of FDA clinical hold. As a reminder, both studies were stopped early before reaching their planned enrollment and duration. The efficacy results should be viewed as exploratory. Joining me on the call are Dr. Manasi Jaiman, our Chief Medical Officer, and Dr. Lynne Bird of Rady Children's Hospital in UC San Diego, who served as an investigator on the HERO trial. Manasi will walk through the HERO and open-label extension data and then moderate a fireside chat with Dr. Bird on her clinical experience with ARD-101 and the needs of patients living with PWS.
I will close with a few remarks before we open the line for questions. Before we start, we would like to remind everyone that we will be making forward-looking statements during this presentation. These statements reflect our current expectations and beliefs and are subject to risks and uncertainties that may cause actual results to differ materially. Please review the risk factors discussed in our press releases, our presentation materials, and in filings with the SEC for additional information. ARD-101 is investigational and not approved. Before I turn the call over to Manasi, I want to briefly recap where the program stands. In February, we voluntarily paused enrollment and dosing in the HERO trial and its open-label extension following reversible cardiac observations at doses above the target therapeutic range in a separate healthy volunteer study.
In May, the FDA placed a full clinical hold on the ARD-101 IND, and in June, we terminated both trials. Since then, we have continued to work collaboratively with the FDA while completing a thorough evaluation of the totality of the unblinded efficacy data and safety data from both studies. Hyperphagia is one of the most challenging aspects of Prader-Willi syndrome, and for the patients and families living with it, the need for effective treatments remains significant. That need has guided our work on ARD-101 from the start, and we believe the data we will share today support its continued development in PWS. As a reminder, both studies were stopped early before reaching their planned enrollment and duration. The efficacy results should be viewed as exploratory. We will also share an update on the FDA clinical hold lift.
With that, I'll turn over the call to Manasi to walk through the data.
Thank you, Tien. Good morning, everyone, and thank you for joining us today. Before I walk through the HERO and OLE results, I'd like to first provide a brief overview of the program. ARD-101 is an oral bitter taste receptor agonist that acts primarily within the gut, where it activates bitter taste receptors known as TAS2Rs to trigger the release of the satiety hormone CCK and GLP-1, a key appetite-regulating hormone. These hormones then signal to the brain through the vagus nerve to dampen both hunger and appetite. We believe this mechanism is particularly well-suited for patients with Prader-Willi syndrome. Hyperphagia, the persistent and often overwhelming hunger that defines the disease, stems from dysfunction in the hypothalamus. By signaling through the vagus nerve, ARD-101 is designed to work around that pathway. This route also avoids the area of the brain associated with the nausea commonly seen with GLP-1 therapies.
Turning your attention to slide three here, we've outlined a historical overview of the ARD-101 clinical program. Our Phase 2 open-label trial in patients aged 17 and older was conducted in two parts. Part one evaluated doses at 200 mg twice daily, and part two included dose escalation to 800 mg twice daily. Hyperphagia was measured by the Hyperphagia Questionnaire for Clinical Trials, or HQ-CT, a caregiver-reported measure of hunger-related behavior, drive, and severity that is the established endpoint in Prader-Willi clinical trials. At day 28, most patients showed an average 8.5 reduction in HQ-CT scores and an approximately nine-point reduction in the 200 mg BID group. ARD-101 was well-tolerated, and these results gave us the confidence to advance into HERO, our global randomized placebo-controlled Phase 3 trial evaluating ARD-101 for hyperphagia in Prader-Willi syndrome. We made several deliberate choices in designing HERO.
To reflect the real-world Prader-Willi population, we expanded eligibility to patients as young as 10 years old since hyperphagia begins in early childhood. Each patient was followed by the same caregiver and site team throughout the trial. During HERO, there was a serious cardiac adverse event that occurred. The DSMB initially assessed the event as unrelated to ARD-101, given there were no cardiac abnormalities in the previous clinical trials. The event was eventually assessed as related, and it was attributed to a drug-drug interaction with pitolisant, not to ARD-101 prolonging QT on its own. Pitolisant is known to cause QT prolongation at higher plasma concentrations and is metabolized by CYP2D6. We now know that ARD-101 is a strong CYP2D6 inhibitor at 800 mg BID, and thus the AE was considered a drug-drug interaction with which the FDA concurred.
In parallel, we were conducting our planned clinical pharmacology program, which included a healthy volunteer study evaluating drug-drug interactions and further characterizing ECG effects at higher doses of ARD-101. This study also provided an opportunity to better understand cardiac safety following the event in HERO. The healthy volunteer study identified QRS prolongation, not QTc prolongation, which led Aardvark to voluntarily pause all clinical trials, including HERO and its open label extension on February 27, 2026. At the time of pause, 67 patients had enrolled in HERO and 19 had entered the extension. The FDA subsequently placed the program on clinical hold in May 2026. Following alignment with the agency, we initiated dedicated thorough QT study in June. The hold was officially lifted last week. I will discuss the cardiac findings in more detail when I walk through the results shortly.
As a reminder, HERO stopped early when we paused the program in February before reaching planned enrollment, which limited its statistical power. Following the pause, we unblinded the clinical data accumulated across both trials to evaluate the totality of the efficacy and safety data and to inform our next steps for the ARD-101 program, and we are pleased to share the results with you today. Overall, in the HERO trial, we saw early and consistent efficacy signals of ARD-101 activity with a well-tolerated safety profile despite early trial termination. The signal is small and early, but it follows the drug. It appears after initiation of ARD-101, fades when ARD-101 stops, and appears again when placebo patients switch to ARD-101. Again, as HERO was ended early, we can only draw directional conclusions based on the unblinded data available. What it does show is a consistent pattern.
Patients improved quickly by week two while still on the dose escalation part of the trial. There was a strong placebo response consistent with other PWS trials. Importantly, when dosing stopped, the ARD-101 group lost its efficacy, and when placebo patients switched to ARD-101 in the extension, they improved by an average of 6 additional points on the hyperphagia score on HQ-CT nine. Regarding safety, the drug was well-tolerated. In HERO, as previously mentioned, there was one serious cardiac event related to a drug-drug interaction, which informs how we manage future studies. There are no additional cardiac SAEs or clinically significant cardiac AEs observed in HERO. Finally, from a regulatory standpoint, we are off clinical hold. On slide five, we have provided a side-by-side safety summary. On the left is why the hold happened.
In healthy volunteers receiving 1,600 mg or 800 mg of ARD-101 twice daily, three of 31 participants had QRS widening of more than 25% from baseline. These were non-serious adverse events and reversed without treatment. On the right is the resolution. As mentioned before, we ran a TQT study to evaluate lower doses at 200 mg and 400 mg twice daily. We saw no QRS prolongation and no QT prolongation in the study at either dose. In conclusion, across all studies, we saw no increases in QTc at any dose in healthy volunteer studies and no additional QTc findings in the PWS studies. Going forward, the maximum dose will be less than 800 mg twice daily. Before we go into detail on the data, I would like to provide a reminder of the HERO OLE trial design. HERO was a 12-week randomized double-blind trial.
Patients were randomized one to one with a planned 45 per arm, total 90 participants. The primary efficacy endpoint was the change in HQ-CT scores in patients starting with the HQ-CT score of 13 or higher. Patients who finished HERO could enter a one-year open-label extension study where everyone received ARD-101. Dosing in both studies started at 200 mg twice daily, stepped up to 400 mg in week two, and 800 mg from day 15 on. The titration matters. The week two results you will see come from the lowest doses. The next set of slides will walk you through baseline demographics. These are the patients in the efficacy analysis. On the left side are the 64 patients in HERO with a starting HQ-CT score of 13 or more, 32 per arm. Mean age was about 20, with a range of 10 to 43.
The arms were well-balanced on hyperphagia severity. HQ-CT scores 22.5 on ARD-101 versus 22.8 on placebo, and clinician and caregiver severity scores were similar. On the right side are the 19 patients who entered the open-label extension, eight from ARD-101 and 11 from placebo. Their starting HQ-CT scores in the extension are lower, which we explain on the next slides. This slide follows the same 19 patients from their HERO start to their OLE start. Both groups improved during HERO by about six points. So they entered the extension already better than at HERO baseline. Note that the eight patients from the ARD-101 arm started HERO with more severe HQ-CT scores at 25 than the 11 from placebo at 20.4. That is why later slides measure change from each patient's HERO baseline. Here is how to read these charts. Bars below zero mean hyperphagia improved.
Teal is ARD-101, white is placebo. On the left, both groups improved during treatment, and those who were given ARD-101 improved more than those who were given placebo through week eight. Because the study was stopped early, many participants never reached the later visits, and the number of participants contributing data decreased over time. The week 12 results are therefore too limited to support reliable interpretation. Earlier time points include more participants and provide a broader view of the enrolled population. Although the early stop of the study limits conclusions across all time points. On the right is what happened when dosing stopped at the pause. On the day of pause, ARD-101 participants were 9.5 points better than baseline, and placebo participants 7.8 points better. Two weeks after stopping, the ARD-101 group was almost back to baseline at - 0.3.
The placebo group held most of its gain at - 4.9 and was still present at four weeks. The loss after stopping was concentrated in the ARD-101 group, which is consistent with a potential drug effect. A placebo effect alone would be expected to affect both groups similarly. The numbers are small. However, we see this as supportive of potential effect. A question we often get is how to read the placebo response in HERO. Placebo improvement is common in PWS hyperphagia trials. So this slide puts our results in that context. On the left are the HERO results for participants with baseline HQ-CT scores of 13 or higher. Both groups improved, with ARD-101 participants showing modest improvement compared to placebo participants at week two, four, and eight.
Again, because the study stopped early, fewer participants contributed to data at later visits, limiting interpretation across all time points, particularly at week 12. On the right, we show DESTINY PWS, which are the results from Vykat's randomized control study for context. The key point is that a substantial placebo response was also observed in that trial. We believe this helps put the placebo response in HERO into perspective. However, the observations are from separate clinical settings and not based on head-to-head studies. This comparison is solely for illustrative purposes and should therefore be viewed with caution, as these are unrelated trials with different designs and characteristics. This is the same pattern in the 19 patients who continued into the open-label extension measured from their HERO baseline. On the left, look at the hatched bars. These are patients who were on placebo in HERO and then switched to ARD-101.
After approximately four weeks on drug, they improved on an average six more points beyond what they achieved on placebo. On the right is what happened when the program paused, and everyone stopped dosing. Both groups lost ground. Patients who had been on ARD-101 throughout went from - 16.4 on the day of pause to - 5.4 four weeks later. Patients who switched from placebo went from - 11.4 to - 3.8. The loss of ARD-101 effect was rapid after withdrawal of the drug, returning close to baseline by four weeks. These results are consistent with the withdrawal effect observed in ARD-101-treated patients in the 12-week double-blind study. In a second setting, improvement follows exposure to ARD-101. The numbers per visit are small, under 10 per group, so we treat this as supportive of potential effect only.
Taken together, these findings suggest encouraging potential for ARD-101's continued development and its potential to make a meaningful difference in the lives of PWS patients. HERO showed modest numerical separation from placebo, with additional support coming from the withdrawal and open-label observations. After dosing stopped, the ARD-101 group lost nearly all of its improvement within about two weeks, while the placebo group retained much of its gain. Participants who switched from placebo to open-label ARD-101 then showed further improvement. Caregiver and clinician severity ratings, CaGI-S and CGI-S, followed a similar pattern. Improvement after starting ARD-101, followed by worsening after stopping it, provides a consistent signal of potential treatment effect. Although these findings are not definitive, we believe they offer an encouraging rationale for further evaluation. For completeness, we collected and reviewed all pre-specified assessments.
Lipids, hemoglobin A1c, weight, body composition, vital signs, and ECGs showed no meaningful differences from placebo participants. Longer treatment and follow-up may be needed to assess potential metabolic effects, particularly given the early study stop. Plasma concentrations were low, consistent with limited systemic exposure, and ARD-101's intended action primarily at target receptors in the gut. In this space, tolerability is as important as efficacy. Given the nature of the disease, PWS patients may be treated for many years. Shown here are the most common adverse events. These were infrequent and balanced across arms. None occurred in more than 9% of patients, and rates were similar between ARD-101 and placebo. Diarrhea and nasal congestion were the most frequent, each at three patients per arm. Across both studies, ARD-101 was generally well-tolerated. In HERO, adverse events occurred in 52% of ARD-101 patients and 50% on placebo, mostly mild to moderate.
Fewer ARD-101 patients had a related event than placebo patients, 15% versus 21%. As mentioned previously, there was one serious cardiac event at 800 mg twice daily attributed to a drug-drug interaction with pitolisant. There were no other cardiac adverse events. In the extension, there were no serious events. All eight related events occurred in patients newly starting ARD-101, and seven of eight were mild. Patients who had already been on ARD-101 in HERO had no related events. We believe this is supportive of promising tolerability over time. I would now like to turn to our fireside discussion with Dr. Lynne Bird. Dr. Bird is a Rare Disease Specialist and Clinical Geneticist at Rady Children's Hospital and a Professor of Clinical Pediatrics at UC San Diego. She is a Medical Director of Rady Children's multidisciplinary Prader-Willi Syndrome Clinic and Co-Founder of the Rady Children's Down Syndrome Center.
Dr. Bird has spent much of her career caring for individuals with Prader-Willi syndrome and their families, and she served as an investigator on the HERO trial. She brings a perspective on both the day-to-day realities of living with hyperphagia and what it means to evaluate a potential new treatment in the clinic. Dr. Bird, thank you for joining us today. We are honored to have you here.
Manasi, it is nice to speak with you again.
Yes. Hello, Dr. Bird. Thank you again for joining. Let us get started with this. Could you tell us a little bit about your background and how you came to focus on Prader-Willi syndrome?
Sure. I am a clinical geneticist. I have been in practice for 32 years. I mostly see children who have birth defects or neurodevelopmental problems that are seeking a diagnosis. In 2005, I believe it was, I was asked to start a Prader-Willi syndrome clinic because the one at UC Irvine was closing due to the retirement of the Director. I did. We have been in operation ever since then, and we follow 40 patients to 50 patients every year, seeing them about once or twice a year, depending on their needs.
Wonderful. Thank you so much. I know the patients must be so grateful because of the fact that there are such few clinics across the country. Because of your vast experience and your background, when you think about Prader-Willi syndrome now, what do you think is their greatest unmet need?
Well, I would have to say it still is hyperphagia. That has been the answer for decades now, and I think it is still the main issue, which makes life just very difficult for families. The children basically feel like they are starving and are so focused and preoccupied with food. It is very difficult to do the usual things that we do in our society, which is to get together and have a meal with friends or family, because the children do not understand why food is coming for another table in the restaurant and not for them, and they have a meltdown. It is very difficult. To compound the hyperphagia, the individuals with Prader-Willi syndrome have slower metabolism, and so they need fewer calories than a typical person.
The combination of having an increased drive for food, an increased sensation of hunger, and not being able to eat nearly as much as a typical person just is an incredibly difficult combination for families.
I am always amazed with the burden that comes with this disease and the fact that families and participants continue to support clinical trials, and we are forever grateful to them, including the sites as well. I always think about from the perspective of the families, the patients, but also as an investigator. Why did you choose to participate as an investigator?
Well, we really do not have any effective treatment for hyperphagia. We call it a treatment, but it is really not when we say, "Secure the food supply." So it is like, lock the food and keep control over the diet. That is not really a treatment. It does not really affect the symptom, it just manages the symptom.
Yeah.
I was fortunate enough in 2016 to be approached to participate in a Prader-Willi syndrome clinical trial, and that was my entry into the entire clinical trial world. I think it is the path forward to finding treatments. So, I am committed, and I know many of my colleagues who see Prader-Willi patients are also equally committed, and more importantly, the families are super engaged. This is a highly sophisticated and engaged population. They are really asking for and wanting to participate in clinical trials. We have never had a struggle with enrollment.
No, that is great. Again, like I said, I am always so grateful for these families and the participants, and I have learned quite a lot from just them. Not just about the disease, but how to even run a clinical trial effectively based on what their needs are, just because, as you described, their day-to-day burden is so high. The fact that they are able to participate in these clinical trials is always so amazing to me. One thing we are always kind of thinking about for them and how to decrease the burden when they participate, but also what is it that makes participation easier? What makes their lives easier when we think about therapy? W hat are some of the factors, including ease of administration? How do they affect Prader-Willi families and participants?
Yeah. So this is a group of patients who, in the modern era, have grown up with daily growth hormone injections.
They don't necessarily shy away from something that has a tougher route of administration. Certainly, an oral drug is going to be far easier, far less traumatic. Especially something that only has to be given twice a day makes it nice that you don't have to synchronize it with meals and that you don't have to worry about a midday dose where you're going to have to arrange for it to be given to the child by the nurse at school. So, twice-a-day dosing is very feasible, very doable.
Great. Now, again, with your experience that you have and your background, and especially as you've seen clinical trials develop over time, how they've been run, the data that's been produced, even with the recent progress in the field, where do you see the largest remaining unmet need for these patients and families? Because, for me, as a pediatric endocrinologist, I think about how many more tools can we give these families. Where do you think we are now in this space, specifically, and especially for hyperphagia?
Well, as you know, there is a drug approved for hyperphagia. It certainly doesn't work for everybody. There are patients that it's probably contraindicated in because of other health morbidities that they have. In my experience, it takes the edge off, but it certainly isn't miraculous in terms of ceasing entirely hyperphagia. For those that it works for, it obviously makes life easier because there's a little less focus on food, and it's a little easier to redirect patients after they're asking for food. I t certainly doesn't allow families to just throw caution to the wind, unlock the cabinets, and have it be a free-for-all. So there's still a huge amount of burden that comes with making sure a person is food secure and not having unrestricted access, which can be a lethal complication.
Patients with unrestricted access to food have eaten to the point of stomach rupture. That's well described in Prader-Willi syndrome. The new drug doesn't take away the need for families to continue to do all the hard work. It just makes the hard work a little easier. We need more things in our tool chest for hyperphagia. Hyperphagia does drive a lot, not all, but a lot of the behavior that we see in Prader-Willi syndrome. There's a tremendous amount of anxiety and perseveration, and a lot of aspects of behavior get better when patients are provided food security and when you take the edge off with a drug like Vykat.
Yeah.
We need more.
We do. This is why we continue to strive forward. We're excited to be able to share the data today. We're so grateful that you were part of this journey and continue to be. We're really grateful for the community advocacy groups, the participants, the families. These insights are so invaluable to continue to improve how we run clinical trials and continue to strive towards bringing new therapies to patients. Dr. Bird, thank you so much for sharing your insights today and for your continued commitment to us and to the PWS community. With that, I'm going to turn this over back to Tien for some closing remarks. Again, thank you so much, Dr. Bird.
Pleasure to be here.
Thank you, Manasi and Dr. Bird. Hyperphagia remains one of the most difficult aspects of Prader-Willi syndrome for patients and their families. Their constant hunger shapes nearly every part of their daily life, and we believe there is still a tremendous need for additional treatment options that can meaningfully reduce it. The data Manasi walked through today are exploratory, but we believe they are directionally consistent with what we saw in phase II and they give us confidence in the continued development of ARD-101 for PWS. Our next step is to request a meeting with the FDA to align on the design of a phase III study intended to support a future marketing application. We will continue to work closely with the agency as we move forward.
Before we open the line for questions, I want to thank the patients, families, caregivers, and investigators who took part in HERO and its extension, as well as the PWS advocacy community, whose partnership has been essential to this work. With that, operator, please open the line for questions.
Thank you. At this time, we will conduct a question and answer session. As a reminder to ask a question, you will need to press star one- one on your telephone and wait for your name to be announced. To withdraw your question, please press star one- one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Josh Schimmer of Cantor Fitzgerald. Your line is now open.
Hey. Thanks for taking the questions. I have two for the management team and one for Dr. Bird. First, just trying to understand for the chart that is on the left side of slide 11, what is the difference between the week 12 and then the study week zero in the open-label period? I thought patients would just roll right into the open label, so 12 and zero should be the same, but they do not look the same, and it actually does not look like there is a difference between the two groups at that zero time week. That is number one. Number two, how do you plan to incorporate ECG monitoring going forward and then through commercialization potentially of 101, including with REMS?
For Dr. Bird, is there a tolerable QRS widening signal that you think would be acceptable for the community if indeed there is an efficacious dose to be found here? Or is that not something that is tolerable at all for patients? Thank you.
Great.
Manasi, you can take those questions, I think.
Great. Yes. Hi, Josh. Great question. Let's start with the first question you had. So slide 11, specifically in the transition from week 12 to open label. Most participants, remember these are small n's, so even with one having even a minor gap between week 12 and open label can shift what that looks like. M ost participants had the same day transition visit from week 12 to open label, but not all. That's where you're seeing the difference. Again, because at each visit, if there was even a small gap, we had them redo the HQ-CT nine to really capture their baseline before entering that second part of the study. That's where that discrepancy comes from.
It could be for multiple reasons, as you know, in clinical trials where participants decide on that day that they want to maybe wait a couple of days before they go into open label extension. But I will say that 100% of those that were able to go into open label extension chose to go into open label extension. That was very encouraging for us. But certainly if there was even a one or 2-day gap, we had to redo the HQ-CT nine. The second part of your question is cardiac monitoring. In terms of cardiac monitoring for future trials, we've certainly learned quite a bit from our HERO and open- label extension trials.
Yes, there will be more cardiac monitoring as we move forward in clinical trials, and especially in our development to ensure patient safety, because that is number one, two, and three for us, to ensure that we're capturing these things. I think what's encouraging for us is that TQT study we did do at these lower doses now, and that we had no further signals, especially in the QRS prolongation piece. For us, it'll just be another safety measure as we move forward. In terms of the label or post-commercialization cardiac monitoring, we'll learn what we do with our next clinical trial, and that will determine what is required post-commercialization. I think the last question is for you, Dr. Bird.
Sure. Obviously, you know that I'm not a cardiologist. I think that a little bit of QRS widening that was not associated with any symptoms at all would likely be considered tolerable by the population. Whether it would be considered tolerable by the FDA is another matter. My understanding is none of the healthy volunteers who exhibited the QRS widening had any symptoms. This was a purely electrical finding and not one that we expect to see with the revised protocol at lower doses.
Thank you very much.
Thank you. One moment for our next question. Our next question comes from the line of Chris Raymond of Raymond James. Your line is now open.
Yeah, thanks. Just two questions, maybe. First on safety. I think there are a few psychiatric meds that are used in PWS that are metabolized by CYP2D6. Have you guys evaluated whether the interaction that you saw with pitolisant could potentially extend to other concomitant meds like antipsychotics or antidepressants? Maybe talk about how you're thinking about that with future trial eligibility. Then just noticing the slides, the last slide in the deck that you guys have shows a pretty impressive average from baseline. I think it's almost 12 HQ-CT reduction. I know that's a little bit messy, right? Because you've got some folks that started on a placebo, et cetera. M aybe put that into the context of what we saw with the HERO unblinding. Thanks.
Sure. Hello, Chris. Yeah, thanks, Tien. I'll take this. Let's start with the first question you had for CYP2D6. I want to caution, so when we did the drug-drug interaction study for CYP2D6, that's when we learned at the higher dose, which is 800 mg twice daily, that we were a strong inhibitor. Yes, there are other medications that are CYP2D6 substrates, and there's a range between being potent versus being mild. What we know at this higher dose that we are a strong inhibitor. What we don't know is how strong of an inhibitor we are at these lower doses. That would be the next step for us is to learn that, which would directly impact what we would include or exclude from our clinical trials. I think we're iterating, and we've learned quite a bit.
We did have participants on these antipsychotics in our clinical trials that did not have this outcome. This, again, was at the 800 mg twice daily. As we propose going at lower doses moving forward, I think we're going to learn more and hopefully not have the same requirements, but there's more to come. Then in terms of that second question for the open label data that you've seen in that last slide, and especially that follow-up, certainly it's encouraging. If you recall our Phase 2 data, especially at the 200 mg twice daily, it was open label as well. We had approximately a nine-point drop in hyperphagia as well. This is more comparison with that data. We are encouraged by this.
In terms of the HERO is an RCT, but we're looking at from baseline all the way going into open -label to see that kind of drop, even outside of having placebo response. I think for us directionally, that's very important to continue to see. On top of the withdrawal data, I think that's what allowed us to present today and have conviction to move this program forward.
All right. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of Leland Gershell of Oppenheimer. Your line is now open.
Great. Thanks for this update and taking our questions. Just wondering, and would love to hear from both the company and Dr. Bird on this. With respect to the changes seen between the drug and the placebo group, both during what we have from the controlled portion and also the jump to the OLE. Just if I recall correctly in the Vykat studies, patients who had a worse baseline HQ-CT score tended to have greater improvement during those studies or that study. Not sure if that was ever resolved to be drug-related or maybe just returned to the mean in the absence of a drug effect. But just wondering how that may weigh in your minds as you look at these data from both the controlled and the open label portion. Thank you.
Manasi, also, are you comfortable taking that one?
Can you clarify that question a little bit for me?
Oh, sure. Yes, in the Vykat studies, I believe it was shown that those patients who had higher HQ-CTs at baseline tended to improve more, versus patients who had lower HQ-CT scores at baseline. I am just wondering, given that there was a difference, if you look at the baseline panel on slide eight, just between ARD-101 and placebo, there are the differences both in the HERO and the OLE between those two, and I am just wondering how those may weigh, either in favor or not, in terms of an actual drug effect. It is small numbers, but just how those may weigh in terms of the potential for ARD-101 here. Thank you.
Okay, great question. Okay, I understand now. In terms of the baseline, yeah, there was a difference. That is why, A, you have a cutoff in the inclusion criteria for, A, introducing participants in this trial. Our ITT population was greater than or equal to 13 against standard in the PWS inclusion criteria for hyperphagia at baseline. That is considered moderate hyperphagia. Even with this difference, it is how you look at it from baseline. We actually did change from their own baseline versus the average change based on cumulative baseline or aggregate data. I think for us, it was really looking at the data from a change perspective. Again, we couldn't run any statistical models here, obviously, because it was a truncated trial.
At this point, we had to look for change from baseline and how we ran the modeling based on just that. I hope that answers your question.
That's helpful. I also wanted to ask with respect to these data, I know it's a partial data set from a trial that was paused early, but any plans for either publication or presentation in medical meetings? Thank you.
Yeah, great question. I think this is valuable data. I think we're working through a publication strategy and what that would entail, but we do hope to deliver something in the future.
Thanks very much.
Thank you. One moment for our next question. Our next question comes from the line of Catherine Novack of JonesTrading. Your line is now open.
Hi. Good morning, and thank you for taking my questions. Is Dr. Bird still available for questions or I did have one on Vykat and safety.
Dr. Bird, are you still on the line?
I'm still on the line, yeah.
Oh, great. Thank you. I would just be curious to understand your thoughts on what are you hearing from the rest of the community in terms of growing potential safety signals coming from Vykat and belief, thoughts on requirements for a safer and potentially more efficacious treatment.
Well, we clearly need a more efficacious treatment. The safety issues that have come up, I do not think there is necessarily any surprises here. I think that whenever you have inclusion criteria that include a fairly healthy and regulated population at the outset, then when the drug gets opened up and is used in the real world, it may be applied to patients who were not ideal candidates. Certainly, there has been some further guidance given out as to how maybe we should monitor patients as they are titrating up on Vykat. As I said, I do not think it is the drug for everybody, because some patients with substantial comorbidities may not be candidates for that drug. So we for sure need more, and we for sure need better options out there.
Got it. Thanks. This one is for Aardvark management. I guess, can you clarify the use of concomitant medication for PWS in the HERO trial? It is my understanding that pitolisant can impact HQ-CT, so what were the requirements to be stable on medication prior to enrollment? Was this something that was meant to be stratified for in randomization? Thanks.
Sure. Great question. I can take that, Tien. In terms of concomitant medications, as with all clinical trials, they do have to be on stable therapy entering the trial. So for us, it was standard, which is approximately three months of stable therapy, no changes in chronic medications. That would be required regardless what medication they come in with, as long as it complied with our inclusion/exclusion criteria.
Got it. Okay. Thank you very much.
No problem.
Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad of Bank of America. Your line is now open.
Okay, great. Thanks for taking my question, and good morning. Now that you have this hold lifted, you've talked about requesting a meeting with FDA to align on Phase 3 design. What is your remaining gating factor between now and when you have the meeting? Is there any additional information you need to collect? When would we get clarity on what the final Phase 3 trial design would be? Also, as part of that, given Vykat is approved, how would you think about ideally handling that in the phase III program? Would you allow patients to be on background Vykat XR? Would you require them to be off of it? What are some suggestions do you think you'd be giving FDA, and what do you think the pushback could be? Thanks.
Okay. Great. Tien, I can take this question. In terms of our next iteration of the trial, we haven't disclosed that yet. We are working through alignment with the FDA and hope to bring you more updates soon. That's as much as I can answer there. In terms of Vykat, I will also remind you that Vykat was approved while we were actively enrolling participants in our Phase 3 HERO and open-label trial. We already have experience with that. I will say that when we are running clinical trials, what you really want to do to have a clear understanding of your own therapy is really to limit other therapies that could interfere with understanding signals.
Even within our HERO and open- label, they were not allowed to be on Vykat during the clinical trial so we can have pure results, and there would be no variability or bias introduced from other therapies that are therapies specifically for hyperphagia. I don't see that changing for our next clinical trial because, again, we want to have a clear understanding of our own drug. That being said, we do not think our drug is mutually exclusive from Vykat in the future. But right now, for a clinical trial, we would want to limit any interference with other drugs specifically for hyperphagia.
In terms of what the FDA may align with on that, this isn't actually atypical for clinical trials because if you are studying a drug in hyperphagia, having another drug that could limit your understanding of it usually is not something that most clinical trials will have.
Okay. Then a quick follow-up. There are other companies that are trying to pursue Prader-Willi with different mechanisms of action. In terms of how long it could take to recruit a trial, and maybe Dr. Bird can also opine, do you have a sense of whenever it is that you start this study, how many sites you might need, and how long it could take to recruit, just given that there might be others also trying? Thank you.
Dr. Bird, I can answer the first part, and then it'd be really great to get your perspective on it as an investigator. I will say this, that I am very encouraged with the space. We are so thrilled to know that, and especially as a pediatric endocrinologist, that more therapies are being worked on for these patients who desperately still need it because of the continued unmet need with addressing hyperphagia. So it's great news for all of us. In terms of recruitment, though, I will also say that even while we were undergoing our HERO in open label extension with an approved product, we were still doing fairly well with recruitment and how we were engaged globally. I don't see that changing.
I think that there is still such space, as Dr. Bird mentioned earlier, there is still such a high unmet need that I think continued development, I think there is still going to be continued participation. I think that the other really key piece in the space, at least as an endocrinologist, but also as someone at this company, is that continued engagement with the families, the participants, the advocacy group. We have such good support from them. I don't see that changing. We've been transparent, and we've always put patient safety first. I feel that we are going to be okay in terms of the recruitment piece. But Dr. Lynne, I'd love to hear your take.
Well, I was just emailed by a family who's listening to the webinar who said, "We're in." H ugely, highly engaged. I know. A highly engaged community. As I said, we've never had problems with enrollment. Obviously, now Vykat's out there, and that's probably going to be an exclusionary criterion. I t may narrow the pool, but there are certainly plenty of families out there who are still interested in research, still committed to the process, and for one reason or another, not on Vykat, not interested in Vykat. So I don't foresee big struggles with enrollment.
Thank you. Thank you for the question.
Thank you. One moment for our next question. Our next question comes from the line of Brian Abrahams of RBC Capital Markets. Your line is now open.
Hey, good morning, guys. Thanks so much for taking our questions, and thanks for the very, very clear and detailed presentation. It is super helpful. One question on data and then one question on path forward. Maybe just on the data, in looking at slide 10 at the 12-week mark, I am just curious, if you look at those 24 patients who made it through the 12-week dosing period, can you talk a little bit about how their HQ-CT scores tracked over time? I guess I am asking because I am wondering if there could be the potential for some waning effect as patients get out to 12 weeks, or if that snapshot of those particular 24 patients just represented a group that maybe was not quite as responsive to ARD-101.
Secondarily, just on the go-forward path, I know it is still being worked out with the FDA, but I guess I am curious, do you have a sense of what dose, 200 mg or 400 mg, you might pursue? Might you pursue an SPA? If you plan for, I guess, a similar effect size as you are seeing signals of here, how large would the Phase 3 need to be in order to be adequately powered for statistical significance? Thanks.
Great. Tien, I can take this, and please add if you need to. The week 12 data, a couple of things to think about, as I mentioned in the webcast as well, is that this trial stopped early. When you look at the earlier weeks, that is where the bulk of the patients, and I think that is a broader representation of the population that entered the clinical trial, but certainly didn't go all the way through because we stopped the study very quickly. On February 27th, where the patients were as they were in the trial, that is where they stopped. The bulk actually didn't even make it all the way through.
That being said, even at week 12, we actually, as you would have, and we had three participants, as you can see in there, that actually didn't. Well, actually, we didn't show you this, but the three participants didn't complete the study because we had three that dropped out. We had a actually very low dropout rate of under 5%. We also had three that were on ARD-101 that didn't make it all the way through. Compile that on top of the fact that we just had a truncated trial where most participants didn't make it through. It is really hard to interpret the week 12. There is also nuance in the HQ-CT nine. It is a two-week look back as well. You really want to look at directionality over a long period of time, not just one time point.
Which is why having a full trial, a completed trial, open label data for a long period of time is very important. For us, when we looked at the data ourselves, it was really looking at directionality, answering that one question, are we seeing something? Are we seeing loss of effect? Both answers are yes. Should we continue to develop this program? The answer was yes for that. In terms of your second part of that question, in terms of path forward, I think that for us, in terms of dosing, I will tell you the data on hand. Our thorough QT study we did was at lower doses. What the trial design will look like, how it will be powered, will be determined based on our clinical trial design that we are still pending alignment with the FDA.
Got it. That's really helpful context. Thanks so much.
No problem.
Thank you. One moment for our next question. Our next question comes on the line of Kelsey Lucerne of William Blair. Your line is now open.
Hi, thank you so much. This is Kelsey Lucerne of William Blair. Appreciate you taking the question. Perhaps related to the prior question, we were curious if you are seeing an observed sort of dose exposure relationship here, and if that is a linear relationship or not, and perhaps if that translates to the efficacy you are seeing by dose in this sort of initial look at the data. How might that inform your approach to the Phase 3? Will you be progressing directly into one, or do you anticipate doing maybe additional dose ranging work? Thank you so much.
Great. I will say so far, there is no clear dose response or exposure. It seems to be similar at week two and at week four, and week two, if you recall, were at the lower doses. The other pieces are Phase 2 showed a nine-point reduction at the 200 mg twice daily dose. We do have data to support these lower doses, but again, as I mentioned, there are no clear dose response.
If I might add a little bit. Based on our Phase 2, when we were going into Phase 2, the reason why we chose 200 mg at that time was because we thought that was going to be more than sufficient based on our understanding of receptor engagement for the receptors that we are targeting. The reason we moved up to 800 mg, because at the time, we had thought that our dose ceiling was effectively a lot higher than it might be limited by now. That was just to accommodate a theorized potential for efficacy dilution effect. Based on first principles, we actually had strong optimism for 200 mg, which is why you see our other Phase 2 studies were also targeting that dose.
That is why we did not expect to see a dose response from the dose ranges that we have had, even reflect back to our Phase 2. Even though we explored higher doses, the low dose group actually did better than the high dose group in our Phase 2. Hope that answers your question.
Yeah. Thank you. Very helpful. If I could sneak in another quick one. Following this update, we were just curious how this might impact your plans for ARD-201 and what you view as key development or decision points for that program going forward.
Yeah.
We haven't announced. Go ahead, Manasi.
No, I think we're going to say the same thing. We haven't really disclosed our development plans moving beyond PWS. Our focus remains on the Prader-Willi community at this time.
Thank you so much.
Thank you. One moment for our next question. Our next question comes from the line of Mike Holtz from Morgan Stanley. Your line is now open.
Good morning, and thanks for taking the question. Maybe just to follow up on some of the earlier questions related to thoughts on the Phase 3 trial design. Just curious if you're considering a randomized withdrawal study. Then when you meet with the FDA, are there specific areas where you're seeking feedback? Thanks.
Great. Hello, Mike. I think in terms of our Phase 3 trial design, it is encouraging that there is an approved pathway for an RWD. That being said, we are still pending alignment with the FDA on what our trial design will look like.
Great. Thank you.
Thank you. One moment for our next question. Our next question comes from the line of William Wood of B. Riley Securities. Your line is now open.
Hi, thank you for taking our questions. We were just thinking about the patients who received the drug only. In terms of your secondary endpoints that you looked at, you compared those to placebo. I was curious when specifically just looking at the active drugs and separating these apart, could you speak to any changes in body weight or other hyperphagia-related endpoints that you may have seen that would support the efficacy that you already saw? Then in thinking about sort of the next steps into Phase 3, is it safe to say that the FDA would view HERO as contributing to the registrational package, or do you think that there would need to be an additional trial after that also, after your next Phase 3? Thank you.
I think I missed the first part. It was a little broken up. But I'll start with the second part, and maybe you can reiterate on that first one. In terms of our current data, certainly it's a truncated trial, but it is still supportive. We have some data from a safety standpoint. We have s ome supportive data. A gain, we have to wait until we work things out with the FDA and get alignment on that next trial and how it could be used for registration. H opefully more to come soon on that piece. Then can you circle back on that first part of that question, please?
Sure. Yeah. Just thinking about the patients who did receive drug, I was curious what the changes in your secondary endpoints were, not specifically related to placebo, but just did they align with the HQ-CT that we saw, specifically thinking about body weight and/or other hyperphagia-related endpoints?
Yeah. Okay, I understand. In terms of the secondary, the secondary endpoints were actually other caregiver assessments and clinician assessments, and they did follow a similar trend with the HQ-CT. With our exploratory measures in one of the slides that I had presented, again, because it's truncated, a lot of these metabolic parameters and even BMI take time for change. Because we had such a truncated trial, we saw minimal changes. I do think that had we run a longer, lengthier period, we would probably have had a bit more dynamic results to share today. W e are absolutely following this, again, in our next trial, and hopefully we'll have more robust results to share.
Thank you very much.
Thank you. One moment for our next question. Our next question comes on the line of Raghuram Selvaraju of H.C. Wainwright & Co. Your line is now open.
Thanks very much for taking our questions. I was just wondering when you might have additional clarity regarding the drug-drug interaction profile of ARD-101 and specifically at which doses there might not be any meaningful risk of such interactions. If you can give us a sense of when you anticipate being able to provide us with further clarity on that front. Then a question for Dr. Bird. You had mentioned that there remains a significant unmet need with respect to addressing hyperphagia in Prader-Willi syndrome patients, and I was just wondering if you could maybe characterize that a little bit more granularly for us in the context of the availability of Vykat XR in terms of how you would gauge, how you would rate the overall efficacy and risk-benefit profile of that drug.
Obviously, you made comments before about the degree to which there are side effects with that agent, the risk of significant adverse events. Just give us a greater sense of the extent to which you believe that the PWS community is currently being served by Vykat XR and what the nature of the unmet medical need is, as well as the specific characteristics of any patient subpopulation. For example, those with poor glycemic control within the Prader-Willi syndrome population as a whole, who might be especially unlikely to be considered candidates for Vykat XR, and whether you would deem these to be particularly well-suited for treatment with a drug like ARD-101. Thank you.
I think-
There's a lot to unpack. Go ahead, Manasi.
No, no. I think go ahead and answer, and then I can go back because I think yours was lengthier.
Certainly there are patients who Vykat may not be a good choice for them because of other comorbidities that they have. E ven those who are put on Vykat, not everybody responds. As I said, even those who respond, it's not like a complete sapping of the appetite entirely, and it just sort of takes the edge off. Something that would allow families to go to a family reunion and not have to worry about keeping their eyes on their kid every single second because there's food out would really be helpful. I think it's too early to know whether this drug is going to be a better choice for individuals with Prader-Willi syndrome or not, but it's very clear that we need more than what we have.
Great. I can address that first part of the question, which is clarity on the DDI. What I will say is that what our information right now, based on our DDI trial that we ran in healthy volunteers at 800 mg twice daily, is that we're a strong CYP2D6 inhibitor. We still have to do a trial that will look at lower doses at lower exposures. Hopefully we will have that to share with you at a future time. Again, I think we have some information on hand, and we'll continue to iterate to understand what this could look like at lower exposures.
Just to clarify what you are-
Sorry. I think you dropped. Just to clarify.
It looks like he has disconnected. Thank you. This concludes the question and answer session. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.