Aardvark Therapeutics, Inc. Common Stock FDA announcement

Good morning, everyone, and thank you for joining us today to review the efficacy and safety data from HERO, our phase III 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 3 here, we've outlined a historical overview of the ARD-101 clinical program. Our phase II open-label trial in patients aged 17 and older was conducted in two parts. Part one evaluated doses at 200 milligrams twice daily, and part two included dose escalation to 800 milligrams twice daily. Hyperphagia was measured by the Hyperphagia Questionnaire for Clinical Trials, or HQCT, 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 HQCT scores and an approximately 9-point reduction in the 200 milligram BID group. ARD-101 was well-tolerated, and these results gave us the confidence to advance into HERO, our global randomized placebo-controlled phase III 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 milligrams 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 2 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 5, we have provided a side-by-side safety summary. On the left is why the hold happened.

In healthy volunteers receiving 1,600 or 800 milligrams of ARD-101 twice daily, 3 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 and 400 milligrams 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 milligrams 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 milligrams twice daily, stepped up to 400 milligrams in week 2, and 800 milligrams from day 15 on. The titration matters. The week 2 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, 8 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 6 points. So they entered the extension already better than at HERO baseline. Note that the 8 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.