Aardvark Therapeutics (NASDAQ:AARD) said the U.S. Food and Drug Administration has lifted the clinical hold on its investigational ARD-101 program after the company completed a thorough QT study at lower doses. The company also reported exploratory efficacy and safety findings from its discontinued Phase 3 HERO trial and open-label extension in patients with Prader-Willi syndrome.
ARD-101 is an oral bitter taste receptor agonist designed to act primarily in the gut. According to Chief Medical Officer Manasi Jaiman, the therapy activates bitter taste receptors to stimulate release of the satiety hormones CCK and GLP-1, which signal through the vagus nerve and are intended to reduce hunger and appetite.
The company is developing the treatment for hyperphagia, the persistent and severe hunger associated with Prader-Willi syndrome. However, management emphasized that HERO and its extension were stopped before planned enrollment and duration were completed, meaning the efficacy results should be considered exploratory.
HERO Trial Ended Early After Cardiac Findings
Aardvark voluntarily paused enrollment and dosing in HERO and its open-label extension on Feb. 27, 2026, following reversible cardiac observations in a separate healthy-volunteer study at doses above the intended therapeutic range. The FDA subsequently imposed a full clinical hold on the ARD-101 investigational new drug application in May, and Aardvark terminated both studies in June.
At the time of the pause, 67 patients had enrolled in HERO and 19 had entered the extension. The randomized, double-blind HERO study had been designed to enroll 90 participants, with 45 patients in each arm, and to evaluate 12 weeks of treatment. Eligible patients were at least 10 years old.
Jaiman said a serious cardiac adverse event in HERO was ultimately attributed to an interaction between ARD-101 and pitolisant, rather than ARD-101 independently prolonging QT. The company determined that ARD-101 was a strong CYP2D6 inhibitor at 800 milligrams twice daily, while pitolisant is metabolized by CYP2D6 and can cause QT prolongation at higher plasma concentrations.
In the healthy-volunteer study, three of 31 participants receiving ARD-101 at 1,600 milligrams or 800 milligrams twice daily experienced QRS widening greater than 25% from baseline. The events were non-serious and resolved without treatment, according to the company.
Aardvark subsequently conducted a thorough QT study at lower doses of 200 milligrams and 400 milligrams twice daily. It reported no QRS or QT prolongation at either dose. Going forward, the company said ARD-101’s maximum dose will be below 800 milligrams twice daily and that future trials will include additional cardiac monitoring.
Exploratory Efficacy Signals
Among 64 HERO participants with baseline Hyperphagia Questionnaire for Clinical Trials, or HQ-CT, scores of at least 13, patients were evenly divided between ARD-101 and placebo. The mean age was about 20 years, with a range of 10 to 43.
Jaiman said the ARD-101 arm showed modest numerical improvement versus placebo at weeks two, four and eight. Both groups improved during the trial, reflecting what the company described as a substantial placebo response that is common in Prader-Willi syndrome studies. Data at week 12 were too limited for reliable interpretation because fewer participants had reached that visit when the program was paused.
The company highlighted withdrawal observations as additional support for potential treatment activity. On the day dosing stopped, ARD-101 participants had improved by 9.5 points from baseline on the HQ-CT, compared with a 7.8-point improvement in the placebo group. Two weeks after treatment stopped, the ARD-101 group was nearly back to baseline, while the placebo group retained more of its improvement.
In the 19-patient open-label extension, patients initially assigned to placebo who switched to ARD-101 improved by an average of six additional HQ-CT points after about four weeks on treatment, Aardvark said. Both groups lost ground after dosing ended. The company cautioned that patient numbers at individual extension visits were fewer than 10 per group.
Caregiver and clinician severity measures followed a similar pattern, Jaiman said. The company reported no meaningful differences versus placebo in weight, body composition, lipids, hemoglobin A1c, vital signs or electrocardiogram assessments, though it said longer treatment and follow-up would be needed to assess metabolic effects.
Safety Profile and Next Steps
In HERO, adverse events occurred in 52% of ARD-101-treated patients and 50% of placebo-treated patients, with most events described as mild to moderate. Related adverse events were reported in 15% of ARD-101 patients and 21% of placebo patients. Diarrhea and nasal congestion were the most common events, each occurring in three patients per arm.
There were no serious events in the open-label extension. Aardvark said all eight related events in the extension occurred among patients newly starting ARD-101, with seven of the eight considered mild.
Founder and Chief Executive Officer Tien Lee said the company plans to request an FDA meeting to align on the design of a new Phase 3 study intended to support a future marketing application. The company did not disclose the expected trial design, dose selection, enrollment target or timing.
Dr. Lynne Bird, a clinical geneticist at Rady Children’s Hospital and investigator in HERO, said hyperphagia remains the central unmet need for people with Prader-Willi syndrome and their families. While an approved treatment is available, she said it does not work for every patient and does not eliminate the need for families to maintain strict food security measures.
About Aardvark Therapeutics (NASDAQ:AARD)
Aardvark Therapeutics, Inc is a clinical-stage biopharmaceutical company based in San Diego, California. The company develops novel therapies for obesity and other metabolic diseases, with a focus on treatments designed to regulate appetite and food intake.
Its lead investigational product, AARD-001, is an orally administered small-molecule candidate intended to activate bitter taste receptors and stimulate signaling pathways in the gastrointestinal tract that may influence appetite and satiety.
