Heart activity changes prompted pause in trial of ARD-101 in PWS
Experimental therapy aimed at easing patients' persistent, insatiable hunger
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Aardvark Therapeutics has provided new details on the safety concerns that led to the pause of a global clinical trial of ARD-101, its experimental treatment for hyperphagia, or persistent, insatiable hunger, in people with Prader-Willi syndrome (PWS).
In a company press release announcing financial results and the latest business updates, Aardvark noted that some healthy volunteers given ARD-101 doses higher than those being tested in PWS patients in the Phase 3 HERO clinical trial (NCT06828861) showed temporary changes in their hearts’ electrical activity, which resolved after stopping the therapy.
These heart-related findings led the company to voluntarily pause the enrollment and dosing in HERO and its open-label extension study (NCT07197034) earlier this month. It is now working closely with the U.S. Food and Drug Administration (FDA) to review these findings and determine next steps, with updates expected in the coming months.
“Patient safety will always be our highest priority, and we are actively engaging with the FDA with urgency to determine the best path forward for our programs,” said Tien Lee, MD, Aardvark’s founder and CEO. “We hope to resume the PWS development program in a timely manner and expect to provide further guidance on each of our programs in the second quarter of 2026 [April to June].”
ARD-101 activates proteins to release hormones that signal satiety
From early childhood, PWS causes persistent, insatiable hunger and an obsession with food. This often results in people with the disease being overweight or obese and engaging in risky food-seeking behaviors. Other symptoms of PWS include developmental delays, learning difficulties, and sleep problems.
ARD-101 is an oral, gut-targeted medication designed to activate bitter taste receptor proteins, called TAS2Rs, in the gut to release hormones that signal satiety, or the feeling of being full. By increasing these hormones, the therapy is expected to ease hyperphagia in people with PWS.
However, TAS2Rs are also found in the heart, so the medication could, in theory, still reach the heart and change its function.
Data from a previous Phase 1 trial in healthy volunteers showed that ARD-101 was generally safe and well-tolerated, with no major safety concerns. In addition, more than 99% of the medication remained in the digestive tract and was not absorbed into the bloodstream, which may contribute to a favorable safety profile.
In addition, in adolescents and adults with PWS in a Phase 2 trial (NCT05153434), the therapy was found to safety and effectively lessen hyperphagia, with favorable changes in body composition. HERO was designed to confirm these findings in a larger patient population.
Heart-related findings in study of healthy volunteers spurred pause
The decision to temporarily stop clinical testing of ARD-101 followed unexpected heart-related findings in a separate healthy volunteer study conducted to meet safety requirements for a future application for the therapy’s approval.
In that study, two out of eight volunteers showed QRS prolongation greater than 25% with ARD-101 treatment, which was considered clinically significant per the study’s protocol. QRS prolongation is a change in the heart’s electrical activity that can indicate the heart is taking longer than normal to send electrical signals.
An additional volunteer had a QRS increase of less than 25%. However, none of the three people experienced serious heart symptoms, and the QRS changes resolved after stopping ARD-101, without the need for additional medication.
These volunteers were given a high dose of ARD-101 — 1,600 mg twice daily — without a gradual dose increase. This is different from the HERO study, where patients are started on a lower ARD-101 dose that is slowly increased over time, from 200 mg twice daily for one week, to 400 mg twice daily for one week, to 800 mg twice daily for 10 weeks.
We strongly believe that ARD-101 retains its potential as a differentiated therapeutic option for hyperphagia in individuals living with PWS,
Aardvark subsequently conducted another study in healthy volunteers testing the 800 mg dose, given twice daily, for up to one week, but without the gradual dose increase. One out of 23 volunteers had a QRS increase greater than 25%, and another had an increase of less than 25%. Again, there were no serious symptoms, and the changes were reversible after stopping ARD-101.
Further analysis showed that higher levels of ARD-101 in the blood were linked to an increased risk of QRS prolongation, indicating an exposure-response relationship. At lower doses, such as 200 mg twice daily, ARD-101 levels in the blood were well below the range where changes in the heart’s electrical activity were seen.
“With positive clinical data, an encouraging safety profile from previous trials and our recently developed understanding of the clear … exposure-response relationship with reversible [heart] QRS prolongation, we have confidence in ARD-101,” Lee said.
Recently published findings from clinical trials testing ARD-101 in adults with obesity and healthy volunteers further supported the therapy’s potential to ease PWS-related hyperphagia.
Specifically, ARD-101 reduced feelings of hunger in obese adults. In healthy volunteers, it increased levels of hormones that signal satiety, showing it engaged gut-brain pathways that control appetite.
“We strongly believe that ARD-101 retains its potential as a differentiated therapeutic option for hyperphagia in individuals living with PWS,” Lee said. “As we evaluate next steps, we want to thank the Prader-Willi Syndrome community for its collaboration throughout this process. The community’s strength and tenacity continue to inspire our work.”
