FDA lifts hold on clinical testing of experimental PWS treatment
Decision clears path for development of redesigned Phase 3 trial of ARD-101
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The U.S. Food and Drug Administration (FDA) has lifted the hold on late-stage clinical testing of ARD-101, an investigational oral therapy for people with Prader-Willi syndrome (PWS) and hyperphagia, an insatiable feeling of hunger.
“We are pleased that the FDA has lifted the clinical hold on ARD-101, allowing us to continue advancing our clinical development program,” said Tien Lee, MD, founder and CEO of Aardvark Therapeutics, the therapy’s developer, said in a company press release.
Earlier trials halted due to safety concerns
Earlier this year, Aardvark voluntarily paused dosing in the Phase 3 HERO clinical trial (NCT06828861) and its open-label extension (OLE) study (NCT07197034). The pause followed the detection of reversible heart rhythm changes in a separate study of healthy volunteers taking a dose that’s twice as high as that used in HERO.
The FDA followed up with a full clinical hold on the HERO and OLE trials. Aardvark terminated both studies in June and said it did not intend to resume them as designed, but noted that further clinical development of ARD-101 could include a redesigned trial.
Still, this would only be possible if the FDA lifted the clinical hold. According to a recent company webcast, Aardvark therefore conducted a heart rhythm study in 87 additional healthy volunteers exposed to ARD-101 doses that were being evaluated in the late-stage trials.
Electrocardiograms (ECGs), which measure the electrical activity of the heart, found no abnormalities, including no signs of the QRS prolongation found with the higher dose in the previous healthy volunteer study. QRS prolongation can indicate the heart is taking longer than normal to send electrical signals. Also, no changes in the QRS interval were seen in available ECGs from PWS patients undergoing ARD-101 treatment.
“With strong alignment and collaboration with the FDA, we completed the work necessary to allow for the resumption of clinical studies,” Lee said. “People living with PWS and their families continue to face profound unmet need, and we look forward to working with the FDA as we advance ARD-101.”
The company plans to resume ARD-101’s clinical development after aligning with the FDA on the design of an upcoming Phase 3 trial.
ARD-101 modestly outperformed placebo in reducing hyperphagia
A hallmark symptom of PWS, hyperphagia typically emerges during early to mid-childhood and can lead to excess weight and obesity. It’s thought that people with PWS have abnormal regulation or responses of hunger-blocking hormones.
ARD-101 is an oral small molecule designed to activate bitter taste receptors in the gut, triggering the release of two gut hormones normally released when the gut is full. Boosting these hormones is expected to help ease hyperphagia in people with PWS.
In HERO, people with PWS, ages 7 and older, were randomly assigned to receive either ARD-101 or a placebo for 12 weeks (about three months). The therapy was started at a 200 mg dose twice daily, which was gradually increased to 800 mg twice daily. Those who completed HERO had the option to start or continue receiving ARD-101 in the one-year OLE study.
In the webcast, Aardvark also shared data collected across both HERO and OLE trials from before and after the clinical pause. According to data from 67 HERO participants, ARD-101 modestly outperformed the placebo in reducing hyperphagia through week eight, as indicated by a greater reduction in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. This caregiver-reported tool assesses the frequency and intensity of obsessive hunger and food-seeking behaviors.
Those originally assigned the placebo experienced pronounced HQ-CT score reductions after switching to ARD-101 in the OLE. Upon ARD-101 discontinuation due to trial termination, HQ-CT scores in both groups increased (worsened), more greatly so among patients originally assigned ARD-101.
Improvement after starting ARD-101 followed by worsening after stopping it provides a consistent signal of potential treatment effect.
A similar pattern was observed for caregiver and clinician outcome measures, such as Caregiver Global Impression and Clinician Global Impression Severity scores.
“Improvement after starting ARD-101 followed by worsening after stopping it provides a consistent signal of potential treatment effect,” Manasi Jaiman, MD, Aardvark’s chief medical officer, said in the webcast. “Although these findings are not definitive, we believe they offer encouraging rationale for further evaluation.”
The therapy was well tolerated across both studies, the company said. Adverse events were infrequent and mostly mild-to-moderate in severity, with no meaningful rate difference between the therapy and placebo groups (52% vs. 50%).
Aardvark also noted that ARD-101 at 800 mg twice daily is a strong suppressor of CYP2D6, a protein involved in the metabolism of certain drugs. In fact, a serious event or irregular heartbeat occurred in one HERO participant who was also taking pitolisant, a medicine metabolized by CYP2D6 and that when combined with ARD-101 can cause irregular heartbeats.
“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,” Jaiman said.
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