Heart data prompts FDA to halt trial of Prader-Willi syndrome drug ARD-101
Developer had earlier paused enrollment and dosing in study and its extension
Written by |
The U.S. Food and Drug Administration has placed a full clinical hold on late-stage clinical trials of Aardvark Therapeutics’ oral therapy candidate ARD-101 in patients with Prader-Willi syndrome (PWS) and hyperphagia, or insatiable hunger.
The company had voluntarily paused enrollment and dosing in the Phase 3 HERO trial (NCT06828861) and its open-label extension study (NCT07197034) earlier this year after reversible heart-related abnormalities were detected in healthy volunteers given a higher dose of the therapy in a separate safety study.
“We are continuing to work collaboratively with the agency to comprehensively evaluate the data and determine the best path forward for ARD-101,” Tien Lee, MD, founder and CEO of Aardvark, said in a company press release. “Patient safety will always be the highest priority for us, and … we remain committed to advancing ARD-101 as a potential therapy for this underserved patient population.”
In the meantime, Aardvark plans to unblind data gathered so far in the HERO and OLE studies, meaning the company will know which participants received the treatment or the placebo and will be able to assess the therapy’s safety and efficacy relative to the placebo.
HERO has dosed 68 of the target 90 participants so far, and its OLE study has dosed 19 patients who have completed HERO. The company expects that these data will help inform the next steps in ARD-101’s clinical development.
ARD-101 designed to release hormones that signal fullness
PWS is caused by genetic defects that result in the loss or inactivation of genes on a region of chromosome 15 called the PWS locus. Symptoms include developmental delays and behavioral problems, as well as hyperphagia and associated extreme food-seeking behaviors.
ARD-101 is an oral small molecule designed to activate TAS2Rs — bitter taste receptor proteins in the gut — to release hormones that signal satiety, or the feeling of being full. This is expected to ease hyperphagia in people with PWS.
Data from a completed Phase 1 trial in healthy volunteers demonstrated that ARD-101 was generally safe and well-tolerated at all doses tested, with no serious adverse events observed. Over 99% of the medication remained in the digestive tract and was not absorbed into the bloodstream, and participants showed increased release of hormones in the gut.
The therapy was also found to safely and effectively reduce hyperphagia in adolescents and adults with PWS enrolled in a Phase 2 trial (NCT05153434). It was also associated with beneficial changes in body composition, indicated by a trend toward decreased body fat and increased lean muscle following 28 days of twice-daily ARD-101 dosing.
Healthy volunteer study shows unexpected heart-related findings
The HERO trial was testing ARD-101 against a placebo in PWS patients ages 7 and older for three months. ARD-101 was started at a dose of 200 mg twice daily and gradually increased to a target dose of 800 mg twice daily. The main goal was to determine whether the treatment was superior to the placebo in reducing hyperphagia.
The decision to temporarily pause ARD-101 clinical testing followed unexpected heart-related findings in a separate healthy volunteer study, conducted as a routine additional heart safety study to satisfy anticipated requirements for a future application seeking ARD-101 approval.
Aardvark reported that some healthy volunteers given an ARD-101 dose higher than that being tested in the HERO trial (1,600 mg twice daily) showed temporary changes in their hearts’ electrical activity, which resolved after stopping the therapy.
Similar heart-related changes were also detected in some participants of a subsequent healthy volunteer study testing the 800 mg dose, given twice daily, but without the gradual dose increase.
Because TAS2Rs are also found in the heart, higher doses of the medication may, in theory, reach the heart and change its function.
