Soleno Therapeutics’ investigational oral therapy diazoxide choline controlled-release (DCCR) failed to significantly lower excessive appetite, but it did improve body composition and behavior in Prader-Willi syndrome (PWS) patients, top-line data from a Phase 3 trial show.
Notably, excessive appetite (hyperphagia) — the hallmark symptom of PWS — was found to be significantly reduced in patients with severe hyperphagia, suggesting that DCCR may be particularly effective in this group of patients.
“While we are disappointed to have not achieved statistical significance on the study’s primary endpoint, we are excited by the results observed in those subjects with severe hyperphagia, as well as the changes in body composition and behavioral endpoints,” Anish Bhatnagar, MD, Soleno’s CEO, said in a press release.
DCCR, an extended-release formulation of diazoxide taken as a once-daily tablet, works by blocking the release of two appetite-stimulating proteins in the brain — neuropeptide Y and agouti-related protein — which are believed to drive hyperphagia in people with PWS.
The therapy is also thought to improve GABA signaling, which suppresses the activity of nerve cells and is impaired in PWS patients, leading to temper outbursts.
Participants had a mean age of 13.5 years. They were randomly assigned to receive DCCR (85 patients) at a dose of 75–450 mg, or a placebo (42 patients), once daily for 13 weeks.
The study’s primary goal was to assess changes in hyperphagia, which was measured through the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), whose scores range from 0 to 36, with higher scores reflecting more severe hyperphagia. Secondary goals included changes in body fat, as well as caregiver and clinician evaluations of clinical progress.
DDCR treatment led to a greater reduction in hyperphagia than the placebo, but this difference was not statistically significant, failing to meet the trial’s main goal, the results showed.
Notably, a significant drop in excessive appetite with DCCR was observed in a subgroup of patients with more severe hyperphagia (HQ-CT scores higher than 22). The 42 participants treated with DDCR within this subgroup had a more than twofold greater drop in hyperphagia, compared with the 19 on the placebo.
Also, DDCR treatment resulted in significant clinical improvements, as assessed by the investigators, and a significant drop in body fat, compared with the placebo.
DDCR-treated patients lost significantly more fat in their trunks and showed a significantly higher lean body mass/fat mass ratio — meaning they had more muscle relative to fat — than those on placebo. Changes in body fat were more pronounced among patients with higher weights (100–135 kg or 220–297 lbs).
Interviews with caregivers of 17 patients in the DCCR group and 10 in the placebo group indicated that about 48% of DCCR-treated patients showed at least some improvement in all three domains (food-related, non-food-related, and daily life), compared with 10% (one patient) of those receiving a placebo. Major improvements were reported by 18%–24% of those treated with DCCR, compared with none of the participants on placebo.
DCCR’s safety profile was consistent with prior trials, with most adverse events being mild in severity and hypertrichosis, or excessive hair growth, being the most common.
Treatment was associated with a higher occurrence of adverse events, including severe events and those leading to treatment discontinuation. No serious unexpected adverse events related to DCCR occurred during the trial.
A total of 120 participants completed the trial, and 115 chose to enter the C602 open-label extension study (NCT03714373), in which all patients receive DCCR for up to three years. Currently, 106 (92.2%) are continuing treatment.
An early analysis of 63 patients completing three months of treatment in this study showed sustained reductions in hyperphagia. Those continuing DCCR treatment (38 patients) had a 48% total reduction in excessive appetite, compared with their levels at enrollment. A similar drop was observed among patients switching from placebo to DCCR.
Similar trends were also observed in participants’ behaviors, with patients switching to DCCR showing behavioral improvements comparable to those reported for patients who had been on DCCR in the first study.
“These data show that DCCR therapy results in meaningful improvements in hyperphagia in severe patients, as well as various other positive impacts in behaviors and body composition, and if approved, could offer a safe and effective treatment to PWS patients struggling to manage their symptoms,” said Jennifer L. Miller, MD, a principal investigator in the trial and professor of pediatric endocrinology at the University of Florida.
Soleno reported that it will continue to evaluate the impact of the COVID-19 pandemic, which affected study visits and clinical evaluations in both trials after mid-March. The company plans to meet with regulatory authorities to decide on next steps.
DCCR has received orphan drug designation in the U.S. and the European Union (EU), and fast track designation in the U.S. These designations are meant to speed up DCCR’s development and review by providing regulatory support and financial benefits, and to ensure market exclusivity for a period of time upon regulatory approval (seven years in the U.S. and 10 years in the EU).
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