Soleno Reports PWS Therapy Missed Primary Endpoint, but Shows Changes in Two of Three Secondary Endpoints

Rare Daily Staff

Soleno Therapeutics reported updated top-line results from the company’s phase 3 trial of its experimental Prader-Willi syndrome therapy saying, while it failed to meet its primary endpoint, significant changes were observed in two of three secondary endpoints.

In June 2020, the company said its phase 3 DESTINY PWS failed to meet its primary endpoint of change from baseline in hyperphagia, measured by the total score of a Hyperphagia Questionnaire for Clinical Trials (HQ-CT, 036). However, it noted improvement in physician assessed Clinical Global Impression of Improvement score and reduction of body fat mass, in subjects receiving its diazoxide choline-controlled release treatment as compared to placebo.

Prader-Willi syndrome (PWS) is associated with hyperphagia, a chronic feeling of insatiable hunger that severely diminishes the quality of life for PWS patients and their families. Additional characteristics of PWS include behavioral problems, cognitive disabilities, low muscle tone, short stature (when not treated with growth hormone), the accumulation of excess body fat, developmental delays, and incomplete sexual development. Hyperphagia can lead to significant morbidities (e.g., stomach rupture, obesity, diabetes, cardiovascular disease) and mortality (e.g., choking, accidental death due to food seeking behavior). There are currently no approved therapies to treat the hyperphagia/appetite, metabolic, cognitive function, or behavioral aspects of the disorder.

Diazoxide choline controlled-release (DCCR) tablet is a novel, proprietary extended-release, crystalline salt formulation of diazoxide, which is administered once-daily. The parent molecule, diazoxide, has been used for decades in thousands of patients in a few rare diseases in neonates, infants, children and adults, but has not been approved for use in PWS. Diazoxide choline has received Orphan Drug designation for the treatment of PWS in the United States and European Union, and Fast Track designation in the United States.

DESTINY PWS is a randomized, double-blind, placebo-controlled phase 3 study of once daily oral administration of DCCR in 127 PWS patients conducted at 29 sites in the United States and United Kingdom. The objective of the study was to assess the efficacy and safety of DCCR in subjects ages four years and older, with genetically confirmed PWS. Patients who completed the double-blind study enrolled in study C602, an ongoing open-label, extension study.

An interim analysis of the subset of patients who completed 13 weeks of treatment on C602 showed a continued improvement in hyperphagia, as well as several other PWS related behaviors.

The company said a significant exposure response relationship between DCCR plasma concentrations and change from baseline in HQ-CT score was observed. Analyses of treatment windows revealed continued efficacy of DCCR over time as compared to worsening effects for placebo.

While there was a larger decrease from baseline to week 4 in placebo compared to DCCR subjects, from week 4 to the end of the study placebo subjects worsened, while DCCR subjects continued to improve.

The company also reported significant improvements for DCCR compared to placebo were observed in leptin and adiponectin, adipokines that are differentially expressed in obesity and cardiovascular diseases. Leptin levels are elevated in obesity due to increased body fat mass and leptin resistance, while adiponectin levels are downregulated in obesity.

The company also said improvement in various PWS related behaviors (anxiety, rigidity, compulsivity, aggression, etc.) was seen with DCCR treatment.

The safety profile of DCCR remains consistent with the known safety profile of diazoxide and the prior experience with DCCR. No serious, unexpected reportable adverse events have been reported with DCCR in the program to date.

“These compelling updated data bolster our confidence in DCCR’s safety and efficacy profile in PWS,” said Anish Bhatnagar, CEO of Soleno Therapeutics. “We continue to treat patients in study C602, our open-label extension. As we have previously communicated, we expect to meet with the U.S. Food and Drug Administration before year-end to determine next steps and a potential path forward to address the unmet need for a safe and effective treatment option for PWS patients.”

Photo: Anish Bhatnagar, CEO of Soleno Therapeutics