Harmony Bio Reports Topline Results from Phase 2 Study of Pitolisant for Excessive Daytime Sleepiness in Prader-Willi Patients

Rare Daily Staff

Harmony Biosciences reported initial topline results from its phase 2 proof-of-concept study in patients with Prader-Willi syndrome, which showed a positive signal on improvement in the primary outcome related to excessive daytime sleepiness.

Prader-Willi syndrome (PWS) is a rare, genetic neurological disorder with many of the symptoms resulting from hypothalamic dysfunction. The hypothalamus is the part of the brain that controls both sleep-wake state stability and signals that mediate the balance between hunger and satiety, resulting in two of the main symptoms in patients with PWS, excessive daytime sleepiness (EDS), and hyperphagia (an intense persistent sensation of hunger accompanied by food preoccupations, an extreme drive to consume food, food-related behavior problems, and a lack of normal satiety). Other features include low muscle tone, short stature, behavioral problems, and cognitive impairment. Approximately 15,000 to 20,000 people in the U.S. live with PWS, and over half of them experience EDS.

The phase 2 clinical trial was a randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of pitolisant in patients with PWS. This proof-of-concept study was not powered to demonstrate statistical significance and was designed for signal detection. The study included patients ages 6 to 65 years and patients were randomized 1:1:1 to low dose pitolisant, high dose pitolisant, or placebo treatment groups. Pitolisant dosing was based on three age cohorts (children 6 to less than 12; adolescents 12 to less than 18; and adults 18 to 65) and another objective of the study was to evaluate for a dose-response to pitolisant in patients with PWS. The primary endpoint of this study was the evaluation of EDS as measured by change from baseline to end of treatment (EOT) on the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) Parent/Caregiver Version.

Topline study results include 65 patients were enrolled in the trial of which 91 percent completed treatment and all but one patient opted to continue into the open-label extension. Mean baseline ESS-CHAD (Parent/Caregiver Version) ranged from 14.7 to 15.7. Mean change from baseline to EOT on the ESS-CHAD Parent/Caregiver Version scores ranged from -3.7 to -5.5 across all age groups and treatment groups, representing a clinically meaningful change (which is defined as a ≥ 2-point improvement on this scale). In two of the three age groups (children and adults), there was a clinically meaningful difference (minimum of 2 points) between pitolisant and placebo, driven by the high dose pitolisant treatment group. In the adolescent age group, there was a high placebo response of a magnitude three times that seen in the other two age groups, which resulted in no clinically meaningful difference between pitolisant and placebo in this age group.

A responder analysis (defined as an improvement on the ESS-CHAD Parent/Caregiver Version of ≥ 3-points or a score at EOT of ≤10 for this analysis) showed response rates of 70 percent in the high dose pitolisant group, 55.6 percent in the low dose pitolisant group, and 52.6 percent in the placebo group.

Overall safety/tolerability profile was consistent with the known safety/tolerability profile of pitolisant. Adverse events were reported in 57 percent of patients on pitolisant and 65 percent of patients on placebo. Treatment-related adverse events were reported in 26 percent of patients on pitolisant and 30 percent of patients on placebo. There was one serious adverse event in a patient in the placebo treatment group.

These results represent the initial topline data with the full data set expected before the end of the year. The full data set will include the results on the secondary outcomes, including caregiver and clinician global impression scores, as well as measurements of behavioral symptoms, cognitive function, and hyperphagia that will be presented at a future medical meeting and submitted for publication in a scientific journal.

“The positive signals observed on the primary outcome of EDS from this proof-of-concept study are encouraging,” said Jeffrey Dayno, chief medical officer at Harmony. “We look forward to receiving the full data set from this initial signal detection study which will further inform our understanding of the data as we plan to advance our clinical development program for pitolisant in PWS.”

Pitolisant is marketed as WAKIX in the U.S. where it is approved to treat excessive daytime sleepiness or cataplexy in adults with narcolepsy.

Photo: Jeffrey Dayno, chief medical officer at Harmony Biosciences