Harmony Biosciences Holdings, Inc. announced the presentation of new secondary endpoint data, including improvements in behavioral disturbances, from its Phase 2 signal-detection study evaluating pitolisant for the treatment of excessive daytime sleepiness (EDS) in Prader-Willi syndrome (PWS) at the 2023 Foundation for Prader-Willi Research (FPWR) Symposium and Family Conference. The company also announced that it anticipates initiating its Phase 3 registrational TEMPO study in Q4 2023.
The poster presentation of secondary outcomes data included improvements in behavioral symptoms (as measured by the Aberrant Behavioral Checklist-2), especially in the higher-dose pitolisant group. Reductions in the caregiver rating of EDS severity were also observed as were some improvements in hyperphagia, even though baseline hyperphagia scores were in the normal to mild range. The overall rate of adverse events was similar for pitolisant and placebo, and the safety/tolerability profile was consistent with the known profile for pitolisant.
“We recognize the urgency for innovative treatments that help alleviate the profound unmet medical needs of individuals with PWS and their dedicated caregivers,” said Kumar Budur, MD, Chief Medical Officer at Harmony Biosciences. “This is particularly crucial given the absence of an FDA-approved treatment for EDS in PWS, coupled with the prevalent and severe behavioral symptoms associated with this condition. We are encouraged by these findings from our Phase 2 signal-detection study, which build upon the favorable primary study outcome and provide additional hope to this community as we pursue a potential new indication for pitolisant.”
The results from the Phase 2 signal-detection study informed the protocol design for the upcoming Phase 3 registrational TEMPO study, a randomized, double-blind, placebo-controlled, multicenter, global clinical study that will further assess the safety and efficacy of pitolisant in patients with PWS, ages ≥ 6 years. This study is expected to be initiated in Q4 2023. There are currently 15,000 – 20,000 people in the US living with PWS. More than half of them experience EDS and the majority of them have behavioral disturbances.
Poster: Secondary Outcomes from a Phase 2, Double-Blind, Placebo-Controlled Signal-Detection, Proof-of-Concept Study of Pitolisant in Prader-Willi Syndrome
The Phase 2 clinical trial was a randomized, double-blind, placebo-controlled signal-detection, proof-of-concept study designed to assess the safety and efficacy of pitolisant in people living with PWS. In the trial, eligible patients who were genetically confirmed to have PWS and who had EDS were enrolled in an 11-week double-blind treatment phase that included a 3-week titration phase and eight weeks of stable dosing. Participants (n=65) were randomized (1:1:1) to receive lower- or higher-dose pitolisant, or a matching placebo based on age. Secondary/exploratory endpoints included change from baseline in Caregiver Global Impression of Severity (CaGI-S) for EDS; behavioral disturbance, as measured using the Aberrant Behavior Checklist-2 (ABC-2); and Hyperphagia, assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) in conjunction with the Food Safe Zone Questionnaire.
This proof-of-concept study was not powered to demonstrate statistical significance and was designed for signal detection.
Key results include:
- Reductions in behavioral disturbances among the youngest age group (6 to <12 years) were observed across all ABC-2 domains especially in the higher-dose pitolisant group.
Irritability: higher-dose, -5.5; lower-dose, -3.0; placebo, -1.5
Social withdrawal: higher-dose, -4.9; lower-dose, -1.6; placebo, -3.1
Hyperactivity/noncompliance: higher-dose, -4.6; lower-dose, -0.9; placebo, -3.0
Inappropriate speech: higher-dose, -2.0; lower-dose, -0.4; placebo, -0.6
Stereotypic behavior: higher-dose, -1.0; lower-dose, -0.2; placebo, -0.6
- Reductions in CaGI-S scores were greater for pitolisant compared with placebo in the children (higher-dose, -1.1; lower-dose, -1.0; placebo, -0.5) and adult (higher-dose, -1.0; lower-dose, -2.0; placebo, -0.7) age groups.
A reduction of -1.0 or more was seen in the mean change from baseline to week 11 in the children and adult subgroups, meeting the clinical significance threshold per The American Academy of Sleep Medicine (AASM).
- Some improvements in hyperphagia were noted in children (higher-dose, -2.0; lower-dose, -2.5; placebo, 0.1) and adults (higher-dose, -3.4; lower-dose, -3.0; placebo, -1.7) even though baseline hyperphagia scores were in the normal/mild range.
Despite the trial not enriching for hyperphagia and HQ-CT scores being relatively low at baseline, encouraging trends toward improvements were seen compared with placebo, especially in the children age group.
- There was an unusually large placebo response in the adolescent age group, due to data from a single outlier, resulting in an outsized impact on the magnitude of the placebo response not only in the adolescent age group but also in the overall study population.
Pitolisant is marketed as WAKIX® in the U.S. and is FDA approved to treat EDS or cataplexy in adult patients with narcolepsy. Pitolisant is not approved for use in patients with PWS and is currently being evaluated as an investigational agent in this patient population.