0648 Phase 3 Randomized Placebo-Controlled Trial of Pitolisant for Excessive Daytime Sleepiness in Prader-Willi Syndrome

Abstract Introduction Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by global hypothalamic dysfunction that results in a variety of symptoms including behavioral disturbance, hyperphagia, and excessive daytime sleepiness (EDS). Pitolisant is approved for the treatment of EDS or cataplexy in adults with narcolepsy. In a phase 2, proof-of-concept study, pitolisant showed trends of reduction in EDS relative to placebo in patients with PWS. Methods This multicenter, randomized, double-blind, placebo-controlled, phase 3 study will evaluate the efficacy and safety of pitolisant in patients with PWS. The study will enroll patients ≥6 years of age with a genetically confirmed diagnosis of PWS, and have EDS as confirmed by the investigator. Selected exclusion criteria include patients with symptoms or diagnosis of psychosis or schizophrenia, inadequately treated sleep disordered breathing, and moderate or severe hepatic or renal impairment. Eligible patients will be randomly assigned (1:1) to receive pitolisant (weight-based dosing: 8.9-44.5 mg/d) or matching placebo tablets. The 11-week double-blind period will be followed by an optional 52-week open-label extension. Results Up to 100 patients per group will be enrolled. The primary endpoint will be change from baseline at Week 11 in EDS as measured by the PROMIS-SRI (Patient-Reported Outcomes Measurement Information System - Sleep Related Impairment Parent Proxy). The secondary endpoints will include behavioral disturbance as measured by the Aberrant Behavior Checklist-Community domains (irritability, social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech), Caregiver Impression of Severity for EDS, Clinician Global Impression of Severity for EDS, Epworth Sleepiness Scale for Children and Adolescents, and the Hyperphagia Questionnaire for Clinical Trials in conjunction with the Food Safe Zone Questionnaire. Safety assessments will include incidence and severity of adverse events, clinical laboratory tests, vital signs, and 12-lead ECG. The study is expected to start enrolling patients in 2024. Conclusion This study is designed to determine whether pitolisant is efficacious in the treatment of EDS in patients with Prader-Willi syndrome and to further characterize its safety profile in this patient population. Support (if any) Harmony Biosciences, LLC