0631 Phase 2, Proof-of-Concept Study of Pitolisant in Prader-Willi Syndrome: Primary and Secondary Efficacy Analyses

Abstract Introduction Prader-Willi Syndrome (PWS) is a complex genetic disorder with symptoms that include hyperphagia, behavioral disturbances, and excessive daytime sleepiness (EDS). Pitolisant is approved for the treatment of EDS or cataplexy in adults with narcolepsy. Methods In this phase 2, proof-of-concept study (which was not powered to show statistical significance), patients with a confirmed diagnosis of PWS and a score ≥12 on the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) were randomized to receive higher-dose pitolisant, lower-dose pitolisant, or placebo (dose based on age group) for 11 weeks (3-week titration, 8-week stable-dose). The primary efficacy endpoint was change from baseline at Week 11 in ESS-CHAD score. Secondary/exploratory endpoints included the Caregiver Global Impression of Severity (CaGI-S) for EDS, Aberrant Behavior Checklist-2 (ABC-2), and Hyperphagia Questionnaire for Clinical Trials (HQ-CT) (in conjunction with the Food Safe Zone Questionnaire). Results Among 65 enrolled patients (50.8% male), 34 (52.3%) were children (6 to < 12 years), 19 (29.2%) were adolescents (12 to < 18 years), and 12 (18.5%) were adults (≥18 years). Overall, mean (SE) change in ESS-CHAD score at Week 11 was greater in the higher-dose (-4.9 [1.23]) and lower-dose (-4.1 [1.06]) pitolisant groups compared with the placebo group (-3.7 [1.13]). There was an unusually large placebo response in the adolescent age group, due to data from a single outlier. Reductions in CaGI-S scores and HQ-CT scores were greater for pitolisant compared with placebo in the children and adult age groups. In children (6 to < 12 years), mean reduction in all ABC-2 domain scores (irritability, social withdrawal, hyperactivity/noncompliance, inappropriate speech, stereotypic behavior) was greater for higher-dose pitolisant compared with placebo. The most common adverse events in pitolisant-treated patients (doses pooled) were irritability (17.4%) and anxiety (13.0%). Conclusion Pitolisant reduced EDS in patients with PWS. Pitolisant may also reduce behavioral disturbances and hyperphagia. An upcoming phase 3 clinical trial (TEMPO) will further evaluate the efficacy and safety of pitolisant in patients ≥6 years old with PWS and EDS. Support (if any) Harmony Biosciences, LLC