Pitolisant Performs Well on Secondary Outcomes in Phase 2 Study of Prader-Willi Syndrome

Kumar Budur, MD

Newly announced data from a phase 2 proof-of-concept study showed that treatment with pitolisant (Wakix; Harmony Biosciences), an FDA-approved agent for excessive daytime sleepiness (EDS), resulted in several significant benefits on secondary and exploratory outcomes among patients with Prader-Willi syndrome (PWS) with EDS. Harmony also announced it anticipates initiating its phase 3 registrational TEMPO study in Q4 of 2023.¹

The trial featured 65 patients with genetically confirmed PWS who were randomly assigned 1:1:1 to either lower- or higher-dose pitolisant, or placebo, for an 11-week double-blind treatment phase. Presented at the 2023 Foundation for Prader-Willi Research Symposium and Family Conference, the secondary and exploratory outcome measures included change in Caregiver Global Impression of Severity (CaGI-S) for EDS; behavioral disturbance, as measured using the Aberrant Behavior Checklist-2 (ABC-2); and hyperphagia, as assessed using the Hyperphagia Questionnaire for Clinical Trials in conjunction with the Food Safe Zone Questionnaire.

Across all secondary and exploratory end points, the most pronounced benefits were observed in the higher-dose pitolisant group, although the study was not powered to demonstrate statistical significance. In the youngest group, aged 6 to 12 years old, treatment with pitolisant resulted in significant impacts on several ABC-2 domains, including irritability (higher dose: –5.5; lower-dose, –3.0; and placebo, –1.5), social withdrawal (–4.9; –1.6; and –3.1), hyperactivity/noncompliance (–4.6; –0.9; and –3.0), inappropriate speech (–2.0; –0.4; –0.6) and stereotypic behavior (–1.0; –0.2; and –0.6).

"We recognize the urgency for innovative treatments that help alleviate the profound unmet medical needs of individuals with PWS and their dedicated caregivers,” Kumar Budur, MD, chief medical officer at Harmony Biosciences, said in a statement.¹ "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."

Additional findings showed greater reductions in CaGI scores among both children (higher-dose, –1.1; lower-dose, –1.0; placebo, –0.5) and adults (higher-dose, –1.0; lower-dose, –2.0; placebo, –0.7) treated with the agent. At the conclusion of the 11-week treatment period, investigators observed a reduction of –1.0 or more in the mean change of CaGI, meeting the clinical significance threshold set by the American Academy of Sleep Medicine. Even though baseline hyperphagia scores were in the normal/mild range, improvements in hyperphagia were still noted among 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) treated groups.

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According to Harmony, this data is expected to help inform the design protocol for the upcoming phase 3 TEMPO study, a randomized, double-blind, placebo-controlled study further assessing the impacts of pitolisant in patients with PWS aged at least 6 years old. Anticipated to initiate in Q4 of 2023, the trial is multicenter and global, spanning across several sites around the world.

The secondary outcome data builds on positive topline findings announced earlier this year at the 2023 SLEEP Annual Meeting. In the overall patient population, mean improvement in the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a validated measure of sleep propensity, was greater for both pitolisant dose groups compared with placebo at the end of the 11-week period. Patients in the higher and lower dose treated groups experienced mean changes of –4.9 and –4.1, respectively, compared with changes of –3.7 for those on placebo. At week 11, 70.0% and 55.6% of high (n = 20) and low dosed (n = 18) pitolisant groups, respectively, were considered responders, compared with 52.6% of those on placebo (n = 19).²

The phase 2 data showed that the safety and tolerability profile of pitolisant in patients with PWS was consistent with its known safety profile, with no new signals observed. Treatment-emergent adverse events (TEAEs) were recorded in 50.0%, 65.0%, and 65.2% of patients in the higher dose pitolisant, lower dose pitolisant, and placebo groups, respectively. There were no serious TEAEs reported in the treated groups, and 1 serious TEAE in the placebo group.

REFERENCES
1. Harmony Biosciences presents new secondary outcome data from phase 2 signal detection study in patients with Prader-Willi syndrome. News release. October 5, 2023. Accessed October 16, 2023. https://www.prnewswire.com/news-releases/harmony-biosciences-presents-new-secondary-outcome-data-from-phase-2-signal-detection-study-in-patients-with-prader-willi-syndrome
2. Revana A, Seiden D, Rapchak KD, et al. Primary efficacy and safety results of a phase 2 double-blind, placebo-controlled proof of concept, signal detection study of pitolisant in Prader-Willi syndrome. Presented at: 2023 SLEEP Annual Meeting; June 3-7. Indianapolis, Indiana. Abstract 510