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Phase 2 Trial Results Suggest Pitolisant is Effective Therapy for Prader-Willi Syndrome

On November 1, Harmony Biosciences announced that their phase 2 proof-of-concept study of pitolisant in patients with Prader-Willi syndrome (PWS) showed that treatment with pitolisant was associated with a reduction in excessive daytime sleepiness. The phase 2 clinical trial of pitolisant in PWS was randomized, double-blind, and placebo controlled. Of the 65 patients enrolled in the trial, 91% completed treatment and all but one opted to continue into the open-label extension. Adverse events were reported in 57% of patients on pitolisant and 65% of patients on placebo. The announcement describes only the initial topline data and Harmony expects to report on the full data set before the end of the year. This will include information about caregiver and clinician global impression scores, as well as measurements of behavioral symptoms, cognitive function, and hyperphagia.

Pitolisant, a selective histamine 3 (H3) receptor antagonist/inverse agonist, is FDA approved to treat excessive daytime sleepiness or cataplexy in adults with narcolepsy and has been available in the US since the end of 2019. It currently does not have any other indications.

PWS is a rare genetic neurological disorder with many symptoms, including excessive daytime sleepiness, resulting from hypothalamic dysfunction. Individuals with PWS also often experience hyperphagia, obsessive-compulsive disorder, anxiety disorders, and mood disorders.

The clinical trial results follow multiple published case reports and case series on the benefits of pitolisant for individuals with PWS. A 2021 case report, for example, described the safe and effective use of pitolisant in a pediatric patient with PWS, obsessive-compulsive disorder, autism spectrum disorder, mild intellectual disability, hypothyroidism, and scoliosis (Pennington et al., 2021). Within ten days of starting pitolisant, the patient’s mother noted that her daughter could more easily complete academic tasks. After two months of receiving a dose of 4.5 mg, the dose of pitolisant was increased from 4.5 mg to 9 mg and the patient experienced improved muscle tone, was walking more quickly with less hyperflexibility, had reductions in daytime sleepiness, was more alert and engaged with others, and had fewer behavioral outbursts and aggression.

Investigators first made the connection between pitolisant and PWS in a clinical vignette published in 2019 (Pullen et al., 2019). The study was one of the first to describe the daytime sleepiness that is commonly seen in individuals with PWS. The paper described three children who experienced improvements in cognitive disability, excessive daytime sleepiness, and poor-quality nighttime sleep in response to treatment with pitolisant. The case series described families self-report of their experience with pitolisant via an at the time novel data gathering platform called TREND Community. Families reported that the children responded within days to treatment with pitolisant.

In the 2019 clinical vignette the authors also noted that pitolisant treatment normalized the children’s relationship to food, a benefit that they described as noteworthy given that hyperphagia is common among patients with PWS.


S Pennington, D Stutzman, and E Sannar. Pitolisant in an adolescent with Prader-Willi Syndrome. J Pediatr Pharmacol Ther. 2021. 26 (4): 405-410.

LC Pullen, M Picone, L Tan, et al. Cognitive Improvements in Children with Prader-Willi Syndrome Following Pitolisant Treatment—Patient Reports. J Pediatr Pharmacol Ther. 2019. 24(2): 166-171.





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