Prader-Willi syndrome (PWS) is a rare genetic disorder affecting approximately 1 in 10,000–30,000 individuals worldwide. It is the leading syndromic cause of obesity, with an estimated 400,000 cases globally and about 20,000 in the United States. The condition results from deletions in paternally inherited genes on chromosome 15q11, impacting hypothalamic pathways that regulate sleep, appetite, and energy balance.
Clinical Features of PWS
Infants with PWS often present with severe hypotonia and feeding difficulties, leading to early diagnosis through genetic testing. By 18–24 months, hyperphagia emerges, progressing to lifelong challenges with food-seeking behaviors. Adolescents and adults frequently exhibit a distinct behavioral profile, including compulsivity, temper outbursts, skin-picking, and mild cognitive impairment.
Sleep disturbances are common in PWS, including sleep-disordered breathing and excessive daytime sleepiness (EDS), which often persists even after treating apnea or hypoventilation. Registry data indicate that over half of individuals with PWS experience EDS, with a subset showing narcolepsy-like features such as cataplexy and abnormal REM patterns.
Why Treating Hypersomnia Matters
As reported in the Journal of Clinical Sleep Medicine, recent evidence suggests that hypersomnia exacerbates behavioral issues in PWS, making effective management critical. However, treatment options for pediatric narcolepsy and related hypersomnia remain limited.
Pitolisant: A Novel Approach
Pitolisant, a histamine H3 receptor antagonist/inverse agonist, enhances wakefulness by increasing histamine release in the brain. Approved by the FDA in 2024 for narcolepsy in children aged six and older, pitolisant has demonstrated benefits in reducing EDS and cataplexy, improving cognition, and maintaining a favorable safety profile.
Early case reports in PWS hinted that pitolisant might do more than alleviate sleepiness: it appeared to improve attention, academic performance, and reduce aggression. These observations prompted a phase 2, randomized, placebo-controlled trial led by Revana et al., published in the Journal of Clinical Sleep Medicine.
Key Findings from the Phase 2 Trial
The study enrolled 59 participants with PWS, comparing low- and high-dose pitolisant to placebo over an 11-week period. The primary endpoint was improvement in the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Results showed:
- High-dose pitolisant (HDP) reduced ESS-CHAD scores by an average of 5 points, outperforming both low-dose and placebo groups.
- Children aged 6–11 experienced the most significant benefit.
- Beyond sleepiness, HDP was associated with reductions in hyperphagia and behavioral issues such as irritability and social withdrawal.
Adverse events were consistent with pitolisant’s known profile, including mild anxiety, irritability, and headache. While the study was not powered for definitive statistical conclusions, the dose-response trend supports further investigation.
Looking Ahead
A phase 3 trial (TEMPO; NCT06366464) is underway to confirm these findings and evaluate pitolisant’s role in managing EDS and related symptoms in PWS. If successful, pitolisant could represent a breakthrough in addressing both sleep and behavioral challenges in this complex disorder.
Disclaimer: Pitolisant is FDA-approved for narcolepsy in children but remains investigational for PWS-related hypersomnia.
