Pitolisant for Daytime Sleepiness in PWS: New Research Findings

Families and caregivers in the Prader-Willi syndrome (PWS) community whose loved one experiences excessive daytime sleepiness (EDS) know just how challenging it can be in daily life.

Data from the Global PWS Registry show that 55% of participants experience significant daytime sleepiness, which makes it a frequently reported concern across all ages.

Importantly, a previous study of Registry data showed that individuals with PWS who had EDS also showed significantly increased behavioral and mental health problems, including anxiety and depression (Shelkowitz et al, 2022).

Recently, two important articles were published in the Journal of Clinical Sleep Medicine, that provide new insights into pitolisant, a medication that promotes wakefulness and is already FDA-approved for children ages 6 and older with narcolepsy. These papers highlight pitolisant’s potential to reduce daytime sleepiness and possibly improve behavior and hyperphagia in people with PWS.

These findings mark meaningful progress, and further research is already underway with a Phase 3 clinical trial of pitolisant for PWS now actively enrolling participants.

Proof-of-Concept Study: Pitolisant for Excessive Daytime Sleepiness in PWS

The first publication presents results from a phase 2, randomized, double-blind, placebo-controlled, proof-of-concept study that included 65 participants aged 6 to 28 years with PWS and excessive daytime sleepiness (Revana et al, 2025).

In the study, participants were randomized into 3 groups:

• Lower-dose pitolisant

• Higher-dose pitolisant

• Placebo

Treatment included a 3-week titration period followed by 8 weeks of maintenance therapy. The primary measure was change in daytime sleepiness as measured by the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD).

Key Findings

• Higher-dose pitolisant showed the greatest improvement in daytime sleepiness (−5.0 points) compared to placebo (−3.9 points).

• Benefits were most pronounced in children ages 6–11, where higher-dose pitolisant outperformed placebo by −3.5 points.

• Additional improvements in certain subgroups of participants were seen in:

  • Irritability

  • Hyperphagia

  • Aberrant behaviors

Safety

Overall, the medication was well tolerated. The most common adverse events were anxiety, irritability, and headache (11.9% each), consistent with pitolisant’s known safety profile.

Conclusion

The study supports further evaluation of pitolisant in PWS, particularly at higher doses and especially for younger children.

Read the full article, "A proof-of-concept study of pitolisant for excessive daytime sleepiness in patients with Prader-Willi syndrome," published in the Journal of Clinical Sleep Medicine.

Commentary on Proof-of Study Trial: Pitolisant’s Potential Beyond Sleepiness

The second published article is a commentary on the proof-of-concept trial summarized above. In her commentary, Madeleine Grigg-Damberger, MD, reviews the findings of Revana et al and suggests that pitolisant could also improve behavior and cognition in some individuals with PWS.

She cites two case reports (four patients total) in which families and clinicians observed:

• Better task completion and focus

• Reductions in aggression and emotional outbursts

• Improvements in daytime sleepiness

Read the full commentary, "Pitolisant may lessen not only sleepiness but improve hyperphagia and behavior problems in Prader-Willi syndrome," published in the Journal of Clinical Sleep Medicine.

Phase 3 Trial Now Enrolling: TEMPO Study (NCT06366464)

The promising findings from the first study of pitolisant in PWS have led to a phase 3 clinical trial, now underway, to further evaluate pitolisant for:

• Excessive daytime sleepiness 

• Hyperphagia

• Behavioral symptoms

The TEMPO study is enrolling individuals 6 years and older with a confirmed diagnosis of PWS.

Families interested in participating can learn more and explore enrollment opportunities here.