Phase 3 Data Support Sustained Safety, Symptom Improvement with Pitolisant in Idiopathic Hypersomnia

According to results from a long-term open-label phase 3 study (NCT05458128), presented at the 2026 SLEEP Annual Meeting, held June 14-17 in Baltimore Maryland, adults with idiopathic hypersomnia (IH) treated with pitolisant for more than 2-years maintained improvements in excessive daytime sleepiness (EDS), sleep inertia, and functional outcomes.¹

In the study, improvements across multiple patient- and clinician-reported outcome measures emerged by week 4 and remained generally stable through month 25 of follow-up. Pitolisant was also generally well tolerated, with treatment-related adverse events reported in 25.2% of participants and no treatment-related serious adverse events observed.

For context, pitolisant is a selective histamine-3 receptor antagonist/inverse agonist that promotes wakefulness by enhancing histaminergic neurotransmission. The therapy was previously approved in the United States for EDS and cataplexy in adults with narcolepsy, but remains investigational for IH. Previous findings from the phase 3 INTUNE program suggested clinically meaningful improvements in patients with IH, supporting continued investigation of the therapy in this population.²

Led by David T. Plante, MD, PhD, medical director of the Wisconsin Institute for Sleep and Consciousness, the analysis included 119 adults with idiopathic hypersomnia (mean age, 40.1 years; 79.8% women) who enrolled in an open-label extension study after completing the phase 3 INTUNE program. Participants received once-daily pitolisant at doses ranging from 8.9 mg to 35.6 mg for up to approximately 3 years, with a median treatment exposure of 97 weeks and a maximum duration of 151 weeks. Overall, 65.8% of patients titrated to the highest dose level of 35.6 mg, and 62 participants (52.1%) completed the study.¹

The study evaluated both safety and effectiveness outcomes over the long-term treatment period. Safety assessments focused on treatment-related treatment-emergent adverse events (TEAEs), serious adverse events, and treatment tolerability. Effectiveness was measured using several validated patient- and clinician-reported instruments, including the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient-Reported Outcomes Measurement Information System Sleep-Related Impairment (PROMIS-SRI), Sleep Inertia Questionnaire (SIQ), Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), Patient Global Impression of Severity (PGI-S) for excessive daytime sleepiness, and Clinician Global Impression of Severity (CGI-S) for idiopathic hypersomnia.¹

Safety analyses showed that treatment-related TEAEs occurred in 30 patients (25.2%). The most commonly reported TEAEs were insomnia (6.7%), headache (5.9%), dizziness (2.5%), and increased weight (2.5%). Six serious adverse events were reported during the study, although none were considered treatment related.¹

As for effectiveness, mean ESS scores improved from a baseline value of 11.4 points, with reductions ranging from 3.0 to 4.0 points across assessed time points. Similar trends were observed on the IHSS, where baseline scores of 27.9 points improved by approximately 5.7 to 6.4 points during treatment. Measures of sleep-related impairment and sleep inertia also demonstrated sustained improvements over time. Functional outcomes improved throughout the study as well. Patients experienced gains on the FOSQ-10, while both patient- and clinician-reported assessments of disease severity showed reductions from baseline that persisted through the final assessment period.¹

Because the current analysis was conducted in an open-label extension without a concurrent placebo control group, conclusions regarding long-term efficacy should be interpreted cautiously. In addition, attrition over time reduced the number of evaluable participants at later assessments, a common limitation of long-duration extension studies.

Nevertheless, the results provide some of the longest follow-up data reported to date for pitolisant in IH and suggest that improvements in daytime sleepiness and other core symptoms may be maintained over extended treatment periods. Additional controlled studies and regulatory decisions will help clarify the role of pitolisant within the evolving treatment landscape for IH.

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REFERENCES
1. Plante DT, Corser B, Drake C, et al. Long-Term Safety and Effectiveness ofPitolisant in Adult Patients with Idiopathic Hypersomnia:Final Results From an Open-Label Phase 3 Trial . Presented at: SLEEP Annual Meeting; June 14-17; Baltimore, Maryland.
2. HARMONY BIOSCIENCES ANNOUNCES TOPLINE DATA FROM PHASE 3 INTUNE STUDY EVALUATING PITOLISANT IN PATIENTS WITH IDIOPATHIC HYPERSOMNIA. Harmony Biosciences. News Release. October 3, 2023. Accessed: June 15, 2026. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-announces-topline-data-phase-3-intune-study/