Interim Analysis Reveals Long-Term Efficacy and Safety of Pitolisant in Narcolepsy Types 1 and 2

Giuseppe Plazzi, MD, PhD

(Credit: Azienda USL di Bologna)

Newly published Sleep Medicine, an interim analysis from a long-term, post authorization safety study European study reported that pitolisant (Wakix; Harmony Biosciences), an approved treatment for excessive daytime sleepiness (EDS) in pediatric patients with narcolepsy, demonstrated safety, tolerability and efficacy among patients with narcolepsy type 1 (NT1) and type 2 (NT2) after 42.6 months of follow-up.¹

In this analysis, investigators included 370 patients with narcolepsy (mean age, 40 [±15 years]; women, 51.4%), of whom 71.4% had NT1 and 28.6% had NT2. Authors reported that a total of 364 patients received at least 1 dose of pitolisant, with safety data available for 356 (97.8%). During the study period, researchers revealed in the analysis that 35.4% of patients discontinued treatment, most commonly because of safety concerns (14.3%), lack of response (8.7%), or patient decision (7.6%).

"Our real-world data confirm the observations of previous clinical studies, revealing no abuse potential for pitolisant. Therefore, pitolisant is the only drug approved for the treatment of narcolepsy in the United States that does not appear on the list of controlled substances," lead author Giuseppe Plazzi, MD, PhD, professor of neurology at the University of Modena and Reggio Emilia, and colleagues wrote.¹ "This may be explained by the mode of action of pitolisant, which increases the activity of brain histaminergic neurons but does not increase dopamine levels in the nucleus accumbens. By blocking the H3 receptor, pitolisant increases histaminergic release in a dose-dependent manner; it is the first H3 receptor inverse agonist proposed for use in clinical practice."

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Authors noted that comorbid conditions were reported as common, with 68.4% of patients reporting at least 1 in the analysis. Notably, obesity was reported in 31.9% of the patient population, followed by neuropsychiatric (31.0%) and cardiovascular comorbidities (22.8%). Prior to treatment with pitolisant, 13.2% of participants had received no treatment for narcolepsy, and 31% switched from a previous therapy. Additionally, the analysis showed that most patients received pitolisant in combination with other treatments (69%).

"The target optimal dose of 36 mg/d was reached by 37.4 % of patients, suggesting that physicians are cautious in the use of the maximum daily dosage when the drug is first marketed and indicating that the dose can be increased to 36 mg," Plazzi et al noted.¹ "No typical withdrawal symptoms were detected upon abrupt discontinuation of pitolisant."

All told, a total of 355 treatment-emergent adverse events (AEs) were reported among 156 patients with narcolepsy (42.9%). Of these, authors noted that 218 events in 109 patients were considered possibly related to treatment (29.9%). Furthermore, researchers reported that 3 serious AEs occurred during the study. The study also reported improvements in excessive daytime sleepiness, cataplexy, and overall quality of life, with noted good adherence and patient satisfaction.

This study had several limitations, including patient discontinuation, the absence of a comparator group, the use of concomitant treatments, and dose adjustments. The data were collected from national sleep centers with experience in narcolepsy research and reflect routine clinical practice. Compared with earlier studies such as HARMONY 3 (NCT01399606), this analysis included a longer follow-up period.² The results suggested that pitolisant was generally well tolerated and associated with improvements in EDS and cataplexy.

REFERENCES
1. Plazzi G, Mayer G, Bodenschatz R, et al. Interim analysis of a post-authorization safety study of pitolisant in treating narcolepsy: A real-world European study. Sleep Med. 2025;129:20-30. doi:10.1016/j.sleep.2025.02.012
2. Dauvilliers Y, Arnulf I, Szakacs Z, et al. Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study. Sleep. 2019;42(11):zsz174. doi:10.1093/sleep/zsz174