FDA Expands Indication for Pitolisant to Treat Cataplexy in Pediatric Narcolepsy

According to a new announcement, the FDA has granted an expanded approval indication to Harmony Biosciences’ pitolisant (Wakix) tablets to include the treatment of cataplexy in pediatric patients aged 6 years and older with narcolepsy. With this decision, pitolisant becomes the only FDA-approved nonscheduled therapy indicated for both pediatric and adult patients with narcolepsy, regardless of the presence of cataplexy.¹

“Given that narcolepsy often onsets in children and young adults, having more FDA-approved treatment options for this younger population is absolutely critical. Finding a good treatment regimen that works well for each child and teen allows them their greatest chance at getting through school and pursuing their dreams,” narcolepsy patient advocate Julie Flygare, JD, the president and CEO at Project Sleep, told NeurologyLive^®.

“It isn't surprising as [the] FDA had broadened its indication in pediatric patients with narcolepsy in children aged 6 and older in June 2024. It is certainly a welcome news since pediatric sleep specialists have very limited pharmacotherapeutic options at this age and since this is not scheduled as a controlled substance, it may gain more popularity,” American Academy of Sleep Medicine (AASM) spokesperson Anuja Bandyopadhyay, MD, an assistant professor of clinical pediatrics at Indiana University School of Medicine, told NeurologyLive.

Pitolisant, a selective histamine H3 receptor inverse agonist, was first approved by the FDA in August 2019 for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. The approval was subsequently expanded in October 2020 to include the treatment of cataplexy in adult patients with narcolepsy, and most recently in June 2024 the indication was further broadened to include treatment of EDS in pediatric patients aged 6 years and older with narcolepsy. At the time of the expanded indication in 2024, the FDA handed Harmony a complete response letter for pitolisant as a treatment of cataplexy in this pediatric population.

Pitolisant's supplemental new drug application (sNDA) for the pediatric approval in cataplexy was supported by findings from a phase 3 trial (NCT02611687), which demonstrated significant reductions in EDS and cataplexy in pediatric patients aged 6 to 17 years with narcolepsy treated with 5 mg to 40 mg a day of the therapy. Published in Lancet Neurology, these findings suggested that pitolisant is a safe and effective treatment for children and adolescents with narcolepsy.³

At the conclusion of the double-blind period of the trial, the mean adjusted difference in Ullanlinna Narcolepsy Scale (UNS) total score, the primary outcome, was -6.3 (SE, 1.1) in patients treated with pitolisant and -2,6 (1,4) in patients treated with placebo (least squares mean difference, -3.7; 95% CI, -6.4 to -1,0, P = 0,007). Similar results were observed irrespective of the analysis set (per -protocol set: –4,0 [IQR, –7.0 to –1.0]; P = 0.01 for the ; completers: –3.8 [–6.5 to –1.1]; P = 0.007 for completers), and all the listed sensitivity analyses (P <0·01).

“Like any new medications, we have to approach with caution. The trial reports 5-6 weeks of use, whereas in real life our patients will use this long term. There was still a 30% chance of insomnia or headaches as side effects, so it may not suit all patients. Close monitoring will be essential as we start using this in our clinical practice. On the other hand, it is so important to have more options in our tool box,” Bandyopadhyay told NeurologyLive.

READ MORE: FDA Accepts New Drug Application for Orexin Agonist Oveporexton in Narcolepsy Type 1, Grants Priority Review

At the time of the issued CRL, lead author Yves Dauvilliers, MD, PhD, professor of neurology, and director, Sleep Disorders Centre, Gui de Chauliac Hospital, Montpellier, and colleagues wrote, “These results are in line with the mechanisms of action of pitolisant, which involve increasing the synthesis and release of histamine in the brain via competitive binding to presynaptic H3 autoreceptors, and also increasing the activity of other wake-promoting neurotransmitters (eg, acetylcholine, dopamine, and norepinephrine) by binding to H3 receptors on nonhistaminergic neurons, without activation of accumbal dopaminergic neurons.”²

This trial was a double-blind, randomized, placebo-controlled, multisite study that recruited patients with narcolepsy with or without cataplexy from 11 sleep centers in 5 countries (Italy, France, Netherlands, Russia, and Finland). To be enrolled, patients required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and had not been on any psychostimulants for at least 14 days prior to the study. The patients that needed anticataplectics such as sodium oxybate were required to have been on a stable dose for at least 1 month.

Between June 6, 2016, and April 3, 2021, 115 participants were screened and 110 were randomly assigned (mean age, 12.9 [SD, 3.0] years, 61 [55%] male, and 90 [82%] with cataplexy; pitolisant: n = 72; placebo: n = 38); 107 (pitolisant: n = 70; placebo: n = 37) completed the double-blind period. The 4-week screening, period which included a 2-week baseline period, had patients enter into a 4-week individual up-titration scheme where they were given a doses from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo.

The treatment was given to patients at a stable dose for 4 weeks followed up with a 1-week placebo period. Investigators assessed pitolisant versus placebo using the UNS total score with change from baseline to the end of double-blind period. Adverse events (AEs) were assessed in the safety population for all participants that had at least one dose of the medication.

All told, the Pediatric Daytime Sleepiness Scale (PDSS) adjusted mean difference showed a greater decrease in the pitolisant group than in the placebo group from baseline to the end of the double-blind period. During the last week of treatment, the pitolisant to placebo rate ratio was 0.4 (95% CI, 0.2 - 1.0, P = 0.05) for the least squares mean weekly rate of cataplexy.

Twenty-two (31%) of 72 patients reported treatment-emergent AEs treated with pitolisant vs 13 (34%) of 38 patients treated with placebo. The most frequently reported AEs (affecting ≥5% of patients) were headache (pitolisant, n = 14 [19%]; placebo, n= 3 [8%]) and insomnia (pitolisant, n = 5 [7%]; placebo, n = 1 [3%]).

“It speaks to how pediatric sleep medicine treatment is more nuanced and needs more validation, safety and effectiveness data. When assessing effectiveness, in particular, pediatric patients may find it difficult to report the outcomes as reliably as adults,” Bandyopadhyay added. “Thus it is very important to focus on them as a special group as they need that attention. A missed day at school for children due to cataplexy/EDS is as debilitating as a missed day at work for adults. By focusing on this group, we are focusing on our next generation's health.”

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REFERENCES
1. Harmony Biosciences Receives U.S. Food and Drug Administration Approval for WAKIX® (pitolisant) for the Treatment of Cataplexy in Pediatric Narcolepsy. News release. Harmony Biosciences. February 17, 2026. Accessed February 17, 2026. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-receives-us-food-and-drug-administration-1
2. Harmony Biosciences Receives U.S. Food and Drug Administration Approval for Wakix® (Pitolisant) in Pediatric Patients With Narcolepsy. News Release. Harmony Biosciences. Published June 24, 2024. Accessed February 17, 2026. http://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-receives-us-food-and-drug-administration-0
3. Dauvilliers Y, Lecendreux M, Lammers GJ, et al. Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2023;22(4):303-311. doi:10.1016/S1474-4422(23)00036-4