FDA Approves Pitolisant for Excessive Daytime Sleepiness in Pediatric Narcolepsy


Pitolisant is the first and only drug in the class of antagonist/reverse agonists of the histamine H3 receptor for the treatment of patients with narcolepsy.

Jeffrey M. Dayno, MD  (Credit: LinkedIn)

Jeffrey M. Dayno, MD

(Credit: LinkedIn)

Months after being granted priority review designation by the FDA, the agency has granted approval to Harmony Biosciences' pitolisant (Wakix), a selective histamine H3 receptor inverse agonist, for the treatment of excessive daytime sleepiness (EDS) in pediatric patients aged 6 years and older with narcolepsy.1 In addition, the agency issued pitolisant a complete response for the treatment of cataplexy in pediatric patients with narcolepsy.

"Following the FDA's decision to grant priority review, we are very pleased with the agency's timely review and approval of Wakix for pediatric narcolepsy patients with EDS," Jeffrey M. Dayno, MD, president and chief executive officer at Harmony Biosciences, said in a statement.1 "EDS is the primary symptom experienced by all patients with narcolepsy and this approval for Wakix, as the first-and-only FDA-approved non-scheduled treatment option for narcolepsy, makes this important treatment option available to pediatric patients 6 years and older living with narcolepsy." 

Pitolisant's supplemental new drug application 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. These findings suggested that pitolisant is a safe and effective treatment for children and adolescents with narcolepsy.2

Dayno added in the statement, "The unique mechanism of action of Wakix and its non-scheduled status are especially important for a pediatric population that has had limited treatment options, all of which are controlled substances. The unique features of pitolisant present an exciting opportunity, and we are currently working on the next-generation formulations that could potentially offer additional benefits to patients, such as greater efficacy and new indications, extend the Wakix franchise, and strengthen our leadership position in the treatment of rare sleep disorders."1

At the conclusion of the double-blind period, the mean adjusted difference in Ullanlinna Narcolepsy Scale (UNS) total score 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).

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.

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%]).

Dauvilliers et al noted, “In clinical practice, when the add-on of a drug with a risk of QT interval prolongation is considered in patients on stable doses of pitolisant, there is an increased risk of cardiac arrhythmias, which must always be carefully assessed.”2

Limitations of the study included the short duration as it did not address whether tolerance to pitolisant will develop with continued treatment. In addition, anticataplectic drugs such as sodium oxybate were allowed in the study which could have underestimated the effects of pitolisant on narcolepsy symptoms. The flexible dosage and multiple visits could also have influenced the treatment efficacy, the authors noted. The investigators added, there might be bias and inaccuracies on the effects of pitolisant on the frequency of cataplexy and not a clear assessment of the efficacy of pitolisant in subpopulations. Additionally, the sample population might not be generalizable to the narcoleptic population as ethnic background was not assessed.

“With our results, pitolisant might be another first-choice treatment option in the management of narcolepsy and cataplexy in children and adolescents. Once daily dosing of pitolisant might also be of advantage in the treatment of narcolepsy symptoms in pediatric patients compared with the twice nightly sodium oxybate and low-sodium oxybate regimen,” Dauvilliers et al wrote.2

A similar study published in Sleep Medicine demonstrated pitolisant as an effective treatment for EDS and cataplexy in children with narcolepsy.3 Among 55 patients with narcolepsy treated with the therapy, the Pediatric Epworth Sleepiness Scale (ESS) score decreased from 19.0 to 13.5 (P <.001) and weekly cataplexy frequency increased from 7.9 to 5.2 (P <.001). Treatment with the therapy was well, as 10 patients had adverse effects, including 5.5% who frequently reported insomnia, followed by nausea and gastric discomfort (both, 3.64%), as well as agitation, dry mouth and nervousness (all, 1.82%).

Following pitolisant treatment, pediatric ESS scores significantly reduced by 28.95% and a few patients (n = 7) reported a deterioration of ESS by an average of 2.3 points. Patients with an ESS score of 16 or higher prior to pitolisant treatment had the greatest effect observed, with reductions of 34.74% in ESS. The moderately affected patients with 11–20 cataplexy attacks per week had a reduction of 40.54%, and a slightly increased reduction was observed in those aged 12 to 18 years (36.23%) versus those aged 6 to 12 years old (31.21%).

1. 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 June 24, 2024. http://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-receives-us-food-and-drug-administration-0
2. 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
3. Triller A, Pizza F, Lecendreux M, et al. Real-world treatment of pediatric narcolepsy with pitolisant: A retrospective, multicenter study. Sleep Med. 2023;103:62-68. doi:10.1016/j.sleep.2023.01.015
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