EMA Approves Pitolisant for Pediatric Narcolepsy

Yves Dauvilliers, MD, PhD

Recently, the European Medicines Agency (EMA) granted approval for the marketing authorization for pitolisant (Wakix, Harmony Biosciences) for the treatment of narcolepsy in pediatric patients age 6 years or older, with or without cataplexy.¹ Pitolisant is the first and only drug in the class of antagonist/reverse agonists of the histamine H3 receptor for the treatment of narcolepsy.

In a randomized trial investigating pitolisant (NCT02611687), 110 pediatric patients with narcolepsy were enrolled, 72 received the treatment and 38 were given placebo. The primary endpoint assessed excessive daytime sleepiness (EDS) and cataplexy attacks using the Ullanlinna Narcolepsy Score (UNS). Findings showed a significant decrease of 6.29 points in the UNS score with pitolisant versus -2.60 points with placebo.1 The secondary endpoints demonstrated that pitolisant significantly reduced sleepiness and cataplexy after 8 weeks compared to placebo.

"The arrival of Wakix offers a new therapeutic option, with a favorable safety profile, in the treatment of narcolepsy in children from the age of 6 years, a rare disease with a strong impact on social life," Yves Dauvilliers, MD, PhD, director, Sleep and Wake Disorders Center, Gui de Chauliac Hospital, emphasized in a statement.¹ “Narcolepsy, especially in children, is widely under-diagnosed, diagnosed too late, and should always be considered when a child is sleeping in class. Confirming the diagnosis allows good management, limiting disability and improving quality of life."

Between June 6, 2016, and April 3, 2021, participants were randomly assigned (mean age, 12.9 [SD, 3.0] years, 61 [55%] male, and 90 [82%] with cataplexy) totreatment 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 mean adjusted difference in UNS total score from baseline to the end of the double-blind period 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). Twenty-two (31%) of 72 patients treated with pitolisant and 13 (34%) of 38 patients treated with placebo reported treatment-emergent AEs. The most frequently reported adverse events (affecting ≥5% of patients) were headache (pitolisant, n = 14 [19%]; placebo, n = 3 [8%]) and insomnia (pitolisant, n = 5 [7%]; placebo, n = 1 [3%]).²

Limitations of the trial included the short duration, as it did not address whether tolerance to pitolisant will develop with continued treatment. In addition, anticataleptic 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.

In January 2023, the European Committee for the Evaluation of Medicinal Products for Human Use (CHMP) opinionated a statement that affirmed pitolisant significantly reduced daytime sleepiness and cataplexy attacks compared with placebo, confirming its effectiveness for wakefulness and anti-cataplectic effect when administrated according to an individual titration scheme based on the individual benefit/tolerance ratio.

A recently published multicenter, retrospective, observational study 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 safe as 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%).

REFERENCES
1. Bioprojet: WAKIX® (pitolisant) receives approval for the treatment of narcolepsy in children over 6 years of age, a rare, under-diagnosed condition. News Release. Bioprojet. Published March 15, 2023. Accessed March 29, 2023. https://www.prnewswire.co.uk/news-releases/bioprojet-wakix-pitolisant-receives-approval-for-the-treatment-of-narcolepsy-in-children-over-6-years-of-age-a-rare-under-diagnosed-condition-301772642.html
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