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Pitolisant (Wakix) in children ages 6 years and up led to clinically meaningful improvements in narcolepsy symptoms in a phase III trial.

Among 110 kids with narcolepsy with or without cataplexy, excessive daytime sleepiness and cataplexy scores improved significantly with pitolisant versus placebo, with mean adjusted differences in Ullanlinna Narcolepsy Scale (UNS) total score of -6.3 and -2.6, respectively, from baseline to week 8 (least squares mean difference -3.7, 95% CI -6.4 to -1.0, P=0.007), reported Yves Dauvilliers, MD, of the University of Montpellier in France, and co-authors.

"Altogether, our results on self-reported sleepiness and cataplexy via the UNS support the efficacy of pitolisant in pediatric patients with narcolepsy," they wrote in .

Secondary outcomes also improved with pitolisant versus placebo, with adjusted mean differences on the Pediatric Daytime Sleepiness Scale (PDSS) of -5.5 and -2.1, respectively (least squares mean difference -3.4, 95% CI -5.5 to -1.3, P=0.002). Similarly, the adjusted mean differences on the UNS cataplexy subscale were -2.9 with active treatment versus -1.1 with placebo (least squares mean difference -1.8, 95% CI -3.3 to -0.2, P=0.023).

While this is the first study to assess the safety and efficacy of pitolisant in pediatric narcolepsy, Dauvilliers and team noted that their findings reflect those from previous clinical trials with or without cataplexy.

"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 (e.g., acetylcholine, dopamine, and norepinephrine) by binding to H3 receptors on nonhistaminergic neurons, without activation of accumbal dopaminergic neurons," the authors wrote.

The FDA approved pitolisant for adults in 2019, making it the first treatment approved for patients with narcolepsy not scheduled as a controlled substance by the DEA.

In addition, the European Medicines Agency recently approved the drug for treatment of type 1 or 2 narcolepsy in patients ages 6 years and older. "Pitolisant might be another first-choice treatment option in the management of narcolepsy and cataplexy in children and adolescents," Dauvilliers and colleagues wrote, given the potential advantage of once-daily dosing versus twice-nightly oxybate regimens.

"Based on the favorable safety profile in people using sodium oxybate as well as pitolisant in our study and a ... clinicians might also consider a combination of these treatments to manage complex or severe cases of pediatric narcolepsy," they suggested.

Despite finding no evidence of "any particular safety issues in patients who were taking other medications ... 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 assessed," they noted.

In an , Suresh Kotagal, MD, of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minnesota, pointed out several factors that may affect the validity of the results, such as possible misdiagnosis of type 2 narcolepsy and potential contribution of concomitant anticataplectic treatment.

These "issues notwithstanding, the trial ... is pivotal in advancing therapy of childhood narcolepsy," Kotagal added. "The study will open the door to a new therapeutic option and improved quality of life for children with narcolepsy."

At least one treatment-related adverse event (TRAE) was reported by 31% of the pitolisant group and 34% of the placebo group. TRAEs affecting ≥5% of patients overall included headache (19% and 8%, respectively) and insomnia (7% and 3%).

For this study, Dauvilliers and colleagues included 110 patients with narcolepsy with or without cataplexy from 11 sleep centers in Italy, France, the Netherlands, Russia, and Finland from June 2016 to April 2021. Participants had severe excessive daytime sleepiness (PDSS >15) and had not received psychostimulants for at least 14 days before enrollment. For those needing anticataplectics (including sodium oxybate), they were required to be on a stable dose for at least 1 month.

Mean age was 12.9 years, 55% were boys, and 82% had cataplexy. They were randomly assigned in a 2:1 ratio, 72 to pitolisant and 38 to placebo. Overall, 13% in the pitolisant group and 5% in the placebo group were taking sodium oxybate.

Over the 4-week double-blind phase, treatment was up-titrated as tolerated from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo, then continued at a stable dose for an additional 4 weeks, followed by a 1-week placebo period.

Overall, 58% of patients were treated with pitolisant 40 mg per day and 24% were treated with pitolisant 20 mg per day. "Median treatment compliance was 100% (IQR 99–100) in both the full analysis set and the safety set," Dauvilliers and team noted.

They acknowledged some limitations to the study, including its short duration, and the use of the UNS, which still needs to be validated in independent populations of pediatric narcolepsy.

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