The U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application for pitolisant (Wakix) tablets to treat excessive daytime sleepiness (EDS) in pediatric patients 6 years of age and older with narcolepsy.
The expanded approval was based on data from a randomized, double-blind, placebo-controlled phase 3 study that assessed the efficacy and safety of pitolisant, a histamine-3 (H3) receptor antagonist/inverse agonist, in patients 6 to 17 years of age with narcolepsy, with or without cataplexy. Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned. 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. Investigators saw the mean adjusted difference in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of the double-blind period was -6.3 in the pitolisant group and -2.6 in the placebo group (95% CI, -6.4 to -1.0; P = .007). In the placebo-controlled phase of the study, the most common adverse reactions (occurring in =5% of patients and greater than the rate of placebo) with the use of pitolisant were headache (19%) and insomnia (7%). These findings suggested that pitolisant is a safe and effective treatment for children and adolescents with narcolepsy.
Pitolisant's efficacy could be mediated through its activity that increases the synthesis and release of histamine in the brain via competitive binding to presynaptic histamine-3 autoreceptors. Pitolisant is a histamine-3 (H3) presynaptic antagonist/inverse agonist at histamine-receptors. The novel mechanism (Figure) for improving wakefulness in narcolepsy is to block the normal action of presynaptic H3 autoreceptors to block histamine release. Inhibiting the presynaptic H3 receptor causes the disinhibition (that is, the release) of presynaptic histamine and this is wake promoting. Additionally, pitolisant is not a controlled substance and has no known abuse potential
Reference:
Dauvilliers Y et al. Lancet Neurol. 2023;22(4):303-311.
Abstract