Efficacy of Pitolisant on the Treatment of Narcolepsy: A Systematic Review

Abstract

Narcolepsy is characterized by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons play an important role in enhancing wakefulness. The objective of our study was to evaluate the efficacy of pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, in patients with a high burden of narcolepsy symptoms. We conducted an advanced PubMed search strategy with inclusion and exclusion criteria. The outcome included the Epworth Sleepiness Scale (ESS) and adverse effects frequency. Our primary outcome included the mean ESS score at the endpoint and showed that pitolisant was superior to the placebo, but not non-inferior to modafinil. Adverse effects were less common and shorter in duration in the pitolisant group compared to the modafinil-treated patients. Pitolisant was efficacious in reducing excessive daytime sleepiness and cataplexy compared with placebo, and it was well-tolerated in patients with severe narcolepsy symptoms as compared with modafinil.

Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder

“…In addition, systemic treatment with samelisant was reported to produce a significant increase in wakefulness with a concomitant decrease in NREM sleep and direct REM sleep onset (DREM) episodes in orexin knockout mice subjected to sleep EEG, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy ( Nirogi et al, 2021a ). Importantly, some positive effects of H3R antagonists/inverse agonists have been reported for the narcoleptic rodent model and for patients with narcolepsy ( Romigi et al, 2018 ; Davis et al, 2021 ; Fabara et al, 2021 ). Accordingly, pitolisant (BF2.649/tiprolisant/Wakix), one of the H 3 R antagonists/inverse agonists, was reported to enhance HA neuronal activity, promote wakefulness, and decrease abnormal onset of REM sleep from the wakefulness in Hcrt knockout mice ( Romigi et al, 2018 ; Davis et al, 2021 ).…”

“…In addition, pitolisant was reported to ameliorate excessive daytime sleepiness with comparable effectiveness to that of modafinil, an approved medicine for narcolepsy ( Romigi et al, 2018 ; Davis et al, 2021 ). Therefore, pitolisant is currently assessed in different ongoing or completed clinical trials ( clinicaltrials.gov ), which may provide more insight into the potential role of brain HA in the excessive sleepiness and cataplexy attacks in narcolepsy ( Shan et al, 2015 ; Carthy and Ellender, 2021 ; Davis et al, 2021 ; Fabara et al, 2021 ).…”

“…This role renders agents such as H3R antagonists/inverse agonists as attractive therapeutic targets in CNS diseases. Moreover, modulation of the sleep–wake cycle was also described to be mediated by HA levels in the brain ( Brown et al, 2001 ; Haas et al, 2008 ; Fabara et al, 2021 ).…”

Solriamfetol for the Use of Narcolepsy: A Systematic Review

“…Pitolisant is an H3 receptor antagonist and inverse agonist that, by blocking histamine autoreceptors, increases the activity of brain histaminergic and noradrenergic neurons, thus helping in the treatment of narcolepsy [ 14 ].…”

“…According to Fabara et al, pitolisant was studied in four randomized clinical trials where the use of pitolisant, modafinil, and placebo was compared [ 14 ]. These showed a significant decrease in ESS in the group that used pitolisant compared to the placebo group.…”