| Wakix (Pitolisant), the first histamine H3-receptor antagonist/inverse agonist to be introduced in therapeutics, the first acting by releasing histamine from brain tuberomammillary neurons, a major wake-promoting system. It exerts wake-promoting and anti-cataplectic effects in a rodent model of narcolepsy but is devoid of psychomotor stimulant and preclinical drug abuse potential. The drug was approved and is commercialized in Europe for treatment of narcolepsy with or without cataplexy and is currently under examination by the FDA. Wakix efficacy on Excessive Daytime Sleepiness (EDS) and cataplexy was mainly assessed in two double-blind placebo-controlled trials (HARMONY I and HARMONY CTP) in which it was administered once-a-day at a maximum 40mg dose for two months. Positive and clinically relevant improvements of EDS over placebo were found both on the Epworth sleepiness scale and the MWT as well as on a sleepiness index combining these two subjective and objective tests, respectively. In both trials the number of cataplexy attacks were significantly reduced by over 50% compared to placebo (Dauvilliers et al Lancet Neurol 2013, 12, 1068; Szakacs et al Lancet Neurol 2017;16,:200 )The long-term efficacy on EDS, cataplexy and hallucinations was confirmed in the open-label HARMONY III trial in which patients were treated for up to one year.The safety profile of Wakix in these various trials was good with the most frequent TEAEs being headache, insomnia, nausea, anxiety and irritability. No drug abuse signal was detected in these trials and and, more specifically, a controlled study in recreational drug users showed no difference with placebo. |