Pitolisant is a histamine H3 receptor inverse agonist. Histaminergic neurones in the hypothalamus are crucial for the maintenance of wakefulness and are thought to mediate the waking action of hypocretins, neuropeptides that are deficient in patients with narcolepsy. By activating these neurones, pitolisant increases wakefulness and alertness.
Evidence for the safety and efficacy of pitolisant comes from the randomised, double-blind HARMONY I trial involving 95 adults with narcolepsy who had an Epworth Sleepiness Scale (ESS) score of at least 14.
Participants were randomly allocated to receive pitolisant, modafinil, or placebo for 8 weeks: 3 weeks of flexible dosing as determined by the investigator (pitolisant 10mg, 20mg, or 40mg daily; modafinil 100mg, 200mg or 400mg daily) followed by 5 weeks of stable dosing. The primary endpoint was the change from baseline in ESS score after 8 weeks.
Over the treatment period, patients treated with pitolisant experienced a greater reduction in ESS score than those treated with placebo and a similar reduction to those treated with modafinil (-5.8 vs -3.4 and -6.9, respectively). Analysis of treatment effects showed that pitolisant was superior to placebo (difference -3.0, 95% CI -5.6 to -0.4; p=0.024) but not non-inferior to modafinil (difference 0.12, 95% CI -2.5 to 2.7; p=0.250).
Wakefulness and attention
Results on the Maintenance of Wakefulness Test (time awake in a dark room; assessed as a secondary endpoint), showed that pitolisant was superior to placebo, with no significant difference from modafinil (treatment differences of 1.47, 95% CI 1.01-2.14; p=0.044 and 0.77, 95% CI 0.52-1.13; p=0.173], respectively).
Change from baseline in total score on the Sustained Attention to Response Task (SART), a measure of vigilance, did not differ significantly between the pitolisant group and the placebo or modafinil groups, although the decrease in score for the 'NO GO' error element of SART (the number of times a button was pressed inappropriately) was significantly greater with pitolisant than placebo (treatment difference 0.81, 95% CI 0.67-0.99; p=0.038).
The randomised, double-blind HARMONY CTP study examined the effect of pitolisant in 105 patients with narcolepsy and high-frequency cataplexy. In participants who experienced at least one episode of cataplexy, the mean weekly rate of episodes decreased from 9.15 to 3.28 in the pitolisant group, compared with a decrease from 7.31 to 6.79 in the placebo group. The difference in effect size was significant (p<0.0001).
No withdrawal symptoms
In HARMONY I, adverse events occurred in 22 patients receiving pitolisant, 26 receiving modafinil, and 10 receiving placebo. The most frequent events were headache in all three groups; insomnia, abdominal discomfort, and nausea in the pitolisant group; and abdominal discomfort, nausea, diarrhoea, dizziness, anxiety, and irritability in the modafinil group. There were no clinically relevant differences between the three groups in the intensity or resolution of adverse events.
Of the six severe adverse events considered treatment-related, one occurred with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amfetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders).
Withdrawal syndrome was not seen in patients receiving pitolisant, but occurred in 3 modafinil-treated patients.