Pitolisant is a histamine 3 (H₃)-receptor antagonist/inverse agonist approved by the European Medicines Agency for the treatment of narcolepsy with or without cataplexy in adults.

HARMONY-1 included 94 patients with EDS, of whom 80.9% had a history of cataplexy. HARMONY-CTP included 105 patients, all with EDS and a high frequency of cataplexy at baseline. Overall baseline ESS score was 18.4 in HARMONY-1 and 17.4 in HARMONY-CTP; baseline cataplexy frequency was 3.1 and 8.3 episodes/week, respectively. Mean change in ESS score was significantly greater for pitolisant compared with placebo in both HARMONY-1 (-5.8 vs -3.4; P=0.024) and HARMONY-CTP (-5.4 vs -1.9; P=0.0001). ESS responders (final score ≤10) were 45.2% for pitolisant and 13.3% for placebo in HARMONY-1 (P<0.001); and 39.2% and 18.0%, respectively, in HARMONY-CTP (P=0.035). Mean reduction in the weekly rate of cataplexy was 62% with pitolisant and 8% with placebo in HARMONY-1 (P=0.034); and 75% and 38%, respectively, in HARMONY-CTP (P<0.0001). The most common adverse events associated with pitolisant (incidence ≥5%) were headache, insomnia, abdominal discomfort/pain, and nausea in HARMONY-1; and headache, anxiety, irritability, and nausea in HARMONY-CTP. Across studies, one pitolisant-treated patient (in HARMONY-CTP) discontinued study participation due to an adverse event.

Data from these 2 pivotal trials demonstrate that pitolisant is generally safe and well tolerated and effective in both improving EDS and reducing cataplexy attacks in adult patients with narcolepsy.