Pitolisant Improves Daytime Sleepiness and Cataplexy in Severely Burdened Patients


Pooled data from 2 clinical trials of the H3-receptor antagonist/inverse agonist show it improved cataplexy and excessive daytime sleepiness in patients with narcolepsy who were most hampered by symptoms.

Michael J. Thorpy, MBChB

Michael J. Thorpy, MBChB

Pitolisant (Wakix; Harmony Biosciences) treatment is associated with improvements in patients with narcolepsy who experience severe symptom burden, the results presented at SLEEP 2020 from 2 pooled trials studies of the histamine 3 (H3)-receptor antagonist/inverse agonist suggest.1

All told, those on pitolisant experienced significantly greater improvements in excessive daytime sleepiness and cataplexy compared with placebo based on a post hoc analysis of 2 randomized trials lasting 7 and 8 weeks in adults. The analysis was conducted by Michael J. Thorpy, MBChB, director, Sleep-Wake Disorders Center, Montefiore Medical Center, and professor of neurology, Albert Einstein College of Medicine, and colleagues.

“Recent literature suggests that histamine may play an important role in narcolepsy,” Thorpy, et al. noted, adding that the results highlight that role in narcolepsy.

The data show that those randomized to pitolisant experienced significantly greater mean changes in Epworth Sleepiness Scale (ESS) scores (—6.1 points) compared to those on placebo (–2.6 points; P = .0002), as well as significant decreases in cataplexy rates (—17.9) compared to placebo (–2.7; rate ratio, 0.35 [95% CI, 0.26–0.47]; P <.001). At baseline, the respective rates of cataplexy for the pitolisant and placebo groups were 21.8 and 20.9, compared to final rates of 3.9 and 18.2.

The analyses included 3 independent patient subgroups: those with a baseline score of >16 on the Epworth Sleepiness Scale (ESS; pitolisant: n = 54; placebo: n = 54), sleep latency of ≤8 minutes on the Maintenance of Wakefulness Test (MWT; pitolisant: n = 59; placebo: n = 46), and ≥15 cataplexy attacks per week (pitolisant: n = 20; placebo: n = 11).

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Notably, a markedly larger percentage of patients treated with pitolisant were deemed responders to treatment compared to placebo for an ESS score reduction of ≥3 (pitolisant: 68.5%; placebo: 35.2%; P = .0006), as well as for a final ESS score ≤10 (pitolisant: 35.2%; placebo: 9.3%; P = .0026). The mean increase in sleep latency on the MWT was also significantly greater for pitolisant patients (7.0 minutes) compared with placebo counterparts (3.4 minutes; P = .0089).

The adverse event (AE) profile in the analysis populations was considered consistent with the known safety profile for the Harmony Biosciences agent. Headache was the most common AE in pitolisant-treated patients, ranging from 10.0% to 20.4%.

Overall, pitolisant was considered well tolerated in clinical trials, with participants typically experiencing few AEs, primarily headache, insomnia, nausea, and anxiety—consistent with its mechanism of action.2,3 Long-term safety data for pitolisant in individuals with narcolepsy are currently limited to the HARMONY III trial in adults (NCT01399606),4 with a complementary prolonged open-label study ongoing in pediatric patients (NCT02611687).

Previously, pitolisant was shown to have minimal risk of abuse in preclinical and clinical studies, and it remains the only antinarcoleptic drug not scheduled as a controlled substance in the United States.2 In the HARMONY CTP (NCT01800045) and HARMONY I (NCT01067222) trials, no patients on pitolisant experienced amphetamine-like withdrawal syndrome during the withdrawal phase, whereas this AE occurred in several patients treated with modafinil.2,3 Patients taking pitolisant also did not experience hypersomnia or fatigue upon treatment interruption, and Beck Depression Inventory scores improved significantly from baseline compared with placebo (P = .02), and the blood chemistry and hematological and cardiovascular parameters were consistent with those of controls.2

Earlier this year, a group of sleep medicine experts, including Russell Rosenberg, PhD, DABSM; Kiran Maski, MD, MPH; Alon Avidan, MD, MPH; and Eveline Honig, MD, MPH, participated in a NeurologyLive Peer Exchange discussion led by Thorpy regarding the use of pitolisant for treatment of excessive daytime sleepiness associated with narcolepsy.

The conversation included thoughts on its unique mechanism of action that increases histamine in the brain, its once-daily dosing, and its classification as a nonscheduled medication. Watch that discussion below.

For more coverage of SLEEP 2020, click here.


1. Davis CW, Kallweit U, Krahn LE, Vaughn B, Thorpy MJ. Efficacy of pitolisant in patients with high burden of narcolepsy symptoms. SLEEP 2020. Abstract 0762.

2. Lamb YN. Pitolisant: a review in narcolepsy with or without cataplexy. CNS Drugs. 2020;34(2):207-218. doi:10.1007/s40263-020-00703-x

3. Dauvilliers Y, Bassetti C, Lammers GJ, et al; HARMONY I Study Group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi:10.1016/S1474-4422(13)70225-4

4. Li S, Yang J. Pitolisant for treating patients with narcolepsy. Expert Rev Clin Pharmacol. 2020;13(2):79-84. doi:10.1080/17512433.2020.1714435

5. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al; HARMONY-CTP Study Group. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200-207. doi:10.1016/S1474-4422(16)30333-7

6. Harmony Biosciences presents 5-year data on pitolisant at international narcolepsy symposium. News release. Harmony Biosciences. September 11, 2018. Accessed August 31, 2020. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-presents-5-year-data-on-pitolisant-at-international/

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