Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials

Abstract

Background: Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy.

Objective: Analyses evaluated the time to onset of clinical response during treatment with pitolisant.

Methods: Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo.

Results: The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]).

Conclusions: Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS.

Gov identifier: NCT01067222 (February 2010), NCT01800045 (February 2013).

Conflict of interest statement

NFW reports serving as a consultant for Harmony Biosciences, LLC, Jazz Pharmaceuticals, and SleepScore Labs. CWD, DZ, and JMD are employees of Harmony Biosciences, LLC. BV is an employee of Rho. YD reports receiving funds for speaking, board engagements, and travel to conferences from Avadel/Flamel, Bioprojet Pharma, Harmony Biosciences, LLC, Idorsia, Jazz Pharmaceuticals, Takeda, Theranexus, and UCB Pharma. JCS is a co-founder of Bioprojet Pharma.

© 2021. The Author(s).

Figures

Fig. 1

Epworth Sleepiness Scale (ESS) scores over the course of treatment in A HARMONY 1 and B HARMONY CTP. Data are shown as mean [standard error of the mean (SEM)] at baseline and least-squares (LS) mean (SEM) at other timepoints with the last observation carried forward. aPlacebo washout phase: HARMONY 1: pitolisant, n = 26; placebo, n = 25; HARMONY CTP: pitolisant, n = 50; placebo, n = 48. bDosing information is based on the number of patients in the study at each timepoint; two patients did not receive a stable dose in HARMONY 1. *p < 0.05 vs placebo; †p = 0.05 vs placebo; **p < 0.01 vs placebo; ***p < 0.001 vs placebo

Fig. 2

Epworth Sleepiness Scale (ESS) responders over the course of treatment for response defined as an A ESS score reduction of ≥3 and B final ESS score ≤10. *p < 0.05 vs placebo; **p < 0.01 vs placebo; ***p < 0.001 vs placebo

Fig. 3

Clinical Global Impression of Change for excessive daytime sleepiness over the course of treatment in A HARMONY 1 and B HARMONY CTP. Response on the Clinical Global Impression of Change was defined by ratings of “much” or “very much” improved. aNo Clinical Global Impression of Change data for one patient in the pitolisant group in HARMONY 1. *p < 0.05 vs placebo

Fig. 4

Weekly rate of cataplexy attacks over the course of treatment in HARMONY CTP. Data are shown as mean (standard error of the mean [SEM]) at baseline and least-squares (LS) mean (SEM) at other timepoints with the last observation carried forward. aPlacebo washout phase, pitolisant, n = 36; placebo, n = 41. **p < 0.01 vs placebo; ***p < 0.001 vs placebo

Fig. 5

Cataplexy responders over the course of treatment in HARMONY CTP for response defined as a ≥ 25% reduction in the A weekly rate of cataplexy attacks and B a ≥ 50% reduction in the weekly rate of cataplexy attacks. *p < 0.05 vs placebo; **p < 0.01 vs placebo; ***p < 0.001 vs placebo

Fig. 6

Clinical Global Impression of Change for cataplexy over the course of treatment in HARMONY CTP. Response on the Clinical Global Impression of Change was defined by ratings of “much” or “very much” improved. **p < 0.01 vs placebo; ***p < 0.001 vs placebo

Fig. 7

Frequency of adverse events over the course of treatment in A HARMONY 1 and B HARMONY CTP