Pitolisant Further Demonstrates Clinical Benefit on Excessive Daytime Sleepiness, Cataplexy

The FDA-approved agent demonstrated meaningful reduction in the frequency of cataplexy attacks in adults with narcolepsy, including patients with a high symptom burden.

Data from 2 post-hoc analyses from the HARMONY-1 (NCT01067222) and HARMONY-CTP (NCT01800045) studies further demonstrate the treatment benefit pitolisant (Wakix; Harmony Biosciences) has on excessive daytime sleepiness (EDS) and cataplexy in patients with narolepsy.1-3

The results, presented at the 2021 SLEEP Virtual Annual Meeting, June 10-13, show a low number needed-to-treat (NNT), large effect sizes, and statistically significant and clinically meaningful reduction in the frequency of cataplexy attacks with treatment of pitolisant.

"The analyses that we are presenting at the SLEEP conference this year highlight the strength of the efficacy data for Wakix,” Jeffrey Dayno, MD, chief medical officer, Harmony, said in a statement.1 “The analyses included both a traditional approach to presenting efficacy data, as well as one that underscores the clinical relevance of the findings, using NNT and effect sizes to capture overall clinical benefit.”

Pitolisant was titrated over a 3-week period to a maximum potential dose of 35.6 mg/day, after which the dose remained stable. Treatment response, observed at week 8 in HARMONY-1 and week 7 in HARMONY-CTP, was defined for EDS based on Epworth Sleepiness Scale (ESS) score reduction (≥3-point decrease from baseline or final score ≤10) and for cataplexy with at least 50% reduction from baseline to stable dose period in the weekly rate of cataplexy (WRC).2

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NNTs were calculated as the inverse of the drug-placebo difference in response rates. In HARMONY-1 (pitolisant, n = 31; placebo, n = 30), 67.7% of pitolisant-treated patients had treatment response for EDS, compared to 43.3% of placebo treated patients (NNT = 5). Treatment response for EDS was observed in 68.6% and 34% of pitolisant- and placebo-treated patients in HARMONY-CTP (pitolisant, n = 54; placebo, n = 51), respectively (NNT = 3).

In HARMONY-CTP, treatment response for cataplexy was observed in 66.7% of pitolisant-treated patients versus 25.5% of placebo-treated patients (NNT = 3). Effect sizes were 0.61 in HARMONY-1 and 0.86 in HARMONY-CTP based on ESS change scores.

The second post-hoc analysis looked at the WRC or daily rate of cataplexy (DRC) from patient diaries.3 All patients included in the studies were required to have at least 3 cataplexy attacks per week at baseline. Investigators observed a significantly greater least-squares (LS) mean change in WRC for those in the pitolisant group compared to placebo at week 2 (–4.1 vs 1.2; P = .004). This effect continued through the end of treatment (week 7; –6.5 vs –0.1; P <.001).

Treatment response for at least 50% WRC reduction was observed in 66.7% of pitolisant-treated patients in HARMONY-CTP, compared to 25.5% of those on placebo (P <.001). Furthermore, 77.8% versus 33.3% of those in the pitolisant and placebo groups respectively, had WRC reduction of at least 25%.

In HARMONY-1, LS mean change in DRC was significantly greater for those treated with pitolisant (–1.04) than those in the placebo group (0.17; P = .047) at week 5 and continued through the end of treatment (week 8; –0.96 vs 0.35; P = .035).

LS mean change in WRC for a subgroup (pitolisant, n = 20; placebo, n = 11) of patients with high burden of cataplexy (≥15 attacks/week) was significantly greater for patients treated with pitolisant (–14.5; baseline, 23.9; final, 9.4) than those on placebo (–0.1; baseline, 23.1; final, 23.0; P = .004). Notably, there was no evidence of rebound cataplexy after a 1-week placebo washout period.

In October 2020, pitolisant became the first and only FDA-approved treatment for both EDS and cataplexy in narcolepsy that is not a scheduled controlled substance.4 Pitolisant is a novel, selective histamine 3 receptor antagonist/inverse agonist that increases the synthesis and release of wake-promoting histamine via a once-daily, oral administration.

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1. Harmony Biosciences to present new data analyses for Wakix (pitolisant) at the SLEEP 2021 Annual Meeting. News release. June 7, 2021. Accessed June 10, 2021. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-to-present-new-data-analyses-for-wakix-r-pitolisant-at/
2. Meskill G, Davis G, Zarycranski D, Doliba M, Schwartz JC, Dayno J. Assessment of the clinical benefits of pitolisant on excessive daytime sleepiness and cataplexy in adults with narcolepsy. Presented at SLEEP 2021 Annual Meeting; June 10-13. Abstract 504
3. Davis G, Zarycranski D, Doliba M, Dayno J, Schwartz JC. Efficacy of pitolisant in the treatment of cataplexy in adults with narcolepsy. Presented at SLEEP 2021 Annual Meeting; June 10-13. Abstract 505
4. Harmony Biosciences receives FDA approval for expanded use of Wakix (pitolisant) for the treatment of cataplexy in adult patients with narcolepsy. News release. Harmony Biosciences. October 14, 2020. Accessed June 10, 2021. https://www.prnewswire.com/news-releases/harmony-biosciences-receives-fda-approval-for-expanded-use-of-wakix-pitolisant-for-the-treatment-of-cataplexy-in-adult-patients-with-narcolepsy-301152078.html