Pitolisant Demonstrates Meaningful Improvement in Daytime Sleepiness and Fatigue in Myotonic Dystrophy Type 1


Pitolisant demonstrated a dose-dependent improvement in excessive daytime sleepiness and fatigue, with a safety profile that was consistent with previous studies. Additional data to be shared in early 2024.

Jeffrey Dayno, MD, president and chief executive officer of Harmony

Jeffrey Dayno, MD

Harmony Biosciences has announced topline data from its phase 2 signal detection study (NCT04886518) of adults with myotonic dystrophy type 1 (DM1), with results showing that treatment with pitolisant (Wakix) improved excessive daytime sleepiness (EDS) and fatigue, 2 common symptoms of DM1. Although not powered for statistical significance, the results suggest that pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, could be a potentially effective therapy for patients with DM1 with these symptoms.1

From baseline to the end of the 11-week double-blind treatment period, patients on high- and low-dose pitolisant reported mean changes of –2.5 and –1.0 in Daytime Sleepiness Scale (DSS) the primary efficacy end point, in comparison with changes of –0.2 for those on placebo. On Epworth Sleepiness Scale (ESS), investigators reported mean changes of –4.88 for the higher dose pitolisant group vs –0.10 for placebo. Above all, the safety profile of the agent was consistent with previous studies, with no new safety signals or serious adverse events (AEs) reported.

"These strong topline results add to the body of evidence supporting the effectiveness of pitolisant for improving EDS," Jeffrey Dayno, MD, president and chief executive officer of Harmony, said in a statement.1 "In addition, a positive signal for pitolisant has been demonstrated for fatigue, suggesting it could be a potential new treatment option for this symptom as well. We are encouraged by these results, which underscore our commitment to translating innovative science into therapeutic possibilities for patients living with unmet medical needs."

The phase 2 signal detection study, which included 30 patients aged 18 to 65 years with DM1, included 3-week titration period, followed by an 8-week stable dose period, and an optional open-label extension phase. Patients were randomly assigned 1:1:1 to high- or low-dose pitolisant or placebo.

The main goals of the study were to evaluate the efficacy and safety of the therapy in treating EDS, as well as its impact on fatigue, cognitive function, and burden of disease. Harmony noted that it will include other secondary outcomes such as the Myotonic Dystrophy Health Index, cognitive functions, and safety and efficacy from the ongoing OLE, in the full dataset, potentially early 2024. Detailed results will also be presented at an upcoming medical meeting and will be submitted for publication.

Kumar Budur, MD, MS, chief medical officer, Harmony Biosciences

Kumar Budur, MD, MS

At the conclusion of the double-blind period, patients in the high-dose pitolisant group demonstrated mean changes of –0.9 on Clinical Global Impression of Severity of EDS in comparison with changes of –0.1 for placebo. Fatigue, a secondary outcome measured by the Fatigue Severity Scale, showed mean changes of –0.86 and –0.36 for the high- and low-dose pitolisant groups, respectively, vs changes of –0.13 for placebo. As the results showed, there was a clear dose-dependent relationship between high doses of pitolisant and greater responses.

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"These positive signals for pitolisant are promising news for the DM1 patient community, where 80-90 percent of the approximately 40,000 diagnosed DM1 patients in the U.S. experience significant EDS and fatigue with no FDA-approved treatments available," Kumar Budur, MD, MS, chief medical officer, Harmony Biosciences, said in a statement.1 "The strong signals for pitolisant reinforce our confidence in it as a potential treatment option worthy of further study in patients with DM1."

Pitolisant, was originally approved for the treatment of EDS in patients with narcolepsy in 2019 and is only investigational for those with DM1. It had its indication expanded in 2020 to include the treatment of cataplexy in adults with narcolepsy, with results from the HARMONY CTP (NCT018000450) and HARMONY 1 (NCT01067222) trials serving as the basis for the decision.2

The therapy remains in development for other conditions such as Prader-Willi syndrome and idiopathic hypersomnia (IH). Most recently, in October, topline results from the phase 3 INTUNE study (NCT05156047) showed that pitolisant failed to distinguish itself from placebo in improving EDS in patients with IH; however, it reached statistical significance in additional prespecified end points of disease severity and functional status. Approximately 83% of patients with IH who completed the 8-week open-label treatment period with pitolisant had a decrease of at least 3 points on the ESS and an average ESS change from baseline of –9.4 points.3

"EDS is the most common non-muscular complaint in patients living with DM1, being present in the majority of patients,” Jean Denis-Brisson, MD, neurologist at the Centre Intégré Universitaire De Santé Et De Services Sociaux du Saguenay-Lac-Saint-Jean, said in a statement.1 "The positive signals from this Phase 2 study are very encouraging, and support pitolisant as a potential treatment option for DM1."

1. Harmony Biosciences announces positive topline data from phase 2 signal detection study evaluating pitolisant in adult patients with myotonic dystrophy type 1. News release. Harmony Biosciences. December 7, 2023. Accessed December 8, 2023. https://www.prnewswire.com/news-releases/harmony-biosciences-announces-positive-topline-data-from-phase-2-signal-detection-study-evaluating-pitolisant-in-adult-patients-with-myotonic-dystrophy-type-1-302008352.html
2. 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 December 8, 2023. 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
3. Harmony Biosciences Announces Topline Data from Phase 3 INTUNE Study Evauating Pitolisant in Patients with Idiopathic Hypersomnia. News Release. Harmony Biosciences. Published October 13, 2023. Accessed December 8, 2023. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-announces-topline-data-from-phase-3-intune-study
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