Pitolisant found to reduce fatigue, daytime sleepiness in DM1 patients
Harmony Biosciences planning pivotal Phase 3 study for next-gen pitolisant
After nearly three months of treatment with pitolisant, adults with myotonic dystrophy type 1 (DM1) experienced a reduction of excessive daytime sleepiness (EDS) and fatigue.
That’s according to data from the Phase 2 trial (NCT04886518), which is testing the safety and efficacy of Harmony Biosciences’ therapy in DM1 patients, ages 18 to 65, with moderate or severe EDS. Study completion is expected by the end of the year.
Results were presented by the company at the annual meeting of the Associated Professional Sleep Societies (SLEEP 2024), held this month in Houston.
“The findings from our signal detection study evaluating pitolisant, which is believed to promote wakefulness through histamine, present an exciting opportunity to develop new treatments for EDS and fatigue in DM1,” Kumar Budur, MD, Harmony’s chief medical and scientific officer, said in a company press release.
DM1 is the most common form of adult-onset muscular dystrophy, and is caused by mutations in the DMPK gene. It is characterized by myotonia — when muscles are unable to relax after they contract — and muscle weakness, mainly affecting the muscles away from the trunk, such as those in the lower legs, arms, neck, and face.
Majority of DM1 patients experience excessive daytime sleepiness, fatigue
“More than 80 percent of DM1 patients experience EDS and fatigue, which patient-reported outcomes research has shown to be nearly as debilitating as the primary symptoms of DM1,” Budur said.
Pitolisant is thought to work by increasing the brain levels of histamine, a chemical that helps people stay awake during the day by increasing the activity of brain areas that regulate waking up while decreasing activity of areas that help sleep.
It is approved as Wakix in the U.S. for the treatment of EDS or cataplexy (sudden and brief muscle weakness triggered by strong emotions) in adults with narcolepsy, a sleep disorder that makes people abnormally drowsy during the day.
The Phase 2 trial enrolled a total of 30 participants, randomized to receive either pitolisant or a placebo, once daily for 11 weeks. The study period includes three weeks for dose adjustment and eight weeks of a stable treatment dose of 35.6 mg (high dose) or 17.8 mg (low dose).
Upon completion, eligible patients could join an open-label extension phase to receive the treatment for about one year.
The main efficacy goal was to evaluate changes on the daytime sleepiness scale (DSS) after 11 weeks, as compared to the baseline (the study’s beginning). Other efficacy measures included the Epworth Sleepiness Scale, the clinician-rated Clinical Global Impression of Severity (CGI-S), as well as assessments of fatigue and patient-reported overall disease burden.
Daytime sleepiness decreased more with higher pitolisant dose
Results showed DSS reductions, representing a decrease in daytime sleepiness, of 2.5 with the higher pitolisant dose and of 1 with the lower dose. The placebo group showed a smaller reduction (0.2). Similar dose-dependent benefits of pitolisant were also demonstrated in measures of EDS, fatigue, and disease burden.
Fatigue severity, assessed using the Fatigue Severity Scale, lowered by 0.9 in patients treated with the higher pitolisant dose and by 0.4 for those on the lower dose, compared to a 0.1 increase in patients on the placebo. Similar findings were reported with CGI-S.
Pitolisant also reduced disease burden, according to the Myotonic Dystrophy Health Index (MDHI). Specifically, MDHI decreased by 9.1 in patients on the higher dose and by 2.9 in those treated with the lower dose. In contrast, a 0.4 worsening was seen in the placebo group.
The most commonly reported adverse events included headache, nausea, and insomnia (difficulty sleeping). The rate of side effects did not differ between pitolisant and the placebo. Overall, the safety profile of pitolisant in this patient population was consistent with the known safety profile of the drug.
“Given the potential opportunity of pitolisant for treating EDS and fatigue in patients with DM1, we plan to progress our DM1 development program through a pivotal Phase 3 study using the Next-Generation 2 (NG2) formulation of pitolisant, which is designed to deliver an optimized pharmacokinetic profile and higher dosage strength,” Budur said.
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