A phase 2 study presented at SLEEP 2024 found pitolisant reduced excessive daytime sleepiness and fatigue in adults with myotonic dystrophy type 1.


Summary: Harmony Biosciences presented data from a phase 2 signal detection study indicating that pitolisant reduced excessive daytime sleepiness (EDS) and fatigue in adults with myotonic dystrophy type 1 (DM1). The study showed greater improvements in EDS and fatigue scores for patients receiving pitolisant compared to placebo, particularly at higher doses. These findings suggest potential for pitolisant to address unmet medical needs in DM1 and other sleep/wake disorders, paving the way for a phase 3 study with an optimized formulation.

Key Takeaways:

  • The study showed that pitolisant led to greater improvements in EDS and fatigue scores compared to placebo, with higher doses showing stronger efficacy.
  • Harmony Biosciences plans to progress to a pivotal phase 3 study using the Next-Generation 2 (NG2) formulation of pitolisant, which aims to deliver an optimized pharmacokinetic profile and higher dosage strength.
  • The research highlights the potential for pitolisant to treat EDS and fatigue in DM1 patients and other sleep/wake disorders, addressing significant unmet medical needs and benefiting over 100,000 patients.

Harmony Biosciences presented data from its phase 2 signal detection study showing that pitolisant reduced excessive daytime sleepiness (EDS) and fatigue in adults with myotonic dystrophy type 1 (DM1).

“More than 80% 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, namely myotonia and muscle weakness,” says Kumar Budur, MD, MS, chief medical and scientific officer of Harmony Biosciences, in a release. “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, narcolepsy, and the other sleep/wake disorders we are investigating through our lifecycle management programs that will involve Next-Generation formulations of pitolisant.” 

Improvement in EDS and Fatigue Scores

Notably, there was greater mean improvement from baseline to week 11 in both EDS (as measured by the Daytime Sleepiness Scale) and fatigue (as measured by the Fatigue Severity Scale) compared to placebo. The overall disease burden also signaled greater improvement for pitolisant compared to placebo, with the higher dose pitolisant group showing a stronger efficacy signal. This study was designed for signal detection and was not powered to demonstrate statistical significance.

Estimates suggest there are 40,000 people currently diagnosed with DM1 in the United States, with up to 90% of them reporting EDS and fatigue. 

“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 says in a release. “The NG2 formulation could be promising given the positive findings we observed across the EDS and fatigue endpoints within the higher dose pitolisant treatment arm. These efforts are integral to our broader life cycle management programs, which, if successful, could benefit over 100,000 patients living with unmet medical needs.”

Study Design and Results

The phase 2 signal detection study was a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of pitolisant in the treatment of EDS and other non-muscular symptoms in adults with DM1. 

Eligible patients were confirmed to have DM1 and enrolled in an 11-week double-blind treatment phase that included a 3-week titration period and an eight-week stable dose period. Participants were randomized to receive higher or lower dose pitolisant, or a matching placebo.

The primary efficacy endpoint was the change from baseline to week 11 in Daytime Sleepiness Scale score. Additional efficacy endpoints included the change from baseline to Week 11 in Epworth Sleepiness Scale score, Fatigue Severity Scale score, Clinical Global Impression of Severity (for EDS) score, and Myotonic Dystrophy Health Index score.

Results from the study include:

  • Mean improvement on the Daytime Sleepiness Scale (primary endpoint) was greater for pitolisant. Compared with placebo, a dose-response relationship was observed from baseline to Week 11:
    • Higher Dose Pitolisant (n=8): -2.5
    • Lower Dose Pitolisant (n=8): -1.0
    • Placebo (n=9): -0.2
  • Mean improvement on the other secondary efficacy endpoints (EDS, fatigue, disease burden) was also greater for pitolisant versus placebo, with higher dose pitolisant showing a stronger efficacy signal from baseline to Week 11.
    • Epworth Sleepiness Scale:
      • Higher Dose Pitolisant (n=8): -4.9
      • Lower Dose Pitolisant (n=9): 1.3
      • Placebo (n=10): -0.1
    • Fatigue Severity Scale:
      • Higher Dose Pitolisant (n=8): -0.9
      • Lower Dose Pitolisant (n=9): -0.4
      • Placebo (n=10): -0.1
    • Clinical Global Impression of Severity (for EDS):
      • Higher Dose Pitolisant (n=8): -0.9
      • Lower Dose Pitolisant (n=9): -0.2
      • Placebo (n=10): -0.1
    • Myotonic Dystrophy Health Index
      • Higher Dose Pitolisant (n=8): -9.1
      • Lower Dose Pitolisant (n=9): -2.9
      • Placebo (n=10): 0.4
  • The rate of adverse events was similar for pitolisant and placebo. The safety and tolerability of pitolisant in patients with DM1 were consistent with its known safety profile.

Pitolisant is marketed as Wakix in the United States and is US Food and Drug Administration-approved to treat EDS or cataplexy in adult patients with narcolepsy. Pitolisant is not approved for use in patients with DM1 and is currently being evaluated as an investigational agent in this patient population.