Despite Missing Primary End Point, Pitolisant Shows Positive Outcomes in Phase 3 INTUNE Trial for Idiopathic Hypersomnia


During the open-label treatment period, 83% of patients with idiopathic hypersomnia who completed treatment saw a significant reduction in sleepiness, with an average Epworth Sleepiness Scale change of -9.4 points.

Kumar Budur, MD, chief medical officer at Harmony Biosciences

Kumar Budur, MD

New topline results from the phase 3 INTUNE study (NCT05156047) assessing pitolisant (Wakix; Harmony Biosciences) in patients with idiopathic hypersomnia (IH) showed no statistically significant difference between the therapy and placebo in the primary end point of improving excessive daytime sleepiness (EDS).1 Despite these results, the treatment reached statistical significance in additional prespecified end points including 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 Epworth Sleepiness Scale (ESS) and an average ESS change from baseline of –9.4 points. During the 4-week double-blind randomized withdrawal period, pitolisant-treated patients achieved statistical significance in comparison with placebo across additional prespecified end points including the Idiopathic Hypersomnia Severity Scale and the Sleep Inertia Questionnaire reached statistical significance.

"We are very encouraged by the magnitude of the response seen in the initial open-label treatment period, where 83% of patients completing this phase responded with an average 9.4 point improvement in the ESS,” Kumar Budur, MD, chief medical officer at Harmony Biosciences said in a statement.1 “Equally encouraging is the number of patients, almost 90%, electing to continue into the long-term extension study, allowing us to generate additional safety and efficacy data in this patient population. Positive trends in other important outcomes like sleep inertia add to the totality of evidence that pitolisant has a clinical benefit for patients with IH."

Clinical Takeaways

  • While pitolisant did not significantly improve excessive daytime sleepiness compared with the placebo in the phase 3 INTUNE study, it did show promise in secondary end points such as disease severity and functional status.
  • Approximately 83% of patients with idiopathic hypersomnia who completed the open-label treatment period with pitolisant experienced reduced sleepiness, indicating its potential benefit for this condition.
  • Harmony Biosciences plans to continue working with the FDA to explore the future potential of pitolisant as a treatment option for idiopathic hypersomnia, based on the supporting data from INTUNE.

INTUNE was conducted at 52 clinical trial sites across the U.S. with 213 adult patients enrolled in the study, of which 139 were randomized. Investigators evaluated the safety and efficacy of pitolisant compared with placebo in treating EDS as well as assessed the impact of the treatment on sleep inertia, daytime functioning, and cognitive performance. The study had 2 periods, an open-label period consisting of 3 weeks of dose titration, 3 weeks of dose optimization and 2 weeks of stable dose followed by a double-blind randomized withdrawal period. The efficacy assessments were performed during the last phase of the study and were analyzed to compare the difference between pitolisant and placebo from the end of stable dose period to the end of the withdrawal phase.

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Following the double-blind period, approximately 88% of patients continued into the ongoing 12-month long-term extension study for further data analyses. The company also noted that the safety and tolerability of pitolisant in adult patients with IH was consistent with the confirmed safety profile and had not observed any new safety signals among the patients.

"We are grateful to the patients, family members and clinicians who participated in the INTUNE study. We remain committed to the IH patient community and understand their strong desire for a non-scheduled treatment option for IH. Following a thorough review of the full data set, we will work closely with the FDA to discuss next steps and a path forward for pitolisant in IH,” Budur said in a statement.1

For more context on the established safety profile of pitolisant, the most common adverse events observed in previous placebo-controlled trials of patients with narcolepsy with or without cataplexy were insomnia (6%), nausea (6%), and anxiety (5%).2 Other adverse events occurring in at least 2% and more frequently than in patients treated with placebo included headache, upper respiratory tract infection, musculoskeletal pain, heart rate increased, hallucinations, irritability, abdominal pain, sleep disturbance, decreased appetite, cataplexy, dry mouth, and rash.

Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, remains the only FDA-approved treatment for both excessive daytime sleepiness and cataplexy in narcolepsy that is not a scheduled controlled substance. It first gained FDA greenlight for EDS in 2019 and later for cataplexy in the following year.2 For years, IH had been treated with off-label agents until 2021, when the FDA approved JZP-258 (Xywav; Jazz Pharmaceuticals), a combination agent of calcium, magnesium, potassium, and sodium oxybates, as the first therapeutic specific for this condition.

1. 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 October 17, 2023.
2. Harmony Biosciences Announces FDA Approval Of WAKIX (pitolisant), A First-In-Class Medication For The Treatment Of Excessive Daytime Sleepiness In Adult Patients With Narcolepsy. News Release. Harmony Biosciences. Published August 15, 2019. Accessed October 17, 2023.

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