The U.S. Food and Drug Administration has issued a Refusal to File (RTF) letter to Harmony Biosciences for its supplemental New Drug Application (sNDA) seeking approval of pitolisant for treating excessive daytime sleepiness in adults with idiopathic hypersomnia.
Clinical Trial Outcomes and Development Plans
The decision follows results from the Phase 3 INTUNE study, which failed to demonstrate statistical significance in its primary endpoint comparing pitolisant to placebo during the randomized withdrawal phase. Despite this setback, the open-label phase showed promising results, with improvements in the Epworth Sleepiness Scale exceeding clinically meaningful thresholds by five-fold. Additionally, most participants maintained normal wakefulness levels for over one year during the long-term extension study.
Dr. Kumar Budur, Chief Medical and Scientific Officer at Harmony Biosciences, emphasized the company's continued commitment to development: "We believe this study design will effectively demonstrate the benefit of pitolisant in patients with IH based on the robust clinical response that was observed in the Phase 3 INTUNE Study."
Strategic Pivot to Enhanced Formulation
In response to the RTF, Harmony Biosciences is shifting focus to Pitolisant HD, an enhanced, higher-dose formulation. Jeffrey M. Dayno, MD, President and Chief Executive Officer, outlined the company's strategy: "Our long-term business strategy has always been to extend our leadership in sleep/wake through the development of Pitolisant HD, which represents the more significant opportunity in IH given its optimized profile and provisional patent filed out to 2044."
Current Therapeutic Status and Mechanism
Pitolisant, marketed as WAKIX, is currently FDA-approved for treating excessive daytime sleepiness or cataplexy in adult narcolepsy patients and excessive daytime sleepiness in narcoleptic children aged 6 and above. The drug functions as a selective histamine 3 (H₃) receptor antagonist/inverse agonist, potentially achieving its therapeutic effect by increasing histamine synthesis and release through H₃ receptor activity.
The company plans to initiate a new Phase 3 registrational trial for Pitolisant HD in Q4 2025, with an anticipated PDUFA date in 2028. This development pathway represents Harmony's strategic approach to addressing the unmet needs of patients with idiopathic hypersomnia while building on their established presence in sleep-wake disorders.
