FDA Rejects Pitolisant NDA for Idiopathic Hypersomnia

Harmony Biosciences has received a Refusal to File (RTF) letter by the FDA for its supplemental new drug application (NDA) for pitolisant for the treatment of excessive daytime sleepiness (EDS) in adult patients with idiopathic hypersomnia (IH).1

“Our planned Phase 3 registrational trial, a double-blind, randomized, parallel-group study in patients with IH, is based on input from the FDA,” Kumar Budur, MD, MS, Chief Medical and Scientific Officer at Harmony Biosciences, said in a statement.1 “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. We are grateful to the patients and clinicians who participated in the INTUNE Study, and our commitment to these patients remains steadfast. With the initiation of this pivotal Phase 3 trial in Q4 2025, we will continue to advance pitolisant-based treatments to address their unmet needs.”

Pitolisant was evaluated for efficacy in adults with IH in the phase 3 INTUNE study, which did not meet the primary outcome for statistical significance in EDS between pitolisant and placebo in the randomized withdrawal phase.2 However, the company noted that the data from the open-label phase demonstrated improvements with pitolisant on the Epworth Sleepiness Scale that were 5 times greater than what is recognized as clinically meaningful, and most patients in the long-term extension study achieved normal levels of wakefulness sustained for over 1 year.

Pitolisant is FDA-approved under the name WAKIX for treating EDS or cataplexy in adult patients with narcolepsy and for treating EDS in pediatric patients at least 6 years of age with narcolepsy. The FDA previously granted the drug orphan drug designation for the treatment of narcolepsy in 2010, and breakthrough therapy designation for the treatment of cataplexy in 2018. Pitolisant is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. While its mechanism of action is unclear, Harmony speculates that its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine. Harmony has an exclusive license from Bioprojet, which designed and developed pitolisant, to develop, manufacture and commercialize pitolisant in the United States.

“We are disappointed with this short-term setback, but our long-term strategy for pitolisant in IH remains firmly on track with our focus on Pitolisant HD,” Jeffrey M. Dayno, MD, President and Chief Executive Officer of Harmony Biosciences, added.1 “We made the decision to submit the sNDA based on our belief in pitolisant’s overall benefit-risk profile in IH and our deep commitment to the patient community, despite the challenge associated with this submission. Our long-term business strategy has always been to extend our leadership in sleep/wake through the development of Pitolisant HD, an enhanced and higher-dose formulation, which represents the more significant opportunity in IH given its optimized profile and provisional patent filed out to 2044. We are on track to initiate a Phase 3 registrational trial of Pitolisant HD in IH in Q4 2025, with a target PDUFA date in 2028.”

REFERENCES

1. Harmony Biosciences Provides Update on the Status of the Supplemental New Drug Application for Pitolisant in Idiopathic Hypersomnia. News release. Harmony Biosciences. February 19, 2025. https://www.businesswire.com/news/home/20250219512387/en/Harmony-Biosciences-Provides-Update-on-the-Status-of-the-Supplemental-New-Drug-Application-for-Pitolisant-in-Idiopathic-Hypersomnia

2. 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. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-announces-topline-data-from-phase-3-intune-study