Harmony Biosciences faces FDA setback for pitolisant in idiopathic hypersomnia

Harmony Biosciences Holdings, Inc. has encountered a regulatory hurdle in its efforts to expand the use of pitolisant for the treatment of excessive daytime sleepiness in adult patients with idiopathic hypersomnia treatment. The company announced that the U.S. Food and Drug Administration (FDA) issued a Refusal to File (RTF) letter for its supplemental new drug application (sNDA), meaning the submission did not meet the FDA’s requirements for a formal review. While this represents a short-term setback, Harmony Biosciences remains committed to its broader strategic vision, particularly with the development of Pitolisant HD, a higher-dose formulation that could significantly impact idiopathic hypersomnia treatment.

Why Did the FDA Reject Harmony Biosciences’ Pitolisant sNDA for Idiopathic Hypersomnia?

The FDA’s refusal to file the sNDA suggests that the agency identified deficiencies in the application that prevent it from proceeding to a full review. Harmony Biosciences has not disclosed the exact issues raised by the FDA but stated that this decision does not impact its financial guidance or its long-term plans for Pitolisant HD development.

Pitolisant, which is marketed as WAKIX, is already approved in the United States for the treatment of excessive daytime sleepiness and cataplexy in adult patients with narcolepsy. It also holds regulatory approval for pediatric narcolepsy treatment in patients aged six and older. However, the drug has not yet been approved for idiopathic hypersomnia treatment, a neurological condition that causes chronic excessive daytime sleepiness without an underlying cause such as narcolepsy or sleep apnea.

Jeffrey M. Dayno, M.D., President and Chief Executive Officer of Harmony Biosciences, expressed disappointment over the FDA’s decision but reaffirmed the company’s commitment to advancing pitolisant as a treatment for idiopathic hypersomnia. He stated that the company had submitted the sNDA based on its confidence in the drug’s benefit-risk profile and its commitment to serving the needs of patients with sleep disorders.

What Is Pitolisant HD and How Does It Differ from the Current Treatment?

Rather than focusing solely on the rejected sNDA, Harmony Biosciences is shifting its attention to Pitolisant HD development, which represents a more significant opportunity in idiopathic hypersomnia. This higher-dose formulation is designed to optimize pitolisant’s therapeutic effects, potentially providing a more effective idiopathic hypersomnia treatment. The company has already filed a provisional patent for Pitolisant HD, extending its exclusivity until 2044.

Harmony Biosciences plans to initiate a Phase 3 registrational trial for Pitolisant HD in the fourth quarter of 2025. This trial will be a double-blind, randomized, parallel-group study, following input from the FDA to ensure it meets regulatory standards. The goal of this study is to provide robust clinical evidence supporting pitolisant’s efficacy in idiopathic hypersomnia, addressing some of the concerns that arose from previous clinical trials.

What Do Clinical Studies Say About Pitolisant’s Effectiveness in Idiopathic Hypersomnia?

Previous research on pitolisant in idiopathic hypersomnia has produced mixed results. The Phase 3 INTUNE Study, which evaluated pitolisant’s effectiveness, failed to achieve statistical significance in its primary outcome for excessive daytime sleepiness during the randomized withdrawal phase. However, open-label data from the same study indicated that patients experienced substantial improvements on the Epworth Sleepiness Scale, a widely used measure of daytime sleepiness. These improvements were five times greater than what is generally considered clinically meaningful.

Additionally, data from a long-term extension study showed that most patients who continued pitolisant treatment maintained normal wakefulness levels for over a year. Despite these positive findings, the lack of statistical significance in the randomized withdrawal phase may have contributed to the FDA’s decision to issue an RTF letter rather than proceed with the application.

Kumar Budur, M.D., M.S., Chief Medical and Scientific Officer at Harmony Biosciences, emphasized that the upcoming Phase 3 registrational trial for Pitolisant HD is designed to build upon previous findings, ensuring that the study is robust enough to demonstrate the drug’s benefits for idiopathic hypersomnia treatment.

What Are the Next Steps for Harmony Biosciences in Idiopathic Hypersomnia Treatment?

Despite the regulatory setback, Harmony Biosciences remains confident in its ability to advance pitolisant-based treatments. The company’s 2025 net revenue guidance of $820-$860 million remains unchanged, indicating that it does not expect the FDA’s decision to impact its overall financial performance.

The company’s next priority is launching the Phase 3 registrational trial for Pitolisant HD, which will provide the necessary data to support a future regulatory submission. If successful, Harmony Biosciences aims for a target PDUFA date in 2028, when the FDA could potentially approve the drug for idiopathic hypersomnia treatment.

Meanwhile, WAKIX continues to be marketed in the U.S. for its approved indications in narcolepsy, offering patients an alternative treatment for excessive daytime sleepiness and cataplexy. However, for those suffering from idiopathic hypersomnia, an FDA-approved treatment with pitolisant remains unavailable.

Harmony Biosciences’ FDA refusal to file its sNDA for pitolisant in idiopathic hypersomnia presents a challenge, but the company remains committed to advancing its sleep disorder portfolio. With Pitolisant HD development now taking center stage, the company is focusing on providing stronger clinical evidence to support the drug’s efficacy in idiopathic hypersomnia.

While the regulatory process may delay the availability of pitolisant for idiopathic hypersomnia treatment, Harmony Biosciences’ long-term vision remains intact. The upcoming Phase 3 registrational trial for Pitolisant HD represents a crucial step in securing FDA approval, positioning the company for future growth in the sleep disorder treatment market.