FDA Rejects Harmony's Wakix Expansion Bid for Idiopathic Hypersomnia

The U.S. Food and Drug Administration (FDA) has dealt a significant blow to Harmony Biosciences' plans to expand the use of its excessive daytime sleepiness (EDS) medication, Wakix (pitolisant). The agency issued a Refusal to File (RTF) letter in response to Harmony's supplemental New Drug Application (sNDA) seeking approval for Wakix in the treatment of EDS associated with idiopathic hypersomnia (IH).

Failed Phase 3 Study Derails Expansion Plans

The FDA's decision comes on the heels of Harmony's phase 3 INTUNE study, which failed to meet its primary endpoint. While the randomized withdrawal phase of the study did not demonstrate statistical significance compared to placebo, Harmony maintains that the open-label portion of the trial showed improvements "five times greater than what is recognized as clinically meaningful."

Despite this setback, Harmony CEO Jeffrey M. Dayno, M.D., defended the company's decision to submit the sNDA, citing their belief in pitolisant's overall benefit-risk profile in IH and their commitment to the patient community.

Shifting Focus to Higher-Dose Formulation

In light of the FDA's rejection, Harmony is pivoting its strategy towards pitolisant HD, a higher-dose formulation of the original drug. The company views this as a "more significant opportunity" in the IH market and plans to initiate a new phase 3 study in the fourth quarter of 2025, with a target FDA decision date in 2028.

Dr. Kumar Budur, Harmony's chief medical and scientific officer, emphasized that the design of this upcoming study incorporates FDA input and aims to "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."

Market Implications and Competition

Wakix, first approved in 2019 for EDS with narcolepsy and later for cataplexy in narcolepsy patients, faces stiff competition in the sleep disorder market. Jazz Pharmaceuticals' Xywav, the first drug approved for IH, remains a dominant force in this therapeutic area. In 2024, Xywav generated $1.35 billion in sales, while Harmony reported full-year revenues of $714 million for Wakix.

Harmony's pursuit of the IH indication for Wakix is particularly significant, as it would directly challenge Xywav in this space. Notably, Wakix holds a potential advantage over Jazz's offerings, as it is not classified as a controlled substance, unlike Xywav and its predecessor Xyrem, which contain gamma-hydroxybutyrate (GHB) and are subject to restricted distribution due to abuse potential.