FDA Won’t Review Harmony’s Application to Expand Wakix to IH

Rare Daily Staff

The U.S. Food and Drug Administration said it would not review Harmony Biosciences’ application to expand the approved uses of its narcolepsy drug pitolisant to include idiopathic hypersomnia, a rare and chronic neurological disease characterized by excessive daytime sleepiness.

Harmony said it did not alter its 2025 net revenue guidance of $820 million to $860 million following the agency’s refusal-to-file letter, which is when the FDA considers an application incomplete.

People with idiopathic hypersomnia (IH) experience sleepiness during the daytime despite sufficient or even long sleep time. In addition to sleepiness, people with IH experience prolonged difficulty waking up from sleep and impaired cognition, attention, and alertness. The cause of IH is unknown, but it is likely due to alterations in areas of the brain that stabilize states of sleep and wakefulness.

WAKIX, a first-in-class medication, is approved by the FDA for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy and the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy. It was granted 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 receptor antagonist/inverse agonist. The mechanism of action of Pitolisant is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake-promoting neurotransmitter. WAKIX was designed and developed by Bioprojet. Harmony has an exclusive license from Bioprojet to develop, manufacture, and commercialize pitolisant in the United States.

The company said that despite the challenges associated with its submission, it decided to apply to expand the use of pitolisant to include IH because of the overall benefit-risk profile in people with the condition.

Although the primary outcome for excessive daytime sleepiness between pitolisant and placebo did not reach statistical significance in the randomized withdrawal phase of the phase 3 INTUNE study in people with IH, the company said the data from the open-label phase showed that patients experienced improvements on the Epworth Sleepiness Scale that were five times greater than what is recognized as clinically meaningful. It also said the majority of patients in the long-term extension study achieved normal levels of wakefulness and sustained this response beyond one year.

“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,” said Jeffrey Dayno, president and CEO of Harmony Biosciences.

He said the company’s long-term business strategy has always been to extend its leadership in sleep/wake through the development of Pitolisant HD, an enhanced and higher-dose formulation. He said Harmony is on track to initiate a phase 3 registrational trial of Pitolisant HD in IH in fourth quarter of 2025. That would put the company for a potential FDA approval in 2028.

Photo: Jeffrey Dayno, president and CEO of Harmony Biosciences