Three years after its European approval, U.S. clearance for the narcolepsy drug Wakix (pitolisant) has arrived. Privately held Harmony Biosciences LLC will market the once-daily medicine, licensed from Bioprojet Societe Civile de Recherche, for the treatment of excessive daytime sleepiness (EDS) in adults with the chronic sleep disorder.

The project was shepherded by a team at Harmony's Plymouth Meeting, Pa.-based headquarters, near Philadelphia, "a region that has had a history of companies that have been innovating and bringing forward unique CNS therapies, especially in sleep," Harmony CEO John Jacobs, told BioWorld.

Noting a label in line with expectations, SVB Leerink analyst Ami Fadia said she saw no "meaningful threat" to Jazz Pharmaceuticals plc's sleep franchise in light of "relatively lighter efficacy" vs. Jazz's recently approved EDS drug, Sunosi (solriamfetol), but did see a potential for Wakix to "expand the treated patient pool" in light of good tolerability and minimal interaction with the current standard of care for EDS, modafinil and Xyrem (sodium oxybate, Jazz).

Shares of Jazz (NASDAQ:JAZZ) fell 1.5% to $131.39 on Thursday amid a down day for the composite.

Wakix represents a first-in-class approval in the U.S. that, in contrast to Sunosi, will be not be scheduled by the Drug Enforcement Agency. Speaking to what that means for Wakix, Harmony's chief medical officer, Jeffrey Dayno, told BioWorld that "especially in the current climate, in terms of the public health issue of prescription drug abuse, it gives physicians a level of comfort in the overall product profile." (See BioWorld, March 22, 2019.)

Both Jacobs and Dayno were involved with the development of Provigil (modafinil) and Nuvigil (armodafinil).

As in the EU, the U.S. label for Wakix includes a warning about QT prolongation, suggesting that risk of the condition may be greater in patients with hepatic or renal impairment. Overall, though, Leerink's Fadia called the drug's label clean.

Pricing for Wakix will be determined over the next several weeks ahead of expected commercial availability in the fourth quarter. Baseline costs for the regulatory win aren't wholly clear, as Harmony is privately held. But Jacobs said that a substantial portion of the $270 million the company raised on the occasion of its October 2017 public debut went to licensing the product. The company declined to say whether an additional milestone payment was triggered by the FDA approval or whether royalties would be due Bioprojet.

Cataplexy quest curtailed

Despite a breakthrough therapy designation for cataplexy, a type of sudden muscle weakness common among people with narcolepsy, the FDA declined to add that indication to the label, an outcome Jacobs called disappointing in light of data indicating the drug's benefit for that condition. On the bright side, the agency outlined a confirmatory study that could support its addition, something he said his team will pursue "assertively and aggressively."

Wakix also received both fast track and orphan status in the U.S., where narcolepsy remains rare, with a prevalence of 0.05% in the general population.

The exact mechanism of action of the drug is unclear, though it is understood to up-regulate histamine – a major wake-promoting neurotransmitter – in the brain, thus reducing EDS. By contrast, EDS drugs such as modafinil and armodafinil are stimulants, while Sunosi is a dual-acting dopamine and norepinephrine reuptake inhibitor. Wakix could be "potentially additive or synergistic to complement those other medications," Dayno said, noting the benefits it delivered in various combinations observed in the long-term open-label study, Harmony 3.

Wakix was also evaluated in two double-blind, placebo-controlled studies, Harmony 1 and Harmony 1bis, including 261 participants randomized to receive Wakix, placebo or an active control. About three-quarters of them had a history of cataplexy. In both studies, Wakix demonstrated a statistically significant improvement in EDS as measured by the Epworth Sleepiness Scale score.

In patients with narcolepsy with or without cataplexy, the most common adverse reactions to Wakix were insomnia (6%), nausea (6%) and anxiety (5%).

Harmony was founded with $270 million in equity financing from Bioprojet, Fidelity Management and Research Co., HBM Healthcare Investments, Nan Fung Life Sciences, Novo Holdings, Paragon Biosciences LLC, Valor Equity Partners, Venbio Partners and Vivo Capital. In 2018, the company raised an additional $25 million from Aisling Capital and Soros Fund Management to further support registration and commercial development of pitolisant.

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