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FDA Grants Pitolisant Breakthrough, Fast Track Designations in Narcolepsy

The FDA has granted a Breakthrough Therapy and Fast Track Designation to pitolisant for cataplexy in patients with narcolepsy, as Harmony Biosciences prepares a new drug application for the drug.

Michael Thorpy, MD

The FDA has granted a Breakthrough Therapy and Fast Track Designation to pitolisant as a potential treatment for cataplexy in patients with narcolepsy, according to a statement from Harmony Biosciences, the company developing the small molecule inhibitor.

In a 106-patient, phase III study, pitolisant was shown to be well tolerated and efficacious in reducing cataplexy in patients with narcolepsy. The weekly cataplexy rate with pitolisant was decreased by 75% from baseline compared with a decrease of 38% with placebo (rate ratio, 0.512; 95% CI, 0.43-0.60; P <.0001). In a post-hoc analysis, this benefit remained consistent across all patient subgroups.

Based on these data, Harmony Biosciences is preparing a new drug application (NDA) for pitolisant as a treatment for patients with narcolepsy. While the NDA is prepared, the company also announced that they were opening the Pitolisant Expanded Access Clinical Evaluation (PEACE) program. As part of the Expanded Access Program (EAP), pitolisant will be accessible to adults in the United States with excessive daytime sleepiness associated with narcolepsy, with or without cataplexy as a symptom.

Michael Thorpy, MD, a professor of neurology at Albert Einstein College of Medicine, and the director of the Sleep-Wake Disorders Center at Montefiore Medical Center in New York City, is serving as the principal investigator on the EAP for pitolisant. He said in a statement that the program will give physicians in the United States an opportunity to gain clinical expertise with a “first-in-class investigational product that works through the histaminergic system to improve wakefulness and inhibit attacks of cataplexy.”

“I am pleased that Harmony Biosciences is making this program available while working on the NDA, as the data suggest that pitolisant could represent a new treatment option which is much needed for our patients with narcolepsy,” he added.

In the phase III study, patients were randomized to receive pitolisant (n = 54) or placebo (n = 51). The median number of cataplexy attacks per week at baseline was 11 in the pitolisant arm compared with 9.2 for placebo. Mean sleep latency was similar in both groups, at approximately 4.5 minutes. Epworth Sleepiness Scale (ESS) score was near 17 in both groups.

There were significant improvements in ESS with pitolisant, with a change of -5.4 for the investigation drug compared with -1.9 with placebo (rate ratio, -3.48; P = .0001). Similar improvements were seen in maintenance of wakefulness test (MWT), with a 1.95-minute improvement with pitolisant compared with 1.06 minutes for placebo (P = .003). Sixty-seven percent of patients in the pitolisant arm had an improvement cataplexy by clinical global impression of change compared with 33% for placebo.

The total number of adverse events did not differ significantly between the pitolisant arm (31%) and placebo (35%). The most frequent adverse events were headache for both treatment groups. In the pitolisant arm, patients also experienced irritability, anxiety, and nausea. Those in the placebo arm had somnolence. Treatment-related adverse events were experienced by 28% of those in the pitolisant group and for 12% in the placebo arm.

“Receiving Breakthrough and Fast Track designations for pitolisant from FDA is welcome news as narcolepsy patients face many challenges,” said Bob Repella, Harmony’s CEO. “As stated in FDA’s Voice of the Patient report on Narcolepsy, it is a debilitating disease that can severely affect a patient’s day-to-day functioning and have a devastating impact on their lives.”

Pitolisant is the first of the histamine H3 receptor-antagonist/inverse agonist class—working by enhancing the histaminergic neurons in the brain. It received approval by the European Medicines Agency in 2016. The goal for approval in the United States is 2019 for patients with narcolepsy.

“We are very pleased that the FDA has granted pitolisant Breakthrough Therapy and Fast Track designations and believe it reflects the Agency’s interest in this investigational product to potentially address an important unmet medical need for patients with narcolepsy,” Jeffrey Dayno, MD, the chief medical officer at Harmony, said in a statement. “We look forward to working with the FDA throughout the submission and review of an NDA for this first-in-class molecule with a novel mechanism of action to treat adult patients with narcolepsy with or without cataplexy.”

Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neuro. 2017;16(3):200-207.