On August 14, 2019, the FDA approved Harmony Biosciences’ WAKIX® (pitolisant) tablets, for treatment of excessive daytime sleepiness in adults with narcolepsy. The FDA granted Orphan Drug, Breakthrough Therapy, and Fast Track designations for pitolisant. Key findings from the FDA’s Clinical Review(s) and Other Review(s):
The applicant demonstrated efficacy of pitolisant for the reduction of daytime sleepiness among patients with narcolepsy in two adequate and well-controlled phase 3 studies, HARMONY I (P07-03) and HARMONY I-bis (P09-15). In addition, the reviewer analyzed the safety endpoints of death and serious adverse events (SAEs) across the entire development program (all indications), the European post-authorisation safety study (PASS), the European Compassionate Use Program (CUP), and the U.S. Expanded Access Program (EAP). Based on review of safety data provided for the current reporting period, as well as review of post-marketing reports from foreign exposure, there are no new safety signals or issues to the established safety profile of pitolisant.
The safety review focused primarily on three phase 3 narcolepsy studies that compared pitolisant to placebo─HARMONY I (P07-03), HARMONY I-bis (P09-15), and additionally HARMONY CTP (P11-05). The reviewer also examined adverse events for HARMONY III (P09-10), the open-label, long-term safety study in patients with narcolepsy, and for HARMONY IV (P10-01), which evaluated the safety and efficacy of pitolisant versus placebo as an add-on to sodium oxybate. In addition, the reviewer examined deaths and SAEs across the entire development program (all indications), the European PASS, the European CUP, and the U.S. EAP.
What was done
- European PASS: Pitolisant was authorized by the EMA on March 31, 2016, so post-marketing data from Europe (gathered from the FDA Adverse Event Reporting System (FAERS), Vigibase, and EudraVigilance databases) were also considered in this review, as were the EMA label and the EMA Public Assessment Report. The reviewer examined the line listing of adverse events in the EudraVigilance database for years 2016 to 2019, and individual safety report forms for potentially life-threatening events, psychiatric adverse events, hepatic effects, cardiovascular events, and seizures and convulsions. In addition, the Division of Pharmacovigilance (DPV) within the Office of Surveillance and Epidemiology assisted with a comprehensive review of the post-marketing data.
The ongoing European PASS (Study P15-11), which will follow patients for five years, had enrolled 279 patients out of a planned 300. No SAEs were reported in the PASS at the time of NDA submission. Two patients with narcolepsy reported seizures in PASS study after the NDA cut-off date.
- European CUP: Although fully authorized throughout the EU, patients in Spain, the Netherlands, and Switzerland have access to pitolisant via the CUP. At the time, two SAEs of pregnancy were reported in patients with narcolepsy.
- U.S. EAP: At the time, the U.S. EAP provided pitolisant to 366 patients; 86 patients had completed at least six months of treatment; in a single patient, the maximum exposure duration was 10 months. 309 patients completed the titration to the 40 mg (35.6 mg) dose. Five patients with narcolepsy experienced SAEs; three of the SAEs were psychiatric adverse events.
- Literature Review: The applicant and the Division of Pediatric and Maternal Health (DPMH) also conducted a review of a published literature and no data with regard to pitolisant exposure during pregnancy were found.
Neither the FDA reviewer nor the DPV identified any new or unexpected safety signals; however, the DPV noted that the total patient exposure to pitolisant is still low.
Limited information about the use of pitolisant in pregnancy is available, so the DPMH recommended a prospective and observational pregnancy registry as well as an additional complimentary pregnancy study that uses a different design from the registry (e.g., case control or a retrospective study using claims or electronic medical records with outcome validation). In addition, the DPMH recommended a post-marketing lactation study.