Harmony Biosciences, LLC (Harmony) presented new data on pitolisant at the 7 th International Symposium on Narcolepsy in Beverly, MA. Pitolisant is an investigational product that has been studied for the treatment of both excessive daytime sleepiness (EDS) and cataplexy in adult patients with narcolepsy. Long term data (up to 5-years) from the Harmony III open-label, naturalistic study were presented in a platform presentation. These data assessed the safety, tolerability and durability of effect of pitolisant, the first potent and highly selective histamine 3 (H3 ) receptor antagonist/inverse agonist. If approved, pitolisant would represent the first new therapy in the U.S. in over a decade for the treatment of both EDS and cataplexy in patients with narcolepsy.
“The Harmony III open-label, long-term study for pitolisant reflects real-world experience of people living with the debilitating effects of excessive daytime sleepiness and cataplexy in narcolepsy,” said Harmony’s Chief Medical Officer, Jeffrey Dayno, M.D. “Pitolisant is a first-in-class molecule with a novel mechanism of action that works through the histaminergic system to improve wakefulness and inhibit attacks of cataplexy. In an extension of the Harmony III long-term study, the safety, tolerability and durability of effect of pitolisant were assessed out to five years in those patients who stayed in the study until the end.”
Patients (n=77) from the French sites in the Harmony III trial were invited to participate in the extension period up to 5 years with follow-up visits every 6 months. Among this cohort, 50 patients (65%) completed the first 12 month period, 48 elected to participate in the extension period, and 32 of those (67%) stayed on pitolisant treatment for 5 years or until the study ended. Eighty to 88% of patients were maintained on pitolisant 40 mg once daily during the study.
Summary findings for the study concluded:
Maintenance of effect for pitolisant in improving EDS was demonstrated using the Epworth Sleepiness Scale (ESS); baseline ESS was 16.8, decreased to 13.4 at year 1, then continued to improve over the course of the study with an ESS of 10.6 at year 5
Symptoms of REM dysregulation were reduced from baseline to year 1 as follows: cataplexy (-76%), hypnagogic hallucinations (-54%) and sleep paralysis (-62%); limited data from patient diaries were available at year 5 to assess these symptoms
The safety and tolerability profile of pitolisant was demonstrated to be consistent with that reported in the randomized controlled trials for pitolisant; common adverse events were headache, insomnia, weight increase, anxiety, depression, nausea, vomiting and irritability; 16% of patients discontinued treatment due to adverse events
There was no evidence of the development of tolerance with long-term use of pitolisant and there were no reports of symptoms related to withdrawal when patients discontinued treatment with pitolisant
Pitolisant is an investigational medication in the U.S. that is not approved by the FDA. It was granted orphan designation for the treatment of narcolepsy, Fast Track designation for the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy, and Breakthrough Therapy designation for the treatment of cataplexy in patients with narcolepsy. Pitolisant is the first potent and highly selective histamine 3 (H 3 ) receptor antagonist/inverse agonist; it enhances the activity of histaminergic neurons in the brain that function to improve a patient’s wakefulness and inhibit attacks of cataplexy. It was developed by Bioprojet who has marketed the product in Europe since its approval by the European Medicines Agency in 2016. The receipt of Breakthrough Therapy and Fast Track designations for pitolisant afforded Harmony the opportunity to request a rolling NDA submission to the FDA, which was granted. Harmony’s goal is to obtain FDA approval to market this new medication in the U.S. in 2019. If approved, pitolisant would represent the first new therapy in the U.S. in over a decade for the treatment of both excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy.
Narcolepsy is a rare, chronic, debilitating neurologic disorder of sleep-wake state instability that impacts up to 200,000 Americans and is primarily characterized by excessive daytime sleepiness, cataplexy, and other manifestations of REM sleep dysregulation, which intrude into wakefulness. In most patients, it is caused by the loss of hypocretin, a neuropeptide in the brain that supports sleep-wake state stability. This disorder affects men and women equally with typical symptom onset in adolescence or young adulthood; however, it can take up to a decade to be properly diagnosed. Narcolepsy can cause significant burden on patients and their families, affecting their ability to perform routine tasks, limit achievement at school and work, impact social relationships and cause impairment in overall quality of life.
Cataplexy is one of several symptoms of narcolepsy that represent elements of REM sleep state intruding into wakefulness, characterized by sudden temporary loss of muscle tone. Cataplexy can be subtle, such as drooping of eyelids, or severe, such as knee buckling or total body collapse. Often times, symptoms of cataplexy may go unrecognized because of the subtle nature of the symptoms in some patients, variability of how cataplexy is expressed, and/or lack of patient complaints or physician recognition of the symptoms as manifestations of cataplexy. This symptom of narcolepsy can often cause significant impact on a person’s ability to carry out normal daily functions. Up to two-thirds of all narcolepsy patients have cataplexy (known as Type 1 narcolepsy); cataplexy is one of the most debilitating symptoms of this chronic, rare neurologic disorder.