A comprehensive interim analysis from a long-term European post-authorization safety study has provided robust real-world evidence supporting the continued use of pitolisant (Wakix; Harmony Biosciences) in narcolepsy patients, with data spanning 42.6 months of follow-up across 370 patients with narcolepsy types 1 and 2.
Study Population and Design
The analysis, published in Sleep Medicine, included 370 patients with narcolepsy (mean age 40 ±15 years; 51.4% women), with 71.4% diagnosed with narcolepsy type 1 (NT1) and 28.6% with narcolepsy type 2 (NT2). Of these patients, 364 received at least one dose of pitolisant, with safety data available for 356 patients (97.8%).
The study revealed significant comorbidity burden, with 68.4% of patients reporting at least one comorbid condition. Obesity was the most common comorbidity, affecting 31.9% of patients, followed by neuropsychiatric conditions (31.0%) and cardiovascular comorbidities (22.8%).
Treatment Patterns and Dosing
Prior to pitolisant treatment, 13.2% of participants had received no narcolepsy treatment, while 31% switched from a previous therapy. Most patients (69%) received pitolisant in combination with other treatments, reflecting real-world clinical practice patterns.
The target optimal dose of 36 mg daily was reached by 37.4% of patients. As lead author Giuseppe Plazzi, MD, PhD, professor of neurology at the University of Modena and Reggio Emilia, and colleagues noted, this "suggesting that physicians are cautious in the use of the maximum daily dosage when the drug is first marketed and indicating that the dose can be increased to 36 mg."
Safety Profile and Discontinuation Rates
During the study period, 35.4% of patients discontinued treatment. The primary reasons for discontinuation were safety concerns (14.3%), lack of response (8.7%), and patient decision (7.6%). A total of 355 treatment-emergent adverse events (AEs) were reported among 156 patients (42.9%), with 218 events in 109 patients considered possibly related to treatment (29.9%). Three serious adverse events occurred during the study.
Importantly, no typical withdrawal symptoms were detected upon abrupt discontinuation of pitolisant, supporting its favorable safety profile.
Unique Mechanism and Abuse Potential
The study confirmed previous clinical observations regarding pitolisant's lack of abuse potential, making it the only narcolepsy treatment approved in the United States that does not appear on the list of controlled substances.
"This may be explained by the mode of action of pitolisant, which increases the activity of brain histaminergic neurons but does not increase dopamine levels in the nucleus accumbens," the authors explained. "By blocking the H3 receptor, pitolisant increases histaminergic release in a dose-dependent manner; it is the first H3 receptor inverse agonist proposed for use in clinical practice."
Clinical Outcomes
The study demonstrated improvements in excessive daytime sleepiness, cataplexy, and overall quality of life, with noted good adherence and patient satisfaction. These findings align with the drug's established mechanism of action as an H3 receptor inverse agonist that enhances histaminergic neurotransmission.
Study Limitations and Clinical Context
The researchers acknowledged several limitations, including patient discontinuation, the absence of a comparator group, the use of concomitant treatments, and dose adjustments. However, the data were collected from national sleep centers with experience in narcolepsy research and reflect routine clinical practice.
Compared with earlier studies such as HARMONY 3, this analysis provided a longer follow-up period, offering valuable insights into the long-term real-world performance of pitolisant in narcolepsy management. The results suggested that pitolisant was generally well tolerated and associated with sustained improvements in excessive daytime sleepiness and cataplexy over extended treatment periods.
