Pitolisant, an agent that originally received FDA-approval in 2019 to treat excessive daytime sleepiness in narcolepsy, will have efficacy and safety evaluated in a cohort of 200 patients with idiopathic hypersomnia.
A newly initiated phase 3 study, dubbed INTUNE (NCT05156047), will evaluate the efficacy and safety of pitolisant (Wakix; Harmony Biosciences) in patients with idiopathic hypersomnia (IH), a condition that currently has only 1 FDA-approved medication, the company announced.1
Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is already FDA-approved to treat excessive daytime sleepiness (EDS) and cataplexy in adults with narcolepsy. INTUNE, a double-blind, placebo-controlled, randomized, withdrawal study that spans across 60 to 80 sites in the US, will include approximately 200 patients with IH.
"There has been much interest by both the patient community and healthcare professionals in pitolisant for the treatment of IH and we are excited about the initiation of our phase 3 INTUNE study in adult patients with this rare neurological disorder," Jeffrey Dayno, MD, chief medical officer, Harmony, said in a statement.1 "Given the novel mechanism of action of pitolisant, which works through histamine, an important wake-promoting neurotransmitter in the brain, we are looking to translate innovative science into therapeutic possibilities that have the potential to improve the health of people living with IH."
The primary outcome measure of the trial will be the Change in Epworth Sleepiness Scale (ESS) score for pitolisant compared with placebo. In addition to evaluating efficacy and safety as the primary objective, investigators will also assess the impact of pitolisant on other symptoms of IH, such as sleep inertia and cognitive impairment. Other outcomes, including patient impression of overall change in symptoms, investigator assessment of overall disease activity, and functional status will also be evaluated in the study. These assessments will be measured via the Patient Global Impression of Change and Severity scales, the functional outcomes of the Sleep Questionnaire 10-item version, the Sleep Inertia Questionnaire, and the Cogstate One Back Test, among others.
Designed to increase the synthesis and release of wake-promoting histamine, pitolisant remains the only FDA-approved treatment for both EDS and cataplexy in narcolepsy that is not a scheduled controlled substance. It was first approved for EDS in 2019 and later for cataplexy in the following year.
"Our mission and values are centered around both supporting people with hypersomnias like IH and scientific discovery," David Burley, board chair, Hypersomnia Foundation, said in a statement.1 "We are excited Harmony is moving forward with a phase 3 clinical trial in people with idiopathic hypersomnia, which may bring us one step closer to finding an important therapeutic advancement for a community with limited treatment options."
For years, patients with IH had no approved treatment options, until the FDA approved JZP-258 (Xywav; Jazz Pharmaceuticals) in August 2021.2 The combination of calcium, magnesium, potassium, and sodium oxybates was greenlit using data from a positive phase 3 study (NCT03533114) in which the agent was shown to be effective and safe for those with IH. JZP-258 has a Boxed Warning as a central nervous system depressant and for its potential for abuse and misuse.
Pitolisant, on the other hand, had its indication expanded based on results from the HARMONY CTP (NCT018000450) and HARMONY 1 (NCT01067222) randomized, controlled clinical trials. The results of these trials were reanalyzed after the FDA originally issued Harmony a complete response letter in August 2019 regarding the data supporting pitolisant. Results from the CTP study demonstrated a 75% reduction in weekly cataplexy rate in patients taking pitolisant compared with 38% in patients in the placebo group (rate ratio 0.512; 95% CI, 0.43-0.60, P< .0001).3 Post hoc analyses from the HARMONY 1 trial showed that pitolisant was superior to placebo but not noninferior to modafinil for improvement in cataplexy rate from baseline.4