Pitolisant earns FDA orphan drug status ahead of Phase 3 trial

Trial of safety, efficacy for daytime sleepiness to start this month

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to Harmony Biosciences’ pitolisant to treat daytime sleepiness in people with Prader-Willi syndrome (PWS).

Orphan drug status is meant to incentivize the development of treatments for rare diseases, or those affecting fewer than 200,000 people in the U.S. It comes with tax credits for clinical trials, waived regulatory fees, and seven years of marketing exclusivity if the therapy is approved.

“The decision to grant orphan drug designation to pitolisant indicates that it could be a promising treatment option for people living with Prader-Willi syndrome,” Kumar Budur, MD, chief medical officer at Harmony, said in a company press release.

“This designation marks an important step forward in our PWS development program, and we are eager to continue working with the FDA and the broader community of PWS patients and caregivers to address their high unmet medical needs,” Budur said.

The company is preparing to launch a Phase 3 clinical trial, TEMPO, to assess pitolisant’s safety and efficacy for treating excessive daytime sleepiness (EDS) and behavioral disturbances in PWS patients, 6 and older. Harmony expects to start the study this month. If results are positive, the company will use them to back applications for regulatory approval of the oral therapy.

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Pitolisant Eases Daytime Sleepiness In Children, Adults With PWS: Top-Line Data

Using histamine to promote wakefulness

Some 15,000 to 20,000 people in the U.S. are living with PWS, a rare disease affecting many genes involved in metabolism, appetite, growth, social behaviors, and cognitive abilities. Most patients develop behavioral problems, and more than half experience EDS.

EDS is thought to arise from dysfunction of a brain region called the hypothalamus. Pitolisant, originally developed by France’s Bioprojet, is designed to work by increasing the release of histamine, a molecule that promotes wakefulness, in the hypothalamus.

Pitolisant is approved in the U.S. under the brand name Wakix for treating EDS or sudden loss of muscle tone in adults with narcolepsy, a sleep disorder.

A proof-of-concept Phase 2 trial (NCT04257929) was launched in 2020 to investigate pitolisant’s safety and efficacy in PWS patients, 6 and older, who were experiencing EDS.

Some 65 patients were enrolled and randomly assigned to receive a once-daily oral tablet of one of two doses of the investigational oral therapy or a placebo for 11 weeks.

Top-line data showed pitolisant led to clinically meaningful reductions in EDS across all doses and age groups, with the strongest reductions in children ages 6-11. The treatment was also associated with greater reductions relative to a placebo in caregiver-reported EDS severity, insatiable hunger — a hallmark PWS symptom — and behavioral abnormalities.

Safety findings were consistent with the known side effects of pitolisant, the most common being anxiety, irritability, and headache.

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Most patients enter open-label extension phase to receive pitolisant daily

Most patients completing the trial’s placebo-controlled phase chose to enter its open-label extension phase, where all will receive daily pitolisant for several years.

While the Phase 2 trial was not designed to detect statistically significant changes in clinical measures between pitolisant and placebo groups, it did support the launch of the larger Phase 3 trial.

TEMPO will enroll up to 134 PWS patients, Harmony said in a recent presentation. Participants will be randomly assigned to receive daily oral pitolisant or a placebo for 11 weeks, followed by a one-year extension study in which all will receive the therapy.

The main goal is to evaluate pitolisant’s effects on EDS severity, with secondary goals related to behavioral changes.

“We are excited about our upcoming Phase 3 TEMPO study and the progress we have made to broaden the clinical utility of pitolisant,” Budur said.