Phase 3 Study of Pitolisant in Prader-Willi Syndrome Updates Following Positive FDA Meeting


Harmony aligned with the FDA on the proposed phase 3 design elements, which is expected to kick off later this year.

Kumar Budur, MD, chief medical officer at Harmony Biosciences

Kumar Budur, MD

According to a recent announcement from Harmony Biosciences, the company has successfully completed an end-of-phase 2 meeting with the FDA, and plans to initiate its phase 3 study assessing pitolisant (Wakix), an approved medication for excessive daytime sleepiness (EDS), in individuals with Prader-Willi syndrome (PWS) in the 4th quarter of 2023.

The meeting was in reference to its recently completed phase 2, proof-of-concept study in which treatment with the agent resulted in reduced EDS in patients with PWS over an 11-week treatment period. The new study will incorporate design elements to further support investigation of pitlosant for children, adolescents, and adults with the condition experiencing EDS.

"We are pleased with the outcome of our End-of-Phase 2 meeting with the FDA as we prepare to initiate our Phase 3 registrational study, which aims to further investigate the efficacy and safety of pitolisant as a potential treatment for excessive daytime sleepiness in individuals with Prader-Willi syndrome," Kumar Budur, MD, chief medical officer at Harmony Biosciences, said in a statement.1 "Building upon the encouraging data obtained from our Phase 2 signal detection study, we remain committed to advancing our development program for pitolisant in pursuit of a new indication in people with PWS, given the high unmet medical need in this population."

PWS is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone, a weak suck and feeding difficulties with poor weight gain and growth, and other hormone deficiency. Besides human growth hormone, there are no FDA-approved products to treat the syndrome, and no specific approved products to treat EDS associated with it.

Budur presented the phase 2 findings at the recently concluded 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana. The trial included patients with genetically confirmed PWS, aged 6-65 years, who were randomly assigned 1:1:1 to either low dose pitolisant, high dose pitolisant, or matching placebo based on age. Investigators used mean scores on the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a validated measure of sleep propensity, as the primary end point.

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Findings showed that in the overall patient population, mean improvement in ESS-CHAD score was greater for both pitolisant dose groups compared with placebo at the end of the 11-week period. Patients in the higher and lower dose treated groups experienced mean changes of –4.9 and –4.1, respectively, compared with changes of –3.7 for those on placebo. At week 11, 70.0% and 55.6% of high (n = 20) and low dosed (n = 18) pitolisant groups, respectively, were considered responders, compared with 52.6% of those on placebo (n = 19).

At SLEEP 2023, Budur told Neurologylive®, "This study was not powered for statistical significance, because it was a proof-of-concept study. Going into the study, the objectives were really three-fold. First, is there a signal of efficacy in patients with PWS. The second, if there is a signal, is there a dose response? And the third looked at safety profile, because that's very important. The answer to all these three questions was yes, yes, and yes."

The phase 2 data showed that the safety and tolerability profile of pitolisant in patients with PWS was consistent with its known safety profile, with no new signals observed. Treatment-emergent adverse events (TEAEs) were recorded in 50.0%, 65.0%, and 65.2% of patients in the higher dose pitolisant, lower dose pitolisant, and placebo groups, respectively. There were no serious TEAEs reported in the treated groups, and 1 serious TEAE in the placebo group.

Budur added, "Pitolisant is a selective histamine 3 (H₃) receptor antagonist/inverse agonist, and we are harnessing a mechanism-based approach to the development of pitolisant. Our knowledge of pitolisant continues to expand beyond narcolepsy as evidenced through our studies in idiopathic hypersomnia (IH) and Prader-Willi syndrome and other activities related to pitolisant."

1. Harmony Biosciences announces plans to initiate phase 3 registrational study of pitolisant in Prader-Willi syndrome following positive end-of-phase 2 meeting with the US Food and Drug Administration. Harmony Biosciences. News release. July 20, 2023. Accessed July 31, 2023.
2. Revana A, Seiden D, Rapchak KD, et al. Primary efficacy and safety results of a phase 2 double-blind, placebo-controlled proof of concept, signal detection study of pitolisant in Prader-Willi syndrome. Presented at: 2023 SLEEP Annual Meeting; June 3-7. Indianapolis, Indiana. Abstract 510
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