Harmony Begins New Phase 3 TEMPO Study of Wake-Promoting Therapy Pitolisant in Prader-Willi Syndrome


The newly initiated phase 3 trial follows a successful phase 2 study where treatment with pitolisant resulted in greater improvement on the Epworth Sleepiness Scale for Children and Adolescents than placebo.

Kumar Budur, MD, MS, chief medical officer at Harmony

Kumar Budur, MD, MS

Following a positive phase 2 study, Harmony Biosciences has initiated a global phase 3 registrational trial to further assess the safety and efficacy of pitolisant (Wakix) as a treatment for excessive daytime sleepiness (EDS) and behavioral symptoms in patients with Prader-Willi syndrome (PWS). Otherwise known as the TEMPO study, the double-blind trial will include those with PWS aged 6 years and older.

Pitolisant, a first-in-class selective histamine 3 receptor antagonist/inverse agonist, has been approved for the treatment of EDS or cataplexy in adults with narcolepsy since 2019. It remains an investigational treatment for those with PWS, a rare, complex, multisystem disorder that encompasses 15,000-20,000 people in the US. Characterized by neonatal hypotonia, a majority of patients in this population experience behavioral symptoms and more than half experience EDS.

"The initiation of our Phase 3 TEMPO study, a global, randomized, double-blind, placebo-controlled, multicenter trial with an open-label extension period, reflects continued positive momentum across our organization spanning our lifecycle management programs in PWS and other indications with high unmet medical need,” Kumar Budur, MD, MS, chief medical officer at Harmony, said in a statement.1 "With the initiation of this study and the FDA's recent decision to grant ODD (orphan drug designation) for pitolisant in PWS, we aim to potentially introduce a new, non-scheduled treatment option for EDS and the common behavioral symptoms in patients living with this condition."

READ MORE: Pediatric Sleep Disorders in Chronic Conditions Linked With Increased Healthcare Utilization, Hospitalizations

A previously conducted phase 2 study highlighted the potential impacts of pitolisant in patients with PWS. 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. In the overall patient population, mean improvement on the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), the primary end point, was greater for both pitolisant dose groups compared with placebo at the end of the 11-week period.

Overall, 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). With no new signals observed, pitolisant demonstrated a safety profile that was consistent with previous studies.2

At the 2023 Foundation for Prader-Willi Research Symposium and Family Conference, additional data from the phase 2 trial showed pitolisant’s impact on several secondary and exploratory outcomes. Across all secondary and exploratory end points, the most pronounced benefits were observed in the higher-dose pitolisant group, although the study was not powered to demonstrate statistical significance. In the youngest group, aged 6 to 12 years old, treatment with pitolisant resulted in significant impacts on several Aberrant Behavior Checklist-2 (ABC-2) domains, including irritability (higher dose: –5.5; lower-dose, –3.0; and placebo, –1.5), social withdrawal (–4.9; –1.6; and –3.1), hyperactivity/noncompliance (–4.6; –0.9; and –3.0), inappropriate speech (–2.0; –0.4; –0.6) and stereotypic behavior (–1.0; –0.2; and –0.6).3

Additional findings showed greater reductions in Caregiver Global Impression of Severity (CaGI) scores among both children (higher-dose, –1.1; lower-dose, –1.0; placebo, –0.5) and adults (higher-dose, –1.0; lower-dose, –2.0; placebo, –0.7) treated with pitolisant. At the conclusion of the 11-week treatment period, investigators observed a reduction of –1.0 or more in the mean change of CaGI, meeting the clinical significance threshold set by the American Academy of Sleep Medicine. Even though baseline hyperphagia scores were in the normal/mild range, improvements in hyperphagia were still noted among children (higher-dose, –2.0; lower-dose, –2.5; placebo, 0.1) and adults (higher-dose, –3.4; lower-dose, –3.0; placebo, –1.7) treated groups.

1. Harmony Biosciences initiates global phase 3 registrational trial (TEMPO study) of pitolisant in patients with Prader Willi syndrome. Harmony Biosciences. April 3, 2024. Accessed April 8, 2024. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-initiates-global-phase-3-registrational
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
3. Harmony Biosciences presents new secondary outcome data from phase 2 signal detection study in patients with Prader-Willi syndrome. News release. October 5, 2023. Accessed April 8, 2024. https://www.prnewswire.com/news-releases/harmony-biosciences-presents-new-secondary-outcome-data-from-phase-2-signal-detection-study-in-patients-with-prader-willi-syndrome
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