Endocrine Abstracts

Background: Prader-Willi syndrome (PWS) is a rare disease characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality and to a significant burden on patients and caregivers. There is no approved treatment for hyperphagia in PWS. Patients with PWS have increased circulating levels of the orexigenic hormone acylated ghrelin (AG) with a relative deficit of unacylated ghrelin (UAG). Livoletide (AZP-531) is a first-in-class UAG analog that was previously shown in a Phase 2 randomized, double-blind, placebo-controlled study of 47 PWS patients to significantly improve hyperphagia, food-related behaviors, and metabolic parameters, and to be well-tolerated. [Allas S et al. (2018) PLoS ONE 13(1): e0190849].

Objective: ZEPHYR (EudraCT 2018-003062-13; NCT03790865) is a pivotal Phase 2b/3 study that is designed to evaluate the long-term safety and efficacy of livoletide in patients with PWS.

Methods: The ZEPHYR study is currently being conducted in North America and Europe. In its Phase 2b portion, approximately 150 patients with PWS will be randomized to receive livoletide ~60 ug/kg, livoletide ~120 ug/kg, or placebo, once daily by subcutaneous injection for a 3-month core period. Patients will then enter a 9-month extension period. The Phase 3 portion will be initiated following results of the Phase 2b core period with patients randomized to livoletide at a dose based on Phase 2b core data or to placebo. After 6 months of treatment in the Phase 3 core period, patients will enter the 6-month Phase 3 extension period. Main entry criteria for ZEPHYR include genetic diagnosis of PWS, age 8–65 years, single primary caregiver available for the duration of the study, and BMI ≤65 kg/m² for adult patients. Patients with type 2 diabetes with HbA1c ≤10% may be enrolled. Use of human growth hormone will be allowed if dosage is stable. The primary outcome measure is the Hyperphagia Questionnaire-Clinical Trials (HQ-CT) score. The HQ-CT has been validated and is considered by regulatory authorities to be a valid primary endpoint. Secondary outcome measures include metabolic and body composition parameters such as fat mass as assessed by DEXA, BMI, and body weight in overweight/obese patients.

Results: The study is ongoing: enrollment began in early 2019 and updates will be reported.

Conclusion: ZEPHYR is a pivotal study that will provide data on the long-term safety and efficacy of the novel UAG analog livoletide on the treatment of hyperphagia and food-related behaviors in patients with PWS.