SAT-100 Trial-in-Progress: ZEPHYR, a Pivotal Phase 2b/3 Randomized, Placebo-Controlled Study of Livoletide, a Novel Unacylated Ghrelin Analog, for the Treatment of Hyperphagia and Food-Related Behaviors in Patients with Prader-Willi Syndrome

Abstract

Abstract Background: Prader-Willi syndrome (PWS) is a rare and complex endocrine 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 placebo-controlled study in a 47-patient PWS cohort to significantly improve hyperphagia, food related behaviors, and metabolic parameters and to be well-tolerated with no serious adverse events or treatment discontinuations over a 14-day period. [Allas S et al. (2018) PLoS ONE 13(1): e0190849] Objective: ZEPHYR (EudraCT 2018-003062-13) 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 will be conducted in centers in North America and Europe. In its Phase 2b portion, approximately 150 patients with PWS will be randomized in a 1:1:1 ratio to receive livoletide low exposure (8 mg/mL), livoletide high exposure (16 mg/mL), or placebo, once a day by sc injection for a three-month core period. Then, patients who received placebo will cross over to livoletide low or high exposure and be treated for 9 months. Patients who received livoletide will continue at their original dose for an additional 9 months. The Phase 3 portion will be initiated following results of the Phase 2b core period with patients randomized 1:1 to livoletide at a dose based on Phase 2b core data or to placebo for a six-month duration. Subsequently, patients who received placebo will be crossed over to livoletide for six months, while patients on livoletide initially will continue for six more months. Main entry criteria for ZEPHYR include genetic diagnosis of PWS, age 8-65 years, single primary caregiver available for the duration of the study, BMI ≤65 kg/m2 for adult patients. Patients with type 2 diabetes with HbA1C ≤10% and stable therapy may be enrolled. Use of human growth hormone will be allowed if dosage is stable. Patients enrolled in Phase 2b will not be eligible for Phase 3. 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 as a valid primary endpoint. Secondary outcome measures include 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 an updated status will be reported. Conclusion: ZEPHYR is a pivotal study that will provide data on the long-term safety and efficacy on hyperphagia and food-related behaviors of the novel UAG analog livoletide in patients with PWS.