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AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial.

ABSTRACT: Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available.Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50-70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures.AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion.AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

SUBMITTER: Allas S

PROVIDER: S-EPMC5761957 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial.

Allas Soraya S Caixàs Assumpta A Poitou Christine C Coupaye Muriel M Thuilleaux Denise D Lorenzini Françoise F Diene Gwenaëlle G Crinò Antonino A Illouz Frédéric F Grugni Graziano G Potvin Diane D Bocchini Sarah S Delale Thomas T Abribat Thierry T Tauber Maithé M

PloS one 20180110 1

<h4>Context and objective</h4>Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved ...[more]

PMID: 29320575

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Project description: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.

Dataset Information

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial.

Publications

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial.

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