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

Abstract

Context and objective: 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.

Methods and design: 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.

Results: 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.

Conclusions: 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.

Fig 1. Enrollment and outcomes.

Fig 2. Changes in Hyperphagia Questionnaire individual items and calculated scores from baseline to Day 14.

Panels A and B show the mean values of each individual item and each calculated score, respectively. The 9-item score excluded item 3 and item 10 as both items were considered to reflect impression of caregiver rather than capturing concept of interest. A reduction in the score indicates improvement. Bars indicate the standard error. *p < .05 versus placebo.

Fig 3. Changes in Hyperphagia Questionnaire 9-item score from baseline to Day 14.

Panels A, B, and C show the mean change from baseline in the Hyperphagia Questionnaire 9-item score for all patients (N = 47), home-resident patients (N = 38) and home-resident patients with a threshold base line HQ 9-item score ≥19 (N = 26). A reduction in the score indicates improvement. Bars indicate the standard error.

Fig 4. Cumulative distribution function of the Hyperphagia Questionnaire 9-item score from baseline to Day 14.

The percentage of treated participants was plotted against the change in Hyperphagia Questionnaire 9-item score from baseline to Day 14.

Fig 5. Post-prandial glucose change in treated patients from baseline to Day 14.

Mean values of the 3-hour post-prandial glucose change from baseline to Day 14 was plotted for all treated patients (Panel A), normoglycemic (NG) patients (Panel B), and patients with Impaired Glucose Tolerance or Type 2 Diabetes (IGT/T2D) (Panel C).