SUN-609 Livoletide (AZP-531), an Unacylated Ghrelin Analogue, Improves Hyperphagia and Food-Related Behaviors Both in Obese and Non-Obese People with Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a rare, complex neuro-developmental genetic disorder characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity and early mortality and to significant burden on patients and caregivers. While a majority of people with PWS is obese, hyperphagia is observed in both obese and non-obese people with PWS. There is currently no approved treatment for hyperphagia in PWS. People with PWS have increased circulating levels of the orexigenic hormone acylated ghrelin (AG) with a relative deficit of unacylated ghrelin (UAG), a hormone which counteracts many of AG’s effects. Livoletide (AZP-531) is a first-in-class UAG analogue previously shown to improve hyperphagia, food-related behaviors, and metabolic parameters, and to be well-tolerated in a Phase 2a trial in PWS. [Allas S et al. (2018) PLoS ONE 13(1): e0190849] Here we present additional analyses that examine the effects of livoletide in obese vs non-obese people with hyperphagia in PWS. Methods: The Phase 2a trial was a randomized, double-blind, placebo-controlled study which included 47 people with PWS. Participants received a daily subcutaneous injection of livoletide (n=23) or placebo (n=24) during a 2-week treatment period. The study population was divided based on the body mass index (BMI) into obese (BMI ≥ 30 kg/m(2)) and non-obese (BMI < 30 kg/m(2)) groups. The effect of livoletide on hyperphagia and food-related behaviors was assessed by the change from baseline in the 9-item Hyperphagia Questionnaire (HQ). Results: There was a total of 34 obese and 13 non-obese subjects in the study. As expected, baseline BMI, body weight (BW) and waist circumference (WC) were significantly higher in obese vs. non-obese PWS subjects (BMI: 42.6 ± 6.0 vs 26.1 ± 2.8, BW: 103.5 ± 23.0 vs 68.5 ± 9.1 and WC: 118.3 ± 15.5 vs 91.8 ± 7.7, respectively, p<0.0001). There was no significant difference with respect to the ratios of males to females or of deletion to non-deletion between the 2 populations. Hyperphagia scores were similar at baseline for obese and non-obese participants (HQ score adjusted for 0 to 36 scale to reflect 9-item HQ-CT: 12.8 ± 7.0 vs 14.0 ± 7.8, p=0.6083, respectively). Fasting AG and UAG levels were lower in the obese vs. non-obese groups (AG: 93.6 ± 72.6 vs 122.1 ± 54.4, p=0.0275, UAG: 123.9 ± 87.2 vs 154.1 ± 62.6, p=0.0219, respectively). Livoletide-treated participants experienced similar improvements in hyperphagia and food-related behaviors as measured by the HQ whether they were obese or non-obese. Conclusions: These results highlight the potential of livoletide for treating hyperphagia in both obese and non-obese people with PWS and hyperphagia. Livoletide is being investigated further in the ZEPHYR Phase 2b/3 trial, an ongoing pivotal study on the long-term safety and efficacy of livoletide in the treatment of hyperphagia and food-related behaviors in people with PWS.