The study, “AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial,” was published in the journal PLOS ONE.
PWS is a rare genetic disease characterized by hyperphagia (excessive eating) after age 3. Hyperphagia, which currently has no pharmacological treatment, impairs socialization and reduces quality of life in both patients and caregivers.
AZP-531 (livoletide) is an analog (meaning similar) to the most common chemical form – called unacylated – of the gut-derived hormone ghrelin.
Compared to the acylated form, unacylated ghrelin (UG) inhibits the increase in appetite, as well as the tendency toward obesity and diabetes.
Research in Prader-Willi patients showed an increase in total ghrelin levels after a meal, compared with lean and obese subjects. This elevation is caused by high levels of acylated ghrelin, which correlates to hunger, whereas UG remains at low levels even when hyperphagia and obesity develop.
Recently, researchers have been studying the therapeutic utility of blocking acylated ghrelin in food intake, body weight, and glucose metabolism, but results in mice have been contradictory.
Therefore, UG, which acts as a functional acylated ghrelin inhibitor, has been receiving increased attention, particularly given the low levels of UG in PWS patients and its protective ability in oxidative stress and inflammation, which is relevant in metabolic disorders.
Previous studies demonstrated that AZP-531 has an improved pharmacological profile and stability in the blood compared to UG. The treatment candidate is suitable for once-daily dosing regimens. Early clinical testing showed that AZP-531 improves glucose control and decreases weight in patients with type 2 diabetes.
The research team designed a two-week, double-blind study to evaluate the safety and efficacy of the investigative treatment in improving food-related behaviors in 47 Prader-Willi syndrome patients ages 12-50 with hyperphagia. The research was conducted at seven sites in France, Spain, and Italy.
Patients received daily subcutaneous injections of either AZP-531 (3 mg for patients between 50-70 kg, and 4 mg for those who weigh more) or placebo 30 minutes before breakfast for 14 days.
Researchers analyzed adverse events, vital signs, patient-reported appetite, effects on hyperphagia (with a nine-item specific questionnaire), body composition, and glucose levels.
Results showed that AZP-531 was well-tolerated. This finding matches earlier results in humans, the researchers observed.
All the different measures in the dedicated questionnaire revealed that the investigative therapy improved hyperphagia compared to placebo, particularly in patients with the highest scores at baseline. Investigators also observed a reduction in appetite scores.
Although no weight loss was seen, the treatment did reduce patients’ waist circumference and fat mass in the study. Glucose levels were also decreased, particularly in patients with impaired glucose tolerance or type 2 diabetes.
“Based on these findings, significant improvement in body composition and metabolic parameters can be reasonably expected in longer-term and larger clinical trials in PWS,” the investigators wrote.
Of note, ghrelin and acylated ghrelin levels were unchanged with the treatment.
“AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS,” researchers wrote.
They cautioned that their results warrant additional study to evaluate long-term safety and effectiveness in patients with Prader-Willi syndrome and hyperphagia, “for whom no approved treatment is currently available.”