Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2016-09, Vol.18 (9), p.868-874
• Main Authors: Allas, S., Delale, T., Ngo, N., Julien, M., Sahakian, P., Ritter, J., Abribat, T., van der Lely, A. J.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age; Aged; antidiabetic drug; Antidiabetics; Blood Glucose - drug effects; Blood Glucose - metabolism; Body mass index; Body weight; Body Weight - drug effects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diarrhea - chemically induced; Dosage; Double-Blind Method; drug development; Female; Ghrelin; Ghrelin - administration & dosage; Ghrelin - pharmacology; Glucose; Glycated Hemoglobin A - drug effects; Glycated Hemoglobin A - metabolism; Healthy Volunteers; Hemoglobin; Humans; Hypoglycemia - chemically induced; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Injections, Subcutaneous - adverse effects; Insulin; Insulin - metabolism; Male; Metformin - therapeutic use; Middle Aged; Obesity - metabolism; Overweight; Overweight - metabolism; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptides, Cyclic - administration & dosage; Peptides, Cyclic - pharmacology; Pharmacodynamics; Pharmacokinetics; phase I-II study; Placebos; randomized trial; type 2 diabetes; Young Adult
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12675

Aim To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP‐531, designed to improve glycaemic control and reduce weight. Methods Assessments, including glucose measurements, were performed in a three‐part randomized study. In Part A, healthy subjects [n = 44, age 18–50 years, body mass index (BMI) 20–28 kg/m2] received a single subcutaneous dose of 0.3, 3, 15, 30, 60 or 120 µg/kg AZP‐531 or placebo. In Part B, overweight/obese subjects (n = 32, age 18–65 years, BMI 28–38 kg/m2) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18–65 years, BMI 20–40 kg/m2, glycated haemoglobin (HbA1c) 7–10%] received AZP‐531 or placebo for 14 days (daily doses of 3, 15, 30 or 60 µg/kg and 15, 2 × 30 or 60 µg/kg, respectively). Results AZP‐531 was well tolerated. Single‐ and multiple‐dose pharmokinetic variables were similar. Maximum AZP‐531 concentrations were typically reached at 1 h post‐dose. Observed maximum concentration (Cmax) and area under the curve were dose‐proportional. The mean terminal half‐life (t1/2) was 2–3 h. In Part B, AZP‐531 doses of ≥15 µg/kg significantly improved glucose concentrations, without increasing insulin levels, suggesting an insulin‐sensitizing effect. AZP‐531 decreased mean body weight by 2.6 kg (vs 0.8 kg for placebo). In Part C, glucose variables improved in all groups, including placebo, suggesting a study effect in uncontrolled patients at baseline. Notwithstanding, AZP‐531 60 µg/kg reduced HbA1c by 0.4% (vs 0.2% for placebo) and body weight by 2.1 kg (vs 1.3 kg for placebo). Conclusions AZP‐531 was well tolerated in this first‐in‐human study. Its pharmacokinetic profile, suitable for once‐daily dosing, and metabolic effects support further clinical development for T2D.