title: 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.
abstract: To explore the safety, pharmacokinetics and pharmacodynamics in humans of the unacylated ghrelin analogue AZP-531, designed to improve glycaemic control and reduce weight.
  
  
  
  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/m(2) ] 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/m(2) ) and in Part C, patients with type 2 diabetes [T2D; n = 36, age 18-65 years, BMI 20-40 kg/m(2) , 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).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: S
authors.initials: S
authors.lastname: Allas
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: T
authors.initials: T
authors.lastname: Delale
authors.affiliation: Quintiles Early Clinical Development PK Department, Overland Park, KS, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ngo
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: M
authors.initials: M
authors.lastname: Julien
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: P
authors.initials: P
authors.lastname: Sahakian
authors.affiliation: Phase 1 Quintiles Unit, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: T
authors.initials: T
authors.lastname: Abribat
authors.affiliation: Department of Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Lely
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D005260:Female; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007279:Injections, Subcutaneous / Q000009:adverse effects; D007328:Insulin / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D050177:Overweight / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C581708:cyclic des-acyl ghrelin (6-13); C517652:hemoglobin A1c protein, human
keywords: antidiabetic drug; drug development; phase I-II study; randomized trial; type 2 diabetes