Preclinical evaluation and first-in-human phase 1 trial of AZD0186, a novel, oral small molecule glucagon-like peptide-1 receptor agonist

Qi, Weier and Boca, Simina M and Boianelli, Alessandro and Fredberg, Monica and Lundqvist, Sara and Davies, Graeme and Field, Joss and Brighton, Cheryl A and Snijder, Arjan and Grundevik, Pernilla and Eckernäs, Daniel and Träff, Annika Maria and Polla, Magnus and Pettersen, Daniel and Omar, Sami and Hansen, Lars and Janzén, David and Melin, Johanna and van Zuydam, Natalie and Logue, Jennifer and Wallenius, Kristina (2025) Preclinical evaluation and first-in-human phase 1 trial of AZD0186, a novel, oral small molecule glucagon-like peptide-1 receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 392 (10): 103683. ISSN 0022-3565

Abstract

Small molecule glucagon-like peptide-1 receptor agonist AZD0186 was developed to provide accessible and convenient treatment for a broad patient population with type 2 diabetes mellitus and/or obesity. We describe the preclinical and first-in-human single ascending dose data (NCT05694741) for this novel small molecule glucagon-like peptide-1 receptor agonist. AZD0186 was profiled in cell lines overexpressing human or cynomolgus glucagon-like peptide-1 receptor (GLP-1R) and in human-derived EndoC-βH5 cells. Glucose-stimulated insulin secretion (GSIS) was assessed following an intravenous glucose tolerance test in obese nonhuman primates and humanized GLP-1R (hGLP-1R) mice. Effects of oral repeated dosing on body weight and food intake were assessed in hGLP-1R mice. AZD0186 was evaluated at 4 oral single ascending dose levels (5, 15, 50, and 150 mg) in healthy participants. Results showed that AZD0186 is potent on the hGLP-1R and showed a concentration-dependent potentiation of GSIS in EndoC-βH5 cells (EC 50 = 0.6 nM). Insulin secretion was enhanced in obese nonhuman primates at all 3 dose levels evaluated following an intravenous glucose tolerance test. In hGLP-1R mice, body weight was reduced 9.9% ± 2.3% (mean ± SD) following 5 days of oral dosing (25 mg/kg per day twice a day). In the healthy participants, AZD0186 was well tolerated, with nausea reported at 150 mg, in keeping with GLP-1RA class effects. Across the dose range, AZD0186 area under the concentration-time curve increased in an approximately dose-proportional manner. Median terminal half-life ranged from 1.95 to 7.58 hours. Findings demonstrate that AZD0186 is a potent agonist of the GLP-1R, and the first-in-human study indicates a favorable safety and tolerability profile. SIGNIFICANCE STATEMENT: AZD0186 is a novel small molecule glucagon-like peptide-1 receptor agonist that allows for oral dosing. We describe the preclinical and first-in-human single ascending dose data for AZD0186. The findings demonstrate that AZD0186 is a potent agonist of the human glucagon-like peptide-1 receptor, improves glucose control and reduces body weight in a human glucagon-like peptide-1 receptor mouse model, and has a favorable safety and tolerability profile in healthy human participants.