Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist

AimsGLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA.Materials and MethodsECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human beta-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days.ResultsECC5004 bound to the hGLP-1R (IC50 = 2.4 nM) augmented cAMP signalling without beta-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-beta H5 cells (EC50 = 5.9 nM) and in vivo in NHPs (EC50 = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses >= 25 mg.ConclusionECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity. Clinical trial registration: NCT05654831.