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

Abstract Aims GLP‐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 Methods ECC5004 was profiled in cell lines overexpressing human GLP‐1R, in glucose‐stimulated insulin secretion (GSIS) assays in a human β‐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. Results ECC5004 bound to the hGLP‐1R (IC 50 = 2.4 nM) augmented cAMP signalling without β‐arrestin‐2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC‐βH5 cells (EC 50 = 5.9 nM) and in vivo in NHPs (EC 50 = 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. Conclusion ECC5004 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.