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

Autor: Haggag AZ; Anaheim Clinical Trials LLC, Anaheim, California, USA., Xu J; Eccogene Inc., Cambridge, Massachusetts, USA., Butcher L; Eccogene Inc., Cambridge, Massachusetts, USA., Pagnussat S; QPS MRA LLC, Miami, Florida, USA., Davies G; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Lundqvist S; Assays, Profiling and Cell Sciences, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Wang W; Data Sciences and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Van Zuydam N; Data Sciences and Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Nelander K; Cardiovascular, Renal and Metabolism Biometrics, Late Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Jha A; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA., Yu H; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA., Boianelli A; DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lindmark B; DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Ollerstam A; Cardiovascular, Renal and Metabolism Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Sun X; Eccogene (Shanghai) Co. Ltd., Shanghai, China., Wang F; Eccogene (Shanghai) Co. Ltd., Shanghai, China., Pan X; Eccogene (Shanghai) Co. Ltd., Shanghai, China., Liu H; Eccogene (Shanghai) Co. Ltd., Shanghai, China., Chen W; Eccogene Inc., Cambridge, Massachusetts, USA., Xu J; Eccogene (Shanghai) Co. Ltd., Shanghai, China., Wallenius K; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Zhou J; Eccogene Inc., Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2024 Nov 04. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1111/dom.16047
Abstrakt: 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.
(© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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