40-week repeat-dose toxicity, toxicokinetics, and immunogenicity of efsubaglutide alfa following subcutaneous administration in cynomolgus monkeys.

Efsubaglutide alfa is a novel humanized long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA) developed for the treatment of type 2 diabetes and other metabolic diseases. To support chronic clinical use, we evaluated the systemic safety, toxicokinetics (TK), and immunogenicity of efsubaglutide alfa in cynomolgus monkeys. Twenty males and twenty females were randomized to receive vehicle control or efsubaglutide alfa (0.3, 1, or 3 mg/kg) by subcutaneous injection twice weekly for 40 weeks, followed by an 8-week recovery period. Endpoints included clinical observations, food intake, body weight, electrocardiography, hematology, clinical chemistry, urinalysis, immunotoxicity, anti-drug antibodies, TK, and full macroscopic and microscopic pathology. There were no deaths and no treatment-related systemic organ toxicities. Reduced food intake and attenuated body weight gain occurred early during dosing and were considered pharmacology-related. The primary microscopic finding was reversible, dose-related inflammation at injection sites. Systemic exposure increased with dose and remained broadly stable over time, with no evidence of marked accumulation. Anti-drug antibodies occurred at low incidence and were not associated with clinically meaningful changes in safety parameters or TK. The NOAEL was 3 mg/kg under the conditions of this study, supporting further clinical development of efsubaglutide alfa.