BACKGROUND AND OBJECTIVES: Efsubaglutide alfa is a long-acting GLP-1 receptor agonist and is designed by fusion of two human GLP-1 molecules with IgG2 Fc via a natural immunoglobulin hinge region. This study evaluates the exposure-response (E-R) relationship of efsubaglutide alfa in patients with type 2 diabetes (T2D) treated with metformin.
METHODS: Data were derived from an operational seamless design of randomized, double blind, placebo clinical trial (YN011-302) involving 406 subjects with T2D on stable metformin therapy. Participants received weekly subcutaneous injections of 1 mg or 3 mg efsubaglutide alfa, or placebo. The trial included a 24-week double-blind period and a 28-week open-label period.
RESULTS: Participants had a median age of 55.0 years, mean body weight of 73.7 kg, fasting plasma glucose (FPG) of 9.72 mmol/L, and glycated hemoglobin (HbA1c) of 8.63%. A robust inverse correlation was observed between efsubaglutide alfa exposure and improvements in HbA1c, FPG, glucose area under the curve (AUC) during mixed-meal tolerance test (MMTT), body weight, and body mass index. Efsubaglutide alfa exposure also positively correlated with C-peptide AUC during MMTT, indicating improved beta-cell function. The E-R model indicates that doubling steady-state trough concentrations (C) reduced HbA1c by 0.211%, while every 100 ng/mL increase in Cled to 0.5 kg reduction in body weight at Week 24. Baseline HbA1c was a predictor of treatment response. Safety analysis revealed a positive correlation between exposure and gastrointestinal adverse events, which decreased over time, suggesting tolerance development. min,ss avg,ss
CONCLUSIONS: Efsubaglutide alfa, combined with metformin, significantly improves glycemic control and weight management, with an acceptable safety profile. This E-R model provides insights for dose optimization and trial design, and supports its use as an effective add-on therapy for patients with T2D, as indicated in the drug specification.
TRIAL REGISTRATION: The trials were registered at Clinicaltrials.gov (identifier: NCT04998032).
