Exposure-Response Analysis of Efsubaglutide Alfa in Patients with Type 2 Diabetes Treated with Metformin

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.

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.

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_min,ss) reduced HbA1c by 0.211%, while every 100 ng/mL increase in C_avg,ss led 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.

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.

The trials were registered at Clinicaltrials.gov (identifier: NCT04998032).