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

Efsubaglutide alfa is a novel glucagon-like peptide-1 receptor agonist composed of dual GLP-1 molecules fused with the fragment crystallizable (Fc) region of human immunoglobulin G2. It is designed for the treatment of type 2 diabetes mellitus (T2DM) and metabolic diseases.

This study aimed to quantitatively describe the exposure-response (E-R) relationship between efsubaglutide alfa exposure and efficacy and safety endpoints in patients with T2DM and to assess the impact of baseline characteristics on the E-R relationship.

An E-R analysis was conducted using data from 465 drug-naïve participants with T2DM in a phase IIb/III trial (YN011-301), which included a 24-week double-blind period followed by a 28-week open-label period. Participants received once-weekly subcutaneous injections of efsubaglutide alfa 1 mg, 2 mg, or 3 mg or placebo. Regression analysis was performed against the steady-state pharmacokinetic exposure, including steady state peak concentration (C_max,ss), steady state minimum concentration (C_min,ss), steady state average concentration (C_avg,ss), and their logarithms.

The median age was 51.0 years, and the mean baseline glycated hemoglobin (HbA1c) was 8.71%. At weeks 24 and 52, reductions in HbA1c, fasting plasma glucose, area under the concentration-time curve for glucose during the mixed-meal tolerance test, body weight, waist circumference, and body mass index correlated positively with drug exposure. The E-R model indicated that a 10-fold increase in C_min,ss led to a 1.150% decrease in HbA1c at week 24. Baseline HbA1c, age, and neutralizing anti-drug antibody influenced the E-R relationship for HbA1c. Safety analysis showed a positive correlation between drug exposure and the incidence of treatment-related adverse events, particularly nausea and diarrhea, with tolerance developing over time.

Efsubaglutide alfa demonstrates a strong E-R relationship for glycemic control and weight reduction in drug-naïve participants with T2DM. The extended half-life and favorable safety profile of efsubaglutide alfa make it well-suited for once weekly or biweekly monotherapy in patients with newly diagnosed T2DM.

The trial was registered at Clinicaltrials.gov (identifier: NCT04994288).