Safety, pharmacokinetics and pharmacodynamics of Efsubaglutide Alfa in healthy participants: A randomised, dose-escalation phase 1 study.

Abstract

Aims: This Phase 1 study aimed to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose subcutaneous Efsubaglutide Alfa, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants.

Materials and methods: This randomised, double-blind, placebo-controlled, single-dose escalation study was conducted at a single centre. A total of 48 healthy adults were randomised (6:2) across six dose cohorts (0.375, 0.75, 1.5, 3, 6 and 9 mg) to receive Efsubaglutide Alfa or placebo. Safety, PK and PD parameters were assessed.

Results: Efsubaglutide Alfa exhibited dose-proportional PK, with a median T_max of 47.5-71.7 h and a mean half-life (T_1/2) of 121.4 h. Exposure increased linearly across doses (C_max: 37.1-832.4 ng/mL, AUC_0-∞: 8699.6-193446.6 ng/mL·h). No serious AEs occurred; mild-to-moderate gastrointestinal AEs (nausea, vomiting, decreased appetite) were the most common in Efsubaglutide Alfa-treated subjects. Post-dose, fasting plasma glucose transiently declined on Day 1, returned to baseline by Day 2, and remained within -0.8 to +1.9 mmol/L relative to baseline (within expected physiological variability) through Day 28. Fasting insulin and C-peptide levels slightly increased on Day 1, normalised by Day 2, and remained stable. At Day 2, OGTT revealed reduced glucose excursions in Efsubaglutide Alfa recipients (p = 0.0150 vs. placebo; AUC ~0.7 mmol/L·2 h lower), while insulin and C-peptide levels remained unchanged. Dose-dependent weight loss peaked at Day 4-7, with up to a 4.0% reduction (p < 0.0001) at the higher dose, followed by a gradual return towards baseline by Day 28.

Conclusions: Efsubaglutide Alfa was well tolerated in healthy participants, with a favourable PK and PD profiles that support further clinical development in type 2 diabetes and metabolic disorders.