Safety and efficacy of GLP-1/FGF21 dual agonist HEC88473 in MASLD and T2DM: a randomized, double-blind, placebo-controlled study

Abstract

Background and aims: Glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 21 (FGF21) are key regulators of glucose and lipid metabolism. In the present study, we assessed the safety and efficacy of a novel GLP-1/FGF21 dual agonist HEC88473 for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) combined with type 2 diabetes mellitus (T2DM).

Methods: This was a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase 1b/2a trial. Sixty patients with MASLD and T2DM were randomized (10:2) to receive HEC88473 (5.1, 15.3, 30.6, 45.9, or 68.0 mg) or placebo via weekly subcutaneous injection for 5 weeks.

Results: After 5 weeks of treatment with HEC88473, the magnetic resonance imaging proton-density fat fraction (MRI-PDFF) was reduced in a dose-proportional manner. The largest relative mean change reached -47.21% (P = 0.0143) in the 30.6 mg cohort, as compared with -15.05% in the placebo group, with proportions of > 30% relative reduction higher in patients with baseline PDFF > 8%. The 5-week treatment with HEC88473 significantly reduced levels of glycated hemoglobin (HbA1c) as well as fasting and postprandial glucose levels. The largest mean change in HbA1c reached -1.10% in the 68.0 mg cohort, as compared with -0.31% in the placebo group. Improvement was also observed in participants' lipid profiles. Most adverse events (AEs) were mild-to-moderate in severity. The most frequently reported AEs were gastrointestinal disorders (n = 29, 48.3%).

Conclusions: Herein, we report the clinical safety and proof of concept data for the GLP-1/FGF21 dual agonist HEC88473. A 5-week treatment with HEC88473 was generally safe and well tolerated, with multiple positive effects observed, including reduced liver fat, and improved glycemic control, insulin resistance and lipid metabolism, together indicating comprehensive improvement in metabolic syndrome.

Clinical trial number: Chinese Drug Trial Identifier (http://www.chinadrugtrials.org.cn/index.html): CTR20211088;ClinicalTrials.govNCT05943886.

Keywords: Clinical trial; GLP-1/FGF21 dual agonist; HEC88473; MRI-PDFF; Metabolic dysfunction-associated steatotic liver disease (MASLD); Type 2 diabetes mellitus (T2DM).