Efinopegdutide

Efinopegdutide is a chimeric peptide with agonist activity at both GLP-1R and GCGR in a balanced ratio. PEGylation with a 40 kDa PEG chain reduces renal clearance and protease degradation, enabling weekly dosing. GLP-1R agonism drives satiety, reduced food intake, and glucose-dependent insulin secretion. GCGR agonism activates hepatocyte cAMP-PKA signaling, upregulating fatty acid oxidation genes and reducing lipogenic gene expression, directly targeting hepatic steatosis independent of weight loss.

In combined GLP-1R/GCGR agonism, the liver-directed GCGR effects are particularly valuable for MASH. Glucagon signaling reduces hepatic de novo lipogenesis, increases mitochondrial beta-oxidation of fatty acids, and promotes VLDL secretion to export triglycerides from the liver. In the context of hyperinsulinemia (common in MASH), GCGR activation partially counteracts the lipogenic effects of insulin. The GLP-1R component simultaneously reduces caloric intake, creating complementary mechanisms for hepatic fat clearance.

In Phase 2 trials in NASH/MASH patients (biopsy-confirmed), efinopegdutide produced significant reductions in liver fat content measured by MRI-PDFF (mean ~70% relative reduction from baseline at top dose) versus placebo. ALT normalization, weight reduction (~10%), and improved fibrosis markers were observed. The degree of liver fat reduction exceeded that typically seen with GLP-1 monotherapy at comparable weight loss, supporting a GCGR contribution beyond weight-loss effects.

Head-to-head Phase 2 comparison with semaglutide 2.4 mg weekly in MASH showed efinopegdutide superior liver fat reduction despite similar weight loss, consistent with an additive hepatic GCGR mechanism. This comparison supports the hypothesis that GLP-1/GCGR dual agonism provides hepatic benefits beyond GLP-1 alone, making this class potentially more appropriate for MASH than pure GLP-1 agonists.