Efsubaglutide Alfa attenuates metabolic dysfunction-associated steatohepatitis in mice with improvements in second harmonic generation-derived fibrosis features.

Abstract

AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited effective treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise for metabolic and hepatic benefits. This study evaluated the therapeutic efficacy of Efsubaglutide Alfa, a novel long-acting GLP-1RA, in a mouse model of MASH. MATERIALS AND METHODS: Male C57BL/6J mice with diet-induced obesity received a high-fat diet and low-dose CClinjections to induce MASH. Mice were randomized to receive vehicle, obeticholic acid (OCA), semaglutide or Efsubaglutide Alfa at low, medium or high doses for 42&#x2009;days. Endpoints included liver histology, collagen quantification by second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging, and serum liver enzymes, lipids and metabolic parameters. RESULTS: By day 41, Efsubaglutide Alfa produced dose-dependent reductions in body weight, liver weight and liver-to-body weight ratio versus MASH controls (all p&#x2009;<&#x2009;0.01). Histology showed reduced steatosis and lowered the NAFLD Activity Scores (NAS), with high-dose treatment achieving a NAS of 3.0&#x2009;&#xb1;&#x2009;0.47 versus 4.5&#x2009;&#xb1;&#x2009;0.22 in MASH controls (p&#x2009;<&#x2009;0.01). Although Sirius Red-based fibrosis area and scoring did not show significant differences among treatment groups, SHG/TPEF imaging analysis showed lower perisinusoidal collagen metrics (%PS: 0.27%-0.30% vs. 0.40% in MASH controls, p&#x2009;<&#x2009;0.05). Furthermore, Efsubaglutide Alfa reduced serum ALT and AST levels and improved fasting glucose and triglycerides; fasting insulin was lower in semaglutide and high-dose Efsubaglutide Alfa groups, consistent with improved glycaemic control. CONCLUSIONS: Efsubaglutide Alfa reduced liver steatosis and improved SHG/TPEF-derived perisinusoidal collagen features, which supported further evaluation of Efsubaglutide Alfa for MASH, particularly for steatosis improvement and suggests potential effects on fibrosis-related features that warrant confirmation in longer duration studies.