Society: AASLD

Background: The glucagon-like-receptor (GLP)-1 agonist semaglutide has demonstrated therapeutic efficacy on clinical endpoints in a recent phase 2 clinical trial in patients with non-alcoholic steatohepatitis (NASH)(Newsome et al. NEJM, 2021). The present study aimed to evaluate therapeutic efficacy of semaglutide on clinical endpoints and outcome in the GAN (Gubra-Amylin NASH) diet-induced obese (DIO) mouse model of NASH with advanced fibrosis and hepatocellular carcinoma (HCC).

Methods: Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for extended 48 weeks prior to study start. Only animals with liver biopsy-confirmed NAFLD Activity Score (NAS ≥5) and advanced fibrosis (stage F3) were included and stratified into treatment groups. DIO-NASH-HCC mice received (SC, QD) vehicle (n=16) or semaglutide (30 nmol/kg, n=15) for 14 weeks. Vehicle-dosed chow-fed C57BL/6J mice (n=9) served as lean healthy controls. Untreated DIO-NASH-HCC mice (n=10) were terminated at baseline. Tumor histopathological classification was performed by an expert clinical pathologist. Pre-to-post liver biopsy histopathology was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Additional endpoints included blood biochemistry and quantitative liver histology.

Results: Compared to baseline, DIO-NASH-HCC mice demonstrated progressive HCC burden over the 14-week study period. Tumors showed consistent architectural and cytologic features of HCC with a marked loss of reticulin-stained fibers. Notably, semaglutide completely prevented progression in HCC burden. Concurrently, semaglutide improved hallmarks of NASH, including transaminases, hepatomegaly and histopathological NAS (≥2 point) without improving fibrosis stage. In agreement, semaglutide reduced quantitative histological markers of steatosis (lipids, hepatocytes with lipid droplets), inflammation (number of inflammatory foci, galectin-3), fibrogenesis (α-SMA), proliferation (Ki67) and progenitor cell activation (CK19).

Conclusion: This is the first study to demonstrate that semaglutide improves both clinical histopathological endpoints for NAFLD Activity Score and HCC burden in a preclinical translational mouse model of NASH-driven HCC. This highlights the suitability of GAN DIO-NASH-HCC mice for profiling novel drug therapies targeting NASH with advanced fibrosis and HCC.

Mathias Bonde Møllerhøj

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