Hepatoprotective effects of the long-acting FGF21 analogue PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogues has emerged as a promising drug candidates for the treatment of non-alcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the aetiology and hallmarks of the human disease. To this end, we evaluated the long-acting FGF21 analogue PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 weeks prior to study start. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg, SC) or vehicle (SC) for 12 weeks. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. Conclusion: PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogues for the treatment of NASH.