ZGN-1061 Improves Metabolic Parameters and Hepatic Pathology in an Obese Mouse Model of Diet-Induced and Biopsy-Confirmed Nonalcoholic Steatohepatitis Free

ZGN-1061 (1061) is a methionine aminopeptidase 2 (MetAP2) inhibitor being developed to improve glycemic control in type 2 diabetes. In diet-induced obese mice, 1061 reduces fat mass and improves glycemic control, lipid metabolism, and other metabolic parameters. This study investigated 8 weeks of treatment with 1061 (0.3 mg/kg, SC, N=11) or vehicle (N=10) on metabolic parameters, hepatic pathology, and nonalcoholic fatty liver disease (NAFLD) activity score (NAS; composite measure of steatosis, inflammation, and ballooning degeneration; range 0-8) in male mice with diet-induced and biopsy-confirmed nonalcoholic steatohepatitis (DIO-NASH). At week 8, there was a vehicle corrected weight loss of 13.1% with 1061 (p<0.001). 1061-treated mice had reduced liver weight (mean±SE: 2.6±0.4 g) vs. vehicle (3.8±0.8 g, p<0.001) and 21% reduction of liver triglyceride (p<0.05). There was no change in food intake. NAS was unchanged in vehicle-treated mice (BL 6.2±0.1, Wk8 6.4±0.2, ns). 1061-treated mice had reduced NAS (BL 6.2±0.2, Wk8 5.0±0.3, p=0.002). Two of the NAS component measures improved: steatosis in vehicle-treated mice was unchanged (BL 3.0±0.0, Wk8 3.0±0.0, ns), whereas ZGN-1061 reduced steatosis (BL 2.9±0.1, Wk8 2.5±0.2, p=0.02), and hepatocellular ballooning was unaffected in vehicle-treated mice (BL 0.7±0.2, Wk8 0.6±0.2, ns), whereas 1061 significantly reduced ballooning severity (BL 0.6 ± 0.2, Wk8 0.0 ± 0.0, p=0.006). There was no treatment effect on fibrosis stage or liver collagen 1A. However, liver galectin-3 was reduced with 1061 vs. vehicle. 1061 produced a reduction in terminal plasma ALT and AST vs. vehicle. In DIO-NASH mice, 1061 markedly reduced body weight in conjunction with liver weight and triglyceride content. Importantly, 1061 improved liver function, steatohepatitis and NAS composite score. These findings introduce 1061 as a promising therapy for obesity-related NASH.