1833-P: A Novel Genetic Modified and Pegylated FGF21 Analog for the Treatment of Nonalcoholic Steatohepatitis in Nonhuman Primates

Nonalcoholic steatohepatitis (NASH) is becoming a major cause of liver diseases with no effective drugs in the clinic. Fibroblast growth factor 21 (FGF-21) has emerged as a potent metabolic regulator with therapeutic prospect to lipids and NASH in animal models and preclinical trials. FGF-21 and the agents mimicking its activity may be developed into the pharmacotherapeutic targets for NASH treatment. Here, we show that B1344, a site-specific PEGylated human FGF-21 analog, shifts physiology of NASH mice or cynomolgus monkeys towards that of the control animals fed with standard diet, and significantly improves their NASH phenotypes. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, methionine and choline deficiency (MCD) diet-fed mouse model of NASH were generated. Both short- and long-term administration of B1344 with the doses of 0.125 mg/kg and 0.2 mg/kg in mice protect against lipotoxicity damage and liver fibrosis. Expression levels of proinflammatory and fibrotic genes are decreased in livers of mice treated with B1344. Moreover, pharmacologic efficacies of B1344 on NASH were evaluated in NAFLD cynomolgus monkeys fed with high-fat diet. Strikingly, administration of B1344 causes a potent reduction of hepatic steatosis and fibrosis as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) and Sirius Red staining, and protects the monkeys from the progression of steatohepatitis. In addition, administration of B1344 results in a reduction of body weight and adiposity, and improvement of lipid profile and glycemic control. The biological properties of the novel FGF-21 analog B1344 is identical to human FGF-21. Together, these demonstrate impressive effects of B1344 on NASH and metabolic parameters, and may represent novel therapeutics for treating these diseases in humans.