Scientists Identify Beneficial Effects of a Novel FGF21 Analog B1344 on Nonalcoholic Steatohepatitis in Nonhuman Primates
Nonalcoholic steatohepatitis (NASH) is associated with increased incidence of cirrhosis, hepatocellular carcinoma and cardiovascular disease. There are currently no approved medications for treating nonalcoholic fatty liver disease (NAFLD) and NASH. Fibroblast growth factor 21 (FGF21) is an important metabolic regulator, and has shown beneficial effects on the improvement of NAFLD and NASH. However, due to the short half-life in vivo, the development of wild-type FGF21 as a drug is challenging.
B1344 is developed as a site-specific PEGylated human FGF21 analog. The reengineering of FGF21 leads to significantly improved biopharmaceutical properties, extends half-life and pharmacokinetics, and reduces immunogenicity.
In collaboration with Tasly Pharmaceutical Co. Ltd and Kunming Biomed International (KBI), a team of scientists led by Professor LI Yu from Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences demonstrated that in L6 myoblasts with the overexpression of βKlotho/FGFR1c, B1344 was sufficient to activate βKlotho/FGFR1c signaling and appeared to show stronger potency in terms of the activation of downstream signaling than that of wild-type FGF21.
Moreover, using high-fat diet-fed cynomolgus monkeys and methionine- and choline-deficient (MCD) diet-induced mice of NASH models, scientists demonstrated the salutary effects of B1344 on the protection against the progression of nonalcoholic steatohepatitis. In the cynomolgus monkeys with NAFLD, administration of B1344 for 11 weeks caused a remarkable reduction of hepatic fat content, inflammation and fibrosis as evidenced by magnetic resonance imaging and histological analysis of the liver biopsy. Meanwhile, the metabolic benefits of B1344 on lowering body weight, blood glucose, glucose tolerance and improving plasma lipid profile were observed in the monkey, whereas no obvious changes of the bone mineral density were observed. Consistently with the monkey data, the anti-NASH effects were also observed in MCD diet-induced rodent model.
This study provides preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.
This work entitled “The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates” was published online in Diabetes on April 30, 2020. It was supported by grants from Tasly Pharmaceutical Co. Ltd, Ministry of Science and Technology of China, National Health Commission of China, National Natural Science Foundation of China, Chinese Academy of Sciences, and Shanghai Science and Technology Commission.
Beneficial effects of B1344 on the progression of nonalcoholic fatty liver disease in obese cynomolgus monkeys. (Image by Dr. LI Yu’s team)
WANG Jin (Ms.)
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences