Fibroblast growth factor 21 (FGF21) is an important metabolic regulator, and has shown beneficial effects on the improvement of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (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 the previous studies, a team of scientists led by Prof. LI Yu from Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences has identified the mechanisms of FGF21 in regulating hepatic insulin sensitivity, metabolic cross-talk between liver-adipose tissue, and liver fibrosis.

In order to promote the clinical application of FGF21 in NASH, the team, collaborating with Tasly Pharmaceutical Co. Ltd and Kunming Biomed International (KBI), compared in vitro bioactivity of B1344 and FGF21 on human- and monkey-derived receptor complex, and demonstrated the therapeutic efficacies of B1344 in rodent and nonhuman primate models. The finding was published online in Diabetes. 

Scientists 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 human FGF21.     

Moreover, using high-fat diet-fed cynomolgus monkeys and methionine- and choline-deficient (MCD) diet-induced mice of NASH models, they 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 mice. 

These results demonstrate beneficial effects of B1344 on lowering hepatic steatosis, fibrosis and inflammation, and on protecting against the progression of nonalcoholic steatohepatitis in rodents and nonhuman primates.

This study provides preclinical validation for an innovative therapeutics to NAFLD, and supports further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

NASH is associated with increased incidence of cirrhosis, hepatocellular carcinoma and cardiovascular disease. There are currently no approved medications for treating NAFLD and NASH.