The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on Nonalcoholic Steatohepatitis in Nonhuman Primates
- 1 August 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (8), 1611-1623
- https://doi.org/10.2337/db20-0209
Abstract
Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting polyethylene glycolylated (PEGylated) fibroblast growth factor 21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the beta Klotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease (NAFLD), administration of B1344 via subcutaneous injection for 11 weeks caused a profound reduction of hepatic steatosis, inflammation, and fibrosis, along with amelioration of liver injury and hepatocyte death, as evidenced by liver biopsy specimen and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkeys, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, B1344 was administered to mice fed a methionine- and choline-deficient diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis in a dose-dependent manner. These results provide preclinical validation for an innovative therapeutic approach to NAFLD and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.Funding Information
- National Key R&D Program of China (2019YFA0802502)
- National Natural Science Foundation of China (81925008)
- Chinese Academy of Sciences (XDA12030210)
- National Science and Technology Major Projects (2019ZX09201001-001-001)
- Shanghai Science and Technology Commission (19140903300)
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