5 Online Appendix (without).pdf (971.12 kB)

The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

Download (971.12 kB)
figure
posted on 30.06.2020 by Ada Admin, Aoyuan Cui, Jian Li, Shaohui Ji, Fengguang Ma, Genbei Wang, Yaqian Xue, Zhengshuai Liu, Jing Gao, Jun Han, Ping Tai, Tony Wang, Jianxun Chen, Xiaohui Ma, Yu Li
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 PEGylated FGF21 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 βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, 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, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide 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.

Funding

This study was supported by Tasly Pharmaceutical Co. Ltd, China. This work was also supported by grants from National Key R&D Program of China (2019YFA0802502), National Natural Science Foundation of China (81925008), Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12030210), Shanghai Science and Technology Commission (19140903300) to Y.L.; and by grants from National Science and Technology Major Projects (2019ZX09201001-001-001) to J.G.

History

Exports

Logo branding

Exports