Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide

Fasiglifam is a selective partial agonist of G-protein-coupled receptor 40 (GPR40), which was developed for the treatment of type 2 diabetes mellitus. However, the clinical development of fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects. Fasiglifam showed an inhibitory effect on sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV) infections. Therefore, in this study, we hypothesised that fasiglifam would be a good candidate for a novel HBV entry inhibitor, and its effects were evaluated by using NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and human hepatocytes (PXB cells) obtained from PXB mice. Pre-treatment with fasiglifam at a concentration of 30 μM prior to HBV infection significantly suppressed supernatant HBV DNA levels after HBV infection in NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and PXB cells. Fasiglifam did not suppress supernatant HBV DNA levels up to 50 μM in HepG2.2.15.7 cells, which are stably transfected with a complete HBV genome without HBV infection. These results indicated that fasiglifam only affect on HBV infection via NTCP inhibition. For HBV treatment of fasiglifam, further investigation including additional non clinical research in addition to the evaluation of safety and efficacy in humans would be needed in the future study.