Lower hepatotoxicity risk in Xelaglifam, a novel GPR40 agonist, compared to Fasiglifam for type 2 diabetes therapy

Fasiglifam, a candidate targeting GPR40, showed efficacy in clinical trials for type 2 diabetes but exerted liver toxicity. This study investigated the drug-induced liver injury (DILI) risk of Xelaglifam, a new GPR40 agonist, based on the potential toxicity mechanism of Fasiglifam; transporter inhibition, mitochondrial dysfunction, reactive metabolite formation, and covalent binding to proteins. In the hepatobiliary transporter assay, Xelaglifam showed a broader safety margin (>10-fold) against bile acid transporters, suggesting its less likelihood to cause bile acids accumulation, unlike Fasiglifam (<10-fold safety margin). Moreover, Xelaglifam showed no effect on glycocholic acid accumulation at higher concentrations than the estimated C_max in the 3D human liver model, whereas Fasiglifam affected the accumulation. In the HepaRG spheroids 3D model, the AC₅₀ values of Xelaglifam for mitochondrial function-related parameters were higher than Fasiglifam. Unlike Fasiglifam, none of the cell parameters for Xelaglifam were below the estimated 5x C_max. Additionally, the glucuronide metabolite of Xelaglifam was negligible (<1 % of the parent) in the Safety Testing, indicating a limited contribution to DILI. Fasiglifam activated genes related to liver disease, whereas Xelaglifam had no effect; instead, it increased FXR activity, a bile acid regulator. Notably, toxicity studies in rats and monkeys showed no adverse liver effects at higher exposure levels than the effective human blood concentration. Overall, these results support a low risk of DILI for Xelaglifam treatment and the justification for its long-term use for treating type 2 diabetes.