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

• Published in: Biomedicine & pharmacotherapy Vol. 181; p. 117674
• Main Authors: Yoon, Jongmin, Song, Haengjin, Park, Ji Soo, Kim, Jeong Ho, Jun, Yearin, Gim, Sang-Ah, Hong, Changhee, An, Kyung Mi, Park, Joon-Tae, Lee, Jung Woo, Yoon, Hongchul, Kim, Yun Seok, Kim, Sang Geon
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01-12-2024; Elsevier
• Subjects: Diabetes; DILI; Fasiglifam; GPR40 Agonist; Xelaglifam; Fasiglifam; DILI; PK/PD; AST; BSEP; GPR40 Agonist; GCA; ALP; AG; RTCA; ALT; MRP; MEC; GPR40; AP-1; CMV; And FXR; CVB; Xelaglifam; NRF2; PPAR; Diabetes
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117674

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 Cmax 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 Cmax. 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.
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•Xelaglifam is a novel GPR40 agonist and has a lower risk of hepatotoxicity compared to fasiglifam.•Xelaglifam has a lower risk of transporter inhibition and mitochondrial toxicity.•Xelaglifam has lower glucuronide metabolite production and risk of covalent binding.•Xelaglifam has no effect on liver disease-related gene activity, instead, it increases FXR activity.•Xelaglifam has no effect on the liver, even at exposures above the effective blood concentration.