In December 2013, Takeda announced voluntary termination of the development of fasiglifam (TAK-875) in Phase 3 clinical trials. TAK-875, a GPR40 agonist being developed for the treatment of type 2 diabetes, caused alanine aminotransferase elevation in 2% of treated subjects indicating drug-induced liver injury (DILI) effects.
Only now are the mechanisms behind the DILI reaction being unravelled, through a combination of in vitro data and quantitative systems toxicology (QST) analysis using the DILIsym® software. Two primary mechanisms were identified as being responsible for the liver toxicity; firstly, inhibition of the human Bile Salt Export Protein (BSEP), and secondly, inhibition of the mitochondrial electron transport chain. Both TAK-875 itself, as well as a glucuronide metabolite of TAK-875, were implicated in these effects.
All the in vitro mitochondrial electron transport chain data was generated by Cyprotex using its Seahorse XFe platform, and these data were corrected for the intracellular concentrations in the HepG2 cells used for the assay. The study was successful in identifying that both mitochondrial electron transport chain disruption and BSEP inhibition were necessary to explain the adverse effects and that these mechanisms act synergistically in producing the observed clinical outcome.
Cyprotex co-presented the study along with Takeda, DILIsym and Solvo at the Society of Toxicology conference in Baltimore from the 12-16th March 2017.