Abstract
Fasiglifam (TAK-875), a GPR40 agonist, which was under development as a type 2 diabetes agent, voluntarily discontinued the development just before NDA in Japan and the US. The cause of discontinuation was the concern of side effects on human liver, which were recognized as Drug Induced Liver Injury (DILI). In fact, various groups have studied the cause of DILI induction by Fasiglifam; however, due to the complexity of its development mechanism, the extrapolation and predictability from animals to humans have not been sufficiently elucidated.
DILI in humans by fasiglifam was not a phenomenon unexpectedly clarified in the clinical trial, but the influence on liver effect of dogs had been confirmed from the early development stage. In fact, FDA asked for a view on the extrapolation of dog hepatotoxicity to humans, and they requested a prospective for human safety after the initiation of Phase 3.
The results of various nonclinical studies eliminated the concern of extrapolation to humans related to the dog hepatotoxicity and the initiation of Phase 3 trial was approved by FDA.
In this symposium, I would like to share the results of nonclinical DMPK studies that wiped out the concerns about human extrapolation on hepatotoxicity in dogs, and consider whether the judgment was appropriate. Also, I would like to consider the relationship between dog hepatotoxicity and adverse effects of human liver in the Phase 3 trial which actually decided to discontinue the development voluntarily.
