Table 4.

Observations from the AKRENDO1 study, supporting the hypothesis that differing mechanisms lead to isolated increases in serum bilirubin and hepatotoxicity in humans

Observation	Timing	Dose-dependency	Predictive value of animal toxicology studies	Hypothesis
Isolated increase in serum bilirubin (total, direct, and indirect)	Within days/2 weeks of exposure to BAY1128688 with tendency towards normalization at visit after 12 weeks of treatment	Directly correlated with exposure	Observed in cynomolgus monkey animal toxicology study with BAY1128688	Result of BAY1128688-mediated inhibition of transporters facilitating uptake and efflux of bilirubin to/from hepatocytes (e.g., via OATP1B1 and MRP2)
Increase in liver transaminases up to liver injury	>8 weeks of exposure to BAY1128688	Risk increased with dose, but extent of ALT increase/liver injury not directly correlated with exposure	Not observed in cynomolgus monkey animal toxicology study with BAY1128688	Result of BAY1128688-mediated inhibition of transporters facilitating exit/export of bile acids/salts from the hepatocyte (e.g., via BSEP)

ALT alanine aminotransferase, BSEP bile salt export pump, MRP2 multidrug resistance-associated protein 2, OATP organic anion-transporting polypeptides