PWE-088 Evaluation of drug-induced serious hepatotoxicity (EDISH) assessment in obeticholic acid-treated patients with nash

IntroductionEvaluation of drug-induced serious hepatotoxicity (eDISH) is a tool used to assess and identify potential cases of drug-induced liver injury (Senior J. Drug Safety. 2014;(37): Suppl 1:S9-S17). eDISH was used to evaluate obeticholic acid (OCA) and placebo profiles in 2 double-blind, placebo-controlled studies in patients with NASH. FLINT was a 72 week study, which demonstrated statistically significant improvements in hepatocellular ballooning, steatosis, lobular inflammation, and fibrosis in patients treated with OCA compared to placebo. CONTROL was a 16 week study, which showed that the addition of low-dose atorvastatin reversed OCA-associated changes in LDL-C. The objective of this analysis was to use eDISH to determine if patients with NASH treated with OCA show increased markers of liver injury or whole liver dysfunction.Methods eDISH Methodology was applied to 278 patients treated with placebo (n=140) or 25 mg OCA (n=138) from FLINT and 84 patients treated with placebo (n=21), 5 mg OCA (n=20), 10 mg OCA (n=21), or 25 mg OCA (n=22) from CONTROL. Individual peak of ALT and total bilirubin values during the double-blind treatment phase were plotted as log10 values of multiples of elevations above the upper limit of the normal (xULN).ResultsOverall, no OCA-treated patients were in the Hy’s law quadrant (>3 x ULN for ALT and >2 x ULN for total bilirubin) compared with 1 placebo-treated patient in FLINT. The proportion of patients with peak ALT and total bilirubin values in the lower left quadrant (representing normal or near normal range) was higher in OCA-treated patients compared with placebo (FLINT: 91% OCA vs 84% placebo; CONTROL: 91% OCA vs 86% placebo). 8% of OCA-treated patients from both FLINT and CONTROL presented in the Temple’s corollary quadrant (>3 x ULN for ALT and 2 x ULN total bilirubin and