EFFECT OF OBETICHOLIC ACID ON APRI SCORE IN PATIENTS AT HIGHER RISK FOR FIBROSIS, AS DETERMINED BY HIGHER BASELINE FIBROSIS-4 SCORE AND LIVER STIFFNESS: SUBANALYSIS OF THE PHASE 3 POISE TRIAL IN PRIMARY BILIARY CHOLANGITIS

Introduction: Transient elastography (TE) is a noninvasive alternative to biopsy for assessment of liver stiffness and indirectly fibrosis, which can be predictive of adverse outcomes in patients with primary biliary cholangitis (PBC). Recent studies suggest that Fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), which have been demonstrated to predict fibrosis progression in liver disease but have not been validated in patients with PBC, may also be surrogate markers of fibrosis in PBC. Obeticholic acid (OCA), a selective, potent farnesoid X receptor agonist, received accelerated approval in 2016 for the treatment of PBC based on biomarker improvement in POISE, a 12-month randomized, double-blind, placebo-controlled phase 3 study. Here, we report the results of a post hoc analysis of the impact of OCA on APRI in patients from POISE, including in subsets of patients with higher TE liver stiffness (at baseline) and FIB-4 score (at month 3, to account for rapid OCA reductions in alanine aminotransferase [ALT]/aspartate aminotransferase [AST]), suggesting higher risk of advanced fibrosis.

Methods: Patients with PBC who could not tolerate or had an incomplete response to first-line ursodeoxycholic acid were randomized to receive placebo, OCA 5 to 10 mg (OCA titration), or OCA 10 mg daily. Liver stiffness was measured by TE at baseline and month 12 at study sites where FibroScan^TM TE was available. FIB-4 was calculated from age, AST, ALT, and platelet count, while APRI was calculated from AST and platelet count at all visits. Change from baseline in APRI at month 12 was calculated in the OCA- and placebo-treated groups in the overall study population as well as in subsets of patients at higher risk for fibrosis (ie, TE >8 kPa at baseline or FIB-4 >1.3 at month 3). Least-squares mean differences among treatment groups were compared using an analysis of covariance model with the baseline value as a covariate and fixed effects for treatment and randomization stratification factors.

Results: Treatment with OCA resulted in a statistically significant reduction from baseline in APRI at month 12 in the overall study population (N=216) as well as in subgroups with FIB-4 >1.3 at month 3 (n=120) and TE >8 kPa at baseline (n=55) when compared with placebo (p<0.05 in all cases; Table). Of note, APRI was higher across all treatment groups in the TE (>8 kPa at baseline) and FIB-4 (>1.3 at month 3) subsets, which is indicative of higher risk of fibrosis.

Conclusions: In the POISE trial, treatment with OCA significantly reduced APRI vs placebo in patients with PBC, including among those at higher risk for fibrosis. Additional studies are warranted to determine whether APRI is a valid and clinically useful surrogate for fibrosis and adverse clinical outcomes in PBC.