A Randomized Trial of Obeticholic Acid Monotherapy in Patients with Primary Biliary Cholangitis

ABSTRACT

Background: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled Phase 2 study in patients with primary biliary cholangitis (PBC) who were then reported for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of UDCA, which is relevant for patients who are intolerant of UDCA and at higher risk of disease progression.

Methods: Patients were randomized and dosed with placebo (n=23), OCA 10-mg (n=20), or OCA 50-mg (n=16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase (ALP) from Baseline to the end of the double-blind phase of the study (EOS). Secondary and exploratory endpoints included change from Baseline to Month 3/Early Termination (ET) in markers of cholestasis, hepatocellular injury, and FXR activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (OLE, N=28).

Results: ALP was reduced in both OCA groups [Median% (Q1, Q3); OCA 10-mg: -53.9% (-62.5, -29.3), OCA 50-mg: -37.2% (-54.8, -24.6)] compared to placebo [-0.8% (-6.4, 8.7); p<0.0001] at EOS with similar reductions observed through 6 years of OLE treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10-mg) and 38% (OCA 50-mg) discontinued due to pruritus.

Conclusions: OCA monotherapy significantly improved ALP and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of OLE treatment. This article is protected by copyright. All rights reserved.

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