A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis

Abstract

Background & aims: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. Methods: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3.0 mg, or OCA 5-10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. Results: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5-3.0 mg (n = 25), and OCA 5-10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5-10 mg vs. placebo (least-square [LS] mean difference = -83.4 [SE = 40.3] U/L; 95% CI -164.28 to -2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5-3.0 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L; 95% CI -162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5-3.0 mg 60%; OCA 5-10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. Conclusions: Treatment with OCA 5-10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.