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

Kowdley, Kris V; Vuppalanchi, Raj; Levy, Cynthia; Floreani, Annarosa; Andreone, Pietro; LaRusso, Nicholas F; Shrestha, Roshan; Trotter, James; Goldberg, David; Rushbrook, Simon; Hirschfield, Gideon M; Schiano, Thomas; Jin, Yuying; Pencek, Richard; MacConell, Leigh; Shapiro, David; Bowlus, Christopher L

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×ULN and total bilirubin <2.5×ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5-3 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 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 (standard error [SE]=40.3) U/L, 95% CI: -164.28, -2.57; p=0.043. Serum ALP was not significantly reduced with OCA 1.5-3 mg vs. placebo at week 24 (LS mean [SE] difference = -78.29 [41.81] U/L, 95% CI: -162.08, 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 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.