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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis
Frederik Nevens1, Pietro Andreone1, Giuseppe Mazzella1
1From University Hospitals KU Leuven, Leuven, Belgium (F.N.); University of Bologna, Bologna (P.A., G.M.), Program for Autoimmune Liver Disease, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan (P.I.), Humanitas Clinical and Research Center, Rozzano (P.I.), and University of Padua, Padua (A.F.) - all in Italy; Royal Prince Alfred Hospital, Camperdown, NSW, Australia (S.I.S.); University of California Davis Medical Center, Sacramento (C.B.), Scripps Clinic, La Jolla (P.J.P.), and Intercept Pharmaceuticals, San Diego (R.H.-R., T.M., S.S., R.P., L.M., M.P., D.S.) - all in California; Radboud University Nijmegen Medical Center, Nijmegen (J.P.H.D.), University of Amsterdam, Amsterdam (U.B.), University Medical Center Utrecht, Utrecht (K.J.E.), and University Medical Center Rotterdam, Rotterdam (B.H.) - all in the Netherlands; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (J.R.); Medical University of Vienna, Vienna (M.T.); Newcastle University Medical School, Newcastle upon Tyne (D.E.J.), and the Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham (G.M.H.) - both in the United Kingdom; Liver Center Munich, Department of Medicine II, University of Munich, Munich, Germany (S.H.); Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond (V.L.), and the Liver Institute of Virginia, Newport News (M.S.) - all in Virginia; the Liver Unit, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas del Instituto de Salud Carlos III, Barcelona (V.V.); Centre Hospitalier de l'Université de Montréal-St. Luc, Montreal (C.V.); University Health Network Toronto Western Hospital, Toronto (H.S.); Arizona State University, Tempe (K.D.L.); Sahlgrenska Academy, University of Gothenburg,
Background:
Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.
Methods:
In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level.
Results:
Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 micromol per liter], respectively, vs. 0.12 mg per deciliter [2.0 micromol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group.
Conclusions:
Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
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