T. Marmon

A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis

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 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol 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.).

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub‐fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non‐alcoholic fatty liver disease or non‐alcoholic steatohepatitis.

P374 LONG-TERM TREATMENT OF PRIMARY BILIARY CIRRHOSIS WITH THE FXR AGONIST OBETICHOLIC ACID SHOWS DURABLE EFFICACY

P372 APOPTOSIS INDUCED BY BILIRUBIN AND LITHOCHOLIC ACID IN HUMAN OSTEOBLASTS IS NEUTRALIZED BY URSODEOXYCHOLIC ACID S. Ruiz-Gaspa, M. Dubreuil, N. Guanabens, A. Combalia, P. Peris, A. Monegal, A. Pares. Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), Liver Unit, Digestive Diseases Institute, Hospital Cĺinic, IDIBAPS, University of Barcelona, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas, Rheumatology, Department of Orthopedics, Metabolic Bone Diseases Unit, Hospital Cĺinic, University of Barcelona, Liver Unit, Hospital Cĺinic, University of Barcelona, IDIBABPS, CIBERehd, Barcelona, Spain E-mail: silvia.ruiz@ciberehd.org

P1137 : Integrated efficacy summary for obeticholic acid in subjects with primary biliary cirrhosis

Background and Aims: Obeticholic acid (OCA), a modified bile acid and farnesoid x receptor (FXR) agonist, is currently in late-phase development for the treatment of primary biliary cirrhosis (PBC), a rare cholestatic liver disease. In two Phase 2 trials (3 months) and in the Phase 3 POISE trial (12 months) 5mg to 50mg OCA, once daily as monotherapy or add-on to UDCA, produced significant improvements in markers of cholestasis and inflammation. The objective of this integrated analysis was to evaluate the efficacy of ≤10mg OCA, the proposed indicated doses for the treatment of PBC, as monotherapy or in combination with UDCA in an integrated fashion across the 3 trials compared to placebo. Methods: Individual subject data from 3 completed, randomized, controlled double-blind trials of OCA once daily were pooled for this analysis (OCA ≤10mg N=201; placebo N=134; OCA 25mg N=48; OCA 50mg N=57). All placebo subjects were pooled as were OCA doses of 5mg, titration from 5 to 10mg, and 10mg (≤10mg OCA). Inclusion criteria included ALP ≥1.67×ULN or total bilirubin >ULN but <2×ULN. Analyses were repeated based on baseline concomitant UDCA use. Efficacy was evaluated using a composite endpoint shown to correlate with long-term survival (ALP <1.67 ULN with a minimum 15% reduction and a normal bilirubin) (Lammers 2014) and assessment of liver biochemistry and inflammation. Results: Baseline characteristics were generally similar between treatment groups. Baseline ALP was higher in monotherapy subjects compared to UDCA combination subjects. Efficacy data are presented in the Table. At the end of double blind treatment significantly more OCA-treated subjects achieved the composite endpoint compared to placebo when used as monotherapy or in combination with UDCA. OCA treatment was associated with statistically significant and clinically meaningful decreases in ALP as well as GGT, ALT, and AST. While the subjects in the monotherapy group had higher ALP at baseline than the OCA plus UDCA group, the two groups reached similar ALP levels by the end of the double-blind period. Pruritus was the most common adverse event associated with PBC and showed a dose-related increase in incidence with OCA.

Clinical application of the GLOBE and United Kingdom‐primary biliary cholangitis risk scores in a trial cohort of patients with primary biliary cholangitis

The GLOBAL Primary Biliary Cholangitis (PBC) Study Group and United Kingdom‐PBC (UK‐PBC) Consortium have demonstrated that dichotomous response criteria are not as accurate as continuous equations at predicting mortality or liver transplantation in PBC. The aim of this analysis was to assess the clinical utility of the GLOBE and UK‐PBC risk scores using data from POISE, a phase 3 trial investigating obeticholic acid (OCA) in patients with PBC. Data (N = 216) at baseline and month 12 were used to calculate the GLOBE and UK‐PBC risk scores to assess the projected change in risk with OCA versus placebo. Additionally, the benefit of OCA was assessed in patients not meeting the POISE primary endpoint. Both the GLOBE and UK‐PBC risk scores predicted a significant reduction in long‐term risk of death and liver transplantation after OCA treatment (P < 0.0001). The differences in the relative risk reduction from baseline in the 10‐year event risk after 1 year for OCA 10 mg versus placebo was 26% (GLOBE) and 37% (UK‐PBC). The scores also predicted a significantly decreased risk in patients treated with OCA who did not meet POISE response criteria after 1 year of treatment compared to an increased risk with placebo (P < 0.0001). Conclusion: This analysis demonstrates the use of the GLOBE and UK‐PBC risk scores to assess risk reduction of a cohort treated with OCA. While validation of this risk reduction in studies with clinical outcomes is needed, this study highlights the potential use of these scores in individualizing risk prediction in PBC both in clinical practice and therapeutic trials. (Hepatology Communications 2018;2:683‐692)