L. Macconell

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.).

Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide and is an increasing cause of liver-related morbidity and mortality. Nonalcoholic steatohepatitis (NASH), the progressive histological subtype of the disease, is a growing target for drug design and development. Currently, no effective drug therapies exist for the management of NASH and multiple challenges exist for NASH-related clinical trials, stressing the need for a focused deliberative approach to facilitate drug development. One such challenge includes the inconsistent measurement of baseline parameters across clinical trials, which makes interpretation and comparison of trial data difficult and impedes drug development effort.

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.