A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis

Kris V Kowdley, Velimir Luketic, Roger Chapman, Gideon M Hirschfield, Raoul Poupon, Christoph Schramm, Catherine Vincent, Christian Rust, Albert Parés, Andrew Mason, Hanns-Ulrich Marschall, David Shapiro, Luciano Adorini, Cathi Sciacca, Tessa Beecher-Jones, Olaf Böhm, Richard Pencek, David Jones, Obeticholic Acid PBC Monotherapy Study Group, Kris V Kowdley, Velimir Luketic, Roger Chapman, Gideon M Hirschfield, Raoul Poupon, Christoph Schramm, Catherine Vincent, Christian Rust, Albert Parés, Andrew Mason, Hanns-Ulrich Marschall, David Shapiro, Luciano Adorini, Cathi Sciacca, Tessa Beecher-Jones, Olaf Böhm, Richard Pencek, David Jones, Obeticholic Acid PBC Monotherapy Study Group

Abstract

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.

Conclusion: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).

© 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

Figures

Figure 1
Figure 1
OCA reduces ALP. (A) Percent change in ALP at EOS. (B) ALP change from baseline. Data are median (Q1, Q3). **P < 0.01, ***P < 0.0001; P values determined by pairwise comparisons using a two‐sided Wilcoxon‐Mann‐Whitney test comparing changes in each OCA group with the placebo group. Note: the primary endpoint includes ET values or last observation carried forward values. ALP change from baseline values at month 3 include the ET visit data for patients who discontinued where available. Abbreviation: BL, baseline.
Figure 2
Figure 2
Effect of OCA on liver biochemistries. (A) GGT change from baseline. (B) AST change from baseline. (C) ALT change from baseline. (D) Conjugated bilirubin change from baseline. Data are median (Q1, Q3). Change from baseline values at month 3 include the ET visit data for patients who discontinued. *P < 0.05, **P < 0.01, ***P < 0.0001; P values determined by pairwise comparisons using a two‐sided Wilcoxon‐Mann‐Whitney test comparing changes in each OCA group with the placebo group. Abbreviation: BL, baseline.
Figure 3
Figure 3
Markers of FXR activation. (A) FGF‐19 change from baseline to month 3/ET. Baseline FGF‐19 was 77.5 (27.6, 85.5), 109.7 (86.3, 228.3), and 74.7 (48.8, 144.3) for placebo, OCA 10 mg, and OCA 50 mg groups, respectively. (B) C4 change from baseline to month 3/ET. Baseline C4 was 18.2 (8.9, 22.3), 8.6 (4.3, 19.0), and 9.1 (6.5, 27.4) for placebo, OCA 10 mg and OCA 50 mg groups, respectively. Data are median (Q1, Q3). Change from baseline values at month 3 include the ET visit data for patients who discontinued. *P < 0.05; P values determined by pairwise comparisons using a two‐sided Wilcoxon‐Mann‐Whitney test comparing changes in each OCA group with the placebo group.
Figure 4
Figure 4
Changes in liver biochemistry over 6 years of OLE. (A) ALP change from baseline. (B) GGT change from baseline. (C) AST change from baseline. (D) ALT change from baseline. (E) Conjugated bilirubin change from baseline. For all plots, values presented are median (Q1, Q3) of all patients participating in the trial at any point regardless of dose or group. Dashed line represents the median change from baseline at the end of the double‐blind phase. Off‐Rx refers to the study period from month 3 and initiating OCA during the OLE. Abbreviation: BL, baseline.

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