Gastroenterology

Gastroenterology

Volume 148, Issue 4, April 2015, Pages 751-761.e8
Gastroenterology

Original Research
Full Report: Clinical—Liver
Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid

https://doi.org/10.1053/j.gastro.2014.12.005Get rights and content
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Background & Aims

We evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.

Methods

We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.

Results

OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%–25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%–63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%–35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline.

Conclusions

Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862.

Keywords

Cholestasis
Bile Acids
FXR
Dose Study

Abbreviations used in this paper

AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BA
bile acid
C4
BA precursor C4 (7α-hydroxy-4-cholesten-3-one)
CDCA
chenodeoxycholic acid
DCA
deoxycholic acid
FGF19
fibroblast growth factor 19
FXR
farnesoid x receptor
GGT
γ-glutamyl transferase
HDL
high-density lipoprotein
mITT
modified intent-to-treat
OCA
α-ethyl-chenodeoxycholic acid
PBC
primary biliary cirrhosis
UDCA
ursodeoxycholic acid
ULN
upper limit of normal

Cited by (0)

Conflicts of interest These authors disclose the following: Gideon M Hirschfield: consultancy for Intercept, BioTie, Lumena, Medigene, Janssen. Andrew Mason: Abbott and Gilead research support; Advisory Board member Novartis. Velimir Luketic: clinical trials Merck, Vertex, BMS, Idenix, Gilead, AbbVie, GSK, Genfit. Keith Lindor: unpaid consultant Intercept Pharmaceuticals and Lumena. Stuart C. Gordon: grant/research support: AbbVie Pharmaceuticals, Bristol-Myers Squibb, Gilead Pharmaceuticals, GlaxoSmithKline, Merck, Roche Pharmaceuticals, Vertex Pharmaceuticals; consultant/Adviser: Bristol-Myers Squibb, CVS Caremark, Gilead Pharmaceuticals, Merck, Vertex Pharmaceuticals; data monitoring board: Tibotec/Janssen. Kris V. Kowdley: grants and research support (paid to institution): AbbVie, Beckman, BMS, Boehinger Ingelheim, Gilead, Ikaria, Intercept Pharmaceuticals, Janssen, Merck, Mochida, Vertex; consultant: Novartis (honorarium paid to institution); service on Advisory Boards: AbbVie, Gilead, Ikaria, Janssen, Merck, Trio Health, Vertex (honorarium paid to institution). Henry C. Bodhenheimer Jr: Intercept: research grant; Lumena: consultant; Vertex: consultant; Novartis: consultant. Michael Trauner: speakers bureau: Falk Foundation; advisor: Falk Pharma, Phenex; travel grants: Falk Foundation; unrestricted research grants: Falk Pharma, Intercept Pharmaceuticals. Luciano Adorini: employed by Intercept Pharmaceuticals. Cathi Sciacca: employed by Intercept Pharmaceuticals. Tessa Beecher-Jones: contracted by Intercept Pharmaceuticals (independent consultant). Erin Castelloe: contracted by Intercept Pharmaceuticals (independent pharmacovigilance consultant). Olaf Böhm: contracted by Intercept Pharmaceuticals; employed by FGK Clinical Research. David Shapiro: employed by Intercept Pharmaceuticals. The remaining authors disclose no conflicts.

Funding Intercept Pharmaceuticals sponsored this clinical trial and supported trial design, data collection, analysis, and trial operation.

Author names in bold designate shared co-first authorship.