Accepted Manuscript Efficacy of Obeticholic Acid in Patients with Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid Gideon M. Hirschfield , Andrew Mason , Velimir Luketic , Keith Lindor , Stuart Gordon , Marlyn Mayo , Kris V. Kowdley , Catherine Vincent , Henry C. Bodhenheimer , Jr., Albert Parés , Michael Trauner , Hanns-Ulrich Marschall , Luciano Adorini , Cathi Sciacca , Tessa Beecher-Jones , Erin Castelloe , Olaf Böhm , David Shapiro PII: DOI: Reference:

S0016-5085(14)01530-3 10.1053/j.gastro.2014.12.005 YGAST 59494

To appear in: Gastroenterology Accepted Date: 8 December 2014 Please cite this article as: Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon S, Mayo M, Kowdley KV, Vincent C, Bodhenheimer Jr. HC, Parés A, Trauner M, Marschall H-U, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Böhm O, Shapiro D, Efficacy of Obeticholic Acid in Patients with Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid, Gastroenterology (2015), doi: 10.1053/j.gastro.2014.12.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

ACCEPTED MANUSCRIPT

Title: Efficacy of Obeticholic Acid in Patients with Primary Biliary Cirrhosis and

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Inadequate Response to Ursodeoxycholic Acid

Short title: OCA Treatment of PBC

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Gideon M Hirschfield,1 Andrew Mason,2 Velimir Luketic,3 Keith Lindor,4 Stuart Gordon,5 Marlyn Mayo,6 Kris V. Kowdley,7 Catherine Vincent,8 Henry C. Bodhenheimer, Jr.9 Albert

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Parés,10 Michael Trauner,11 Hanns-Ulrich Marschall,12 Luciano Adorini,13 Cathi Sciacca,13 Tessa Beecher-Jones,13 Erin Castelloe, 13 Olaf Böhm,14 David Shapiro13

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Center for Liver Research, NIHR Biomedical Research Unit, University of Birmingham,

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Birmingham, UK; 2Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada; Virginia Commonwealth University School of Medicine, Richmond, VA, and McGuire

Research Institute, McGuire VA Medical Center, Richmond, VA; 4Division of Gastroenterology

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& Hepatology, Mayo Medical School, Rochester, MN, USA and Arizona State University, Phoenix, AZ, USA; 5Division of Hepatology, Henry Ford Health Systems, Detroit, MI, USA Division of Digestive and Liver Diseases, University of Texas, Southwestern Medical Center,

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Dallas, TX, USA; 7Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA; 8Hopital Saint-Luc/CHUM Montreal, Canada; 9Mount Sinai School of Medicine and Division of Digestive Diseases, Beth Israel Medical Center, New York, NY, USA; 10Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain; 11Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna,

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Austria; 12Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;

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Intercept Pharmaceuticals, San Diego, CA, USA;

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FGK

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Clinical Research, Munich, Germany.

Support:

Intercept Pharmaceuticals sponsored this clinical trial and supported trial design, data collection,

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analysis, and trial operation. All authors had access to the datasets and statistical analysis plan and had rights to audit data. GMH, LA, CS, TBJ, EC, OB and DS finalized analysis and data

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presentation. H-U M was responsible for bile acid and OCA assays. GMH, LA and DS had final responsibility to submit the manuscript after obtaining the agreement of all the authors

Abbreviations: alanine

aminotransferase;

AMA,

anti-mitochondrial

antibody;

AST,

aspartate

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ALT,

aminotransferase; BA, bile acids; C4, BA precursor C4 (7α-hydroxy-4-cholesten-3-one); CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; ELISA, enzyme-linked immunoabsorbant

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assay; ET, end of therapy; FGF19, fibroblast growth factor 19; FXR, farnesoid x receptor; ITT, intent-to-treat; GGT, γ-glutamyl tranferase; LCA, lithocholic acid; mITT, modified intent-to-

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treat; OCA, α-ethyl-chenodeoxycholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal

Corresponding author: Dr. Gideon Hirschfield, Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK. Email: [email protected]. Tel: 0121 415 8700;

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Fax: 0121 415 8701. Disclosures: Results from these studies were presented in part in abstract form at the European Association

Diseases (2010 and 2011) annual meetings.

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for the Study of the Liver (2010 and 2012) and American Association for the Study of Liver

Secretary; Tilman Oltersdorf, MD; Timothy Morgan, MD.

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Contributors’ statement:

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The Data Safety Monitoring Committee: Edward Krawitt, MD, Chair; Helen Young, MD,

Trial design, implementation and patient recruitment: GMH, AM, VL, KL, SG, MM, KVK, CV, HCB, AP, MT, LA, CS, TB-J, DS. Study analyses and interpretation: GMH, H-U M, LA, EC, CS, TB-J, OB, DS. Manuscript preparation, revisions, resubmissions and final version: GMH,

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LA, CS and DS with final approval by all authors.

Conflicts of Interest relevant to submission

Medigene, Janssen.

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Gideon M Hirschfield: Study investigator. Consultancy for Intercept, BioTie, Lumena,

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Andrew Mason: Study investigator.

Abbott and Gilead research support. Advisory Board

member Novartis.

Velimir Luketic: Study investigator. Clinical trials Merck, Vertex, BMS, Idenix, Gilead, Abbvie, GSK, Genfit

Keith Lindor: Study investigator. Unpaid consultant Intercept Pharmaceuticals and Lumena

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Stuart Gordon: Study investigator. Grant/Research support: Abbvie Pharmaceuticals, BristolMyers Squibb, Gilead Pharmaceuticals, GlaxoSmithKline, Merck, Roche Pharmaceuticals, Vertex Pharmaceuticals. Consultant/Adviser: Bristol-Myers Squibb, CVS Caremark, Gilead

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Pharmaceuticals, Merck, Vertex Pharmaceuticals. Data Monitoring Board: Tibotec/Janssen. Marlyn Mayo: Study investigator. None relevant to paper.

Kris V. Kowdley: Study investigator. Grants and Research Support (paid to institution): AbbVie,

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Beckman, BMS, Boehinger Ingelheim, Gilead, Ikaria, Intercept Pharmaceuticals, Janssen, Merck, Mochida, Vertex; Consultant: Novartis (honorarium paid to institution); Service on

to institution)

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Advisory Boards: AbbVie, Gilead, Ikaria, Janssen, Merck, Trio Health, Vertex (honorarium paid

Catherine Vincent: Study investigator. None relevant to paper.

Henry C. Bodhenheimer, Jr.: Study investigator. Intercept: research grant; Lumena: consultant

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Vertex: consultant; Novartis: consultant. Albert Parés: Study investigator.

Michael Trauner: Study investigator. Speakers bureau: Falk Foundation; Advisor: Falk Pharma,

Pharmaceuticals.

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Phenex; Travel grants: Falk Foundation; Unrestricted research grants: Falk Pharma, Intercept

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Hanns-Ulrich Marschall: Study investigator. None relevant to paper. 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).

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Olaf Böhm: Contracted by Intercept Pharmaceuticals. Employed by FGK Clinical Research.

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David Shapiro: Employed by Intercept Pharmaceuticals.

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Abstract:[379/260] Background & Aims: We evaluated the efficacy and safety of obeticholic acid (OCA, α-

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ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis (PBC) who had an inadequate response to ursodeoxycholic acid (UDCA) therapy.

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Methods: We performed a double-blind study of 165 patients with PBC (95% women) and levels of alkaline phosphatase (ALP) 1.5–10-fold the upper limit of normal. Patients were

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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 UDCA 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

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patients were enrolled and 61 completed the first year.

Results: OCA was superior to placebo in achieving the primary endpoint. Subjects given OCA

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had statistically significant relative reductions in mean ALP from baseline to the end of the study (P1.5 mg/dL (133 µmol/L); use of colchicine, methotrexate, azathioprine, or systemic corticosteroids at any time during the 3 months prior to screening; history or presence of hepatic decompensation. Patients with other concomitant liver diseases, including

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autoimmune hepatitis overlap were also excluded. Patients maintained their existing dose of UDCA throughout the study.

The study protocol and subsequent amendments were reviewed and approved by the

registered

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appropriate Ethics Committees or Institutional Review Boards at each site. The trial was pre(www.clinicaltrials.gov;

NCT00550862

and

www.controlled-trials.com;

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ISRCTN67465025). The study protocol is available on request. All authors had access to complete datasets. GMH, LA, CS, TBJ, EC, OB and DS finalized analysis and data presentation. GMH, LA and DS had final responsibility to submit the manuscript after all authors reviewed and approved the manuscript.

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Sample size. The study sample size was calculated in terms of effect size: 35 patients per group provided 80% power to detect an effect size of 0.70 which translates to approximately a 10%

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mean greater reduction in ALP levels between groups (see Supplementary Table 1).

Randomization and masking. Eligible patients were randomly assigned (1:1:1:1) to one of four treatment groups for 85 days (3 months): OCA 10 mg, OCA 25 mg, OCA 50 mg or a matching

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placebo administered once daily. The computerized randomization schedule used a block size of

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4 at each center.

Recruitment and the double-blind study phase occurred between November 2007 and May 2009. Study assessment visits were performed on Day 0 (randomization), 15, 29, 57, 85 (i.e. 3 months; End of Treatment [ET]). Patients had a follow up visit (off drug therapy) 14 days later. ALP and

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liver enzymes levels were determined at each visit by a central laboratory. Safety assessments included adverse events (AEs), pruritus, physical examinations, vital signs, clinical laboratory testing including lipids, and electrocardiograms. Blood samples for bile acids, fibroblast growth

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ET, if earlier.

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factor-19 (FGF19), C4, C-reactive protein and IgM assays were obtained at day 0 and 85 or at

Open-label OCA therapy was offered to patients completing the double-blind portion of the study at 13 centers. These patients were dosed for at least an additional 12 months (unless they discontinued earlier). Patients were re-started on OCA 10-mg once-daily dosing or the dose assigned during the double-blind phase and allowed to titrate up or down at the discretion of the investigator based on individual ALP response and tolerability. Average daily OCA doses of