1 Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.
2 Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition, Paris, France.
3 NAFLD Rsearch Center, University of California San Diego, San Diego, CA, USA.
4 Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
5 The Newcastle Liver Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
6 Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Paris, France.
7 Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany.
8 St Josef-Krankenhaus Kupferdreh, Essen, Germany.
9 National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
10 Institute of Translational & Stratified Medicine, University of Plymouth and University Hospitals Plymouth NHS Trust, Plymouth, UK.
11 Fresno Clinical Research Center, Fresno, CA, USA.
12 Baylor Health, Liver Consultants of Texas, Dallas, TX, USA.
13 Arkansas Gastroenterology, North Little Rock, AR, USA.
14 Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
15 Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, USA.
16 Swedish Liver Center, Seattle, WA, USA.
17 Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada.
18 HIFIH Laboratory, UPRES EA3859, SFR 4208, Angers University, Angers, France; Hepato-Gastroenterology Department, Angers University Hospital, Angers, France.
19 Hepato-gastroenterology, CHU Lille, Lille, France.
20 Department of Medical Sciences, University of Turin, Turin, Italy.
21 Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna, Bologna, Italy.
22 Department of Gastroenterology, Hospital Universitario La Paz, Madrid, Spain.
23 Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
24 Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain; Institut D'investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
25 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
26 The Gastrounit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
27 University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland.
28 Intercept Pharmaceuticals, San Diego, CA, USA.
29 Pinnacle Clinical Research Center, San Antonio, TX, USA.
30 Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: email@example.com.
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.
FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).
INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.
FUNDING: Intercept Pharmaceuticals.