Elsevier

The Lancet

Volume 385, Issue 9972, 14–20 March 2015, Pages 956-965
The Lancet

Articles
Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(14)61933-4Get rights and content

Summary

Background

The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.

Methods

We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.

Findings

Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.

Interpretation

Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Introduction

Non-alcoholic steatohepatitis is an increasingly common cause of chronic liver disease worldwide and it is associated with increased liver-related mortality and hepatocellular carcinoma, even in the absence of cirrhosis.1, 2, 3 Non-alcoholic steatohepatitis progresses to cirrhosis in 15–20% of affected individuals and is a rising indication for liver transplantation4 but at present there are no approved therapies.

Obesity, diabetes, and insulin resistance (especially in adipose tissue) are all associated with non-alcoholic steatohepatitis and probably contribute to its pathogenesis.5, 6 Consequently, dietary changes and lifestyle modification to achieve weight reduction and improve insulin sensitivity are recommended.7, 8 The long-term effectiveness of these interventions is debatable because many patients are unable to initiate or maintain dietary and lifestyle changes,7, 9 underscoring the need for pharmacological therapy. Vitamin E and thiazolidinediones are the best studied drugs for the treatment of non-alcoholic steatohepatitis.10 Although both improve liver histology in patients without diabetes, their effects in patients with diabetes are unknown. Moreover, thiazolidinediones are associated with weight gain and other adverse outcomes, and the long-term efficacy and safety of vitamin E also remain uncertain.11, 12

Over the last decade, lipophilic bile acids have emerged as potent modulators of metabolism and insulin sensitivity.13, 14 When bound to the farnesoid X nuclear receptor, lipophilic bile acids promote insulin sensitivity and decrease hepatic gluconeogenesis and circulating triglycerides.15 These beneficial effects are mediated by decreased hepatic lipid synthesis and enhanced peripheral clearance of VLDL.16, 17, 18 Farnesoid X nuclear receptor activation also increases the expression of hepatic scavenger receptors (SRB1), which accelerates reverse cholesterol transport by increasing the clearance of HDL. Based on these metabolic effects, pharmacological activation of farnesoid X nuclear receptor has been proposed as a target for the treatment of non-alcoholic steatohepatitis.19

6-ethylchenodeoxycholic acid (obeticholic acid), a synthetic variant of the natural bile acid chenodeoxycholic acid, is a potent activator of farnesoid X nuclear receptor. In pre-clinical studies, it improved hepatic steatosis, fibrosis, and portal hypertension.20, 21, 22 In a small group of patients with type 2 diabetes and suspected non-alcoholic fatty liver disease, obeticholic acid improved insulin sensitivity and reduced serum alanine aminotransferase concentrations.23 The less lipophilic bile acid ursodeoxycholic acid binds negligibly to farnesoid X nuclear receptor and in a randomised clinical trial it did not show efficacy in non-alcoholic steatohepatitis.24

With this background, we designed and undertook a clinical trial to assess the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.

Section snippets

Study design and participants

The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial was a multicentre, randomised trial of 72 weeks of obeticholic acid versus placebo in patients with biopsy evidence of non-alcoholic steatohepatitis. Between March 16, 2011, and Dec 3, 2012, we enrolled patients at eight participating medical centres in the USA (appendix). Details of the trial were approved by local institutional review boards and a central data safety and monitoring board (DSMB) appointed by the

Results

283 patients with histologically proven non-alcoholic steatohepatitis or borderline non-alcoholic steatohepatitis based on the site pathologist reading of the liver biopsy were randomly assigned to receive obeticholic acid (n=141) or placebo (n=142) (figure 1). 15 (5%) patients had minor protocol deviations, mainly from timing targets (entry liver biopsies outside the stated 90-day window by up to 11 days, and baseline laboratory results outside stated time windows, but never after

Discussion

In this randomised, placebo-controlled, clinical trial, the farnesoid X nuclear receptor agonist obeticholic acid improved the biochemical and histological features of non-alcoholic steatohepatitis compared with placebo in patients without cirrhosis. Importantly, all components of the NAFLD activity score (steatosis, hepatocellular ballooning, and lobular inflammation) and fibrosis improved. The improvement in fibrosis, although small, shows that this therapy might be beneficial in preventing

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