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

Abstract

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 1·9, 95% CI 1·3 to 2·8; 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.

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

“…An interesting example of this strategy is the use of a farnesoid X receptor ( FXR , formally NR1H4 ) agonist (obeticolic acid) for the treatment of both primary biliary cholangitis38 and NASH 39…”

Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

“…In a phase IIb, randomized, controlled study of 283 patients with noncirrhotic NASH (the FLINT study), OCA 25 mg daily was more effective than placebo in inducing histologic improvement in the NAS by 2 points or more with no worsening in fibrosis 31. Moreover, 35% of patients treated with OCA had a reduction in their fibrosis score by at least one stage compared to only 19% in the placebo arm.…”

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

“…Recently, there has been considerable interest in this field, with the appreciated that subtle changes in the bile acid structure can profoundly influence their efficacy as signalling molecules. For adding an ethyl group at carbon position 6 in chenodeoxycholic acid, it markedly affects the ligandbinding capability of chenodeoxycholic acid to the nuclear hormone FXR.Treatment with obeticholic acid has recently shown promise in treating NASH in the Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment (FLINT) trial with improvement in liver histology in approximately 50% of patients with non-cirrhotic NASH [35]. …”

“…Considering that insulin resistance is the hallmark of NAFLD, drugs acting on glucose metabolism have long been considered for NAFLD treatment [35,58,[72][73][74][75][76][77][78][79][80]. Insulin sensitizers have been tested in several clinical trials of different duration.…”

“…Bile acids have been reported to regulate hepatic lipid and glucose metabolism through FXR, a member of the nuclear hormone receptor superfamily, and TGR5, a G protein-coupled bile acid receptor 1. Whereas no solid data are available for a beneficial effect of ursodeoxycholic acid on histology in NASH patients, obeticholic acid has recently been reported to promote NASH remission in a phase II study [35]. However, no advantage on glucose metabolism was reported and the use of this compound may be limited by some important side effects (e.g., pruritus and increase in LDL-cholesterol concentrations).…”