The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of the disease, which results in cirrhosis, liver failure, and death in a substantial proportion of patients. Treatment approaches to NAFLD in adults and children target reduction in insulin resistance and oxidative stress. Several agents have been found to be promising as therapy of NAFLD in small clinical trials, but none have been proven to alter its natural history or outcome, and none are approved for general use in this disorder. The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was established by the NIDDK in 2002 to investigate the natural history, pathogenesis, and therapy of NAFLD and NASH in both children and adults. The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) trial was a multicenter, randomized, placebo-controlled clinical trial conducted by the NASH CRN to investigate the safety and efficacy of treatment of obeticholic acid compared to placebo in adults with nonalcoholic fatty liver disease.

Individuals with histologic evidence of NASH, based on a liver biopsy and a disease activity score (NAS) of at least 4 (with a score of at least 1 in each component of the NAS 8-point scale), were enrolled and randomized to treatment with either obeticholic acid (25 mg) or placebo for 72 weeks. Each participant received a baseline oral glucose tolerance test and a baseline MRI scan to determine liver fat content. Additionally, information was collected on demographics, alcohol consumption, and medication use. The primary outcome measure was improvement in the NAS score by at least 2 points with no worsening of liver fibrosis and was assessed by liver biopsy at 72 weeks. Secondary outcome measures included change in NASH diagnosis (from determinate or indeterminate to not-NASH), fibrosis score, hepatocellular ballooning score, hepatic fat fraction, serum aminotransferase and gamma-glutamyl transpeptidase (GGT) levels, fasting glucose levels, and health related quality of life scores.

A planned interim analysis of end-of-treatment liver biopsies from 58% (164/283) of enrolled patient demonstrated that the primary endpoint had been reached and the statistical significance crossed the preset boundry set for efficacy (p ≤ 0.0031). Accordingly, further liver biopsies were not performed. Additionally, because of the observation of disproportionate lipid abnormalities among patients receiving OCA and in the context of the study having met its primary endpoint, further treatment with OCA and placebo was discontinued and remaining patients completed a 24-week follow-up off treatment.