No Significant Effects of Ethyl-eicosapentanoic Acid on Histologic Features of Nonalcoholic Steatohepatitis in a Phase 2 Trial

Background & Aims: n-3 polyunsaturated fatty acids reduce insulin resistance, lipogenesis, and inflammation, which are features of nonalcoholic steatohepatitis (NASH). Ethyl-eicosapentanoic acid (EPA-E) is a synthetic polyunsaturated fatty acid that reduces hypertriglyceridemia. We report the final results of a phase 2b multicenter, prospective, double-blind, randomized, placebo-controlled trial of EPA-E for NASH.

Methods: Our study, performed at 37 sites in North America, included subjects with NASH and nonalcoholic fatty liver disease (NAFLD) activity scores ≥ 4, with minimum scores of 1 for steatosis and inflammation, along with either ballooning or at least stage 1a fibrosis. A total of 243 subjects were randomly assigned to groups given placebo (n = 75), low-dosage EPA-E (1800 mg/d; n = 82), or high-dosage EPA-E (2700 mg/d; n = 86) for 12 months. Subjects were examined at 4-week intervals for 3 months, 6-week intervals for the next 3 months, and every 3 months thereafter, until 1 month after the last dose was taken. Liver biopsies were collected 2 weeks after the last dose of EPA-E or placebo. The primary efficacy end point was NAFLD activity score ≤ 3, without worsening of fibrosis; or a decrease in NAFLD activity score by ≥ 2 with contribution from >1 parameter, without worsening of fibrosis, 1 year after the last dose of EPA-E or placebo was given.

Results: Similar proportions of subjects in each group met the primary end point (40%, 37%, and 35.9% for placebo, low-dosage, and high-dosage EPA-E, respectively). EPA-E had no significant effects on steatosis, inflammation, ballooning, or fibrosis scores. There were no significant effects on levels of liver enzymes, insulin resistance, adiponectin, keratin 18, high-sensitivity C-reactive protein, or hyaluronic acid. High-dosage EPA-E reduced levels of triglyceride (-6.5 mg/dL vs an increase of 12 mg/dL in the placebo group; P = .03). There were no treatment-related serious adverse events.

Conclusions: In a phase 2 trial, EPA-E had no significant effect on the histologic features of NASH. EPA-E reduced subjects' levels of triglyceride compared with placebo, without any increase in serious adverse events. Clinicaltrials.gov Number: 01154985.