Effects of Epeleuton, a Novel Synthetic Second‐Generation n‐3 Fatty Acid, on Non‐Alcoholic Fatty Liver Disease, Triglycerides, Glycemic Control, and Cardiometabolic and Inflammatory Markers

Abstract

Background Epeleuton is 15‐hydroxy eicosapentaenoic acid ethyl ester, a second‐generation synthetic n‐3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers. Methods and Results In a multicenter, randomized, double‐blind, placebo‐controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Primary end points of changes in alanine aminotransferase and liver stiffness did not improve at week 16. Secondary and post hoc analyses investigated changes in cardiometabolic markers. Epeleuton 2 g/day significantly decreased triglycerides, very‐low‐density lipoprotein cholesterol, and total cholesterol without increasing low‐density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA 1C ; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA 1c (−0.4%; P =0.026). Among patients with baseline HbA 1c >6.5%, epeleuton 2 g/day decreased HbA 1c by 1.1% ( P =0.047; n=26). Consistent dose‐dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo. Conclusions While epeleuton did not meet its primary end points on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA 1C , plasma glucose, and inflammatory markers. These data suggest epeleuton may have potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT02941549.

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

“…In support of this finding, although administration of a second-generation synthetic EPA-ester — epeleuton — did not reduce liver stiffness and alanine aminotransferase activity in a phase IIa study in patients with non-alcoholic fatty liver disease, secondary analyses revealed intriguing metabolic effects. Specifically, the study investigators observed decreased levels of plasma triglycerides, vLDL and total cholesterol together with decreases in plasma glucose, HbA1c, insulin resistance and markers of endothelial activation 172 . These findings are further supported by experimental evidence that EPA-derived RvE1 decreases hyperinsulinaemia and hyperglycaemia in obese mice 173 .…”

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

“…Epeleuton is a synthetic n-3 fatty acid derivative of eicosapentaenoic acid that decreased triacylglycerols, improved glycaemic control and decreased markers of inflammation in a Phase II exploratory study (16 weeks) in individuals with obesity and NAFLD [134]. Epeleuton at the highest dose significantly decreased hepatic fat from baseline, although not significantly, vs placebo but it did not meet the primary endpoints of decreased ALT concentrations or liver stiffness.…”

Orally administered epeleuton inhibits SARS-CoV-2 viral load, replication and pathology in the Syrian Hamster model

“…In a phase 2a clinical trial of epeleuton in patients with obesity and NAFLD, serum biomarker data provides several hints regarding systemic effects of epeleuton on the host lipidome which may impact SARS-CoV-2 replication. In this phase 2a clinical trial epeleuton significantly decreased concentrations of plasma free fatty acids 11 , an observation that may be partly explained by the known inhibition of fatty acid synthase (FAS) by polyunsaturated fatty acids 25 . FAS is a homodimeric multifunctional enzyme that catalyzes fatty acid synthesis, synthesising palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH 26 .…”

“…A recent review by Theken et al outlined the important roles that lipids play in the viral life cycle both through direct interactions with viruses and by modulating various aspects of host biology 12 . As such, the observed effects of epeleuton in the Syrian hamster model are likely to consist of both direct antiviral effects and protection conferred by epeleuton’s effects on host immune response, including its known anti-inflammatory effects 11 . Recent studies suggest several potential targets for fatty acid binding to SARS-CoV-2 and provide evidence that polyunsaturated fatty acids can exert direct antiviral effects independent of host factors.…”

“…15(S)-HEPE, at much lower concentrations, is an endogenous downstream 15-lipoxygenase metabolite of EPA. Epeleuton is associated with cardiometabolic and anti-inflammatory effects in clinical and preclinical studies 11 . The therapeutic effects of 15(S)-HEPE are thought to be induced by pleiotropic modes of action.…”