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 (HbA1C; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA1c (-0.4%; P=0.026). Among patients with baseline HbA1c >6.5%, epeleuton 2 g/day decreased HbA1c 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, HbA1C, 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.

Keywords: 15‐HEPE; DS102; epeleuton; n‐3 fatty acid.

Conflict of interest statement

Dr Climax is the CEO and a shareholder of Afimmune and DS Biopharma. Dr Newsome has received grants, consultancy, and nonfinancial support from Novo Nordisk; consultancy from Shire; grants and consultancy from Boehringer Ingelheim; consultancy from Intercept Pharmaceuticals; consultancy from Afimmune; speaker fees from Norgine; consultancy from Gilead Sciences; and consultancy from Pfizer. Drs Hamza, Weissbach, and Coughlan are employees of Afimmune and DS Biopharma. Dr Sattar has consulted for, or received speaker fees from, Afimmune, Amgen, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi, and Janssen and has received research grant support from Boehringer Ingelheim. Dr McGuire has received honoraria for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai Inc, GlaxoSmithKline, and Esperion and honoraria for consultancy from AstraZeneca, Sanofi Aventis, Eli Lilly and Company, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Metavant, Applied Therapeutics, and Afimmune. Dr Bhatt discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease] trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co‐Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co‐Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda.

Figures

Figure 1. Consolidated Standards of Reporting Trials flow diagram of subject disposition.

mITT indicates modified intention‐to‐treat.

Figure 2. Change in HbA1c, glycemic, and insulin resistance parameters.

A, Change in HbA1C (%) in placebo and epeleuton groups. B, Proportion of patients with HbA1c >6.5% at baseline which is normal at week 16. C, Change in fasting plasma glucose in placebo and epeleuton groups. D, Change in plasma free fatty acids in placebo and epeleuton groups. E, Change in insulin in placebo and epeleuton groups. F, LS mean change in HOMA‐IR in placebo and epeleuton groups. G, LS mean change in Adipo‐IR in placebo and epeleuton groups. For (A, C, D and E) error bars denote standard error. For (F and G) error bars denote 95% CIs. Adipo‐IR indicates adipose tissue insulin resistance; HbA1c, hemoglobin A1c; HOMA‐IR, homeostatic model assessment for insulin resistance; and LS, least squares. * denotes nonsignificant P values (>0.05) compared with placebo.

Figure 3. Median percentage change in lipid levels in patients receiving placebo, epeleuton 1 g/day or epeleuton 2 g/day (intention‐to‐treat population).

A, Changes in lipid levels at week 16. B, Changes in triglycerides levels at week 16 in the mITT population and subgroups excluding outliers and with elevated triglycerides at baseline. P values are from the Wilcoxon rank‐sum test. Error bars denote 95% CIs. HDL‐C indicates high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; RLP‐C, remnant‐like particle cholesterol; and VLDL‐C, very‐low‐density lipoprotein cholesterol. *Denotes nonsignificant P values (>0.05) compared with placebo.