First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

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.

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.