Identifying Predictive Plasma Proteomic Biomarkers for Clinical Response to AXA1125, an Endogenous Metabolic Modulator (EMM) Composition Being Developed for the Treatment of NAFLD/NASH

INTRODUCTION Proteomics and metabolomics data represent opportunities to identify stable and dynamic biomarkers that are measurable in biological fluids. In nonalcoholic steatohepatitis (NASH), these biomarkers are being explored for classifying disease, monitoring disease progression, and assessing treatment response, using signatures representing different components of disease biologies (steatosis, inflammation, ballooning, fibrosis). AXA1125, a novel endogenous metabolic modulator composition of 5 specific amino acids and N-acetylcysteine, was developed to simultaneously target pathways related to liver metabolism, inflammation, and fibrosis. The AXA1125-003 study (NCT04073368), a multicenter, 16-week, single-blind study in subjects with nonalcoholic fatty liver disease (NAFLD) showed that AXA1125 had consistently greater effect than placebo in reducing magnetic resonance imaging-proton density fat fraction (MRI-PDFF), a measure of liver fat content. At Week 16, a greater proportion of subjects who received AXA1125 (35%–40%) versus placebo (8%–25%) achieved a 30% reduction in MRI-PDFF, a threshold associated with histopathologic improvement in NASH. AXA1125 is currently being studied in a phase 2b study (AXA1125-101) in subjects with NASH and fibrosis (NCT04880187). As a part of our systems biology platform, we explored stable plasma protein biomarkers that might predict clinically relevant treatment effects with AXA1125 in NAFLD/NASH.