Abstract 1694 | The Liver Meeting® 2020, the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
Authors: Stephen A. Harrison, Nadege T. Gunn, Seth J. Baum, Ziad H. Younes, Anita Kohli, Rashmee Patil, Margaret J. Koziel, Harinder Chera, Jeff Zhao, and Manu V. Chakravarthy
Nonalcoholic fatty liver disease (NAFLD) is associated with a spectrum of histologic manifestations, including isolated steatosis, steatohepatitis, fibrosis, and cirrhosis. Patients with complex multifactorial diseases like NAFLD and nonalcoholic steatohepatitis (NASH) may benefit from approaches that concordantly address multiple metabolic and fibroinflammatory pathways. Endogenous metabolic modulators (EMMs) encompass a broad set of molecular families that include amino acids (AAs), fatty acids and other lipids, bile acids, ketone bodies, hormones, and other molecules. EMMs can be selectively combined to form EMM compositions to simultaneously support multiple metabolic nodes and pathways key to multifactorial diseases and liver health. AXA1125 and AXA1957 are novel, orally administered EMM compositions of AAs and related metabolites and precursors specifically designed to simultaneously support pathways related to liver metabolism, inflammation, and fibrosis. AXA1125 is composed of leucine, isoleucine, valine, arginine, glutamine, and N-acetylcysteine (LIVRQNac). AXA1957 is isonitrogenous to AXA1125 and is composed of leucine, isoleucine, arginine, glutamine, N-acetylcysteine, carnitine, and serine (LIRQNacCarS); it was designed to examine additional biological activity. In a prior pilot, open-label non-IND clinical study of AXA1125 (AXA1125-002), AXA1125 demonstrated positive trends in biomarkers related to liver structure (steatosis, fibrosis) and function (insulin sensitivity, inflammation) in subjects with NAFLD and type 2 diabetes (T2D); these results were supported by targeted plasma metabolomic and lipidomic data. Additionally, nonclinical data from primary human cells and NASH rodent models confirm multitargeted activity of LIVRQNac on core NASH pathophysiologic features. There is increasing evidence linking reductions in specific biomarkers (corrected T1 [cT1], N-terminal type III collagen propeptide [ProC3], magnetic resonance imaging-proton density fat fraction [MRI-PDFF], and alanine aminotransferase [ALT]) with improved histologic or clinical outcomes.