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The Digital International Liver Congress | August 27 - 29, 2020

Authors: Stephen A. Harrison, Seth J. Baum, Nadege T. Gunn, Ziad H. Younes, Anita Kohli, Rashmee Patil, Margaret J. Koziel, Harinder Chera, Jeff Zhao, and Manu V. Chakravarthy

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is associated with a spectrum of histologic
manifestations, including simple steatosis, steatohepatitis, fibrosis, and cirrhosis
• Because multiple metabolic and fibroinflammatory pathways are dysregulated in NAFLD
and nonalcoholic steatohepatitis (NASH), patients may benefit from approaches that
support multiple pathways related to normal health processes
• 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
liver health and multifactorial diseases
• 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 a distinct EMM composition that is isonitrogenous to AXA1125 and
was developed to examine additional biological activity; it is composed of leucine,
isoleucine, arginine, glutamine, N-acetylcysteine, carnitine, and serine (LIRQNacCarS)
• In a prior non-IND clinical study (AXA1125-002) that assessed the safety, tolerability, and
biological activity on liver structure and function with AXA1125 in subjects with NAFLD
and type 2 diabetes (T2D), AXA1125 demonstrated positive trends in biomarkers related
to liver structure (steatosis, fibrosis) and function (insulin sensitivity, inflammation)
– Additionally, nonclinical data in primary human cells and rodents confirm the
simultaneous activity of LIVRQNac on core pathophysiological features of NASH

AIM: To assess the safety, tolerability, and biological activity on liver structure and function with
AXA1125 and AXA1957 in subjects with NAFLD (AXA1125-003; NCT04073368)

METHODS: This was a 16-week, placebo-controlled, multicenter, randomized, single-blind, multi-arm,
non-IND clinical study of adults with NAFLD
• Subjects were eligible for inclusion if they had proton density fat fraction (PDFF) ≥10%,
corrected T1 (cT1) ≥830 mSec by multiparametric magnetic resonance imaging (MRI), and
fasting aspartate aminotransferase (AST) >20 IU/L; subjects with a diagnosis of T2D were
eligible to enroll in the study
• Key exclusion criteria included current or history of significant alcohol consumption, liver
disease (other than NAFLD or NASH), and/or hepatic decompensation
• Subjects were stratified based on T2D status and randomized in a 2:2:2:1 ratio to receive
orally administered AXA1125 24 g; AXA1957 13.5 g or 20.3 g; or a calorie, excipient, and
color-matched placebo 24 g twice daily for 16 weeks
• Changes in diet, physical activity, and body weight were recorded at every visit, with the
expectation that subjects would maintain their body weight within 5% of baseline
• Assessments were carried out on Day 1 (baseline) and at Weeks 1, 2, 4, 8, 12, and 16;

CONCLUSIONS: AXA1125 and AXA1957 were safe, well tolerated, and resulted in clinically relevant
multitargeted activity on biomarkers of metabolic and fibroinflammatory pathways,
which are associated with NAFLD and NASH
• The potential of these EMM compositions to simultaneously address the
multifactorial pathogenesis of NASH and its key comorbidities (eg, T2D) represents
a novel modality with a unique mechanism of action
• Biological activity was consistently greater among those treated with AXA1125 than
with both doses of AXA1957, warranting further study of AXA1125
• Future development of AXA1125 for the treatment of adult and pediatric subjects
with NASH are planned in IND-enabled clinical trials
a follow-up visit occurred 2 weeks after each subject’s last visit
• Safety and tolerability were evaluated through adverse events (AEs), clinical safety
laboratory tests, vital signs, body weight, electrocardiograms, and other safety parameters
• Activity on liver structures and functions was assessed by measuring change from
baseline in key parameters of metabolism (eg, MRI-PDFF and homeostasis model
assessment of insulin resistance [HOMA-IR]) and fibroinflammation (eg, alanine
aminotransferase [ALT], cT1, cytokeratin-18 [CK-18] M65, N-terminal type III collagen
propeptide [ProC3])
– Key thresholds of activity were also assessed: proportion of subjects achieving
reductions of ≥30% in MRI-PDFF, ≥17 U/L in ALT, and ≥40 mSec in cT1
• Analysis of covariance for continuous endpoints and the Cochrane–Mantel–Haenszel test
for binary endpoints were applied (both adjusted for baseline T2D status), and summary
statistics were reported based on the observed data collected at each visit
• This non-IND clinical study was exploratory in nature and not designed to evaluate
impact on disease nor to have statistical power to compare biological assessments
versus placebo
• Here, we report top-line results from all subjects who received ≥1 dose of study product
based on the dose received on Day 1 (safety population)