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AXA1125 and NASH

AXA1125 is an EMM composition of six amino acids and derivatives.

This product candidate was designed to support the underlying pathways of metabolism, inflammation and fibrosis, and we believe they have the potential to address substantial unmet needs in NASH. BCAAs can promote glucose uptake, increase insulin sensitivity, and decrease lipotoxicity. Arg functions to reduce ammonia and liver cell damage. Gln and Arg also may reduce inflammation through their impact on gut epithelial cells. Additionally, Nac works as an anti-inflammatory agent by promoting glutathione synthesis and reducing reactive oxygen species (ROS).

NAFLD is an increasingly common condition in which excess fat accumulates in the liver as a result of various factors including obesity, insulin resistance and/or diabetes. This condition can progress to a more severe disease known as NASH, which is characterized by liver inflammation, cell death and fibrosis. NASH has been linked to cardiovascular disease and may ultimately lead to life-threatening conditions such as cirrhosis or liver cancer, requiring liver transplant.

  • One of the most common liver diseases in the U.S.
  • The prevalence of NASH in the U.S. is estimated to be over 15 million.
  • The prevalence of NASH in the five major European countries (France, Germany, Italy, Spain and the United Kingdom) is also estimated to be over 15 million.

Explore how AXA1125 works

Group Inflammation Fibrosis

Select a focus area to learn more:

In NAFLD/NASH, the liver cannot properly metabolize fatty acids and carbohydrates, resulting in build-up of toxic lipids and insulin resistance.

 

AXA1125 was designed to support pathways related to liver metabolism:

  • BCAAs Leu, Ile, and Val promote glucose uptake and increase insulin sensitivity.
  • BCAAs lead to the production of ketones and decrease non-dosed amino acids, which restores glucose sensitivity, and promotes fatty acid oxidation and lipolysis through activation of PPARa and AMPK.
  • Arg increases NO and drives the urea cycle, which reduces ammonia and prevents liver cell damage.
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In NAFLD/NASH, inflammation leads to stress, injury and death of liver cells:

  • Systemic and chronic inflammation at the cellular level drives tissue damage and activates fibrogenic pathways, leading to fibrosis.

AXA1125 was designed to support pathways related to liver inflammation:

  • Gln and Arg play a role in increasing mucosal integrity and tight junctions of gut epithelial cells, thereby reducing bacterial endotoxin translocation.
  • Nac promotes GSH synthesis, which can help decrease ROS and pro-inflammatory pathways such as NfKb and Hif1a.
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The activation of stellate cells in NAFLD/NASH causes an accumulation of collagen in the liver that can lead to a thickening and scarring of tissue, called fibrosis.

AXA1125 was designed to support pathways related to fibrosis:

  • Nac promotes GSH synthesis, which decreases ROS and pro-fibrotic pathways such as TGFb.
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Abbreviations:  AMPK, AMP-activated protein kinase; BCAAs, branched chain amino acids; EMM, endogenous metabolic modulators; Hif1a, hypoxia-inducible factor 1-alpha; GSH, glutathione; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NH3, ammonia; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; PPARa, peroxisome proliferator-activated receptor alpha; ROS, reactive oxygen species; TGFb, transforming growth factor beta;
Amino acids and derivatives: Arg, arginine; Carn, carnitine; Gln, glutamine; Ile, isoleucine; Leu, leucine; NAC, N-acetylcysteine; Ser, serine; Val, valine.

Clinical Studies

AXA1125-002 was multi-center, open-label Clinical Study in subjects with type 2 diabetes (T2D) and NAFLD. The purpose was to evaluate the safety and tolerability of AXA1125 and its effects on biomarkers of metabolism, inflammation, and fibrosis.AXA1125 was generally well tolerated and showed positive effects on key markers of metabolism (including reduction in liver fat by MRI-PDFF and HOMA-IR, a measure of insulin resistance), inflammation (including a reduction in ALT), and fibrosis (including a reduction in ProC3) compared with baseline.

AXA1125-003 was a placebo-controlled, randomized, multi-arm Clinical Study assessing the impact of AXA1125 and AXA1957 on safety, tolerability and effects on structures and functions of the liver, as measured by a comprehensive panel of imaging and soluble biomarkers related to metabolism, inflammation and fibrosis. In this study, 102 adult NAFLD subjects with presumed nonalcoholic steatohepatitis, based on inclusion criteria, were enrolled and dosed in a 2:2:2:1 ratio to receive AXA1125, one of two AXA1957 doses, or placebo administered twice daily for 16 weeks. Study subjects were stratified based on the presence or absence of type 2 diabetes.

Results from the study showed that AXA1125 and AXA1957 were generally well-tolerated, with sustained reductions noted for both product candidates versus placebo in key biomarkers of metabolism, inflammation and fibrosis over 16 weeks. Overall, as compared to placebo, AXA1125 demonstrated larger and more consistent reductions in clinically relevant biomarkers than AXA1957.

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