AXA1665 Shows Dose-Dependent Alterations in Metabolic Profile, Including Reduction of Non-dosed Aromatic Amino Acids, That Differentiate it From Protein Supplement in Healthy Subjects

Introduction

Dysregulated nitrogen metabolism in cirrhosis, i.e., elevated plasma ammonia and amino acid imbalance (decreased branched chain amino acids [BCAAs] and elevated aromatic amino acids [ArAAs]), is associated with complications of sarcopenia and cognitive dysfunction. Impaired hepatic detoxification of ammonia leads to accelerated catabolism of BCAAs in skeletal muscle. This cascade contributes to the development of sarcopenia and to hepatic encephalopathy (HE) in patients with cirrhosis. High-protein intake or protein supplementation is recommended as part of standard-of-care management of cirrhosis to counter muscle wasting, although concern remains about potential ammoniagenesis and ArAA elevation, which may exacerbate the risk of overt HE and associated outcomes. Dietary BCAA supplementation stimulates protein synthesis in skeletal muscle in cirrhosis and is effective in reducing episodes of HE, 4 but has the potential to enhance ammonia production in the intestine and kidney. Dietary supplementation with the urea-cycle amino acids L-ornithine and L-aspartate (LOLA) lowers plasma ammonia and may also be of benefit in preventing HE7. An alternative approach, using a unique stoichiometric ratio of specific amino acids to target multiple biologies, may be superior to protein supplementation in rebalancing cellular homeostasis in the liver and muscle. AXA1665 is an investigational fixed-ratio composition of BCAAs (leucine, isoleucine, and valine), other proteogenic essential amino acids (histidine, lysine, and threonine), and urea-cycle amino acids (LOLA), which has shown clinical potential in mitigating the core metabolic derangements associated with cirrhosis.