Publications

BACKGROUND Developing drug candidates for complex diseases may involve selection from a library of molecules. An investigational product must demonstrate clinical benefit with an acceptable safety profile to be authorized for commercial use. Therapeutic candidates with a mixture of active components must demonstrate each component’s contribution to the mix’s overall efficacy profile. Combinations with multiple…

INTRODUCTION: Physical frailty is strongly correlated with reduced cognitive function not only in the elderly but also in patients of all ages with end-stage liver disease (ESLD). The Stroop Color and Word test is a neuropsychological test that assesses the ability to inhibit the cognitive interference that occurs when the processing of one stimulus impedes…

INTRODUCTION: Complex diseases involve dysregulation of multiple biological pathways, limiting the effectiveness of single-targeted therapies. Endogenous metabolic modulators (EMMs) are naturally occurring compounds with signaling and regulatory properties that, when selectively combined, may elicit multifactorial effects in complex diseases. In a 16-week clinical study, administration of AXA1125, a novel EMM composition of 5 specific amino…

The use of Disease progression models (DPMs) in Drug Development has been widely adopted across therapeutic areas as a method for integrating previously obtained disease knowledge to elucidate the impact of novel therapeutics or vaccines on disease course, thus quantifying the potential clinical benefit at different stages of drug development programs. This paper provides a…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is prevalent in >25% of the global population and in 50% to 90% of obese adults. Once nonalcoholic steatohepatitis (NASH) occurs, there may be progression to cirrhosis. Patients with NASH may benefit from approaches that concurrently address multiple metabolic and fibroinflammatory pathways; however, at present, there are no approved…

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…

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. AXA1125 and AXA1957 in NAFLD. Methods: In this multicenter, 16-week, placebo-controlled, single-blind,…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition that is mediated by dysregulated metabolic and fibroinflammatory pathways. Insulin resistance, commonly manifested as type 2 diabetes (T2D), is an important driver of NAFLD and targeting these metabolic pathways is a potential therapeutic strategy.  Endogenous metabolic modulators (EMMs), a broad set of physiologically intrinsic molecules…

ABSTRACT Nonalcoholic steatohepatitis (NASH) is a complex metabolic disease of heterogeneous and multifactorial pathogenesis that may benefit from coordinated multitargeted interventions. Endogenous metabolic modulators (EMMs) encompass a broad set of molecular families, including amino acids and related metabolites and precursors. EMMs often serve as master regulators and signaling agents for metabolic pathways throughout the body…

INSTITUTIONS (ALL): 1. Virginia Commonwealth University, Richmond, VA, United States. 2. Axcella Health Inc., Cambridge, MA, United States. 3. Panax Clinical Research, Miami, FL, United States. 4. Ann Storck Centre, Fort Lauderdale, FL, United States. 5. Orange County Research Centre, Tustin, CA, United States. 6. Texas Liver Institute, San Antonio, TX, United States. 7. Pittsburgh…

INTRODUCTION: Recent advances in network biology have assisted in unraveling the complex pathophysiological processes underlying nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) and cirrhosis1 The close inter-connectivity of the contributory molecular pathways suggests that effective pharmacotherapy may require a coordinated multitargeted approach Per this premise, endogenous metabolic modulators (EMMs) have…

INTRODUCTION: 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…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is multifactorial, mediated by dysregulated metabolic and fibroinflammatory pathways. Because NAFLD and type 2 diabetes (T2D) have a well-established bidirectional link, with insulin resistance serving as a common metabolic driver, targeting insulin resistance is a potential strategy for managing NAFLD. Endogenous metabolic modulators (EMMs) encompass a broad set of…

INTRODUCTION: Multifactorial disease pathophysiology is complex and incompletely addressed via existing targeted pharmacotherapies. Amino acids (AAs) and related metabolites and precursors are a class of endogenous metabolic modulators (EMMs) that have diverse biological functions and, thus, have been explored for decades as potential multifactorial disease treatments. Here, we review the literature on this class of…

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)…

INTRODUCTION: AXA1665 is a novel investigational amino acid (AA) composition specifically designed to impact AA imbalance, ammoniagenesis, and dysregulated anabolic activity associated with cirrhosis. METHODS: This 2-part study examined AXA1665 effects on safety, tolerability, and hepatic/muscle physiology in subjects with Child–Pugh A and B cirrhosis. Part 1 established plasma ammonia and AA concentration baselines with…

INTRODUCTION: Skeletal muscle disuse leads to atrophy, declines in muscle function, and metabolic dysfunction that are often slow to recover. Strategies to mitigate these effects would be clinically relevant. In a double-blind randomized-controlled pilot trial, we examined the safety and tolerability as well as the atrophy mitigating effect of a novel amino acid composition (AXA2678),…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) pathogenesis and progression are complex, heterogeneous, and multifactorial. The human diet typically contains thousands of bioactive molecules that orchestrate a variety of metabolic and signaling processes in health and disease, comprising a natural combination approach. Although food composition varies widely, cumulative evidence suggests that specific dietary macronutrients and micronutrients…

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and is associated with significant morbidity and mortality worldwide, with a high incidence in Western countries and non‐Western countries that have adopted a Western diet. NAFLD is commonly associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular…

INTRODUCTION: Dysregulation of metabolic, inflammation and fibrotic pathways are linked to NAFLD progression. Effective therapies may require coordinated combinatorial approach to address multifactorial pathology. One potential modality is via endogenous molecules, such as amino acids (AAs), which when optimally combined can elicit meaningful effects. AXA1125, comprised of 6 AAs (LIVRQNac), designed to target liver function,…

INTRODUCTION: Dysregulated metabolism contributes to muscle wasting which results in decreased quality of life and morbidity and mortality in aging and disease. We previously published that AXA2678, a composition of Endogenous Metabolic Modulators (EMMs) anchored by amino acids (AA), promotes maintenance of muscle mass, prevents muscle fat accumulation, decreases pro-inflammatory cytokines and promotes myogenic myokines…

INTRODUCTION: In sickle cell disease (SCD), red blood cell (RBC) sickling propagates hemolysis, inflammation, vascular and endothelial injury with associated disruption in metabolic pathways including nitric oxide depletion, oxidative stress and an increased anabolic and energetic demand due to high RBC turnover. These metabolic functions highlight the role of amino acid biology in blood health…

INTRODUCTION: Dysregulated nitrogen (N) handling due to impaired ureagenesis and amino acid (AA) metabolism results in a distinct plasma AA profile (eg ↓BCAA, ↑AAA) with hyperammonemia and muscle wasting in cirrhosis. While protein supplementation is standard‐of‐care for cirrhotic patients, it carries the risk of hyperammonemia and hepatic encephalopathy due to the underlying defective N metabolism…

INTRODUCTION: Convergent dysregulation of metabolism, inflammation, and fibrosis appears to be central to NASH pathogenesis. Previously [Hepatology 68(1) Suppl, pg 67A: #106], we showed AXA1125, a unique composition of amino acids (LIVRQNac), positively impacted lipotoxicity, insulin resistance, inflammation and fibrosis markers in T2D subjects with NAFLD as evidenced by reductions in liver fat, HOMA‐IR, ALT,…

INTRODUCTION: Sarcopenia has emerged as an independent risk factor for important clinical outcomes in cirrhosis, including hepatic encephalopathy (HE). It is closely linked to protein-malnutrition and perturbation in amino acid metabolism. A late evening snack (LES), considered part of routine care, appears to improve quality-of-life parameters in cirrhotic patients. While protein supplementation is advised, it…