AXA1125 Now in Phase 2a and 2b Development
AXA1125 IN LONG COVID
It has been estimated that nearly a quarter of the people who contract the COVID-19 virus will suffer from long-term effects, continuing to experience a wide range of symptoms months after their initial diagnosis. Similar to NASH and many other conditions and diseases, mitochondrial dysfunction is increasingly being implicated as a key driver of Long COVID-induced fatigue, which is the most common symptom associated with the condition.
In two prior successful clinical studies and in preclinical models, AXA1125 has demonstrated an ability to reverse mitochondrial dysfunction and improve energetic efficiency via increased fatty acid oxidation, restored cellular homeostasis, and reduced inflammation. This provides the potential to help the growing number of patients who are suffering from COVID’s debilitating effects long after contracting the virus.
- As of February, there had already been more than 415 million confirmed cases of COVID-19
- It is estimated that 20-30% of COVID patients experience continued symptoms weeks and months after their diagnosis
- The most common Long COVID symptom is fatigue, impacting a majority of people with Long COVID
AXA1125 IN NASH
AXA1125 is an EMM composition of six amino acids and derivatives.
This product candidate has shown the potential to effect pathways related to metabolism, inflammation and fibrosis 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.
- Up to 40 million NASH patients in the U.S. alone; population growing rapidly
- Approximately 10% of U.S. children are estimated to have NASH
- >40% of NASH patients also have type 2 diabetes (T2D)
- Lifetime costs for all U.S. NASH patients exceeds $300 billion
Explore how AXA1125 works in NASH
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.
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.
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.
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.
Axcella has completed multiple Clinical Studies of AXA1125 and is continuing its development in NASH and Long COVID. AXA1125-002 was multi-center, open-label 12-week Clinical Study in subjects with type 2 diabetes (T2D) and presumed NASH. AXA1125-003 was a placebo-controlled, randomized, multi-arm 16-week Clinical Study in subjects with and without type 2 diabetes (T2D) and presumed NASH. In both studies, AXA1125 was generally well tolerated and showed positive effects on key markers of metabolism, inflammation and fibrosis.
In the first half of 2021, Axcella initiated its EMMPACT℠ Phase 2b Clinical Trial of AXA1125. This randomized, double-blind, placebo-controlled, multi-center investigation is evaluating the efficacy and safety of AXA1125 in patients with biopsy-confirmed F2/F3 NASH. Approximately 270 patients will be enrolled and randomized 1:1:1 to receive either 45.2 or 67.8 grams per day of AXA1125 or a matched placebo in two divided doses for 48 weeks, with a four-week safety follow-up period. Patients will be stratified based on the presence or absence of type 2 diabetes.
EMMPACT will be conducted globally across more than 70 clinical sites with a primary endpoint assessing the proportion of patients with a biopsy-confirmed ≥2 point improvement in NAFLD Activity Score (NAS) after the 48-week treatment period. Secondary endpoints will include the proportion of patients achieving biopsy-confirmed resolution of NASH without worsening of fibrosis and the proportion of patients achieving a ≥1 stage improvement in fibrosis without worsening of NASH. A range of non-invasive biomarkers, including MRI-PDFF and Fibroscan, will be utilized for additional endpoints and an interim analysis in the trial. Additional information can be found on https://clinicaltrials.gov/ via the identifier NCT04880187.
In late 2021, Axcella initiated a randomized, double-blind, placebo-controlled Phase 2a Clinical Trial to evaluate the efficacy and safety of AXA1125 in patients with exertional fatigue related to Long COVID. Approximately 40 patients will be enrolled and randomized evenly to receive either 67.8 grams per day of AXA1125 or a matched placebo in two divided doses for 28 days, with a one-week safety follow-up period.
The trial’s primary endpoint will assess the improvement of mitochondrial function (oxidative phosphorylation) of the skeletal muscle mitochondria, as measured by changes in phosphocreatine (PCr) recovery time, from baseline to Day 28. PCr recovery time is a well-established and highly sensitive tool that has been strongly correlated with a registrational endpoint (i.e. 6-minute walk test) in a number of other diseases in which muscle fatigue plays a central role, including amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy, and chronic kidney disease. Key secondary endpoints include lactate levels, a 6-minute walk test, fatigue scores, and safety and tolerability.