AXA1665 & Overt Hepatic Encephalopathy (OHE)
AXA1665 is an EMM composition of 8 amino acids and derivatives that targets three key nodes: ammonia toxicity, amino acid imbalance, and muscle wasting. Asp and Orn are intended to promote the function of the urea cycle. BCAAs are aimed at improving amino acid balance and increase protein synthesis. His, Lys, and Thr, in conjunction with other amino acids, are included to support protein synthesis and improve muscle function.
Cirrhosis is a late-stage liver disease in which function is impaired because of damage and scarring. OHE is one of the most common complications of cirrhosis. It is characterized by a decline in brain function due to a buildup of toxins – primarily ammonia – in the blood.
Emerging data in the field suggest that muscle mass and function are key independent factors associated with the progression to and severity of OHE, and this condition is well-established as a significant cause of morbidity and mortality in patients with cirrhosis. Current treatments for OHE include rifaximin and lactulose. Their effects on impacting plasma amino acid levels and muscle wasting in subjects with cirrhosis remains to be elucidated.
- The U.S. prevalence of cirrhosis is estimated to be 633,000 adults.
- Nearly 70% of these individuals report they were unaware of having liver disease.
- 10% to 14% of those with cirrhosis also have OHE.
- In the United States, we estimate that there are approximately 63,000 to 130,000 people with cirrhotic sarcopenia (muscle wasting) and OHE.
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The liver’s ability to metabolize ammonia is reduced in cirrhosis:
- Normally, the liver removes nitrogen from circulation in the form of ammonia and converts it to urea, which is cleared by the kidneys.
- In cirrhosis, ammonia’s conversion to urea is reduced. Thus, it remains in circulation and can cross the blood-brain barrier.
- High levels of ammonia are a primary factor in the development and recurrence of OHE.
AXA1665 is designed to support pathways related to ammonia handling:
- Asp and Orn promote the function of the urea cycle.
- Improved muscle mass and function promote ammonia handling within skeletal muscle.
In cirrhosis and OHE, BCAA levels decline and AAAs increase, which has been shown to result in worsening clinical outcomes.
AXA1665’s is designed to support metabolic pathways related to the balance of amino acids:
- The BCAAs Leu, Ile and Val are expected to be key contributors to the balance of amino acids.
- Increased muscle protein synthesis is expected to decrease AAAs in the blood.
In cirrhosis and OHE, a vicious cycle of muscle wasting and ammonia toxicity exists in which:
- Ammonia is processed through muscle, contributing to muscle wasting.
- As muscle mass declines, ammonia increases in circulation, which can contribute to OHE events.
AXA1665 is designed to support pathways related to muscle structure and function:
- BCAAs promote positive nitrogen balance within the liver and skeletal muscle.
- BCAAs stimulate mTORC1, a complex that signals to increase protein synthesis.
- His, Lys, and Thr complement amino acids that are elevated in cirrhosis (Tyr, Phe, and Met). Together, they provide raw materials for muscle synthesis.
Abbreviation Glossary: AAAs, aromatic amino acids; BCAAs, branched chain amino acids; EMM, endogenous metabolic modulators; mTORC1, mammalian target of rapamycin complex 1; OHE, overt hepatic encephalopathy. Amino acids and derivatives: Asp, aspartate; His, histadine; Ile, isoleucine; Leu, leucine; Lys, lysine; Met, methionine; Orn, ornithine; Phe, phenylalanine; Thr, threonine; Tyr, tyrosine; Val, valine
AXA1665-001 was a two-part, 15-day controlled crossover Clinical Study in subjects with mild and moderate hepatic insufficiency. The primary purpose of the study was to evaluate the safety, tolerability, and effect on biomarkers of two doses of AXA1665. AXA1665 was found to be generally well tolerated, and the higher dose of this product candidate showed positive effects on key markers of ammonia handling (reduction in plasma ammonia), amino acid balance (increase in Fischer’s Ratio) and muscle structure and function (improvement in dry lean mass and liver frailty index).
AXA1665-002 is an ongoing 12-week (with a four-week follow-up), randomized placebo-controlled Clinical Study. The purpose of this study is to assess the safety, tolerability and physiological impact of two doses of AXA1665 in 60 subjects with mild and moderate hepatic insufficiency.