AXA1665 Now in Phase 2 Development
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
Axcella has completed two Clinical Studies of AXA1665. 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 Ratio, a measure of the ratio of branched chain amino acids to aromatic amino acids) and muscle structure and function (improvement in dry lean mass and liver frailty index).
AXA1665-002 was a 12-week (with a four-week follow-up), randomized placebo-controlled Clinical Study. The purpose of this study was to assess the safety, tolerability and physiological impact of two doses of AXA1665 in 60 subjects with mild and moderate hepatic insufficiency.
Results from the study showed that AXA1665 was generally well-tolerated, with activity noted across multiple biologies. For instance:
- Positive, dose dependent trends were observed in the AXA1665 arms across all three of the study’s psychometric tests
- A dose dependent and statistically significant (p <0.05) percentage increase in Fischer Ratio was seen in the AXA1665 arms relative to placebo from baseline through week 12
- In a subset of subjects with evidence of minimal hepatic encephalopathy at baseline, a mean reduction in fasted plasma ammonia levels was observed in subjects receiving both doses of AXA1665 compared to an increase in ammonia from baseline to week 12
- A higher proportion of subjects in the AXA1665 arms achieved a ≥0.3 absolute reduction in the liver frailty index versus placebo
In the first half of 2021, Axcella initiated its EMMPOWERSM Phase 2 Clinical Trial of AXA1665. This randomized, double-blind, placebo-controlled, multi-center investigation is evaluating the efficacy and safety of AXA1665 in patients who have experienced at least one prior OHE event and have neurocognitive dysfunction at screening. Approximately 150 patients on lactulose ± rifaximin (stratified by rifaximin use) will be randomized 1:1 to receive either 53.8 grams per day of AXA1665 or a calorie-matched placebo in three divided doses for 24 weeks, with a four-week safety follow-up period.
The EMMPOWER trial will be conducted globally at more than 70 clinical sites with a primary endpoint assessing the proportion of patients with a ≥2 point increase in the psychometric hepatic encephalopathy score (PHES) after the 24-week treatment period. The trial’s key secondary endpoints will focus on the proportion of patients experiencing an OHE breakthrough event and time to first OHE breakthrough event, including time to hospitalization. Other secondary endpoints include changes in physical function and patient-reported outcomes. Measures of circulating ammonia, amino acids and inflammation-related markers will also be included as endpoints.
Additional information can be found on https://clinicaltrials.gov/ via the identifier NCT04816916.