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LIVER

Axcella is investigating DAAC candidates across a spectrum of liver conditions spanning from non-alcoholic fatty liver (NAFL) at the earliest stage of liver disease, to steatohepatitis (NASH), to cirrhosis at the later stage of liver disease. 

Non-alcoholic fatty liver disease (NAFL) is one of the most common causes of liver disease in the United States and encompasses NAFL (simple steatosis, affecting 30-40% of adults in the US) and can progress to NASH (non-alcoholic steatohepatitis, affecting 3-12% of adults in the US), with liver inflammation and fibrosis putting patients at greater risk of developing cirrhosis or liver cancer. 

While the pathologies of NAFL and NASH manifest primarily in the liver, they are heterogeneous diseases that are driven by multiple biological pathways affecting different cell types, making them ideal indications for the potential multifunctional activity of DAAC candidates. NAFL and NASH may increase the risk of death due to cardiovascular disease and are also closely associated with type 2 diabetes and obesity, two major drivers of multiple co-morbidities and rising healthcare costs. There are no drugs currently approved to treat NAFL or NASH.

NAFLD can affect people of any age, including children. Research suggests that close to 10 percent of U.S. children ages 2 to 19 have NAFLD. While people are more likely to develop NAFLD as they age, pediatric NAFLD (pNAFLD) presents an area of high unmet need.

Cirrhotic sarcopenia, or profound muscle wasting, is one key manifestation of frailty associated with cirrhosis, which is a significant cause for functional decline, a worsening of other cirrhosis-related complications, increased hospitalizations and mortality. Cirrhosis is associated with many complications including portal hypertension, variceal bleeding, hepatic encephalopathy and ascites among others. Among these, frailty is increasingly being recognized as the “6th vital sign” of cirrhosis. Greater than 50% of patients wait listed for a liver transplant experience muscle wasting that results in physical decline, independent of liver disease severity, and is associated with an increased risk of removal from transplant wait lists. Currently, there are no approved pharmacological interventions for this specific muscle wasting complication of cirrhosis, and current nutrition-based approaches have had limited impact on clinical outcomes.


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MUSCLE DISEASE

Muscle wasting, or atrophy, is a decrease in the mass of muscle in an area of the body. This occurs in two basic forms: disuse atrophy in which the muscles waste away due to lack of exercise and proper nutrition, and neurogenic atrophy, a more severe condition in which muscles deteriorate due to nerve disease or nerve injury.

Many muscle diseases have complex origins, and understanding the cause of atrophy is a crucial step in finding a solution.

When a muscle remains unused, even for a short period of a few days, it begins to waste away and lose functionality. The decrease in the mass of the muscle is most common in people suffering temporary disablement such as hospitalization or an immobilized limb after injury. Muscle atrophy leads to weakness, which further complicates recovery, since movement is one of the ways to induce muscle growth. In the case of rotator cuff injury and hip fractures, surgical intervention only addresses the primary injury and has no effect on muscle mass/function or fat infiltration that might have occurred prior to surgery. Furthermore, commonly used anti-inflammatory medications following surgery (including corticosteroids) can worsen atrophy and lengthen recovery times.


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CENTRAL NERVOUS SYSTEM (CNS)

Central nervous system (CNS) diseases are a group of neurological disorders that affect the structure or function of the brain or spinal cord. Axcella’s DAAC approach leverages the growing understanding of how targeting AA biology may impact complex integrated biological pathways in many CNS indications including mild traumatic brain injury (mTBI) and epilepsy.

Mild traumatic brain injury (mBTI), also known as concussion, is the most prevalent form of traumatic brain injury. It is identified as the result of the forceful motion of the head or impact causing a brief change in mental status (confusion, disorientation or loss of memory) or loss of consciousness for less than 30 minutes. Common symptoms of mTBI include fatigue, headaches, visual and gait/balance disturbances, memory loss, poor attention/concentration and seizures among others. 

While these symptoms may not be present or noticed at the time of injury as they may be delayed days or weeks before they appear, the symptoms are often subtle and are frequently missed by the injured person, family and doctors.

Epilepsy is a chronic disorder, the hallmark of which is recurrent, unprovoked seizures. About one percent of Americans, approximately 2.5 – 3 million people, will be diagnosed with epilepsy in their lifetime. The seizures in epilepsy may be related to a brain injury or a family history, but often the cause is completely unknown.

About one-third of people with epilepsy are being treated with medicines that do not work well, or at all, to control their seizures. Their condition is named Intractable, or refractory epilepsy. Some of the reasons that medications are not successful with this group of people are over-sensitivity to the side effects of seizure medications, or a built-up tolerance, when the drugs no longer work. These chronic, complex disorders present ideal situations to test the multifunctional approach of DAAC candidates across the network of dysregulated pathways within the brain.