The liver is one of the largest and most complex organs in the body. It stores vital energy and nutrients, manufactures proteins and enzymes necessary for good health, protects the body from disease, and breaks down (or metabolizes) and helps remove harmful toxins, like alcohol, from the body.

Because the liver is the chief organ responsible for metabolizing alcohol, it is especially vulnerable to alcohol-related injury. Even as few as three drinks at one time may have toxic effects on the liver when combined with certain over-the-counter medications, such as those containing acetaminophen.

Alcoholic liver disease (ALD), a major cause of morbidity and mortality worldwide, includes a broad spectrum of disorders, ranging from simple steatosis (fatty liver) to severe forms of liver injury such as alcoholic hepatitis (steatohepatitis), cirrhosis and hepatocellular carcinoma. Almost all heavy drinkers develop fatty liver, but only 20–40% of them develop more severe forms of ALD.

Steatosis is the earliest stage of alcoholic liver disease and the most common alcohol-induced liver disorder. Steatosis is marked by an excessive buildup of fat inside liver cells. This condition can be reversed, however, when drinking stops. Drinking heavily for longer periods may lead to a more severe, and potentially fatal condition, alcoholic hepatitis— an inflammation of the liver. Symptoms include nausea, lack of appetite, vomiting, fever, abdominal pain and tenderness, jaundice, and, sometimes, mental confusion. If drinking continues, in some patients this inflammation eventually leads to alcoholic cirrhosis, in which healthy liver cells are replaced by scar tissue (fibrosis), leaving the liver unable to perform its vital functions. Recent data indicate that the 5-yr survival rate for alcoholic cirrhosis is between 23% and 50%, which is significantly worse than that observed in nonalcoholic cirrhosis. Hepatic inflammation (alcoholic hepatitis) is the single most important prognostic factor, and patients with both cirrhosis and hepatitis have a much poorer prognosis. Patients with severe alcoholic hepatitis have been reported to have 30-day mortality of up to 50%.

We are developing GRI-0621 for ALD, with a focus on chronic ALD patients and severe alcoholic hepatitis patients. The objective for treating patients with chronic ALD is to slow and/or reverse the progression of disease in order to prevent liver decompensation and the need for a liver transplant or the time to liver transplantation, which is currently the only definitive treatment for severe (end stage) liver failure. The objective for treating patients with severe alcoholic hepatitis is to decrease overall mortality, which can be as high as a 50% mortality at 30-days.