A Study of IDN-6556 in Subjects With Liver Cirrhosis

Numerous studies have shown that caspase cleaved cytokeratin 18 (cCK18) is elevated in the serum of liver disease patients and has been associated with disease severity, thus associating both excessive apoptosis and caspase activity with disease. Studies have also shown that caspase cleaved cytokeratin 18 is generally elevated to an even greater degree in cirrhosis than in other liver diseases. In addition, increasing stages of cirrhosis from Child-Pugh A, Child-Pugh B to Child-Pugh C are associated with progressively higher levels of caspase cleaved cytokeratin 18. Therefore, it appears that apoptosis and caspase activity tend to correlate with the stage of cirrhosis. A caspase inhibitor like IDN-6556 could have clinical utility by reducing the rate of apoptosis in cirrhotic patients and potentially reduce the progression of disease as determined by clinical markers of progression.

Inclusion criteria

• Male or female subjects of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and able to understand and willing to comply with the requirements of the study
• Clinical, radiological, or biochemical evidence of liver cirrhosis
• Model for End-Stage Liver Disease (MELD) Score of 11 to 18 during the Screening period
• Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug.

Exclusion criteria

• Known infection with human immunodeficiency virus (HIV)
• Auto-immune hepatitis
• Subjects with evidence of uncontrolled infection, defined as persistent bacterial culture positivity despite adequate antibiotic therapy
• HCV infected subjects who are receiving or plan to receive anti-viral therapy during the study
• Untreated esophageal varices with high risk stigmata for hemorrhage
• Variceal hemorrhage within 3 months of Screening
• Ascites not adequately controlled on stable background medication
• Other non-liver organ failure
• Child-Pugh score of 10-15 (Child-Pugh C classification)
• Use of vasoactive drugs (at or within 3 months of Screening) that may impair hepatic blood flow
• Change in dose or regimen within 3 months of Screening of:

• Fibrates or statins
• Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE) inhibitor
• Use of chronic anticoagulation therapy including but not limited to Vitamin K/Factor Xa antagonists/inhibitors
• Use of the following drugs within 2 months of Screening:

• Systemic corticosteroids
• Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated)
• Concomitant pancreatitis
• Active inflammatory bowel disease
• Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA)
• Subjects with active or history of malignancies other than hepatocellular carcinoma (HCC) within Milan criteria or curatively treated skin cancer (basal cell or squamous cell carcinomas), unless adequately treated or in complete remission for five or more years