A Study of IDN-6556 in Cirrhotic Subjects With Portal Hypertension

Studies in patients with liver disease have demonstrated that cCK18 is elevated in the serum
of patients and has been associated with disease severity. Studies have also shown that
cCK18 is generally elevated to a higher 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. This suggests
that apoptosis and caspase activity are associated with the severity of disease. IDN-6556
and its ability to inhibit inflammation and apoptosis may have a beneficial impact on both
the dynamic and structural components associated with the pathogenesis of portal
hypertension in cirrhosis.

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

- Evidence of portal hypertension as evidenced by any of the following:

1. Splenomegaly, on imaging and/or clinical evaluation, with platelet count of
<120,000 at study entry, or

2. Presence of small sized varices on screening endoscopy and/or collateral
circulation on imaging, or

3. Presence of medium/large varices that have never bled and have been obliterated
with endoscopic ligation

- Portal hypertension defined as a hepatic venous pressure gradient (HVPG) >5 mmHg at
Screening

- 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:

- Decompensated cirrhosis as defined by the presence of overt ascites (requiring
diuretics), overt encephalopathy (requiring specific therapy), or history of variceal
hemorrhage.

- Known infection with HIV

- Hepatic failure defined as total bilirubin ≥12 mg/dL

- Other non-liver organ failure

- Child-Pugh score of 10-15

- Use of concomitant 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:

1. Fibrates or statins

2. Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE)
inhibitor

- Use of the following drugs within 2 months of Screening:

1. Systemic corticosteroids

2. Pentoxifylline

3. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically
prescribed or indicated)

- Concomitant pancreatitis

- Evidence of portal vein thrombosis on Doppler ultrasound of the portal vasculature

- Active inflammatory bowel disease

- Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis
(RA)

- Autoimmune hepatitis

- Hepatocellular carcinoma (HCC) at entry into the study