Lonafarnib for Chronic Hepatitis D

Chronic delta hepatitis is a serious form of chronic liver disease caused by infection with
the hepatitis D virus (HDV), a small RNA virus that requires farnesylation of its major
structural protein (HDV antigen) for replication. We propose to treat between 12 and 14
patients with chronic delta hepatitis using the farnesyltransferase inhibitor (FTI)
lonafarnib for a duration of twenty-eight days. Farnesyltransferase inhibitors have not been
used in the therapy of delta hepatitis. Patients with HBsAg and HDV RNA in serum, elevated
aminotransferases, or moderate-to-severe chronic hepatitis and HDV antigen on liver biopsy
will be enrolled. Before receiving therapy, patients will be monitored for at least three
months with regular testing for alanine aminotransferase (ALT) levels and will undergo
Clinical Center admission for medical evaluation and percutaneous liver biopsy. Two dosing
groups of lonafarnib will be assessed, with a placebo cohort in each group. At each clinic
visit, patients will be questioned about side effects and symptoms, undergo focused physical
examination, and have blood drawn for complete blood counts, HDV RNA, and routine liver
tests (including ALT, AST, alkaline phosphatase, direct and total bilirubin, and albumin).
At two-week intervals, for a period of 28 days, patients will also be tested for HBsAg,
anti-HBs, HBV DNA, and prothrombin time. At the end of 28 days of treatment, patients will
undergo repeat physical examination, assessment of symptoms (using a symptom scale
questionnaire), complete blood counts, routine liver tests, and hepatitis B and D viral
markers. The primary therapeutic endpoint will be an improvement in quantitative serum HDV
RNA levels after 28 days of lonafarnib therapy. The primary safety endpoint will be the
ability to tolerate the drug at the prescribed dose for the 4 week duration. Several
secondary endpoints will be measured, including side effects, ALT levels, and symptoms.
Therapy will be stopped for intolerance to lonafarnib (which will be carefully defined).
This study is designed as a phase 2a study assessing the safety, tolerance and antiviral
activity of two dose levels of lonafarnib, a farnesyltransferase inhibitor.

- INCLUSION CRITERIA:

1. Age 18 years or above, male or female.

2. Serum alanine or aspartate aminotransferase activities above the upper limit of
normal (ALT > 41 or AST > 31 U/L) on an average of three determinations taken
during the previous 6 months. The mean of the three determinations will be
defined as baseline levels.

3. Presence of anti-HDV in serum.

4. Evidence of chronic hepatitis on liver biopsy done within the previous 12 months
with a necroinflammatory score in histology activity index of at least 5 (out of
a maximum of 18) and at least 1 for hepatic fibrosis (out of a maximum of 6).

5. Presence of HDV antigen in liver tissue or HDV RNA in serum.

6. Written informed consent.

EXCLUSION CRITERIA:

1. Decompensated liver disease, defined by bilirubin > 4mg/dL, albumin < 3.0 gm/dL,
prothrombin time > 2 sec prolonged, or history of bleeding esophageal varices,
ascites or hepatic encephalopathy. Laboratory abnormalities that are not thought to
be due to liver disease may not necessarily require exclusion. Patients with ALT
levels greater than 1000 U/L (> 25 times ULN) will not be enrolled but may be
followed until three determinations are below this level.

2. Pregnancy or inability to practice adequate contraception, in women of childbearing
potential or in spouses of such women. Adequate contraception is defined as vasectomy
in men, tubal ligation in women, or use of two barrier methods such as condoms and
spermicide combination, birth control pills, an intrauterine device, Depo-Provera, or
Norplant.

3. Significant systemic or major illnesses other than liver disease, including, but not
limited to, congestive heart failure, renal failure (eGFR < 50 ml/min), organ
transplantation, serious psychiatric disease or depression (only if felt to be at
high risk by the NIH psychiatric consultation service), and active coronary artery
disease.

4. Systemic immunosuppressive therapy within the previous 2 months.

5. Evidence of another form of liver disease in addition to viral hepatitis (for example
autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis,
Wilson disease, alcoholic liver disease, nonalcoholic steatohepatitis (but not
steatosis), hemochromatosis, or alpha-1-antitrypsin deficiency).

6. Active substance abuse, such as alcohol, inhaled or injection drugs within the
previous year.

7. Evidence of hepatocellular carcinoma.

8. Evidence of concurrent hepatitis C infection with positive serum HCV RNA.

9. Any experimental therapy apart from pegylated interferon within 6 months prior to
enrollment.

10. Diagnosis of malignancy in the five years prior to the enrollment with exception
granted to superficial dermatologic malignancies.

11. Evidence of HIV co-infection; HIV (Omega) antibody positivity on serum testing.

12. Concurrent usage of statins as these drugs inhibit mevalonate synthesis which reduces
protein prenylation.

13. Concurrent usage of moderate and strong CYP3A inhibitors and inducers.

14. Inability to understand or sign informed consent.

15. Any other condition, which in the opinion of the investigators would impede the
patient s participation or compliance in the study.