Lonafarnib for Chronic Hepatitis D
Lonafarnib for Chronic Hepatitis D
Background:

 -  Chronic hepatitis D is a severe disease of the liver caused by infection with the
 hepatitis D virus. The hepatitis D virus can only infect a person who also has hepatitis
 B; therefore, people with delta hepatitis have both hepatitis B and hepatitis D virus
 infection. Most people with hepatitis D eventually develop cirrhosis, which causes
 scarring and damage to the liver. There is currently no effective treatment for chronic
 hepatitis D.

 -  Lonafarnib is a drug that was originally designed to treat different types of cancer. It
 may be able to prevent the hepatitis D virus from reproducing itself. However, it has
 not been tested on people with hepatitis D. Researchers want to study different doses of
 lonafarnib to see how they affect virus levels and other symptoms of hepatitis D.

 Objectives:

 - To test the safety and effectiveness of lonafarnib as a treatment for chronic hepatitis D.

 Eligibility:

 - Individuals at least 18 years of age who have chronic hepatitis D.

 Design:

 -  Participants will be screened with a medical history and physical exam. They will have
 blood and urine tests, eye exams, and imaging studies of the liver and gall bladder. A
 liver biopsy may also be performed.

 -  Participants will receive either lonafarnib or placebo twice a day for 28 days. For the
 first 3 days, participants will stay in the hospital to have frequent blood tests.
 Participants will have four more clinic visits (on days 7, 14, 21, and 28) for blood and
 urine tests. Eye exams and heart function tests will also be given. Men may be asked to
 provide sperm samples for further testing.

 -  After the 28 days of treatment, participants will stop taking the drug or placebo. They
 will have regular followup visits for up to 6 months after stopping treatment....
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.