Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir

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 21 adult patients with
chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI)
lonafarnib (LNF) and the protease inhibitor ritonavir (RTV). LNF has been shown to decrease
serum quantitative HDV RNA in patients with chronic delta hepatitis infection, but dosing is
limited by its side effects. RTV inhibits one of the cytochrome P-450 systems that
metabolizes LNF leading to higher serum levels of LNF with minimal side effects. In this
randomized, double-blinded, placebo-controlled study, there will be six groups of patients;
Group 1(4 patients) will receive LNF/RTV 50/100 mg daily for 24 weeks, Group 2 (4 patients)
will receive LNF/RTV 75/100mg daily for 24 weeks, Group 3 (4 patients) will receive LNF/RTV
100/100mg daily for 24 weeks, Group 4, 5 and 6 (3 patients for each group) will initially
receive placebo for 12 weeks followed by either LNF/RTV 50/100 mg daily (3 patients) or
LNF/RTV 75/100mg daily (3 patients) or LNF/RTV 100/100 mg daily (3 patients) for 12 weeks.
After dosing, all patients will be monitored for 24 weeks off therapy. Nucleos(t)ide analogue
therapy will be instituted during this study to prevent the possibility of hepatitis B virus
reactivation/flare; Patients on pre-existing nucleos(t)ide analogues will be continued and
patients not on pre-existing therapy will receive either entecavir or tenofovir for 48 weeks.
Patients with quantifiable HDV RNA in serum and elevated aminotransferases will be enrolled.
Before receiving therapy, patients will be evaluated for at least 3 visits with regular
testing for HDV RNA quantitation and alanine aminotransferase (ALT) levels and will undergo
Clinical Center admission for medical evaluation, timed blood draws and to start therapy. At
each clinic visit, patients will be questioned about side effects, symptoms and quality of
life, undergo focused physical examination, and have blood drawn for complete blood counts,
HDV RNA, and routine liver tests (including ALT, aspartate aminotransferase , alkaline
phosphatase, direct and total bilirubin, and albumin). At the end of the 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 a decline of HDV RNA viral titer of 2 logs
at the end of therapy. The primary safety endpoint will be the ability to tolerate the drugs
at the prescribed dose for the full course of therapy. Several secondary endpoints will be
measured, including side effects, ALT levels, maintained virological response, undetectable
HDV RNA in the serum, loss of HBsAg and symptoms. Therapy will be stopped for intolerance to
lonafarnib and/or ritonavir (which will be carefully defined). This clinical trial is
designed as a phase 2a study assessing the antiviral activity, safety and tolerance of three
different doses of lonafarnib and ritonavir.

- INCLUSION CRITERIA:

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

2. Serum alanine or aspartate aminotransferase (ALT or AST) activities above the
upper limit of normal (ALT greater than or equal to 20 or AST greater than or
equal to 20 U/L in females and ALT greater than or equal to 30 or AST greater
than or equal to 30 U/L in males) on an average of three determinations taken
during the previous 6 months at the NIH clinical center. The mean of the three
determinations will be defined as baseline levels.

3. Presence of anti-HDV in serum.

4. Presence of quantifiable HDV RNA in serum.

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, active breast-feeding, 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. In total, the participant and their partner must
utilize two forms of contraception and one method must include a barrier method.

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 hepatitis c virus
(HCV) RNA.

9. Any experimental therapy or pegylated interferon therapy 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 1/2 viral RNA or antigen on serum testing.

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

13. Concurrent usage of moderate and strong cytochrome p450, family 3, subfamily A (CYP3A)
inhibitors and inducers.

14. Use of any prescription, nonprescription or natural medicine (herbal) medications
unless the use of medication is medically necessary with appropriate monitoring.

15. Concurrent usage of alpha 1 adrenoreceptor antagonist, antiarrhythmic, pimozide,
sildenafil, sedative and hypnotics, ergot and St. John s Wort due to possible effect
of ritonavir on hepatic metabolism of these drugs resulting in potentially life
threatening side effects.

16. Clinically significant baseline EKG abnormalities.

17. Uncontrolled elevated triglycerides.

18. History of pancreatitis as a result of hypertriglyceridemia.

19. Inability to understand or sign informed consent.

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