Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon

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. Based on previous and ongoing clinical
trials demonstrating effectiveness against HDV, we propose to treat 26 adult patients with
chronic delta hepatitis using the combination of the farnesyltransferase inhibitor (FTI)
lonafarnib (LNF), the protease inhibitor ritonavir (RTV) and peginterferon lambda-1a(lambda).
In this phase 2a open label study, the safety and antiviral effects of triple therapy with
LNF, RTV and lambda for a period of 6 months. After dosing, all patients will be monitored
for 24 weeks off therapy. Nucleos(t)ide analogue therapy will be instituted/continued during
this study to prevent the possibility of HBV reactivation/flare for the duration of
participation in this clinical trial. Patients with quantifiable HDV RNA in serum will be
enrolled. 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, AST, alkaline phosphatase,
direct and total bilirubin, and albumin). At the end of the treatment, patients will be
admitted to the clinical center and will undergo repeat liver biopsy and HVPG measurements,
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. This clinical trial is designed as a phase 2a
study assessing the antiviral activity, safety and tolerance of fixed doses of lonafarnib,
ritonavir and peginterferon lambda.

- INCLUSION CRITERIA:

- Age 18 years or above, male or female.

- Presence of anti-HDV in serum.

- Presence of quantifiable HDV RNA in serum at three time pre-treatment points with a
mean HDV RNA level >2 log10 above the lower limit of quantification (LLOQ) of the HDV
RNA assay.

- Demonstration of chronicity as evidenced by the presence of HDV RNA in serum for >/= 6
months, or presence of Anti-HDV antibody >/= 6months.

INCLUSION CRITERIA:

- 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. Patients with an absolute neutrophil count
<1000/dL and platelets <75,000/dL will be excluded from the study as well.

- Pregnancy, active breast-feeding, or inability to practice adequate contraception, in
women of childbearing potential or in partners of such women. Adequate contraception
is defined as vasectomy in male sexual partners of female participants, tubal ligation
in women, or use of two contraceptive methods such as condoms and spermicide
combination with an intrauterine device or Depo-Provera, or Norplant.

- 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), or active coronary artery disease.

- Systemic immunosuppressive therapy within the previous 2 months before enrollment.

- 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, ongoing drug induced liver disease,
nonalcoholic steatohepatitis (but not steatosis), hemochromatosis, or
alpha-1-antitrypsin deficiency).

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

- Evidence of hepatocellular carcinoma. This will be determined on the basis of imaging
with ultrasound/ CT scan or MRI performed a maximum of 6 months prior to enrollment.
Elevated AFP levels will be evaluated clinically and further imaging may be performed
if felt necessary.

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

- Any experimental therapy or pegylated interferon therapy within 6 months prior to
enrollment.

- Active, serious autoimmune disease such as systemic lupus erythematosus, ulcerative
colitis, Crohn s disease or rheumatoid arthritis, that is in the opinion of the
investigators might be exacerbated by therapy with lambda interferon. This will be
evaluated at baseline and during follow-up laboratory testing (including blood and
urine studies) in addition to described symptoms at each outpatient visit.

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

- Evidence of HIV co-infection; HIV 1/2 antibody positivity on serum testing.

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

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

- 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.

- Clinically significant baseline EKG abnormalities such as QTc interval >450 ms and/or
prolonged PR interval.

- Uncontrolled elevated triglycerides (>500 mg/dL). Patients on lipid lowering therapy
other than statins will be eligible for this study.

- History of pancreatitis from causes other than gallstone pancreatitis. Subjects with a
baseline amylase and/or lipase level >3 ULN will be excluded from the study.

- Inability to understand or sign informed consent.

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