Treatment of Chronic Delta Hepatitis With Lonafarnib
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.
Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Double-Blind, Primary Purpose: Treatment
The primary endpoint of therapy will be an improvement in quantitative serum HDV RNA levels after 28 days of lonafarnib therapy.
Theo Heller, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
United States: Federal Government
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