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Updated: Jun 3, 2026
Development of a Hepatitis B Virus Reporter System to Monitor the Early Stages of the Replication Cycle
Published on: February 1, 2017
A twenty-eight-day mechanistic time course study in the rhesus monkey with hepatitis C virus protease inhibitor BILN
James H Stoltz1, Jerry O Stern, Qihong Huang
1Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, USA. jim.stoltz@boehringer-ingelheim.com
Abstract:
BILN 2061 is a potent, reversible inhibitor of hepatitis C virus NS3/NS4A serine protease. Early clinical proof of principle with the drug was offset by the results of subsequent safety studies in Rhesus monkeys revealing cardiotoxicity that featured myocardial vacuolation corresponding to mitochondrial swelling. Here we describe an investigation into the nature, onset, and reversibility of the lesion, and an assessment of potentially predictive biomarkers for the change. Rhesus monkeys were orally administered 1,000 mg/kg/day BILN 2061 and either necropsied after one, three, fourteen, or twenty-eight doses or afforded a ten-week recovery period. The results of electrocardiographic and plasma troponin I and T measurements were unaffected by BILN 2061, but cardiac myocytic vacuolation, correlated with mitochondrial swelling, was observed after three or more doses. Echocardiographic traces obtained after twenty-eight consecutive days of dosing revealed two animals with diminished left ventricular cardiac ejection fraction. One animal was immediately necropsied and exhibited marked cardiotoxicity. The other was afforded a ten-week treatment-free period during which the left ventricular ejection fraction returned to normal. All recovery animal hearts were microscopically and ultrastructurally normal. High-dose BILN 2061 cardiotoxicity in Rhesus monkeys appeared early in the treatment regimen and exhibited reversibility. A reliable biomarker has yet to be identified.
Insights
Hepatitis C protease inhibitor BILN 2061 caused reversible heart damage in Rhesus monkeys, characterized by mitochondrial swelling. Biomarkers for this cardiotoxicity remain unidentified, despite early clinical promise.
Area of Science:
- Hepatology
- Toxicology
- Cardiovascular Research
Background:
- BILN 2061 is a potent inhibitor of the hepatitis C virus NS3/NS4A serine protease.
- Early clinical studies showed promise, but Rhesus monkey safety studies revealed cardiotoxicity, specifically myocardial vacuolation linked to mitochondrial swelling.
Purpose of the Study:
- To investigate the nature, onset, and reversibility of BILN 2061-induced cardiotoxicity in Rhesus monkeys.
- To assess potential biomarkers for predicting this adverse effect.
Main Methods:
- Rhesus monkeys received high-dose oral BILN 2061 (1,000 mg/kg/day).
- Animals were necropsied after varying doses or underwent a ten-week recovery period.
- Electrocardiography, plasma troponin levels, and echocardiography were used to monitor cardiac function.
Main Results:
- Cardiac myocytic vacuolation and mitochondrial swelling were observed after three or more doses.
- Two animals showed diminished left ventricular ejection fraction after 28 days; one exhibited marked cardiotoxicity upon necropsy.
- The other animal's ejection fraction normalized after a ten-week recovery period; all recovered hearts were ultrastructurally normal.
Conclusions:
- High-dose BILN 2061-induced cardiotoxicity in Rhesus monkeys is an early-onset, reversible condition.
- Despite reversibility, a reliable predictive biomarker for this specific cardiotoxicity has not yet been identified.
