A Twenty-Eight-Day Mechanistic Time Course Study in the Rhesus Monkey with Hepatitis C Virus Protease Inhibitor BILN 2061

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.

Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C

“…Of note, the cardiotoxicity of BILN 2061 (Boehringer Ingelheim), a reversible inhibitor of HCV NS3/NS4A serine protease, halted its clinical development. Initial pathological examination suggested mitochondrial dysfunction with minimal myonecrosis, although metabolomic assessments were not performed . Consistent with our findings for BMS‐986094, biomarkers of cardiac dysfunction (i.e., cardiac troponins and BNP) were insensitive measures of BILN 2061‐associated myocardial injury, and for both agents, cardiac function normalized over time.…”

Single- and Multiple-Ascending-Dose Studies of the NS3 Protease Inhibitor Asunaprevir in Subjects with or without Chronic Hepatitis C

“…In particular, these studies suggest that asunaprevir does not increase the incidence of either rash or anemia with short-term monotherapy. Because some inhibitors of HCV and human immunodeficiency virus protease inhibitors have shown evidence of cardiotoxicity (18,19), a detailed analysis of cardiac safety was undertaken. Detailed ECG analysis provided no evidence of an increased risk of cardiac adverse events associated with asunaprevir.…”

Myo-pericarditis secondary to ledipasvir-sofosbuvir therapy

“…BMS-986094, the same nucleotide polymerase inhibitor class as SOF, was terminated in August 2012 [1]. BILN 2061, an NS3 inhibitor, was terminated in 2011 [2]; this class is weakly linked to NS5A protein activity, which is the target of LDV [3]. The cardiotoxicity of BMS-986094 was identified after the death of a 25 year old from systolic congestive heart failure.…”

“…Under normothermic perfusion conditions, as stated in the studies by Foley et al, dual blood perfusion supply is essential for biliary function and epithelial viability [2,3]. The hypothermic perfusion setting, however, fundamentally differs from normothermic physiological conditions.…”