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An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

DANIEL LAMARRE¹, PAUL C. ANDERSON², MURRAY BAILEY², PIERRE BEAULIEU², GORDON BOLGER¹, PIERRE BONNEAU¹, MICHAEL BÖS², DALE R. CAMERON^2,*, MIREILLE CARTIER¹, MICHAEL G. CORDINGLEY¹, ANNE-MARIE FAUCHER², NATHALIE GOUDREAU², STEPHEN H. KAWAI², GEORGE KUKOLJ¹, LISETTE LAGACɹ, STEVEN R. LAPLANTE², HANS NARJES³, MARC-ANDRÉ POUPART², JEAN RANCOURT², ROEL E. SENTJENS⁴, ROGER ST GEORGE⁵, BRUNO SIMONEAU², GERHARD STEINMANN³, DIANE THIBEAULT¹, YOULA S. TSANTRIZOS², STEVEN M. WELDON⁵, CHAN-LOI YONG⁵ & MONTSE LLINÀS-BRUNET²

¹ Departments of Biological Sciences Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
² Chemistry, Research and Development, Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
³ Clinical Research, Boehringer Ingelheim Pharma KG, Biberach 88397, Germany
⁴ Academisch Medisch Center, 1105 AZ, Amsterdam, The Netherlands
⁵ Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877-0368, USA
* Present address: Micrologix Biotech Inc., BC Research Complex, 3650 Wesbrook Mall, Vancouver, British Columbia, V6S 2L2, Canada

Correspondence and requests for materials should be addressed to D.L. (dlamarre@lav.boehringer-ingelheim.com).

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.