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May 12, 2011
 |  BC Innovations  |  Cover Story

Making the most of the host

Although recent attention in the HCV space has focused on positive FDA panel recommendations for the protease inhibitors telaprevir and Victrelis

boceprevir from Vertex Pharmaceuticals Inc. and Merck & Co. Inc., respectively,1 a French-led academic group has now uncovered targets on host cells that could also be inhibited to impede HCV entry.2

The new targets include a pair of receptor tyrosine kinases-epidermal

growth factor receptor 1 (EGFR1; HER1; ERBB1) and EPH receptor A2 (EPHA2)-that are inhibited by the marketed cancer drugs Tarceva erlotinib and Sprycel dasatinib (see "Host factors involved in HCV entry and their potential as therapeutic targets").

The team, led by Thomas Baumert, began to suspect that tyrosine kinase inhibitors (TKIs) could have antiviral activity in humans after University Hospital Pontchaillou researchers published a case study in which a hepatocellular carcinoma patient cleared his HCV infection after receiving erlotinib.3

Baumert is a professor of medicine at the University of Strasbourg and head of the Strasbourg Virology Unit U748 at the Institut National de la Santé et de la Recherche Médicale(INSERM).

Using a functional small interfering RNA kinase screen, Baumert's team identified 58 kinases that affected the HCV life cycle, including EGFR1 and EPHA2.

In vitro, the EGFR1 inhibitor Tarceva and the EPHA2 inhibitor Sprycel blocked entry, infection and cell-to-cell transmission of different HCV genotypes compared with vehicle.

Tarceva, from Astellas Pharma Inc. and partner Roche, is marketed to treat pancreatic cancer and non-small cell lung cancer (NSCLC) and is in Phase III testing for liver cancer. Sprycel, from Bristol-Myers Squibb Co. and partner Otsuka Pharmaceutical Co. Ltd., is marketed to treat acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) and is in Phase III trials for prostate cancer and Phase II testing for breast cancer.

The two drugs inhibited both the major genotypes of HCV and diverse strains of the virus. In addition, the drugs were HCV specific and did not inhibit other viruses.

In chimeric mice infected with HCV genotype 2a, Tarceva decreased HCV RNA levels by more than 90% compared with placebo....

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