HepaBloc™ Program

HCV infects more than 170 million people worldwide and is a major contributor to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV is also the most common cause for liver transplantation in the United States. HCV is comprised of multiple genotypes, and significant heterogeneity exists even within genotype subgroups. Therefore, drug resistance is a major issue, and combinatorial drug therapy is required for sustained efficacy. About 50% of patients do not respond to the current standard of care: combination therapy with pegylated interferon and the nucleoside analogue ribavirin. The treatment also has significant side effects, including severe flu-like symptoms from interferon and anemia from ribavirin. Current anti-HCV drugs in development almost exclusively target the viral enzymes protease and polymerase, and many of these have encountered safety issues in clinical trials. Therefore, there is an urgent need for new classes of anti-HCV drugs.

Our HCV program focuses on HCV virus entry, thus targeting the very first step in virus infection. Entry inhibitors are expected to effectively synergize with other antiviral drugs. Currently, there are no HCV entry inhibitors in clinical development. Our efforts have led to the discovery of a novel cellular receptor for the virus, which would serve as a proprietary target for the development of small molecule or antibody therapeutics. We have also established sophisticated screening assays to identify small molecule compounds that inhibit infection by virus particles containing envelope proteins of different HCV genotypes. We have identified two compound series that specifically inhibit HCV entry at nanomolar potency. One series of compounds acts by binding selectively to the viral envelope protein E2, with the greatest affinity to the E2 of genotype 1a and 1b, the most prevalent genotypes in the developed countries. To our knowledge this is the first example of an HCV entry inhibitor with a defined mechanism. The other compound series inhibits all HCV genotypes with equal efficiency, and likely acts on a cellular factor. Our goal is to file IND on selected clinical candidates from one or both of these compound series in 2008.