About Hepatitis C
Chronic hepatitis C is an insidious liver disease that results from infection with the hepatitis C virus (HCV). It is estimated that ~170 million people or 3% of the population worldwide have been infected with HCV. Chronic infection can lead to liver fibrosis, cirrhosis, end-stage liver disease and hepatocellular carcinoma over the course of 15 to 30 years. Chronic hepatitis C (CHC) is the leading cause for liver transplantation in the United States, Japan and in the European Union.
Current treatment for CHC is based on a combination of pegylated interferon administered in combination with ribavirin and in some cases with an HCV protease inhibitor. The side effect profile and need for weekly injections limits the utility of this approach to treatment. Side effects result in the premature discontinuation of treatment in 10-20% of patients, and require dose modifications in another 20-30%. In addition, interferon is contraindicated for use in some patient populations, such as patients with decompensated liver disease or preexisting cardiac conditions where there are significant medical needs. These drawbacks have heightened the need to discover new classes of drugs for the treatment of CHC that can reduce or ameliorate the deleterious side effects of current therapies while improving efficacy. Recently, there have been significant breakthroughs identifying essential functions within the HCV replication cycle that have led to advances in drug discovery efforts. The first viral proteins to be clinically validated as therapeutic targets for Direct-acting Antiviral Agents (DAAs) were the NS3/4A protease and the NS5B polymerase. These targets are non-structural proteins with defined enzymatic functions that can be inhibited with small molecules. Similar to advancements against HIV, the recent development of protease and polymerase inhibitors brings hope for new treatment options for CHC.
Combination therapy using several drugs with different mechanisms of action has been shown to lead to higher rates of efficacy and better clinical outcomes when treating viral infections. The ultimate goal of treatment for CHC is to develop an interferon free, oral DAA regimen that can be given to all patient groups and results in higher rates of sustained virologic response while at the same time improving on the safety profile of current therapies. It is anticipated that nucleoside analog HCV NS5B polymerase inhibitors will become essential components of combination therapy for the treatment of CHC due to their broad activity across HCV genotypes, and their high barrier to the selection of drug-resistant virus variants compared to other HCV treatments currently in development. Few nucleoside analogs have advanced beyond Phase II trials and there is a need to develop additional nucleosides to address this unmet medical need.