The most remarkable and alarming aspects of HCV infection are its high rate of persistence and its ability to induce chronic liver disease. As many as 80% of patients have evidence of chronic hepatitis, and 20% to 30% develop cirrhosis. Furthermore, it has become increasingly apparent that persistent infection with this virus is closely associated with hepatocellular carcinoma.

HCV is an RNA virus and its singe-stranded genome has been completely sequenced. HCV is a quasi-species with heterogeneity in viral sequences indicative of a high rate of mutation – exceeding that of HIV. These mutations are the result of the low fidelity of the HCV-induced RNA dependent RNA polymerase that replicates the viral genome. That it is a quasi-species and has a small, information-dense genome makes it a viable candidate for Viral Decay Accleration (VDA) drug development.

Until recently interferon-a was the only drug approved as a single therapy for hepatitis C in Europe and North America. In the short term, about 50% of patients have a response to interferon, but the long-term results have been disappointing. Recently approved peginterferon-a has reduced systemic clearance which enables once weekly administration while maintaining the same side effect profile. Sustained virologic responses (SVR, defined as undetectable HCV RNA 24 weeks after 48 weeks of treatment) were 18-25% for peginterferon-a versus 12% for interferon-a. Among patients with viral genotype 1, the majority of patients in the U.S., the SVR was 14% while other viral genotype had a 45% response rate. The addition of ribavirin to peginterferon can increase SVR to 34-42% in patients with viral genotype 1.

Ribavirin is a synthetic nucleoside analog currently approved for the treatment of respiratory syncytial virus and for the treatment of HCV in combination with interferon-a. Very interestingly, ribavirin's predominant mode of action is as a viral mutagen thus confirming the therapeutic value of Koronis' technology platform. Combination therapy is becoming the standard of care for treatment-naive patients and interferon relapsers. However, in addition to the low SVR rates, interferon therapy is complicated by the finding that the majority of patients in some care settings are not candidates for therapy based on such contraindications as psychiatric illness or ongoing alcohol abuse.

Because HCV cannot be grown consistently in cell culture, Koronis is using a combination of model systems to screen its inventory of potential Viral Decay Acceleration™ (VDA) molecules. Bovine viral diarrhea virus and the synthetic HCV replicon systems allow convenient and relevant screening for potential efficacy by VDA molecules in our inventory. Potential lead candidates have already been discovered.