HCV Program

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Approximately 170 million people are believed to be infected with HCV worldwide (WHO, 2000), and an estimated 12,000 deaths from liver disease occur each year in the USA due to HCV infection (CDC, 2008).

HCV is a member of the Flaviviridae family, with 7 major genotypes and a large number of subtypes. HCV infection is a highly dynamic process, with a viral half-life of a few hours and an average daily production and clearance rate of ≥10¹² viral particles. The lack of a proof-reading function of the HCV RNA polymerase provides the basis for the genetic variability observed in cell culture and in the clinic. These findings provide a rationale for the development and implementation of multi-drug antiviral combination therapies.

Current therapy with (peg)ylated IFN-α and ribavirin results in sustained virologic response (SVR) in 40-80% of patients, depending on the HCV genotype. However, such therapy is prolonged, associated with significant side effects and not suitable for many patients. Also, clinical studies have shown that infection with genotypes 1a and 1b, the major genotypes found throughout the developed world, is associated with a poor response to IFN-α therapy. Thus, there is an urgent need to develop more effective and well-tolerated therapeutics for HCV infection.

NS5A

The single-stranded RNA genome of HCV is translated upon entry into the cell into a precursor polyprotein, which is subsequently cleaved into individual proteins. Based on their functions in the viral life cycle, these individual proteins can be divided into 2 groups: structural proteins (C, E1 and E2) and non-structural proteins (p7, NS2, NS3 [protease], NS4A, NS4B, NS5A, NS5B [replicase]).

NS5A is a 447-amino acid protein that plays a critical role in HCV replication, modulation of cellular signaling pathways and interferon response. It contains a putative interferon sensitivity-determining region and appears to be involved in resistance to α interferon. The essential nature of NS5A has been demonstrated in vivo with a single amino acid substitution in the protein.

Genetic studies with different mutants also demonstrated that NS5A is required for HCV subgenomic RNA replication in the cell-based replicon system. As an active component of the viral replication complex, NS5A directly interacts with NS5B replicase, viral RNA and multiple cellular proteins. As a multifunctional protein required for in vivo and in vitro replication, NS5A represents an attractive target for therapeutic intervention (reviewed in Schmitz & Tan, 2008).

Presidio’s NS5A inhibitor program, currently in preclinical development, is well positioned to compete in the growing HCV therapy market, based on the overall profile of the compounds in development.

HCV References:
CDC Viral Hepatitis Statistics and Surveillance (2008). Available (as of 24 September 2008) at http://www.cdc.gov/hepatitis/Statistics.htm.

Schmitz U and Seng-Lai Tan. 2008. NS5A – From obscurity to new target for HCV therapy. Recent Patents on Anti-Infective Drug Discovery 3(2): 1-16.

WHO Fact Sheet on HCV (2000). Available at http://www.who.int/mediacentre/factsheets/fs164/en/.

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