GS-9669: a novel non-nucleoside inhibitor of viral polymerase for the treatment of hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) is an RNA virus that chronically infects 2–3% of the world’s population. About 25% of these chronic carriers evolve towards liver cirrhosis, a disease that is significantly associated with reduced survival and quality of life. Antiviral therapy can eradicate the infection − a process that is associated with a reduced disease progression rate. Several oral direct agents have been developed and tested for the treatment of HCV infection. This review focuses on the mechanism of action, pharmacokinetics, efficacy, safety and resistance of GS-9669, a non-nucleoside inhibitor of viral polymerase, active against HCV genotype 1. In combination with other oral antivirals, GS-9669 results: in very high rates of viral eradication (90–100%) in patients with HCV genotype 1 infection, with a good tolerability and safety profile. In conclusion, GS-9669 is a good candidate to be used in interferon-free combinations for the treatment of chronic HCV infection.

Keywords::

• GS-9669
• interferon-free
• ledipasvir
• pegylated-interferon
• resistance
• ribavirin
• sofosbuvir

Acknowledgements

The authors thank Gilder JA (Scientific Communication srl., Naples, Italy) for text editing.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• HCV infects as many as 150,000,000 people worldwide and is responsible for up to half million deaths per year. Antiviral treatment can increase survival and improve quality of life of HCV-infected subjects.

• GS-9669 is a non-nucleoside inhibitor of viral polymerase.

• Pharmacokinetic studies showed a good profile with once-daily administration and the lack of interaction with sofosbuvir and ledipasvir.

• GS-9669 has a good antiviral activity and, when associated with sofosbuvir and ribavirin for 12 weeks, achieves very high rates of SVR (92–100%).

• Genetic barrier to resistance of GS-9669 is low. In fact, most patients develop mutations conferring resistance when the drug is used as monotherapy. However, GS-9669 shows no cross-resistance with antiviral drugs belonging to different classes.

• Tolerability and safety profiles are good.