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Sofosbuvir (GS-7977)

Sofosbuvir is an oral antiviral against hepatitis C (DAA or direct acting antiviral). It belongs to a category of medications called nucleotide analogues. Sofosbuvir is currently not approved by the FDA, but it is actively being investigated in several clinical trials, nowadays in phase 3 studies. There is significant clinical interest in sofosbuvir, as it could be used as a backbone for interferon-free regimens for hepatitis C treatment.

Sofosbuvir, acts by inhibiting a key hepatitis C virus (HCV) enzyme called RNA polymerase (NS5B), acting as a chain terminator. This enzyme is critical for the replication of the virus.

Some features of sofsobuvir:

  • It is taken orally (by mouth) once daily in a dose of 400 mg QD.
  • Sofosbuvir has been shown so far to be safe and very well tolerated.
  • Sofosbuvir has a pangenotypic activity, meaning that it is active against all hepatitis C virus genotypes.
  • Sofosbuvir is potent inhibitor, with an IC50 in the picomolar range. IC50 refers to the concentration of the drug necessary for inhibiting HCV replication. If a drug has a low IC50, it means it is more potent.
  • Sofosbuvir has a high barrier to resistance. This means that the chance that using this medication results in selection of viral mutations that confer resistance to the medication is low. In order for selecting resistance mutants, the virus has to develop mutations in the active site of the HCV RNA polymerase. A mutation at this site will also decrease replication fitness of the virus, explaining this high barrier to resistance.
  • It has been co-formulated with an NS5A inhibitor (GS-5885) in a fixed dose single pill.

Sofosbuvir was developed by Pharmasset, and initially was known as PSI-7977. Pharmasset was acquired by Gilead in 2012, so the name of the drug changed to GS-7977, and now has the official name sofosbuvir.

Several studies, most published in abstract form, have shown impressive clinical results of using sofosbuvir in hepatitis C virus infected patients, including the Electron and the Proton studies. More recently, the Electron trial has been published in the New England Journal of Medicine [zotpressInText item="{NF73UMNJ}" format="%num%"].

Sofosbuvir is currently being evaluated in several phase 3 trials:

  • POSITRON: Sofosbuvir + ribavirin in interferon ineligible or intolerant patients with genotypes 2 and 3 for 12 weeks (results for Q4 2012).
  • FISSION: Sofosbuvir + ribavirin in treatment naive genotype 2 and 3 patients for 12 weeks (results for Q1 2013).
  • FUSION: Sofosbuvir + ribavirin in treatment experienced genotype 2 and 3 patients for 12 or 16 weeks (results for Q1 2013).
  • NEUTRINO: Sofosbuvir + peginterferon alfa 2a + ribavirin in treament naive patients with genotype 1, 4, 5 and 6 for 12 weeks (results for Q1 2013).
  • ION-1: Sofosbuvir + GS-5885 with or without ribavirin in treatment naive genotype 1 patients for 12 or 24 weeks (results for Q4 2014).

References

Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem. 2010 Oct 14;53(19):7202-18.

Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother. 2012 Jun;56(6):3359-68.

http://www.gilead.com/pr_1757156

[zotpressInTextBib style="Hepatology" sortby="default" sort="ASC"]

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