Sofosbuvir

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

The Foster City, CA-based Gilead said that its experimental drug GS-7977, originally known as PSI-7977 before the acquisition, when combined with ribavirin, cured a group of genotype 1 hepatitis C patients after four weeks of treatment. The clinical study involved hepatitis C patients who either failed to respond to previous therapies or had not been treated before. The genotype 1 is the most common form of HCV in the United States. It affects 70 to 90 percent of the people in this country who have hepatitis C.

Norbert Bischofberger, chief scientific officer at Gilead said patients with genotype 1 hepatitis C had no detectable signs of the virus after treated with GS-7977 combination therapy for a course of close to a month. Previous study showed the drug candidate could also cure patients with genotype 2 and 3 HCV.

Gilead gained rights to GS-7977 through the $11 billion Pharmasset acquisition deal, which enable the company to be in an advanced position to compete with a few pharma companies seeking to develop an all-oral regimen for hepatitis C. The 100 percent cure rate data suggested that GS-7977 may be one of the most promising therapies for hepatitis C.

Last year, GS-7977, an oral uridine nucleotide analog polymerase inhibitor of HCV, received fast track designation from the U.S. FDA for the treatment of HCV infection.

The World Health Organization estimated that 3–4 million people are infected with HCV each year. Some 130–170 million people are chronically infected with HCV and at risk of developing liver cirrhosis and/or liver cancer,  and more than 350,000 people die yearly from hepatitis C-related diseases.

Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.^[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.^[2]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.^[3]

Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.^[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.^[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.^[6]

1. Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “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”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
2.  “PSI-7977”. Gilead Sciences.
3.  Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977”. Journal of Biological Chemistry 285 (45): 34337–34347. doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
4.  Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
5.  Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
6.  http://www.gilead.com/pr_1757156
7.  AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
8.  Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
9.  CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.