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Sofosbuvir

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Sofosbuvir
Clinical data
Trade namesSovaldi, Virunon
Other namesPSI-7977; GS-7977
License data
ATC code
Legal status
Legal status
Identifiers
  • 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
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.224.393 Edit this at Wikidata
Chemical and physical data
FormulaC22H29FN3O9P
Molar mass529.458 g·mol−1
3D model (JSmol)
  • C[C@@H](C(=O)OC(C)C)N[P@](=O)(OC[C@@H]1[C@H]([C@@]([C@@H](O1)n2ccc(=O)[nH]c2=O)(C)F)O)Oc3ccccc3
  • InChI=1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1
  • Key:TTZHDVOVKQGIBA-IQWMDFIBSA-N

Sofosbuvir (brand names Sovaldi and Virunon) is a drug used for hepatitis C virus (HCV) infection, with a high cure rate.[2][3] It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.[4]

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic Hepatitis C.[5]

In 2013, the FDA approved sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4.[5] Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, compared to 24 weeks for treatment of genotype 3. The label furhter states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.[6] Sofosbuvir will cost $84,000 for 12 weeks of treatment and $168,000 for the 24 weeks, which some patient advocates have criticized as unaffordable.

Interferon-free therapy for treatment of hepatitis C eliminates the substantial side-effects associated with use of interferon. Up to half of hepatitis C patients cannot tolerate the use of interferon.[7]

Mechanism of action

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate.[8] Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) polymerase.[9] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

FDA approval

The New Drug Application for Sofosbuvir was submitted on April 8, 2013 and received the FDA's Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.[10]

On 6th December 2013, the U.S. Food and Drug Administration approved sofosbuvir for the treatment of chronic hepatitis C.[11]

Medical uses

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[12][13] It has shown 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.[14]

Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[15][16]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[17] Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Cost

Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3.[18] This represents a substantial pricing increase from previous treatments consisting of interferon and ribavirin, which cost between $15,000 and $20,000.[19] The price is also significantly higher than that of Johnson & Johnson's recently approved drug simeprevir (Olysio), which costs $50,000 and also treats chronic hepatitis C.[19] The high cost of the drug has resulted in a push back from insurance companies and the like, including Express Scripts, which has threatened to substitute lower priced competitors, even if those therapies come with a more unfriendly dosing schedule.[19] Other treatments that have recently entered the market have not matched the efficacy of sofosbuvir, however, allowing Gilead to set a higher price until additional competition enters the market.[19] Patient advocates such as Doctors Without Borders have complained about the price, which is particularly difficult for underdeveloped countries to afford.[20]

Patents: US patent number 7964580, US patent number 8415322, US patent number 8334270,US patent number 7429572 Patent Expiration Date: March 26, 2029 for US patent number 7964580 and 8334270 (2028 in EU)； April 3, 2025 for US patent number 7429572 and 8415322

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
  3. ^ Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA (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". J. Med. Chem. 53 (19): 7202–18. doi:10.1021/jm100863x. PMID 20845908. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ "PSI-7977". Gilead Sciences.
  5. ^ a b Tucker M (December 6, 2013). "FDA Approves 'Game Changer' Hepatitis C Drug Sofosbuvir". Medscape.
  6. ^ "U.S. Food and Drug Administration Approves Gilead's Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C - See more at: http://www.gilead.com/news/press-releases/2013/12/us-food-and-drug-administration-approves-gileads-sovaldi-sofosbuvir-for-the-treatment-of-chronic-hepatitis-c#sthash.T9uTbSWK.dpuf". Gilead. December 6, 2013. {{cite web}}: External link in |title= (help)
  7. ^ "Sofosbuvir is safer than interferon for hepatitis C patients, say scientists". News Medical. April 25, 2013.
  8. ^ Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA (2010). "Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977". J. Biol. Chem. 285 (45): 34337–47. doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  9. ^ Alejandro Soza (November 11, 2012). "Sofosbuvir". Hepaton.
  10. ^ "FDA Advisory Committee Supports Approval of Gilead's Sofosbuvir for Chronic Hepatitis C Infection". Drugs.com. October 25, 2013. {{cite web}}: Italic or bold markup not allowed in: |publisher= (help)
  11. ^ "FDA approves Sovaldi for chronic hepatitis C". FDA New Release. U.S. Food and Drug Administration. 2013-12-06.
  12. ^ Murphy T (November 21, 2011). "Gilead Sciences to buy Pharmasset for $11 billion". Bloomberg Businessweek. {{cite web}}: Italic or bold markup not allowed in: |publisher= (help)
  13. ^ Asselah T (2014). "Sofosbuvir for the treatment of hepatitis C virus". Expert Opin Pharmacother. 15 (1): 121–30. doi:10.1517/14656566.2014.857656. PMID 24289735. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ "AASLD 2012: Sofosbuvir and daclatasvir dual regimen cures most people with HCV genotypes 1, 2, or 3". News. European Liver Patients Association. 2012-11-21.
  15. ^ AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
  16. ^ Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (2013). "Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C". N. Engl. J. Med. 368 (1): 34–44. doi:10.1056/NEJMoa1208953. PMID 23281974. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
  18. ^ Pollack A (December 6, 2013). "F.D.A. Approves Pill to Treat Hepatitis C". NYTimes.com.
  19. ^ a b c d Campbell T (December 11, 2013). "Gilead's Sofosbuvir Gets New Name, Price, Headaches". The Motley Fool.
  20. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1126/science.342.6164.1302, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1126/science.342.6164.1302 instead.
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