Sofosbuvir

From Wikipedia, the free encyclopedia - View original article

Sofosbuvir structure.svg
Systematic (IUPAC) name
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
Clinical data
Trade namesSovaldi
Licence dataUS FDA:link
Pregnancy cat.B (US)
Legal status-only (US)
Pharmacokinetic data
Protein binding61–65%
MetabolismQuickly activated to triphosphate
Half-life0.4 hrs (sofosbuvir)
27 hrs (GS-331007)
Excretion80% feces, 14% urine (mostly as GS-331007)
Identifiers
CAS number1190307-88-0
ATC codeJ05AB
PubChemCID 45375808
ChemSpider26286922
UNIIWJ6CA3ZU8B YesY
KEGGD10366
ChEMBLCHEMBL1259059
SynonymsPSI-7977; GS-7977
Chemical data
FormulaC22H29FN3O9P 
Mol. mass529.453 g/mol
 
Jump to: navigation, search
Sofosbuvir structure.svg
Systematic (IUPAC) name
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
Clinical data
Trade namesSovaldi
Licence dataUS FDA:link
Pregnancy cat.B (US)
Legal status-only (US)
Pharmacokinetic data
Protein binding61–65%
MetabolismQuickly activated to triphosphate
Half-life0.4 hrs (sofosbuvir)
27 hrs (GS-331007)
Excretion80% feces, 14% urine (mostly as GS-331007)
Identifiers
CAS number1190307-88-0
ATC codeJ05AB
PubChemCID 45375808
ChemSpider26286922
UNIIWJ6CA3ZU8B YesY
KEGGD10366
ChEMBLCHEMBL1259059
SynonymsPSI-7977; GS-7977
Chemical data
FormulaC22H29FN3O9P 
Mol. mass529.453 g/mol

Sofosbuvir (brand name Sovaldi) is a drug used for hepatitis C infection, with a high cure rate.[1][2] It inhibits the RNA polymerase that the hepatitis C virus (HCV) uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.[3]

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C.[4] Interferon-free therapy for treatment of hepatitis C reduces the side effects associated with use of interferon.[5][6]

In 2013, the Food and Drug Administration (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.[4] Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for treatment of genotype 3. This is typically half the time as with prior treatments. The label further states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.[7]

The price of sofosbuvir, quoted in various media sources as $84,000 to $168,000 for a course of treatment in the U.S. and £35,000 for 12 weeks in the UK,[8] has engendered considerable controversy, particularly with respect to accessibility in developing countries.[9][10]

Medical uses[edit]

Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3 and 4, in combination with pegylated interferon and ribavirin, or with ribavirin alone. It is also used in HCV patients with an HIV coinfection.[6] The treatment is based on a number of clinical trials, for example the ELECTRON trial which 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.[11][12]

In early 2014, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir and ribavirin, with or without pegylated interferon, are part of all first-line treatments for HCV genotypes 1 to 6, and are also part of some second-line treatments.[13]

Adverse effects[edit]

As sofosbuvir is always combined with other drugs such as ribavirin and interferon, only the adverse effects of these combinations have been evaluated. Common side effects are fatigue, headache, nausea, rash, and irritability. Most side effects are significantly more common in interferon containing regimens as compared to interferon-free ones. For example, fatigue and headache are nearly cut in half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.[6][14]

Interactions[edit]

Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore it is theorised that inducers of intestinal P-glycoprotein, such as rifampicin and St. John's Wort, could reduce the absorption of sofosbuvir.[6]

Mechanism of action[edit]

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, and thus acts as an inhibitor of viral RNA synthesis. Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as anti-hepatitis C treatments, but these exhibited relatively low potency. This low potency arises in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell.[15][16] The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.

Sofosbuvir prodrug chemistry.svg

Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure.[17][18]

History[edit]

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.[19]

In December 2013, the FDA approved sofosbuvir for the treatment of chronic hepatitis C.[20]

Research[edit]

Combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or ledipasvir, have shown sustained virological response rates of up to 100% in people infected with HCV.[21]

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.[22] Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Society and culture[edit]

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.[23] The price in the United Kingdom is expected to be £35,000 (~$59,000) for 12 weeks. [24] The California Technology Assessment Forum, a group of independent experts on evaluating medical evidence, [25] voted on March 10, 2014, that the drug should be considered a low value treatment compared to older treatments. The Forum concluded that health care costs in California could increase by $18-29 billion/year because of this medication.[26]

The price has stirred controversy, with critics contending the drug is unaffordable and supporters suggesting that the drug brings price savings relative to older treatments associated with severe side effects, lengthy treatment, and low cure rates.[27]

Some patient advocates, such as Jennifer Cohn of Doctors without Borders and the organization Doctors of the World have sharply criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of patients in developing countries.[28][29] As of January 2014 Gilead was reported to be in discussions with several Indian generics manufacturers to make sofosbuvir available in India at a price below that of existing generic products.[30][31] The company has stated that it expects the price of treatment with sofosbuvir-based regimens to be in the "high hundreds to low thousands" in developing markets.[32]

References[edit]

  1. ^ News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
  2. ^ 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 (October 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. 
  3. ^ "PSI-7977". Gilead Sciences. 
  4. ^ a b Tucker M (December 6, 2013). "FDA Approves 'Game Changer' Hepatitis C Drug Sofosbuvir". Medscape. 
  5. ^ "Sofosbuvir is safer than interferon for hepatitis C patients, say scientists". News Medical. April 25, 2013. 
  6. ^ a b c d Gilead: Sovaldi Prescribing Information
  7. ^ "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. 
  8. ^ "New drug Sovaldi heralds the end of hepatitis C in Britain". Daily Mail. 1 February 2014. 
  9. ^ Stanton, Tracy. "Activists pounce on $1,000-a-day price for Gilead's hep C wonder drug, Sovaldi Read more: Activists pounce on $1,000-a-day price for Gilead's hep C wonder drug, Sovaldi - FiercePharma". FiercePharma. Fierce. Retrieved 22 February 2014. 
  10. ^ Waldman, Ron. "Gilead’s HCV drug sofosbuvir approved by the FDA but accessible for how many?". Doctors of the World. Retrieved 22 February 2014. 
  11. ^ AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
  12. ^ Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (January 2013). "Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C". N. Engl. J. Med. 368 (1): 34–44. doi:10.1056/NEJMoa1208953. PMID 23281974. 
  13. ^ "Recommendations for Testing, Managing, and Treating Hepatitis C". AASLD and IDSA. Retrieved 2 February 2014. 
  14. ^ Sofosbuvir Side Effects
  15. ^ 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 (November 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. 
  16. ^ Alejandro Soza (November 11, 2012). "Sofosbuvir". Hepaton. 
  17. ^ Chae HB, Park SM, Youn SJ (2013). "Direct-acting antivirals for the treatment of chronic hepatitis C: open issues and future perspectives". ScientificWorldJournal 2013: 704912. doi:10.1155/2013/704912. PMC 3687480. PMID 23844410. 
  18. ^ Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O (December 2013). "Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review". World J. Gastroenterol. 19 (47): 8940–8948. doi:10.3748/wjg.v19.i47.8940. PMC 3870547. PMID 24379619. 
  19. ^ "FDA Advisory Committee Supports Approval of Gilead’s Sofosbuvir for Chronic Hepatitis C Infection". Drugs.com. October 25, 2013. 
  20. ^ "FDA approves Sovaldi for chronic hepatitis C". FDA New Release. U.S. Food and Drug Administration. 2013-12-06. 
  21. ^ "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. 
  22. ^ CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
  23. ^ Pollack A (December 6, 2013). "F.D.A. Approves Pill to Treat Hepatitis C". NYTimes.com. 
  24. ^ "New drug Sovaldi heralds the end of hepatitis C in Britain". Daily Mail online. 1 February 2014. 
  25. ^ "Providing credible, evidence-based information about medical technologies, treatments, and models of care | California Technology Assessment Forum". 
  26. ^ Hepatitis drug cost
  27. ^ "$1,000 Pill For Hepatitis C Spurs Debate Over Drug Prices : Shots - Health News : NPR". 
  28. ^ Stanton, Tracy. "Activists pounce on $1,000-a-day price for Gilead's hep C wonder drug, Sovaldi Read more: Activists pounce on $1,000-a-day price for Gilead's hep C wonder drug, Sovaldi - FiercePharma". FiercePharma. Fierce. Retrieved 22 February 2014. 
  29. ^ Waldman, Ron. "Gilead’s HCV drug sofosbuvir approved by the FDA but accessible for how many?". Doctors of the World. Retrieved 22 February 2014. 
  30. ^ "Gilead, local generic players in talks to bring hepatitis C drug into India". The Hindu Business Line. 3 February 2014. 
  31. ^ "Sofosbuvir Access Ex-USA". 
  32. ^ "$1,000 Pill For Hepatitis C Spurs Debate Over Drug Prices : Shots - Health News : NPR".