Drugs

, Volume 73, Issue 18, pp 2093–2106 | Cite as

Simeprevir: First Global Approval

R&D Insight Report

Abstract

Simeprevir (SovriadTM) is a new direct-acting antiviral drug and a second-generation small-molecule NS3/4A serine protease inhibitor developed by Janssen and Medivir for the oral treatment of adults with genotype 1 and/or genotype 4 chronic hepatitis C virus (HCV) infection (chronic hepatitis C). Simeprevir antiviral activity is achieved by its non-covalent binding to HCV protease, with a fast association and slow dissociation rate. The capsule formulation is approved in Japan and Canada for use in combination with pegylated interferon (peginterferon) and ribavirin for genotype 1 chronic hepatitis C, and has been filed for approval in the US in this indication. In addition, the capsule formulation has been filed for approval in the EU for use in combination with peginterferon and ribavirin for genotype 1 and 4 chronic hepatitis C. Phase III trials of the capsule formulation of simeprevir are underway in several other regions, including China. In the pivotal phase III trials, simeprevir was administered once daily for 12 weeks in combination with peginterferon and ribavirin for 24 or 48 weeks. This article summarizes the milestones in the development of simeprevir leading to this first approval for chronic hepatitis C.

References

  1. 1.
    World Health Organization. Hepatitis C: Fact sheet N°164. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed 14 Oct 2013.
  2. 2.
    World Health Organization. Hepatitis C. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed 7 Nov 2013.
  3. 3.
    Liang Y, Ishida H, Lenz O, et al. Antiviral suppression vs restoration of RIG-I signaling by hepatitis C protease and polymerase inhibitors. Gastroenterology. 2008;135(5):1710–8.e2.Google Scholar
  4. 4.
    Centers for Disease Control and Prevention. Hepatitis C information for health professionals. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#-. Accessed 7 Nov 2013.
  5. 5.
    Perry C. Telaprevir: a review of its use in the management of genotype 1 chronic hepatitis C. Drugs. 2012;72(5):619–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Garnock-Jones K. Boceprevir: a review of its use in the management of chronic hepatitis C genotype 1 infection. Drugs. 2012;72(18):2431–56.PubMedCrossRefGoogle Scholar
  7. 7.
    Pockros PJ. Interferon-free hepatitis C therapy: how close are we? Drugs. 2012;72(14):1825–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin T-I, Lenz O, Fanning G, et al. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother. 2009;53(4):1377–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Bae A, Sun S-C, Qi X, et al. Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother. 2010;54(12):5288–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Rutter K, Hofer H, Beinhardt S, et al. Durability of SVR in chronic hepatitis C patients treated with peginterferon-alpha2a/ribavirin in combination with a direct-acting anti-viral. Aliment Pharmacol Ther. 2013;38(2):118–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Medivir AB. Simeprevir has been approved in Japan for the treatment of genotype 1 chronic hepatitis C infection. 2013. http://www.medivir.com. Accessed 7 Nov 2013.
  12. 12.
    Medivir AB. The regulatory process in Japan for simeprevir. 2013. http://www.medivir.com. Accessed 7 Nov 2013.
  13. 13.
    Medivir AB. Regulatory Application has now been filed for simeprevir (TMC435) in Japan for the treatment of genotype 1 hepatitis C patients. 2013. http://www.medivir.com. Accessed 7 Nov 2013.
  14. 14.
    Medivir. Simeprevir has been approved in Canada as a new treatment for hepatitis C. http://www.medivir.se/v5/en/uptodate/pressrelease.cfm
  15. 15.
    Janssen Research Development LLC. U.S. FDA grants priority review to simeprevir (TMC435) for combination treatment of genotype 1 chronic hepatitis C. 2013. http://www.janssenrnd.com. Accessed 7 Nov 2013.
  16. 16.
    Janssen Research Development LLC. Janssen submits New Drug Application to U.S. FDA for simeprevir (TMC435) for combination treatment of adult patients with genotype 1 chronic hepatitis C. 2013. http://www.janssenrnd.com. Accessed 7 Nov 2013.
  17. 17.
    Medivir AB. Medivir: New Drug Application has been filed with FDA for Simeprevir (TMC435) for combination treatment of adult patients with genotype 1 chronic hepatitis C. 2013. http://www.medivir.com. Accessed 7 Nov 2013.
  18. 18.
    Medivir. TMC435 has received fast track designation from the FDA and TMC435 will be studied in combination with Pharmasset’s PSI-7977 for HCV genotype-1. 2011. http://www.medivir.com. Accessed 7 Nov 2013.
  19. 19.
    Medivir AB. Marketing Authorization Application for simeprevir to the EMA for the treatment of patients with genotype 1 and genotype 4 hepatitis C is now filed. 2013. http://www.medivir.se. Accessed 7 Nov 2013.
  20. 20.
    Janssen Therapeutics EMEA. Janssen creates new division to launch TMC435 and help conquer hepatitis C in EMEA. 2012. http://emea.janssentherapeutics.com. Accessed 7 Nov 2013.
  21. 21.
    Medivir. Medivir: Tibotec files application to start a phase I clinical trial for HCV inhibitor. 2006. http://www.medivir.se. Accessed 7 Nov 2013.
  22. 22.
    Medivir. Tibotec files application to start a phase I clinical trial for HCV inhibitor. 2006. http://www.medivir.se. Accessed 7 Nov 2013.
  23. 23.
    Medivir AB. Medivir AB enters into license and research collaboration agreement on hepatitis C. 2004. http://www.medivir.se/OuterFrameEng.asp. Accessed 7 Nov 2013.
  24. 24.
    Medivir AB. Medivir announces TMC435 in an expanded clinical collaboration. 2012. http://www.medivir.com. Accessed 7 Nov 2013.
  25. 25.
    Medivir AB. An all-oral combination phase II study of simeprevir and samatasvir (IDX719) for the treatment of hepatitis C virus infection initiated. 2013. http://www.medivir.com. Accessed 7 Nov 2013.
  26. 26.
    Idenix Pharmaceuticals Inc. Idenix Pharmaceuticals announces collaboration with Janssen to initiate phase II all-oral combination studies including IDX719, simeprevir (TMC435) and TMC647055 for the treatment of hepatitis C virus (HCV). 2013. http://www.idenix.com. Accessed 7 Nov 2013.
  27. 27.
    Janssen Pharmaceuticals I. Janssen announces collaboration with Vertex on phase 2 study to investigate an all-oral regimen of simeprevir (TMC435) and VX-135 for treatment of hepatitis C. 2012. http://www.janssenrnd.com. Accessed 7 Nov 2013.
  28. 28.
    Vertex Pharmaceuticals I. Vertex announces collaboration with Janssen to initiate phase 2 all-oral study of VX-135 and simeprevir (TMC435) for the treatment of hepatitis C. Media Release. 2012.Google Scholar
  29. 29.
    Bristol-Myers Squibb Company. Bristol-Myers Squibb enters clinical collaboration agreement with Tibotec Pharmaceuticals for phase II combination study in patients chronically infected with hepatitis C. 2011. http://www.bms.com. Accessed 7 Nov 2013.
  30. 30.
    Pepscan Therapeutics. Pepscan therapeutics achieves milestones in research collaboration with Janssen R and D Ireland. 2012. http://www.pepscan.com. Accessed 7 Nov 2013.
  31. 31.
    Hayashi N, Seto C, Kato M, et al. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2013. doi: 10.1007/s00535-013-0875-1
  32. 32.
    Bourgeois S, Reesink HW, Leempoels J, et al. Combination therapy of TMC647055 with simeprevir (TMC435) in chronic hepatitis C patients. J Hepatol. 2013;58:S483.CrossRefGoogle Scholar
  33. 33.
    Simmen K, Lenz O, Lin TI, et al. In vitro activity and preclinical pharmacokinetics of the HCV protease inhibitor, TMC435350. Hepatology. 2007;46(Suppl. 1):857.Google Scholar
  34. 34.
    Manns MP, Reesink HW, Moreno C, et al. Safety and antiviral activity of TMC435350 in treatment-naive genotype 1 HCV- infected patients [abstract no. LB8]. 59th Annual Meeting of the American Association for the Study of Liver Diseases; 2008 Oct 31–Nov 1; San Francisco (CA); 2008.Google Scholar
  35. 35.
    Reesink HW, Fanning GC, Farha KA, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138(3):913–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Manns M, Reesink H, Berg T, et al. Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther. 2011;15:1021–33.CrossRefGoogle Scholar
  37. 37.
    Marcellin P, Reesink H, Berg T, et al. Antiviral activity and safety of TMC435 combined with peginterferon alpha-2A and ribavirin in patients with genotype 1 hepatitis C infection who failed previous IFN-based therapy [abstract no. 1058]. 44th Annual Meeting of the European Association for the Study of the Liver; 2009 Apr 22–26; Copenhagen, Denmark, S385; 2009.Google Scholar
  38. 38.
    Lenz O, Vijgen L, Berke JM, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol. 2013;58(3):445–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Moreno C, Berg T, Tanwandee T, et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study. J Hepatol. 2012;56(6):1247–53.PubMedCrossRefGoogle Scholar
  40. 40.
    Lenz O, De Bruijne J, Vijgen L, et al. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology. 2012;143(5):1176–8.e6.Google Scholar
  41. 41.
    Lenz O, Vijgen L, Lin Tl, et al. Virologic analysis of genotype-1-infected patients treated with once-daily Tmc435 during the optimal protease inhibitor enhancement of response to therapy (Opera)-1 study [abstract no. 812]. 61st Annual Meeting of the American Association for the Study of Liver Diseases; 2010 Oct 30–Nov 3 Boston (MA); 2010.Google Scholar
  42. 42.
    Lenz O, Fevery B, Vijgen L, et al. Resistance profile of TMC435 in HCV genotype- 1-infected patients: Virological analyses of the PILLAR and ASPIRE Phase IIb trials. Antivir Ther. 2012;17:A28.Google Scholar
  43. 43.
    Lenz O. Resistance analyses of HCV isolates from patients treated with simeprevir in phase 2b/3 studies [poster plus abstract no. 1101]. 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5 Washington, DC; 2013.Google Scholar
  44. 44.
    Sekar V, Vis P, Lenz O, et al. Pharmacokinetic-pharmacodynamic (pk-pd) analyses of TMC435 in treatment-naive hepatitis C (HCV)-infected patients in the Opera-1 study [poster no. 1075]. J Hepatol. 2010;52:S319–457.Google Scholar
  45. 45.
    van ‘t Klooster GA, Vanwelkenhuysen I, Verloes R, et al. Pharmacokinetics of once-daily regimens of the novel HCV NS3/4A-protease inhibitor TMC435350, with and without PEGIFN and ribavirin, in HCV-infected individuals [abstract]. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AALSD); 2008 Oct 31–Nov 1; San Francisco (CA); 2008.Google Scholar
  46. 46.
    Verloes R, Farha KA, van Vliet A, et al. Results of a phase I placebo-controlled trial in healthy volunteers to examine the safety, tolerability and pharmacokinetics of the HCV protease inhibitor TMC435350 after single and repeated dosing. Hepatology. 2007;46(Suppl. 1):823–4.Google Scholar
  47. 47.
    van t Klooster GAE, Vanwelkenhuysen I, Hooijmaijers R, et al. Once-daily regimens of the HCV NS3/4A-protease inhibitor TMC435350 are predicted to provide therapeutic exposure in plasma and liver. 43rd annual meeting of the European Association for the Study of the Liver. 2008.Google Scholar
  48. 48.
    Reesink H, Verloes R, Farha KA, et al. Safety of the HCV protease inhibitor TMC435350 in healthy volunteers and safety and activity in chronic hepatitis C infected individuals: a phase I study. 43rd annual meeting of the European Association for the Study of the Liver. 2008.Google Scholar
  49. 49.
    Janssen. Antiviral Drugs Advisory Committee Meeting Briefing Document Simeprevir (TMC435) Treatment of patients with chronic hepatitis C NDA 205123. October 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM371624.pdf. Accessed 11 Nov 2013.
  50. 50.
    Ouwerkerk-Mahadevan S, Simion A, Spittaels K, et al. Pharmacokinetics of simeprevir (TMC435) in volunteers with moderate or severe hepatic impairment. J Hepatol. 2013;58:S365.CrossRefGoogle Scholar
  51. 51.
    Sekar V, Verloes R, Meyvisch P, et al. Evaluation of metabolic interactions for TMC435 via cytochrome P450 enzymes in healthy volunteers [abstract no. 1076]. 45th Annual Meeting of the European Association for the Study of the Liver; 2010 Apr 14–18; Vienna, Austria.Google Scholar
  52. 52.
    Ouwerkerk-Mahadevan S, Sekar V, Peeters M. The pharmacokinetic Interactions of HCV protease inhibitor TMC435 with RPV, TDF, EFV, or RAL in healthy volunteers [abstract no. 49]. 19th Conference on Retroviruses and Opportunistic Infections, March 5–8, 2012, Seattle (WA); 2012.Google Scholar
  53. 53.
    Ouwerkerk-Mahadevan S, Beumont M, Spittaels KF, et al. No pharmacokinetic interaction between the investigational HCV protease inhibitor TMC435 and an oral contraceptive containing ethinylestradiol and norethindrone. Hepatology. 2012;56:565A–6A.Google Scholar
  54. 54.
    Ouwerkerk-Mahadevan S, Simion A, Mortier S, et al. No clinically significant interaction between the investigational HCV protease inhibitor TMC435 and the immunosuppressives cyclosporine and tacrolimus. Hepatology. 2012;56:231A.Google Scholar
  55. 55.
    Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013. doi: 10.1002/hep.26641
  56. 56.
    Janssen Pharmaceuticals I. Efficacy and safety data from phase 2B trials of Janssen’s Simeprevir in hepatitis C patients with advanced fibrosis of the liver presented at annual meeting of the American Association for the Study of Liver Diseases. Media Release; 2012.Google Scholar
  57. 57.
    Lenz O, Fevery B, Vijgen L, et al. TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analyses of the aspire trial. J Hepatol. 2012;56:S5.CrossRefGoogle Scholar
  58. 58.
    Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the aspire trial. J Hepatol. 2012;56:S1–2.CrossRefGoogle Scholar
  59. 59.
    Zeuzem S, Foster G, Fried M, et al. The ASPIRE trial: once-daily TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment. Hepatol Int. 2012;6(1):187–8.Google Scholar
  60. 60.
    Zeuzem S, Foster GR, Fried MW, et al. The Aspire Trial: Tmc435 in treatment-experienced patients with genotype-1 Hcv infection who have failed previous Pegifn/Rbv treatment [abstract no. 1376]. 46th annual meeting of the European Association for the Study of the Liver; 2011 Mar 30–Apr 3; Berlin, Germany; 2011.Google Scholar
  61. 61.
    Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology epub 2013 Oct 31. 2013.Google Scholar
  62. 62.
    Jacobson IM, Ghalib RM, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study [abstract LB-3]. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5; Washington, DC; 2013.Google Scholar
  63. 63.
    Medivir. Results from the COSMOS study with simeprevir and sofosbuvir in cirrhotic and non-cirrhotic HCV genotype 1 patients presented at AASLD. 2013. http://www.medivir.se/v5/en/uptodate/pressrelease.cfm. Accessed 21 Nov 2013.
  64. 64.
    Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders [abstract no. 155LB]. 20th Conference on Retroviruses and Opportunistic Infections; 2013 Mar 3–6; Atlanta (GA); 2013.Google Scholar
  65. 65.
    Lawitz E, Ghalib R, Rodriguez-Torres M, et al. SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin (RBV) in HCV GT 1 null responders. Gastroenterology. 2013;1:S374–5.Google Scholar
  66. 66.
    Medivir AB. Medivir announces interim results from Cohort 2 of the COSMOS study evaluating simeprevir and sofosbuvir in HCV patients with METAVIR scores F3-F4. 2013. http://www.medivir.com. Accessed 21 Nov 2013.
  67. 67.
    Manns M, Reesink H, Moreno C, et al. OPERA-1 Trial: interim analysis of safety and antiviral activity of TMC435 in treatment-naive genotype 1 HCV patients [abstract no. 11]. 44th Annual Meeting of the European Association for the Study of the Liver; 2009 Apr 22–26; Copenhagen, Denmark, S7; 2009.Google Scholar
  68. 68.
    Reesink HW, de Bruijne J, Weegink CJ, et al. Antiviral activity and safety of TMC435 combined with pegylated interferon and ribavirin in hepatitis C patients with genotype-1 who had previous exposure to TMC435 [poster no. 1563]. 60th annual meeting of the American Association for the Study of Liver Diseases; 2009 Oct 30–Nov 3; Boston, (MA); 2009.Google Scholar
  69. 69.
    Johnson & Johnson. Primary efficacy and safety findings from four phase 3 Japanese studies of simeprevir administered once daily demonstrate sustained virologic response in genotype 1 chronic hepatitis C adult patients http://www.investor.jnj.com/releasedetail.cfm?ReleaseID=769679. Accessed 17 Oct 2013.
  70. 70.
    Medivir AB. Primary efficacy and safety data from four phase III Japanese studies of Simeprevir presented at The Japan Society of Hepatology. Media Release. 2013. http://news.cision.com/medivir/r/primary-efficacy-and-safety-data-from-four-phase-iii-japanese-studies-of-simeprevir-presented-at-the,c9425114
  71. 71.
    Jacobson IM, Dore GJ, Foster G, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from Quest-1, a phase III trial [abstract no. Sa2072]. Digestive Disease Week; 2013 May 18–21; Orlando (FL); 2013.Google Scholar
  72. 72.
    Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from quest-1, a phase III trial. J Hepatol. 2013;58:S574.CrossRefGoogle Scholar
  73. 73.
    Manns M, Marcellin P. Fred Poordad FP, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from Quest-2, a phase III trial. J Hepatol. 2013;58:S568.CrossRefGoogle Scholar
  74. 74.
    Poordad F, Manns MP, Marcellin P, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic hcv genotype-1 infection in treatment-naive patients: results from Quest-2, a phase III trial. Gastroenterology. 2013;1:S151.Google Scholar
  75. 75.
    Jacobson I. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: efficacy in difficult-to-treat patient sub-populations in the QUEST 1 and 2 phase III trials [abstract no. 1122]. 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5; Washington, DC; 2013.Google Scholar
  76. 76.
    Lawitz E, Forns X, Zeuzem S, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic hcv genotype 1 infection in patients who relapsed after previous interferon-based therapy: results from promise, a phase III trial. Gastroenterology. 2013;1:S151.Google Scholar
  77. 77.
    Forns X. Simeprevir (TMC435) with peg-interferon alpha-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMISE phase III trial [poster and abstract no. 1092]. 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5; Washington, DC; 2013.Google Scholar
  78. 78.
    Scott J. Adding simeprevir to peginterferon/ribavirin for HCV shortens time with patient-reported symptoms and impairment in quality of life: Results from the simeprevir Phase III QUEST 1, QUEST 2 and PROMISE studies [poster and abstract no. 1116] 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5; Washington, DC; 2013.Google Scholar
  79. 79.
    Nakajima T. Comparison of simeprevir plus peginterferon/ribavirin and telaprevir plus peginterferon/ribavirin for patients with HCV genotype 1 [abstract no. 1930]. 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD 2013); 2013 November 1–5; Washington, DC; 2013.Google Scholar
  80. 80.
    Simion A, Janssens L, Peeters M, et al. Absence of photosensitivity potential of TMC435 in healthy volunteers. J Hepatol. 2012;56:S458.CrossRefGoogle Scholar
  81. 81.
    ClinicalTrials.gov. TMC435 Clinical studies. http://clinicaltrials.gov/ct2/results?term=TMC435&Search=Search. Accessed 7 Nov 2013.
  82. 82.
    ClinicalTrials.gov. A study of TMC435 plus pegylated interferon alfa-2a and ribavirin in participants with chronic HCV infection (NCT01846832). http://clinicaltrials.gov/show/NCT01846832. Accessed 7 Nov 2013.
  83. 83.
    ClinicalTrials.gov. IDX719 in combination with simeprevir and ribavirin for 12 weeks in subjects with chronic hepatitis C infection (NCT01852604). http://clinicaltrials.gov/ct2/show/NCT01852604?term=NCT01852604&rank=1. Accessed 7 Nov 2013.
  84. 84.
    ClinicalTrials.gov. A study of pharmacokinetics, efficacy, safety, tolerability, of the combination of simeprevir (TMC435), daclatasvir (BMS-790052), and ribavirin (RBV) in patients with recurrent chronic hepatitis C genotype 1b infection after orthotopic liver transplantation (NCT01938625) http://clinicaltrials.gov/ct2/show/NCT01938625?term=NCT01938625&rank=1. Accessed 7 Nov 2013.

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Adis R & D InsightAucklandNew Zealand
  2. 2.AdisAucklandNew Zealand

Personalised recommendations