PEGylated α interferons: two different strategies to achieve increased efficacy

  • Gianfranco Pasut
Part of the Milestones in Drug Therapy book series (MDT)


Conjugation of poly(ethylene glycol) to proteins is a well known technique used to prolong half-life and reduce immunogenicity. In the case of interferon α, improving pharmacokinetics to reduce dosing frequency was the driving force in the development of two long-acting derivatives: PEG-Intron® by Schering-Plough and Pegasys® by Roche Pharmaceuticals. These conjugates, even though developed with a similar approach and for the same clinical use, present several differences that offer the possibility for an interesting and unique comparison. The basic PEGylation chemistry and characterization of the conjugates will be described together with an analysis of the pharmacokinetic/pharmacodynamic behaviors.


Chronic Hepatitis Sustained Virological Response Advance Drug Delivery Consensus Interferon Hepatitis Interventional Therapy Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cohen J. (1999) The scientific challenge of hepatitis C. Science 285: 26–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Liang TJ, Rehermann B, Seeff LB, and Hoofnagle JH. (2000) Pathogenesis, natural history, treatment, and prevention of hepatitis C. Annals of Internal Medicine 132: 296–305.PubMedGoogle Scholar
  3. 3.
    Simmonds P. (1999) Viral heterogeneity of the hepatitis C virus. Journal of Hepatology 31 (Suppl 1): 54–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Souvignet C, Lejeune O, and Trepo C. (2007) Interferon-based treatment of chronic hepatitis C. Biochimie 89: 894–898.CrossRefPubMedGoogle Scholar
  5. 5.
    Palumbo E. (2007) PEG-interferon alpha-2b for acute hepatitis C: a review. Mini Rev Med Chem 7: 839–843.CrossRefPubMedGoogle Scholar
  6. 6.
    Zeuzem S. (2008) Interferon-based therapy for chronic hepatitis C: current and future perspectives. Nat Clin Pract Gastroenterol Hepatol. 5: 610–622.CrossRefPubMedGoogle Scholar
  7. 7.
    Heathcote EJ, Keeffe EB, Lee SS, Feinman SV, Tong MJ, and Reddy KR et al. (1998) Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 27: 1136–1143.CrossRefPubMedGoogle Scholar
  8. 8.
    Blatt LM, Davis JM, Klein SB, and Taylor MW. (1996) The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon. Journal of Interferon and Cytokine Research 16: 489–499.CrossRefPubMedGoogle Scholar
  9. 9.
    Melian EB and Plosker GL. (2001) Interferon alfacon-1: a review of its pharmacology and therapeutic efficacy in the treatment of chronic hepatitis C. Drugs 61: 1661–1691.CrossRefPubMedGoogle Scholar
  10. 10.
    Keeffe EB and Hollinger FB. (1997) Therapy of hepatitis C: consensus interferon trials. Consensus Interferon Study Group. Hepatology 26: 101S–107S.CrossRefPubMedGoogle Scholar
  11. 11.
    Heathcote EJ, James S, Mullen KD, Hauser SC, Rosenblate H, and Albert DG Jr (1999) Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group. Hepatology 30: 562–566.CrossRefPubMedGoogle Scholar
  12. 12.
    Sjogren MH, Sjogren R, Holtzmuller K, Winston B, Butterfield B, and Drake S et al. (2005) Interferon alfacon-1 and ribavirin versus interferon alpha-2b and ribavirin in the treatment of chronic hepatitis C. Digestive Diseases and Sciences 50: 727–732.CrossRefPubMedGoogle Scholar
  13. 13.
    Thomas HC, Torok ME, Forton DM, Taylor-Robinson SD. (1999) Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C. J. Hepatol. 31 (Suppl. 1): 15229.Google Scholar
  14. 14.
    Dusheiko G, Main J, Thomas H, Reichard O, Lee C, and Dhillon A et al. (1996) Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J. Hepatol. 25: 591–598.CrossRefPubMedGoogle Scholar
  15. 15.
    Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, and Yurdaydin C et al. (1995) Rivabirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 123: 897–903.PubMedGoogle Scholar
  16. 16.
    Weiland O. (1999) Treatment of naive patients with chronic hepatitis. C. J. Hepatol. 31 (Suppl. 1): 168–173.CrossRefPubMedGoogle Scholar
  17. 17.
    Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, and Ideo G et al. (1998) Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 352: 1426–1432.CrossRefPubMedGoogle Scholar
  18. 18.
    McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, and Rustgi VK et al. (1998) Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. New England Journal of Medicine 339: 1485–1492.CrossRefPubMedGoogle Scholar
  19. 19.
    Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, and Layden TJ. (1997) Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alpha. Hepatology 26: 226–231.CrossRefPubMedGoogle Scholar
  20. 20.
    Veronese FM, and Harris JM. (2002) Introduction and overview of peptide and protein pegylation. Advanced Drug Delivery Reviews 54: 453–456.CrossRefPubMedGoogle Scholar
  21. 21.
    Veronese FM, and Pasut G. (2005) PEGylation, successful approach to drug delivery. Drug Discovery Today 10: 1451–1457.CrossRefPubMedGoogle Scholar
  22. 22.
    Gilbert CW, and Park-Cho M-O. (1999) Interferon Polymer Conjugates US 5951974.Google Scholar
  23. 23.
    Zalipsky S, Seltzer R, and Menon-Rudolph S. (1992) Evaluation of a new reagent for covalent attachment of polyethylene glycol to proteins. Biotechnology and Applied Biochemistry 15: 100–114.PubMedGoogle Scholar
  24. 24.
    Miron T, and Wilchek M. (1993) A simplified method for the preparation of succinimidyl carbonate polyethylene glycol for coupling to proteins. Bioconjugate Chemistry 4: 568–569.CrossRefPubMedGoogle Scholar
  25. 25.
    Pasut G, Guiotto A, and Veronese FM. (2004) Protein, peptide and non-peptide drug PEGylation for therapeutic application. Expert Opinion on Therapeutic Patents 14: 859–894.CrossRefGoogle Scholar
  26. 26.
    Kozlowski A, Charles SA, and Harris JM. (2001) Development of pegylated interferons for the treatment of chronic hepatitis C. BioDrugs 15: 419–429.CrossRefPubMedGoogle Scholar
  27. 27.
    Kozlowski A, and Harris JM. (2001) Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C. J Control Release 72: 217–224.CrossRefPubMedGoogle Scholar
  28. 28.
    Zalipsky S. (1995) Chemistry of polyethylene glycol conjugates with biologically active molecules. Advanced Drug Delivery Reviews 16: 157–182.CrossRefGoogle Scholar
  29. 29.
    Roberts MJ, Bentley MD, and Harris JM. (2002) Chemistry for peptide and protein PEGylation. Advanced Drug Delivery Reviews 54: 459–476.CrossRefPubMedGoogle Scholar
  30. 30.
    Wylie DC, Voloch M, Lee S, Liu YH, Cannon-Carlson S, and Cutler C et al. (2001) Carboxyalkylated histidine is a pH-dependent product of pegylation with SC-PEG. Pharmaceutical Research 18: 1354–1360.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang Y-S, Youngster S, Grace M, Bausch J, Bordens R, and Wyss DF. (2002) Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Advanced Drug Delivery Reviews 54: 547–570.CrossRefPubMedGoogle Scholar
  32. 32.
    Grace M, Youngster S, Gitlin G, Sydor W, Xie L, and Westreich L et al. (2001) Structural and biologic characterization of pegylated recombinant IFN-alpha-2b. Journal of Interferon and Cytokine Research 21: 1103–1115.CrossRefPubMedGoogle Scholar
  33. 33.
    Peginterferon alfa-2b Product Information. Kenilworth, NJ, USA: Schering Corporation.Google Scholar
  34. 34.
    Wang YS, Youngster S, Bausch J, Zhang R, McNemar C, and Wyss DF. (2000) Identification of the major positional isomer of pegylated interferon alpha-2b. Biochemistry 39: 10634–10640.CrossRefPubMedGoogle Scholar
  35. 35.
    Nagabhushan TL, Reichert P, Walter MR, and Murgolo NJ. (2002) Type I interferon structures: Possible scaffolds for the interferon-alpha receptor complex. Canadian Journal of Chemistry 80: 1166–1173.CrossRefGoogle Scholar
  36. 36.
    Chou CP, Yu CC, Lin WJ, Kuo BY, and Wang WC. (1999) Novel strategy for efficient screening and construction of host/vector systems to overproduce penicillin acylase in Escherichia coli. Biotechnology and Bioengineering 65: 219–226.CrossRefGoogle Scholar
  37. 37.
    Monkarsh SP, Ma Y, Aglione A, Bailon P, Ciolek D, and DeBarbieri B et al. (1997) Positional isomers of monopegylated interferon alpha-2a: isolation, characterization, and biological activity. Analytical Biochemistry 247: 434–440.CrossRefPubMedGoogle Scholar
  38. 38.
    Nieforth KA, Nadeau R, Patel IH, and Mould D. (1996) Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects. Clinical Pharmacology and Therapeutics 59: 636–646.CrossRefPubMedGoogle Scholar
  39. 39.
    Bailon P, Palleroni A, Schaffer CA, Spence CL, Fung WJ, and Porter JE et al. (2001) Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C. Bioconjugate Chemistry 12: 195–202.CrossRefPubMedGoogle Scholar
  40. 40.
    Reddy RK, Modi MW, and Pedder S. (2002) Use of peginterferon alfa-2a (40 KD) (Pegasys) for the treatment of hepatitis C. Advanced Drug Delivery Reviews 54: 571–586.CrossRefGoogle Scholar
  41. 41.
    Peginterferon alfa-2a Complete Product Information. Nutley, NJ, USA: Roche Pharmaceuticals.Google Scholar
  42. 42.
    Algranati NE, Sy S, and Modi M. (1999) A branched methoxy 40 KDA polyethylene glycol (PEG) moiety optimizes the pharmacokinetics (PK) of peginterferon alpha-2a (peginterferon) and may explain its enhanced efficacy in chronic hepatitis C (CHC). Hepatology 30:190A. Abstract 120.Google Scholar
  43. 43.
    Harris JM, Martin NE, and Modi M. (2001) Pegylation: A novel process for modifying pharmacokinetics. Clin. Pharmacokinet. 40: 539–551.CrossRefPubMedGoogle Scholar
  44. 44.
    Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, and Gupta SK et al. (2000) Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clinical Pharmacology and Therapeutics 68: 556–567.CrossRefPubMedGoogle Scholar
  45. 45.
    Wills RJ. (1990) Clinical Pharmacokinetics of interferons. Clin. Pharmacokinetic. 19: 390–399.CrossRefGoogle Scholar
  46. 46.
    Lamb MW, and Martin NE. (2002) Weight-based versus fixed dosing of peginterferon (40 kDa) alfa-2a. Ann Pharmacothe 36: 933–935.CrossRefGoogle Scholar
  47. 47.
    Modi M, Fulton JS, Buckman DK, Wright TL, and Moore D. (2000) Clearance of PEGylated (40 kDa) Interferon Alfa-2a (PEGASYS) is Primarily Hepatic. Hepatology 32: 371A.Google Scholar
  48. 48.
    Martin NE, and Modi MW. (2000) Characterization of pegylated (40KDA) interferon alfa-2a (PEGASYS) in the elderly. Hepatology 32: 348A. Abstract 755.CrossRefGoogle Scholar
  49. 49.
    Bruno R, Sacchi P, Ciappina V, Zochetti C, Patruno S, and Maiocchi L et al. (2004) Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naïve patients with chronic hepatitis C: a randomized, controlled study. Antiviral Therapy 9: 491–497.PubMedGoogle Scholar
  50. 50.
    Formann E, Jessner W, Bennett L, and Ferenci P. (2003) Twice-weekly administration of pegin-terferon-a-2b improves viral kinetics in patients with chronic hepatitis C genotype 1. J. Vir. Hep. 10:271–276.CrossRefGoogle Scholar
  51. 51.
    Sporea I, Danila M, Sirli R, Popescu A, Laza A, and Baditoiu L. (2006) Comparative study concerning the efficacy of Peg-IFN-2a versus Peg-IFN alpha-2b on the early virological response (EVR) in patients with chronic viral C hepatitis. J. Gastrointestin. Liver Dis. 15: 125–130.PubMedGoogle Scholar
  52. 52.
    Yenice N, Mehtap O, Gümrah M, and Arican N. (2006) The efficacy of pegylated alpha 2a or 2b plus ribavarin in chronic hepatitis C patients. Turk. J. Gastroenterol. 17: 94–98.PubMedGoogle Scholar
  53. 53.
    Escudero A, Rodriguez F, Serra MA, Del Olmo JA, Montes F, and Rodrigo JM. (2008) Pegylated alpha-interferon-2a plus ribavarin compared with pegylated alpha-interferon-2b plus ribavarin for initial treatment of chronic hepatitis C virus: prospective, non-randomized study. J. Gastroenterol. Hepatol. 23: 861–866.CrossRefPubMedGoogle Scholar
  54. 54.
    Laguno M, Cifuentes C, Murillas J, Veloso S, Larrousse M, Payeras A et al. (2009) Randomized trial comparing pegylated interferon α-2b versus pegylated interferon α-2a, both plus ribavarin, to treat chronic hepatitis C in human immunodeficiency virus patients. Hepatology 49: 22–31.CrossRefPubMedGoogle Scholar
  55. 55.
    Chou R, Carson S, and Chan BKS. (2008) Pegylated interferons for chronic hepatitis C virus infection: an indirect analysis of randomized trials. J. Viral Hep. 15: 551–570.CrossRefGoogle Scholar
  56. 56.
    Manns MP, McHutchinson J, Gordon S, Rustgi VK, Shiffman M, Reindollar R et al. (2001) Peginterferon alfa-2b plus ribavarin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 358: 958–965.CrossRefPubMedGoogle Scholar
  57. 57.
    Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, Reindollar R et al. (2001) Efficacy and safety of pegylated (40-KD) interferon alpha-2a compared with interferon alpha-2a in patients with in noncirrhotic patients with chronic hepatitis C. Hepatology 33: 433–438.CrossRefPubMedGoogle Scholar
  58. 58.
    Zeuzem S, Feinman SV, Rasenack EJ, Heathcote EJ, La MJ, Gane E et al. (2000) Peginterferon alfa-2a in patients with chronic hepatitis C. New Eng. J. Med. 343: 1666–1672.CrossRefPubMedGoogle Scholar
  59. 59.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marino G, Goncales F et al. (2001) Pegylated interferon alfa-2a (Pegasys) in combination with ribavarin: efficacy and safety results from a phase III, randomized, actively controlled, multicenter study. Gastroenterology 120: A55.Google Scholar
  60. 60.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr et al. (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 347: 975–982.CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Gianfranco Pasut
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of PaduaPaduaItaly

Personalised recommendations