Skip to main content
SpringerLink
Log in
Book cover

HCV: The Journey from Discovery to a Cure pp 261–291Cite as

Development and Marketing of INCIVEK (Telaprevir; VX-950): A First-Generation HCV Protease Inhibitor, in Combination with PEGylated Interferon and Ribavirin

  • Chapter
  • First Online:

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 31))

Abstract

In the years before the development of direct-acting antiviral (DAA) drugs, patients were treated with a toxic combination of PEGylated interferon (P) and ribavirin (R) which was associated with a low success rate in patients with the most common genotype 1 hepatitis C virus (HCV) infection (40–50%), significant treatment-limiting side effects, and a long (48-week) duration of treatment. The HCV protease inhibitor telaprevir (VX-950) was discovered as part of a research collaboration between Vertex and Eli Lilly scientists. Clinical development of telaprevir in combination with PEGylated interferon alfa plus ribavirin (PR) was in collaboration with Tibotec (Janssen) and Mitsubishi Tanabe Pharma. INCIVEK (telaprevir) in combination with PR was approved in 2011, 10 days after the approval of Schering-Plough/Merck’s HCV protease inhibitor VICTRELIS (boceprevir), also in combination with PR. Both INCIVEK and VICTRELIS had similar safety and tolerability concerns, similar efficacy, three times daily dosing, and similarly complex treatment plans requiring significant attention by medical personnel. INCIVEK’s list price was higher than VICTRELIS, and INCIVEK was Vertex’s first launch, whereas Schering-Plough had been a HCV market leader with sales of Peg-INTRON/Rebetron. This chapter will briefly review the scientific challenges faced in the development of telaprevir and INCIVEK, as this story has been the subject of numerous review articles and book chapters. More emphasis will be given to the lesser-known story of how Vertex worked to prepare the HCV market, and we will unpack the variables contributing to the conundrum of why, despite being similar drugs, INCIVEK significantly outsold VICTRELIS.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Houghton M (2009) The long and winding road leading to the identification of the hepatitis C virus. J Hepatol 51(5):939–948

    Article  CAS  PubMed  Google Scholar 

  2. Lindenbach BD, Rice CM (2005) Unravelling hepatitis C virus replication: from genome to function. Nature 436:933–938

    Article  CAS  PubMed  Google Scholar 

  3. Lohmann V, Korner F, Koch J-O, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113

    Article  CAS  PubMed  Google Scholar 

  4. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle 2nd DR, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465(7294):96–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pyenson B, Fitch K, Iwasaki K (2009) Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. Milliman Inc., New York. This report was commissioned by Vertex Pharmaceuticals, Inc

    Google Scholar 

  6. Shatin D, Schech SD, Patel K, McHutchison JG (2004) Population-based hepatitis C surveillance and treatment in a national managed care organization. Am J Manag Care 10:250–256

    PubMed  Google Scholar 

  7. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW (2010) Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 138:513–521

    Article  PubMed  Google Scholar 

  8. Bartenschlager R, Ahlborn-Laake L, Yasargil K, Mous J, Jacobsen H (1995) Substrate determinants for cleavage in cis and in trans by the hepatitis C virus NS3 proteinase. J Virol 69(1):198–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kwong AD, Kim JL, Rao G, Lipovsek D, Raybuck SA (1999) Hepatitis C virus NS3/4A protease. Antivir Res 41:67–84

    CAS  PubMed  Google Scholar 

  10. Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA, Chambers SP, Markland W, Lepre CA, O’Malley ET, Harbeson SL, Rice CM, Murcko MA, Caron PR, Thomson JA (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87:343–355

    Article  CAS  PubMed  Google Scholar 

  11. Pasquo A, Nardi MC, Dimasi N, Tomei L, Steinkuhler C, Delmastro P, Tramontano A, De Francesco R (1998) Rational design and functional expression of a constitutively active single-chain NS4A-NS3 proteinase. Fold Des 3(6):433–441

    Article  CAS  PubMed  Google Scholar 

  12. Taremi SS, Beyer B, Maher M, Yao N, Prosise W, Weber PC, Malcolm BA (1998) Construction, expression, and characterization of a novel fully activated recombinant single-chain hepatitis C virus protease. Protein Sci 7(10):2143–2149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yao N, Reichert P, Taremi SS, Prosise WW, Weber PC (1999) Molecular views of the viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease-helicase. Structure 7:1353–1363

    Article  CAS  PubMed  Google Scholar 

  14. Lin C, Kwong AD, Perni RB (2006) Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. Infect Disord Drug Targets 6(1):3–16

    Article  CAS  PubMed  Google Scholar 

  15. Perni RB, Britt SD, Court JJ, Courtney LF, Deininger DD, Farmer LJ, Gates CA, Harbeson SL, Kim JL, Landro JA, Levin RB, Luong YP, O’Malley ET, Pitlik J, Rao BG, Schairer WC, Thomson JA, Tung RD, Van Drie JH, Wei Y (2003) Inhibitors of hepatitis C virus NS3•4A protease 1. Non-charged tetrapeptide variants. Bioorg Med Chem Lett 13(22):4059–4063

    Article  CAS  Google Scholar 

  16. Perni RB, Chandorkar G, Chaturvedi PR, Courtney LF, Decker CJ, Gates CA, Harbeson SL, Kwong AD, Lin C, Luong YP, Markland W, Rao BG, Tung RD, Thomson JA (2003) VX-950: the discovery of an inhibitor of the hepatitis C virus NS3-4A protease and a potential hepatitis C virus therapeutic. Hepatology 38:624

    Article  Google Scholar 

  17. Perni RB, Chandorkar G, Cottrell KM, Gates CA, Lin C, Lin K, Luong YP, Maxwell JP, Murcko MA, Pitlik J, Rao G, Schairer WC, Van Drie J, Wei Y (2007) Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics. Bioorg Med Chem Lett 17(12):3406–3411

    Article  CAS  Google Scholar 

  18. Perni RB, Farmer LJ, Cottrell KM, Court JJ, Courtney LF, Deininger DD, Gates CA, Harbeson SL, Kim JL, Lin C, Lin K, Luong Y-P, Maxwell JP, Murcko MA, Pitlik J, Rao BG, Schairer WC, Tung RD, Van Drie JH, Wilson K, Thomson JA (2004) Inhibitors of hepatitis C virus NS3•4A protease 3. P2 proline variants. Bioorg Med Chem Lett 14(8):1939–1942

    Google Scholar 

  19. Perni RB, Kwong AD (2002) Inhibitors of hepatitis C virus NS3.4A protease: an overdue line of therapy. Prog Med Chem 39:215–255

    Article  CAS  PubMed  Google Scholar 

  20. Perni RB, Pitlik J, Britt SD, Court JJ, Courtney LF, Deininger DD, Farmer LJ, Gates CA, Harbeson SL, Levin RB, Lin C, Lin K, Moon Y-C, Luong Y-P, O’Malley ET, Rao BG, Thomson JA, Tung RD, Van Drie JH, Wei Y (2004) Inhibitors of hepatitis C virus NS3•4A protease 2. Warhead SAR and optimization. Bioorg Med Chem Lett 14(6):1441–1446

    Article  CAS  Google Scholar 

  21. Landro JA, Raybuck SA, Luong YP, O’Malley ET, Harbeson SL, Morgenstern KA, Rao G, Livingston DJ (1997) Mechanistic role of an NS4A peptide cofactor with the truncated NS3 protease of hepatitis C virus: elucidation of the NS4A stimulatory effect via kinetic analysis and inhibitor mapping. Biochemistry 36(31):9340–9348

    Article  CAS  PubMed  Google Scholar 

  22. Llinas-Brunet M, Bailey M, Fazal G, Goulet S, Halmos T, Laplante S, Maurice R, Poirier M, Poupart MA, Thibeault D, Wernic D, Lamarre D (1998) Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg Med Chem Lett 8(13):1713–1718

    Article  CAS  PubMed  Google Scholar 

  23. Steinkühler C, Biasiol G, Brunetti M, Urbani A, Koch U, Cortese R, Pessi A, De Francesco R (1998) Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 37(25):8899–8905

    Article  PubMed  Google Scholar 

  24. Grillot AL, Farmer L, Rao B, Taylor W, Weisberg I, Jacobson I, Perni R, Kwong A (2011) Telaprevir. In: Kakzmierski W (ed) Antiviral drugs from basic discovery through clinical trials. Wiley-VCH, Weinheim

    Google Scholar 

  25. Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, Decker CJ, Dinehart K, Gates CA, Harbeson SL, Heiser A, Kalkeri G, Kolaczkowski E, Lin K, Luong YP, Rao BG, Taylor WP, Thomson JA, Tung RD, Wei Y, Kwong AD, Lin C (2006) Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 50(3):899–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yip Y, Victor F, Lamar J, Johnson R, Wang QM, Barket D, Glass J, Jin L, Liu L, Venable D, Wakulchik M, Xie C, Heinz B, Villarreal E, Colacino J, Yumibe N, Tebbe M, Munroe J, Chen SH (2004) Discovery of a novel bicycloproline P2 bearing peptidyl alpha-ketoamide LY514962 as HCV protease inhibitor. Bioorg Med Chem Lett 14(1):251–256

    Article  CAS  PubMed  Google Scholar 

  27. Yip Y, Victor F, Lamar J, Johnson R, Wang QM, Glass JI, Yumibe N, Wakulchik M, Munroe J, Chen SH (2004) P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl alpha-ketoamides as HCV protease inhibitors. Bioorg Med Chem Lett 14(19):5007–5011

    Google Scholar 

  28. Lin K, Kwong AD, Lin C (2004) Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells. Antimicrob Agents Chemother 48(12):4784–4792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tzantrizos YS, Bolger G, Bonneau P, Cameron DR, Goudreau N, Kukolj G, LaPlante SR, Lllinas-Brunet M, Nar H, Lamarre D (2003) Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew Chem 42:1355–1360

    Google Scholar 

  30. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Forns X, Erhardt A, Cronlein J, Chaves RL, Yong CL, Nehmiz G, Steinmann GG (2004) Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127(5):1347–1355

    Article  CAS  PubMed  Google Scholar 

  31. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG, Faucher AM, Goudreau N, Kawai SH, Kukolj G, Lagace L, LaPlante SR, Narjes H, Poupart MA, Rancourt J, Sentjens RE, George RS, Simoneau B, Steinmann G, Thibeault D, Tsantrizos YS, Weldon SM, Yong CL, Llinas-Brunet M (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426(6963):186–189

    Article  CAS  PubMed  Google Scholar 

  32. Lin K, Perni RB, Kwong AD, Lin C (2006) VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells. Antimicrob Agents Chemother 50(5):1813–1822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vertex Pharmaceuticals Incorporated (2004) Vertex Pharmaceuticals and Mitsubishi Pharma sign agreement for development and commercialization of the oral HCV protease inhibitor VX-950 in Japan and Far East Countries

    Google Scholar 

  34. Kwong A, Kauffman R, Hurter P, Mueller P (2011) Discovery and development of telaprevir: an NS3-4a protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 29(w11):993–1003

    Article  CAS  PubMed  Google Scholar 

  35. Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Kauffman R, Alam J, Jansen PL (2006) Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 131(4):997–1002

    Article  CAS  PubMed  Google Scholar 

  36. McHutchison JG, Everson GT, Gordon SC, Jacobson I, Kauffman R, McNair L, Muir A (2008) PROVE1: results from a phase 2 study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C. In: Proceedings of 43rd annual meeting of the European Society for the Study of the Liver (EASL), Milan, Italy, Journal of Hepatology

    Google Scholar 

  37. Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourliere M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S (2009) Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 360(18):1839–1850

    Article  CAS  PubMed  Google Scholar 

  38. McHutchison J, Manns M, Muir A, Terrault N, Jacobson IM et al (2010) Telaprevir for previously treated chronic HCV infection. N Engl J Med 362:1292–1303 [Erratum in: N Engl J Med. 2010, 1362:1647]

    Article  CAS  PubMed  Google Scholar 

  39. McHutchison J, Manns M, Muir A et al (2010) Retreatment with telaprevir, peginterferon, and ribavirin for chronic HCV infection. N Engl J Med 362(14):30–41

    Article  Google Scholar 

  40. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364:2405–2516

    Article  CAS  Google Scholar 

  41. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F (2011) Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 365(11):1014–1024

    Article  CAS  PubMed  Google Scholar 

  42. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster G, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio P, Beumont M, REALIZE Study Team (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364:2417–2428

    Article  CAS  Google Scholar 

  43. Vertex Pharmaceuticals Incorporated (2011) INCIVEK [US product insert] vertex website. Vertex Pharmaceuticals Incorporated, Cambridge

    Google Scholar 

  44. Kieffer T, Kwong A, Picchio G (2009) Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 65:202–212

    Article  PubMed  CAS  Google Scholar 

  45. Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, Kwong AD, Zeuzem S (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46(3):631–639

    Article  CAS  PubMed  Google Scholar 

  46. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, Welker M, Wincheringer D, Zhou Y, Chu HM, Lin C, Weegink C, Reesink H, Zeuzem S, Kwong AD (2007) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132(5):1767–1777

    Article  CAS  PubMed  Google Scholar 

  47. Butt AA, Kanwal F (2012) Boceprevir and telaprevir in the management of hepatitis C virus-infected patients. Clin Infect Dis 54(1):96–104

    Article  PubMed  CAS  Google Scholar 

  48. FDA (2011) INCIVEK (telaprevir) highlights of prescribing information. FDA. accessdata.fda.gov

  49. FDA (2011) VICTRELIS (boceprevir) highlights of prescribing information. accessdata.fda.gov

  50. Hutchison C, Kwong A, Ray S, Struble K, Swan T, Miller V (2014) Accelerating drug development through collaboration: the hepatitis C drug development advisory group. Clin Pharmacol Ther 96(2):162–165

    Article  CAS  PubMed  Google Scholar 

  51. Smith B, Morgan R, Beckett G, Falck-Ytter Y, Holtzman D, Teo C-G, Jewett A, Baack B, Rein D, Patel N, Alter M, Yartel A, Ward J (2012) Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 61(RR04):1–18

    PubMed  Google Scholar 

  52. USPSTF (2013) Hepatitis C: screening, published final recommendations. USPSTF, Rockville

    Google Scholar 

  53. Moorman AC, Rupp LB, Gordon SC, Zhong Y, Xing J, Lu M, Boscarino JA, Schmidt MA, Daida YG, Teshale EH, Spradling PR, Holmberg SD, Investigators CH (2018) Long-term liver disease, treatment, and mortality outcomes among 17,000 persons diagnosed with chronic hepatitis C virus infection: current chronic hepatitis cohort study status and review of findings. Infect Dis Clin N Am 32(2):253–268

    Article  Google Scholar 

  54. CDC (2015) Know more hepatitis. V. H. Division of Viral Hepatitis and National Center for HIV/AIDS, STD, and TB Prevention

    Google Scholar 

  55. Valeii K (2017) Why are baby boomers more prone to Hep C? Connection, risk factors, and more

    Google Scholar 

  56. Merck Sharp & Dohme Corp (2011) Merck and Roche expand agreement in fight against chronic hepatitis C. https://www.merck.com/licensing/our-partnership/Roche-expandagree-partnership.html

  57. Weissman R (2014) Vertex to stop selling hepatitis C drug Incivek. Boston Globe, Boston https://www.bostonglobe.com/business/2014/08/12/vertex-stop-selling-hepatitis-drug-incivek/El0jtOpH9I1CaIgQpSUKWO/story.html

    Google Scholar 

  58. Unitaid (2018) HCV diagnostics market intelligence report 2017 first report on screening and diagnosis market growth. https://www.finddx.org/wp-content/uploads/2018/04/HCV-Diagnostics-Market-Intelligence-Report_18APR2018.pdf

  59. Bartenschlager R, Baumert TF, Bukh J, Houghton M, Lemon SM, Lindenbach BD, Lohmann V, Moradpour D, Pietschmann T, Rice CM, Thimme R, Wakita T (2018) Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy: considerations for scientists and funding agencies. Virus Res 248:53–62

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethical Standards

Conflict of Interest Robert B. Perni, Camilla S. Graham, and Ann D. Kwong were employees of Vertex Pharmaceuticals.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all patients who participated in the studies.

Author information

Authors and Affiliations

  1. Kwong Pharma Consulting, LLC, Pepperell, MA, USA

    Ann D. Kwong

  2. JMD Pharma Creativity LLC, Marlborough, MA, USA

    Robert B. Perni

  3. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Camilla S. Graham

Authors
  1. Ann D. Kwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert B. Perni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Camilla S. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ann D. Kwong .

Editor information

Editors and Affiliations

  1. Arbutus Biopharma, Inc., Warminster, PA, USA

    Michael J. Sofia

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kwong, A.D., Perni, R.B., Graham, C.S. (2019). Development and Marketing of INCIVEK (Telaprevir; VX-950): A First-Generation HCV Protease Inhibitor, in Combination with PEGylated Interferon and Ribavirin. In: Sofia, M. (eds) HCV: The Journey from Discovery to a Cure. Topics in Medicinal Chemistry, vol 31. Springer, Cham. https://doi.org/10.1007/7355_2018_57

Download citation

Publish with us

Policies and ethics

Search

Navigation