Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection

Current Opinion in Investigational Drugs

Volumn 10, Issue 2, 2009, Pages 181-189

  Mederacke, I ^a   Wedemeyer, H ^a   Manns, M P ^a  

^a Department of Gastroenterology Hepatology and Endocrinology ^*  (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BOCEPREVIR; NONSTRUCTURAL PROTEIN 3; PEGINTERFERON ALPHA2B; PLACEBO; RIBAVIRIN; RITONAVIR; SERINE PROTEINASE INHIBITOR; TELAPREVIR; VIRUS RNA;

AREA UNDER THE CURVE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG LIVER LEVEL; DRUG MEGADOSE; DRUG METABOLISM; DRUG STRUCTURE; DRUG TOLERABILITY; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; LOW DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; RAT; REVIEW; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; VIRUS LOAD; VIRUS REPLICATION; VIRUS RESISTANCE;

ANIMALS; CAPSULES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG COMBINATIONS; DRUG EVALUATION, PRECLINICAL; HEPACIVIRUS; HEPATITIS C; HUMANS; MOLECULAR STRUCTURE; PROLINE; SERINE PROTEINASE INHIBITORS; VIRAL NONSTRUCTURAL PROTEINS;

EID: 62249141788     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (49)

1. 249377 Schering-Plough researchers identify promising drug target in hepatitis C virus. Schering-Plough Corp PRESS RELEASE 1997 June 02
2. 250162 Schering-Plough and Corvas announce collaboration on hepatitis research. Corvas International Inc PRESS RELEASE 1997 June 13
3. 285609 Corvas announces extension of hepatitis C research program with additional funding of approximately $1.6 million. Corvas International Inc PRESS RELEASE 1998 April 28
4. 324298 Corvas and Schering-Plough extend hepatitis C program; additional $1.6 million funding. Corvas International Inc PRESS RELEASE 1999 May 11
5. 352865 Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M Science 1989 244 4902 359-362
6. 352876 Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R Science 1999 285 5424 110-113
7. 368039 Corvas to receive $2.5 million from Schering-Plough; under terms of amended hepatitis C agreement. Corvas International Inc PRESS RELEASE 2000 May 23
8. 511549 Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago G, Carosi D, Dhumeaux D, Craxi A et al N Engl J Med 2002 347 13 975-982
9. 605086 Side effects of therapy of hepatitis C and their management. Fried MW Hepatology 2002 36 5 Suppl 1 S237-S244
10. 606773 Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Reiser M, Hinrichsen H, Benhamou Y, Reesink HW, Wedemeyer H, Avendano C, Riba N, Yong CL, Nehmiz G, Steinmann GG Hepatology 2005 41 4 832-835
11. 639204 Immunology of hepatitis B virus and hepatitis C virus infection. Rehermann B, Nascimbeni M Nat Rev Imunol 2005 5 3 215-29
12. 647361 American Association for the Study of Liver Diseases (AASLD) - 56th Annual Meeting. Phend C IDRUGS 2006 9 2 96-100
13. 647541 Schering-Plough reports FDA grants fast track designation to oral HCV protease inhibitor SCH 503034. Schering-Plough Corp PRESS RELEASE 2006 January 30
14. 656485 Schering-Plough and PTC Therapeutics announce collaboration for development of PTC's preclinical hepatitis C compounds. Schering-Plough Corp PRESS RELEASE 2006 March 20
15. 685306 Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor - Reduced RNA replication fitness and partial rescue by second-site mutations. Yi MK, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG J BIOL CHEM 2006 281 12 8205-8215
16. 720634 An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bos M, Cameron DR, Cartier M, Cordingley MG, Faucher AM et al Nature 2003 426 6963 186-189
17. 720723 Short term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, Calleja JL, Forns X, Erhardt A, Croenlein J, Chaves R, Yong C-L et al Gastroenterology 2004 127 5 1347-1355
18. 751299 Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK LANCET 2001 358 9286 958-965
19. 10 for patients receiving PEGylated IFNα2b monotherapy.
20. 837364 Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH-503034 by co-dosing with ritonavir. Kempf DJ, Klein C, Chen HJ, Klein LL, Yeung C, Randolph JT, Lau YY, Chovan LE, Guan ZW, Hernandez L, Turner TM et al ANTIVIR CHEM CHEMOTHER 2007 18 3 163-167
21. 840703 Initial results of phase II study with HCV protease inhibitor boceprevir in treatment-naïve hepatitis C patients show a high rate of early virologic response. Schering-Plough Corp PRESS RELEASE 2007 October 18
22. 885649 Vertex Pharmaceuticals and Tibotec announce start of phase 3 'ADVANCE' study with telaprevir in treatment-naïve, genotype 1 HCV patients. Vertex Pharmaceuticals Inc PRESS RELEASE 2008 March 13
23. 887671 Challenges in modern drug discovery: A case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Njoroge FG, Chen KX, Shih NY, Piwinski JJ ACC CHEM RES 2008 41 1 50-59 •• This paper provides an overview of the chemical modifications that were necessary to improve the bioavailability of boceprevir. Some preclinical and pharmacokinetic data are also presented.
24. 897660 ViroPharma announces discontinuation of HCV-796 development. ViroPharma Inc PRESS RELEASE 2008 April 16
25. 908340 Schering-Plough to initiate phase III studies with HCV protease inhibitor boceprevir in previously untreated hepatitis C patients and those who failed prior treatment. Schering-Plough Corp PRESS RELEASE 2008 May 21
26. 914754 Vertex reports 52% SVR 12 rate for a 24-week telaprevir-based regimen in genotype 1 hepatitis C patients who failed prior treatment. Vertex Pharmaceuticals Inc PRESS RELEASE 2008 June 9
27. 926259 How hepatitis C virus NS3-4A protease R155K/T strains can discriminate VX-950 and ITMN-191 but affect differentially SCH-503034. Courcambeck J, Bouzidi M, Roche G, Pepe G, Halfon P ANTIVIR THER 2008 13 4 A43
28. 940815 Antiviral effects and safety of telaprevir, peginterferon α2a, and ribavirin for 28 days in hepatitis C patients. Lawitz E, Rodriguez-Torres M, Muir AJ, Kieffer TL, McNair L, Khunvichai A, McHutchison JG J Hepatol 2008 48 2 163-169
29. 156T in the liver of an untreated chronic hepatitis C patient. Cubero M, Esteban JI, Otero T, Sauleda S, Bes M, Esteban R, Guardia J, Quer J Virology 2008 370 2 237-245 • This paper provides an overview of resistance mutations affecting the activity of boceprevir and telaprevir.
30. 90 values, determined in a bicistronic, subgenomic, cell-based replicon assay run over 72 h using Huh-7 hepatoma cells, were 200 and 400 nM, respectively.
31. 951592 Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA Antiviral Research 2006 70 2 28-38
32. 951597 Characterization of resistance mutations against HCV ketoamide protease inhibitors. Tong X, Bogen S, Chase R, Girijavallabhan V, Guo Z, Njoroge FG, Prongay A, Saksena A, Skelton A, Xia E, Ralston R Antiviral Research 2008 77 3 177-185
33. 951666 Treatment of acute hepatitis C with interferon α2b. Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP N Engl J Med 2001 345 20 1452-1457
34. 951690 Unravelling hepatitis C virus replication from genome to function. Lindenbach BD, Rice CM Nature 2005 436 7053 933-938
35. 951709 Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Vanwolleghem T, Meuleman P, Libbrecht L, Roskams T, De Vos R, Leroux-Roels G Gastroenterology 2007 133 4 1144-1155
36. 952042 Treating viral hepatitis C: Efficacy, side effects and complications. Manns MP, Wedemeyer H, Cornberg M GUT 2006 55 9 1350-1359
37. 10.
38. 952237 Boceprevir (B) combination therapy in null responders (NR): Response dependent on interferon responsiveness. Schiff E, Poordad F, Jacobson I, Flamm S, Bacon B, Lawitz E, Gordon S, McHutchison J, Ghalib R, Poynard T, Sulkowski M et al J HEPATOL 2008 48 S46 Abs 104
39. 952321 Clonal analysis of mutations selected in the HCV NS3 protease domain of genotype 1 non-responders treated with boceprevir (SCH503034). Susser S, Welker MW, Zettler M, Wohnsland A, Hughes E, Ralston R, Tong X, Zeuzem S, Sarrazin C J Hepatol 2008 48 S29 Abs 65
40. 952579 Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034. Madison V, Prongay AJ, Guo Z, Yao N, Pichardo J, Fischmann T, Strickland C, Myers J Jr, Weber PC, Beyer BM, Njoroge FG et al J SYNCHROTRON RADIAT 2008 15 3 204-207
41. 953050 Treatment of chronic hepatitis C with telaprevir (TVR) in combination with peginterferon-α2a with or without ribavirin: Further interim analysis results of the PROVE2 study. Dusheiko GM, Hezode C, Pol S, Goeser T, Bronowicki J-P, Bourtiere M, Buggisch P, Serfaty L, Berg T, Couzigou P, Benhamou Y et al ANN MEET EUR ASSOC STUDY LIVER 2008 48 2 Abs 58
42. 965229 Acute hepatitis C: High rate of both spontaneous and treatment-induced viral clearance. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC, Ulsenheimer A, Schraut WW, Schirren CA, Waechtler M, Backmund M, Pape GR GASTROENTEROLOGY 2003 125 1 80-88
43. 965265 Hepatitis C virus genotypes and quasispecies. Davis GL AM J MED 1999 107 6B 21S-26S
44. 965290 Discovery of (1R,5S)-N-[3-amino-1- (cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino] carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: A potential therapeutic agent for the treatment of hepatitis C infection. Venkatraman S, Bogen SL, Arasappan A, Bennett F, Chen K, Jao E, Liu YT, Lovey R, Hendrata S, Huang Y, Pan W et al J MED CHEM 2006 49 20 6074-6086
45. 968531 Interim results from HCV SPRINT-1: RVR/EVR from phase 2 study of boceprevir plus PEGintron (PEGinterferon α2b)/ribavirin in treatment-naïve subjects with genotype-1 CHC. Kwo P, Lawitz E, McCone J, Schiff E, Vierling J, Pound D, Davis M, Galati J, Gordon S, Ravendhran N, Albrecht J et al EUR ASSOC STUDY LIVER DIS 2008 April 23-27
46. 968555 A combination of direct antiviral compounds can achieve sustained viral response in hepatitis C virus-infected chimpanzees. Olsen DB, Handt L, Koeplinger K, Ludmerer S, Graham D, MacCoss M, Liverton NJ, Vacca JP, McCauley JA, Hazuda D, Carroll SS HEP DART: FRONT DRUG DEV VIRAL HEPATITIS 2007 December 9-13
47. 969065 Combination therapy with the HCV protease inhibitor, SCH 503034, plus PEG-intron in hepatitis C genotype-1 PEG-intron non-responders: Phase Ib results. Zeuzem S, Sarrazin C, Wagner F, Rouzier R, Forestier N, Samir G, Hussain M, Shah A, Cutler DL, Zhang J HEPATOLOGY 2005 42 4 Abs 201
48. 970375 Treatment of hepatitis C infection. Stribling R, Sussman N, Vierling JM Gastroenterol Clin N Am 2006 35 2 463-486
49. 971398 Boceprevir plus peginterferon α-2b/ribavirin for treatment of genotype 1 chronic hepatitis C in previously untreated patients: Interim results from the HCV SPRINT-1 study. Kwo P, Lawitz E, McCone J, Schiff E, Vierling J, Pound D, Davis M, Galati J, Gordon S, Ravendhran N, Rossaro L et al ANN MEET AM ASSOC STUDY LIVER DIS 2008 November 01 Abs LB16 •• This abstract reports data from a phase II clinical trial in patients (n = 595) with HCV infection receiving a lead-in dose of PEGylated IFNα2b (1.5 μg/kg/week) and ribavirin (800 to 1400 mg/day) for 4 weeks prior to the addition of boceprevir (800 mg po, tid) for a further 24 weeks; or PEGylated IFNα2b (1.5 μg/kg/week) and ribavirin (800 to 1400 mg/day) as control. At week 24 following cessation of treatment, response rates in patients who had received the lead-in-phase treatment of PEGylated IFNα2b and ribavirin, prior to dosing with boceprevir, was 56%. The response rate for the control group was 38%.