Gastroenterology
Volume 135, Issue 4 , Pages 1130-1141 , October 2008

A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

Data were presented on May 21, 2007 at Digestive Disease Week 2007 (Washington, DC).

  • William J. Sandborn

      Affiliations

    • Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
    • Corresponding Author InformationCorresponding author: William J. Sandborn, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 266-0335
  • ,
  • Brian G. Feagan

      Affiliations

    • London Health Sciences Center, London, Ontario, Canada
  • ,
  • Richard N. Fedorak

      Affiliations

    • Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
  • ,
  • Ellen Scherl

      Affiliations

    • Jill Roberts Inflammatory Bowel Disease Center, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York
  • ,
  • Mark R. Fleisher

      Affiliations

    • Borland–Groover Clinic, Jacksonville, Florida
  • ,
  • Seymour Katz

      Affiliations

    • Long Island Clinical Research Associates, LLP, Great Neck, New York
  • ,
  • Jewel Johanns

      Affiliations

    • Clinical Biostatistics, Centocor, Inc, Malvern, Pennsylvania
  • ,
  • Marion Blank

      Affiliations

    • Clinical Biostatistics, Centocor, Inc, Malvern, Pennsylvania
  • ,
  • Paul Rutgeerts

      Affiliations

    • University Hospital Gasthuisberg, Leuven, Belgium
  • ,
  • Ustekinumab Crohn's Disease Study Group

Received 15 April 2008 ,Accepted 10 July 2008.

References 

  1. Hanauer SB, Sandborn W. The Practice Parameters Committee of the American College of Gastroenterology (Management of Crohn's disease in adults). Am J Gastroenterol. 2001;96:635–643
  2. Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut. 2006;55(Suppl 1):i16–i35
  3. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. N Engl J Med. 1997;337:1029–1035
  4. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549
  5. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC I trial. Gastroenterology. 2006;130:323–333
  6. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132:52–65
  7. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357:228–238
  8. Schreiber S, Khaliq-Kareemi M, Lawrance I, et al. Certolizumab pegol maintenance therapy for Crohn's disease. N Engl J Med. 2007;357:239–250
  9. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology. 2004;126:402–413
  10. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146:829–838
  11. Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol. 2006;12:5606–5610
  12. Neurath MF. IL-23: a master regulator in Crohn disease. Nat Med. 2007;13:26–28
  13. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–1463
  14. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–146
  15. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest. 2006;116:1218–1222
  16. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007;25:221–242
  17. Neurath MF, Fuss I, Kelsall BL, et al. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995;182:1281–1290
  18. Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132:2359–2370
  19. Becker C, Dornhoff H, Neufert C, et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006;177:2760–2764
  20. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–1316
  21. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med. 2004;351:2069–2079
  22. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665–1674
  23. Papp KA, Langley RG, Lobwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371:1675–1684
  24. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356:580–592
  25. Kasper LH, Everitt D, Leist TP, et al. A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis. Curr Med Res Opin. 2006;22:1671–1678
  26. Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index (National Cooperative Crohn's Disease Study). Gastroenterology. 1976;70:439–444
  27. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology. 2002;122:512–530
  28. Sandborn WJ, Feagan BG, Radford-Smith G, et al. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn's disease: a randomised, double-blind, placebo-controlled trial. Gut. 2004;53:1485–1493
  29. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005;353:1912–1925
  30. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology. 2005;129:807–818
  31. Su C, Lichtenstein GR, Krok K, et al. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease. Gastroenterology. 2004;126:1257–1269
  32. Sands BE, Steinhart AH, Lewis JD, et al. Optimal Crohn's disease activity index (CDAI) response criteria is defined by decrease ≥ 100 points. Gastroenterology. 2003;124(Suppl S):A206
  33. Rao KL, Varalakshmi C, Ali AM, et al. Administration of anti-IL-12 antibody in vivo inhibits rejection of a rat histiocytoma and suppresses cytokine response in a tumour-bearing host. Immunology. 1997;92:381–387
  34. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–465
  35. Laurence A, O'Shea JJ. TH-17 differentiation: of mice and men. Nat Immunol. 2007;8:903–905

 Some of the results presented in this article were previously published in abstract form in Gastroenterology 2007;132(Suppl 2):A-51.

 Centocor, Inc (Malvern, PA) provided support for this study (C0379T07; clinical trials registration: clinicaltrials.gov #NCT00265122). Marion Blank and Jewel Johanns are employees of Centocor, Inc; William J. Sandborn received research funding in conjunction with the conduct of this study, he also received a research grant (1-UL1-RR024150-01) from the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research and is a consultant to Centocor, Inc (fees paid to the Mayo Clinic); Brian G. Feagan received research funding in conjunction with the conduct of this study, he also received other research grants and is a consultant to Centocor, Inc; Richard N. Fedorak received research funding in conjunction with the conduct of this study; Ellen Scherl received research funding in conjunction with the conduct of this study and other research grants and served as a consultant to Centocor, Inc; Mark R. Fleischer received research funding in conjunction with the conduct of this study and speaker payments, and has served as a consultant to Centocor, Inc; Seymour Katz received research funding in conjunction with the conduct of this study and other research grants from Centocor, Inc; Paul Rutgeerts received research funding in conjunction with the conduct of this study, he also received other research grants and speaker payments, and is a consultant to Centocor, Inc.

 Members of the Ustekinumab Crohn's Disease Study Group are listed at the end of the article.

PII: S0016-5085(08)01322-X

doi: 10.1053/j.gastro.2008.07.014

Gastroenterology
Volume 135, Issue 4 , Pages 1130-1141 , October 2008