Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study

The Lancet Neurology

Volumn 7, Issue 9, 2008, Pages 796-804

  Segal, Benjamin M ^a   Constantinescu, Cris S ^b   Raychaudhuri, Aparna ^c   Kim, Lilianne ^c   Fidelus Gort, Rosanne ^c   Kasper, Lloyd H ^d  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b QUEEN S MEDICAL CENTRE   (United Kingdom)

^c CENTOCOR INC   (United States)

^d DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GADOLINIUM; INTERLEUKIN 12P40; PLACEBO; UNCLASSIFIED DRUG; USTEKINUMAB;

ADULT; ARTICLE; BLOOD SAMPLING; CEREBROVASCULAR DISEASE; CLINICAL ASSESSMENT; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DEPRESSION; DISEASE EXACERBATION; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG SAFETY; FATIGUE; HEADACHE; HUMAN; INFECTION; INJECTION SITE ERYTHEMA; INJECTION SITE REACTION; LABORATORY TEST; MAJOR CLINICAL STUDY; MULTICENTER STUDY; MULTIPLE SCLEROSIS; NAUSEA; NUCLEAR MAGNETIC RESONANCE IMAGING; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; UPPER RESPIRATORY TRACT INFECTION;

ADOLESCENT; ADULT; AGED; ANTIBODIES, MONOCLONAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; HUMANS; IMMUNOCOMPROMISED HOST; IMMUNOSUPPRESSION; INJECTIONS, SUBCUTANEOUS; INTERLEUKIN-12; INTERLEUKIN-23; MALE; MIDDLE AGED; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; NEOPLASMS; OPPORTUNISTIC INFECTIONS; PLACEBOS; PROTEIN SUBUNITS; TREATMENT OUTCOME;

EID: 48849087125     PISSN: 14744422     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1474-4422(08)70173-X     Document Type: Article

References (53)

1. Martin R., and McFarland H.F. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 32 (1995) 121-182
2. Miller D.H., Khan O.A., Sheremata W.A., et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348 (2003) 15-23
3. Weber M.S., Hohlfeld R., and Zamvil S.S. Mechanism of action of glatiramer acetate in treatment of multiple sclerosis. Neurotherapeutics 4 (2007) 647-653
4. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45 (1995) 1277-1285
5. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352 (1998) 1498-1504
6. Cartwright M.S., Jeffery D.R., Lewis Z.T., Koty P.P., Stewart W.T., and Molnar I. Mitoxantrone for multiple sclerosis causing acute lymphoblastic leukemia. Neurology 68 (2007) 1630-1631
7. Johnson K.P., Brooks B.R., Cohen J.A., et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45 (1995) 1268-1276
8. Kleinschmidt-DeMasters B.K., and Tyler K.L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353 (2005) 369-374
9. Cua D.J., Sherlock J., Chen Y., et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421 (2003) 744-748
10. Langrish C.L., Chen Y., Blumenschein W.M., et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201 (2005) 233-240
11. Segal B.M., Dwyer B.K., and Shevach E.M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187 (1998) 537-546
12. Segal B.M., and Shevach E.M. IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med 184 (1996) 771-775
13. Oppmann B., Lesley R., Blom B., et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13 (2000) 715-725
14. Trinchieri G., and Scott P. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions. Res Immunol 146 (1995) 423-431
15. Kikly K., Liu L., Na S., and Sedgwick J.D. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 18 (2006) 670-675
16. Windhagen A., Newcombe J., Dangond F., et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 182 (1995) 1985-1996
17. Li Y., Chu N., Hu A., Gran B., Rostami A., and Zhang G.X. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 130 (2007) 490-501
18. Balashov K.E., Smith D.R., Khoury S.J., Hafler D.A., and Weiner H.L. Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. Proc Natl Acad Sci USA 94 (1997) 599-603
19. Vaknin-Dembinsky A., Balashov K., and Weiner H.L. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 176 (2006) 7768-7774
20. Brok H.P.M., van Meurs M., Blezer E., et al. Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody. J Immunol 169 (2002) 6554-6563
21. Ichikawa H.T., Williams L.P., and Segal B.M. Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J Immunol 169 (2002) 2781-2787
22. Constantinescu C.S., Wysocka M., Hilliard B., et al. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol 161 (1998) 5097-5104
23. Lock C., Hermans G., Pedotti R., et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8 (2002) 500-508
24. Woodroofe M.N., and Cuzner M.L. Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization. Cytokine 5 (1993) 583-588
25. Chen Y., Langrish C.L., McKenzie B., et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116 (2006) 1317-1326
26. Komiyama Y., Nakae S., Matsuki T., et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177 (2006) 566-573
27. Ferber I.A., Brocke S., Taylor-Edwards C., et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156 (1996) 5-7
28. Bagaeva L.V., Williams L.P., and Segal B.M. IL-12 dependent/IFN gamma independent expression of CCR5 by myelin-reactive T cells correlates with encephalitogenicity. J Neuroimmunol 137 (2003) 109-116
29. Deshpande P., King I.L., and Segal B.M. IL-12 driven upregulation of P-selectin ligand on myelin-specific T cells is a critical step in an animal model of autoimmune demyelination. J Neuroimmunol 173 (2006) 35-44
30. Panitch H.S., Hirsch R.L., Schindler J., and Johnson K.P. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37 (1987) 1097-1102
31. 't Hart B.A., Brok H.P., Remarque E., et al. Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. J Immunol 175 (2005) 4761-4768
32. Kasper L.H., Everitt D., Leist T.P., et al. A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis. Curr Med Res Opin 22 (2006) 1671-1678
33. McDonald W.I., Compston A., Edan G., et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50 (2001) 121-127
34. Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33 (1983) 1444-1452
35. Cutter G.R., Baier M.L., Rudick R.A., et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122 (1999) 871-882
36. Sormani M.P., Miller D.H., Comi G., et al. Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets. J Neurol Neurosurg Psychiatry 70 (2001) 494-499
37. Sormani M.P., Molyneux P.D., Gasperini C., et al. Statistical power of MRI monitored trials in multiple sclerosis: new data and comparison with previous results. J Neurol Neurosurg Psychiatry 66 (1999) 465-469
38. Jonckheere A., and Terpstra T. A distribution-free test for ordered alternatives (1973), John Wiley and Sons, New York
39. Tukey J.W., Ciminera J.L., and Heyse J.F. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 41 (1985) 295-301
40. Leonardi C.L., Kimball A.B., Papp K.A., et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371 (2008) 1665-1674
41. Papp K.A., Langley R.G., Lebwohl M., et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371 (2008) 1675-1684
42. Sandborn W., Feagan B., Fedorak R., et al. A multicenter, randomized, phase 2a study of human monoclonal antibody to IL-12/23p40 (Cnto 1275) in patients with moderately to severely active Crohn's disease. Gastroenterology 132 (2007) A51
43. Becher B., Durell B.G., and Noelle R.J. IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J Clin Invest 112 (2003) 1186-1191
44. Filippi M., Rocca M.A., Martino G., Horsfield M.A., and Comi G. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 43 (1998) 809-814
45. Thakker P., Leach M.W., Kuang W., Benoit S.E., Leonard J.P., and Marusic S. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol 178 (2007) 2589-2598
46. Sriram S., and Steiner I. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol 58 (2005) 939-945
47. Jiang H., Zhang S.I., and Pernis B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256 (1992) 1213-1215
48. Wolf S.D., Dittel B.N., Hardardottir F., and Janeway Jr. C.A. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 184 (1996) 2271-2278
49. Babbe H., Roers A., Waisman A., et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192 (2000) 393-404
50. Niland B., Banki K., Biddison W.E., and Perl A. CD8+ T cell-mediated HLA-A*0201-restricted cytotoxicity to transaldolase peptide 168-176 in patients with multiple sclerosis. J Immunol 175 (2005) 8365-8378
51. Magliozzi R., Howell O., Vora A., et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130 (2007) 1089-1104
52. Hauser S.L., Waubant E., Arnold D.L., et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358 (2008) 676-688
53. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53 (1999) 457-465