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Expert
Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: Vol. 7; Issue 16; 24 August 2005 Abstract
PDF
Summary of rheumatoid arthritis therapeutics in development
Sandra M. Sacre, Evangelos Andreakos, Peter Taylor, Marc Feldmann and Brian M. Foxwell
| Table 1. Summary of rheumatoid arthritis therapeutics in development | ||||
| Name | Type / Target | Manufacturer | Clinical stage | Refs |
|
Remicade® (infliximab) |
Monoclonal antibody / TNF-a | Centocor Inc. | FDA approved | 25 |
|
Enbrel® (etanercept) |
Receptor / TNF-a | Immunex/Wyeth | FDA approved | 26 |
|
Humira® (adalimumab) |
Monoclonal antibody /TNF-a | Abbott | FDA approved | 27 |
|
CDP 870 |
Monoclonal antibody /TNF-a | Celltech | Phase III | 32 |
|
PEGylated soluble TNFR type I |
Receptor / TNF-a | Amgen | Phase II | 33 |
|
ISIS 104838 |
Antisense oligonucleotide / TNF-a | ISIS | Pre-clinical | 36 |
|
TMI-1 |
Small molecule / TACE | Wyeth | Pre-clinical | 37 |
| Kineret® (anakinra) | Protein / IL-1 | Amgen | FDA approved | 46, 47 |
| IL-1 TRAP | Receptor / IL-1 | Regeneron | Phase IIb | 48 |
|
CDP 484 |
PEGylated antibody fragment / IL-1b | Celltech | Phase I | Further reading box |
| Pralnacasan | Small molecule / Caspase I / IL-1 | Vertex/Aventis | Discontinued after Phase IIb | 49 |
|
MRA |
Monoclonal antibody / IL-6 | Chugai/Roche | Phase III | 60, 152 |
|
ABX-IL8 |
Monoclonal antibody / IL-8 | Abgenix | Discontinued after Phase IIa | Further reading box |
|
ABT-874 |
Monoclonal antibody / IL-12 | CAT/Abbott | Phase II (Phase I/II) | Further reading box |
|
HuMax-IL-15 |
Monoclonal antibody / IL-15 | Genmab/Amgen | Phase II | 69 |
|
IL-18bp (Tadekinig-a) |
Protein / IL-18 | Serono | Phase IIa | Further reading box |
|
Trocade (Ro 32-3555) |
Small molecule / MMP-1 | Roche | Discontinued after Phase I | 79 |
|
IKK2 inhibitors |
Small molecule / IKK2 | Various companies | Pre-clinical | Reviewed in Ref. 101 |
|
p38 MAPK inhibitors |
Small molecule / p38 MAPK | Various companies | Some in Phase I/II; many discontinued | 111, 112, 113, 114, 115 |
|
Abatacept (CTLA4-Ig) |
Fusion protein / CTLA4 | Repligen Corporation | Phase III | 127 |
|
Rituxan (Rituximab/MabThera) |
Monoclonal antibody / CD20 | Genentech | Phase III | Further reading box |
| Abbreviations: CTLA4, cytotoxic T-lymphocyte-associated antigen 4; IKK2, IkB kinase 2; IL, interleukin; MAPK, mitogen-activated protein kinase; MMP-1, matrix metalloproteinase 1; TACE, TNF-a-converting enzyme; TNF-a, tumour necrosis factor a. | ||||
| References cited
in Table 1
25 Elliott, M.J. et al. (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105-1110, PubMed 26 Moreland, L.W. et al. (1999) Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 130, 478-486, PubMed 27 Weinblatt, M.E. et al. (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48, 35-45, PubMed 32 Rose-John, S. and Schooltink, H. (2003) CDP-870. Celltech/Pfizer. Curr Opin Investig Drugs 4, 588-592, PubMed 33 Darlington, C. (2003) PEG-sTNF-RI. Amgen. Curr Opin Investig Drugs 4, 583-587, PubMed 36 Kennewell, P. (2003) Technology evaluation: ISIS-104838, OraSense. Curr Opin Mol Ther 5, 76-80, PubMed 37 Zhang,
Y. et al. (2004) Identification and characterization of 4-[[4-(2-butynyloxy) 46 Bresnihan, B. et al. (1998) Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 41, 2196-2204, PubMed 47 Campion, G.V. et al. (1996) Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum 39, 1092-1101, PubMed 48 Economides, A.N. et al. (2003) Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9, 47-52, PubMed 49 Siegmund, B. and Zeitz, M. (2003) Pralnacasan (vertex pharmaceuticals). IDrugs 6, 154-158, PubMed 60 Maini, R. (2003) Chaisma study group. Double blind, randomised, parallel group, controlled, dose ranging study of the safety, tolerability, pharmacokinetics & efficacy of repeat doses of MRA lone or with MTX in RA patients. Ann Rheum Dis 62, 64 69 Baslund, B. (2003) First use of a human monoclonal antibody against IL-15 (HUMAX-IL-15) in patients with active rheumatoid arthritis (RA): Results of a double-blind, placebo-controlled phase I/II trial. Ann Rheum Dis 62, 66 79 Hemmings, F.J. et al. (2001) Tolerability and pharmacokinetics of the collagenase-selective inhibitor Trocade in patients with rheumatoid arthritis. Rheumatology (Oxford) 40, 537-543, PubMed 101 Karin, M., Yamamoto, Y. and Wang, Q.M. (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3, 17-26, PubMed 111 Badger, A.M. et al. (1996) Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 279, 1453-1461, PubMed 112 Jackson, J.R. et al. (1998) Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. J Pharmacol Exp Ther 284, 687-692, PubMed 113 Badger, A.M. et al. (2000) Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 43, 175-183, PubMed 114 Wadsworth, S.A. et al. (1999) RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 291, 680-687, PubMed 115 McLay, L.M. et al. (2001) The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem 9, 537-554, PubMed 127 Kremer, J.M. et al. (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349, 1907-1915, PubMed 152 Nishimoto, N. et al. (2004) Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 50, 1761-1769, PubMed |
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