Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192.

OBJECTIVE To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta1 (TGFbeta1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). METHODS Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2. RESULTS Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). CONCLUSION We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.

[1]  J. Ioannidis,et al.  Design and quality considerations for randomized controlled trials in systemic sclerosis. , 2002, Arthritis and rheumatism.

[2]  S. Ledbetter,et al.  A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. , 2004, Arthritis and rheumatism.

[3]  Gerard C Blobe,et al.  Role of transforming growth factor Beta in human cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Richard W. Martin,et al.  Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. , 2002, Arthritis and rheumatism.

[5]  A. Silman,et al.  Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. , 1999, Arthritis and rheumatism.

[6]  A. Gabrielli,et al.  Serological assessment of type I collagen burden in scleroderma spectrum disorders: a systematic review. , 2004, Clinical and experimental rheumatology.

[7]  D. Abraham,et al.  Activation of Key Profibrotic Mechanisms in Transgenic Fibroblasts Expressing Kinase-deficient Type II Transforming Growth Factor-β Receptor (TβRIIΔk)* , 2005, Journal of Biological Chemistry.

[8]  J. Seibold,et al.  Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin". , 2010, Arthritis and rheumatism.

[9]  L. Moreland,et al.  Recombinant Human Relaxin in the Treatment of Scleroderma , 2000, Annals of Internal Medicine.

[10]  T. Medsger,et al.  Improvement in skin thickening in systemic sclerosis associated with improved survival. , 2001, Arthritis and rheumatism.

[11]  M. Suarez‐Almazor,et al.  Current status of outcome measure development for clinical trials in systemic sclerosis. Report from OMERACT 6. , 2003, The Journal of rheumatology.

[12]  James F. Fries,et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. , 1980, Arthritis and rheumatism.

[13]  Yan Zhang,et al.  Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. , 1999, Journal of immunology.

[14]  N. Bellamy,et al.  A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. , 2001, Arthritis and rheumatism.

[15]  R. Vancheeswaran,et al.  Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon. , 1994, Arthritis and rheumatism.

[16]  C. Denton,et al.  Scleroderma--clinical and pathological advances. , 2004, Best practice & research. Clinical rheumatology.

[17]  C. Black,et al.  Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1 , 1994 .

[18]  T. Medsger,et al.  Soluble serum interleukin 2 receptors in patients with systemic sclerosis. , 1996, The Journal of rheumatology.

[19]  D. Pennington,et al.  Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. , 2000, Experimental cell research.

[20]  M. Irwin,et al.  Validation of single-factor structure and scoring protocol for the Health Assessment Questionnaire-Disability Index. , 2005, Arthritis and rheumatism.

[21]  F. V. D. van den Hoogen,et al.  Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. , 1996, British journal of rheumatology.

[22]  Richard W. Martin,et al.  Skin thickness score in systemic sclerosis , 1993 .

[23]  T. Medsger,et al.  The palpable tendon friction rub: an important physical examination finding in patients with systemic sclerosis. , 1997, Arthritis and rheumatism.

[24]  T. Medsger,et al.  The palpable tendon friction rub , 1997 .

[25]  Richard W. Martin,et al.  High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. , 1999, Arthritis and rheumatism.

[26]  P. Lachenbruch,et al.  Immunosuppression with chlorambucil, versus placebo, for scleroderma. Results of a three-year, parallel, randomized, double-blind study. , 1989, Arthritis and rheumatism.

[27]  T. Medsger,et al.  The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. , 1997, Arthritis and rheumatism.

[28]  J. Massagué,et al.  Controlling TGF-β signaling , 2000, Genes & Development.

[29]  A. Masi.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). , 1980, Bulletin on the rheumatic diseases.

[30]  D. Abraham,et al.  Transforming growth factor-&bgr; and connective tissue growth factor: key cytokines in scleroderma pathogenesis , 2001, Current opinion in rheumatology.

[31]  Jesús Prieto,et al.  Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. , 2005, The Journal of investigative dermatology.

[32]  C. Denton,et al.  Non-invasive measurement of biomechanical skin properties in systemic sclerosis , 2002, Annals of the rheumatic diseases.

[33]  H. Ihn,et al.  Increased transcriptional activities of transforming growth factor beta receptors in scleroderma fibroblasts. , 2002, Arthritis and rheumatism.

[34]  David Botstein,et al.  Systemic and cell type-specific gene expression patterns in scleroderma skin , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  C. Querfeld,et al.  Expression of TGF-β1, -β2 and -β3 in localized and systemic scleroderma , 1999 .

[36]  L. McCormick,et al.  Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. , 2003, The Journal of investigative dermatology.

[37]  P. Lachenbruch,et al.  Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis. , 1995, Arthritis and rheumatism.

[38]  J. Massagué,et al.  Controlling TGF-beta signaling. , 2000, Genes & development.

[39]  D. Pisetsky,et al.  A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. , 1996, The Journal of rheumatology.

[40]  L. Wakefield,et al.  TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression , 2003 .

[41]  J. Seibold.  Clinical trials: types, design, and end-points. , 2001, Current opinion in rheumatology.

[42]  Hong-Jian Zhu,et al.  Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation. , 2002, Journal of the American Society of Nephrology : JASN.