Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192

Christopher P. Denton, Peter A. Merkel, Daniel E. Furst, Dinesh Khanna, Paul Emery, Vivien Hsu, Nancy Silliman, James Streisand, John Powell, Anita Åkesson, John Coppock, Frank Van Den Hoogen, Ariane Herrick, Maureen D. Mayes, Douglas Veale, Joanna Haas, Stephen Ledbetter, Joseph H. Korn, Carol M. Black, James R. Seibold

Research output: Contribution to journalArticle

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Abstract

Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth Factor β1 (TGFβ1), 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 TGFβ1 and TGFβ2. 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-TGFβ1 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.

Original languageEnglish (US)
Pages (from-to)323-333
Number of pages11
JournalArthritis and rheumatism
Volume56
Issue number1
DOIs
StatePublished - Jan 1 2007

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Systemic Scleroderma
Transforming Growth Factors
Placebos
Diffuse Scleroderma
Skin
Antibodies
Procollagen
Interleukin-2 Receptors
Therapeutics
Multicenter Studies
Collagen
Pharmacokinetics
Outcome Assessment (Health Care)
Morbidity
Safety
Messenger RNA
Mortality
Health
Serum
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Denton, Christopher P. ; Merkel, Peter A. ; Furst, Daniel E. ; Khanna, Dinesh ; Emery, Paul ; Hsu, Vivien ; Silliman, Nancy ; Streisand, James ; Powell, John ; Åkesson, Anita ; Coppock, John ; Van Den Hoogen, Frank ; Herrick, Ariane ; Mayes, Maureen D. ; Veale, Douglas ; Haas, Joanna ; Ledbetter, Stephen ; Korn, Joseph H. ; Black, Carol M. ; Seibold, James R. / Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis : A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. In: Arthritis and rheumatism. 2007 ; Vol. 56, No. 1. pp. 323-333.
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title = "Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192",
abstract = "Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth Factor β1 (TGFβ1), 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 TGFβ1 and TGFβ2. 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-TGFβ1 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.",
author = "Denton, {Christopher P.} and Merkel, {Peter A.} and Furst, {Daniel E.} and Dinesh Khanna and Paul Emery and Vivien Hsu and Nancy Silliman and James Streisand and John Powell and Anita {\AA}kesson and John Coppock and {Van Den Hoogen}, Frank and Ariane Herrick and Mayes, {Maureen D.} and Douglas Veale and Joanna Haas and Stephen Ledbetter and Korn, {Joseph H.} and Black, {Carol M.} and Seibold, {James R.}",
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Denton, CP, Merkel, PA, Furst, DE, Khanna, D, Emery, P, Hsu, V, Silliman, N, Streisand, J, Powell, J, Åkesson, A, Coppock, J, Van Den Hoogen, F, Herrick, A, Mayes, MD, Veale, D, Haas, J, Ledbetter, S, Korn, JH, Black, CM & Seibold, JR 2007, 'Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192', Arthritis and rheumatism, vol. 56, no. 1, pp. 323-333. https://doi.org/10.1002/art.22289

Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis : A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. / Denton, Christopher P.; Merkel, Peter A.; Furst, Daniel E.; Khanna, Dinesh; Emery, Paul; Hsu, Vivien; Silliman, Nancy; Streisand, James; Powell, John; Åkesson, Anita; Coppock, John; Van Den Hoogen, Frank; Herrick, Ariane; Mayes, Maureen D.; Veale, Douglas; Haas, Joanna; Ledbetter, Stephen; Korn, Joseph H.; Black, Carol M.; Seibold, James R.

In: Arthritis and rheumatism, Vol. 56, No. 1, 01.01.2007, p. 323-333.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis

T2 - A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192

AU - Denton, Christopher P.

AU - Merkel, Peter A.

AU - Furst, Daniel E.

AU - Khanna, Dinesh

AU - Emery, Paul

AU - Hsu, Vivien

AU - Silliman, Nancy

AU - Streisand, James

AU - Powell, John

AU - Åkesson, Anita

AU - Coppock, John

AU - Van Den Hoogen, Frank

AU - Herrick, Ariane

AU - Mayes, Maureen D.

AU - Veale, Douglas

AU - Haas, Joanna

AU - Ledbetter, Stephen

AU - Korn, Joseph H.

AU - Black, Carol M.

AU - Seibold, James R.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth Factor β1 (TGFβ1), 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 TGFβ1 and TGFβ2. 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-TGFβ1 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.

AB - Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth Factor β1 (TGFβ1), 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 TGFβ1 and TGFβ2. 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-TGFβ1 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.

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