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

Authors

  • Christopher P. Denton,

    Corresponding author
    1. Royal Free Hospital, London, UK
    • Centre for Rheumatology, Royal Free and University College Medical School, Royal Free Hospital, Pond Street, London NW3 2QG, UK
    Search for more papers by this author
  • Peter A. Merkel,

    1. Boston University School of Medicine, Boston, Massachusetts
    Search for more papers by this author
  • Daniel E. Furst,

    1. University of California, Los Angeles
    Current affiliation:
    1. University of Cincinnati, and VAMC, Cincinnati, Ohio
    Search for more papers by this author
  • Dinesh Khanna,

    1. University of California, Los Angeles
    Current affiliation:
    1. University of Cincinnati, and VAMC, Cincinnati, Ohio
    Search for more papers by this author
  • Paul Emery,

    1. Leeds University, Leeds, UK
    Search for more papers by this author
  • Vivien M. Hsu,

    1. University of Medicine and Dentistry of New Jersey, New Brunswick
    Search for more papers by this author
  • Nancy Silliman,

    1. Genzyme, Boston, Massachusetts
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • James Streisand,

    1. Genzyme, Boston, Massachusetts
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • John Powell,

    1. Cambridge Antibody Technology, Cambridge, UK
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • Anita Åkesson,

    1. Lund University Hospital, Lund, Sweden
    Search for more papers by this author
  • John Coppock,

    1. Walsgrave Hospital, Coventry, UK
    Search for more papers by this author
  • Frank van den Hoogen,

    1. University Hospital, Nijmegen, The Netherlands
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • Ariane Herrick,

    1. Hope Hospital, Salford, UK
    Search for more papers by this author
  • Maureen D. Mayes,

    1. University of Texas Health Science Center at Houston
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • Douglas Veale,

    1. St. Vincent's Hospital, Dublin, Ireland
    Search for more papers by this author
  • Joanna Haas,

    1. Genzyme, Boston, Massachusetts
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • Stephen Ledbetter,

    1. Genzyme, Boston, Massachusetts
    Search for more papers by this author
    • Drs. Silliman, Streisand, Haas, and Ledbetter own stock and/or hold stock options in Genzyme. Dr. Powell owns stock and/or holds stock options in Cambridge Antibody Technology. Dr. van den Hoogen has received consulting fees and/or honoraria (less than $10,000 each) from Abbott and Bristol-Myers Squibb. Dr. Mayes has received consulting fees or honoraria (less than $10,000 each) from Actelion, Encysive, and Novartis.

  • Joseph H. Korn,

    1. Royal Free Hospital, London, UK
    2. Boston University School of Medicine, Boston, Massachusetts
    3. University of California, Los Angeles
    4. Leeds University, Leeds, UK
    5. University of Medicine and Dentistry of New Jersey, New Brunswick
    6. Genzyme, Boston, Massachusetts
    7. Cambridge Antibody Technology, Cambridge, UK
    8. Lund University Hospital, Lund, Sweden
    9. Walsgrave Hospital, Coventry, UK
    10. University Hospital, Nijmegen, The Netherlands
    11. Hope Hospital, Salford, UK
    12. University of Texas Health Science Center at Houston
    13. St. Vincent's Hospital, Dublin, Ireland
    14. University of Michigan, Ann Arbor
    Search for more papers by this author
    • Dr. Korn is deceased.

  • Carol M. Black,

    1. Royal Free Hospital, London, UK
    Search for more papers by this author
  • James R. Seibold,

    1. University of Michigan, Ann Arbor
    Search for more papers by this author
  • on Behalf Of The Cat-192 Study Group The Scleroderma Clinical Trials Consortium


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.

Ancillary