An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: A three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents

Authors

  • Mark C. Genovese,

    Corresponding author
    1. Stanford University, Palo Alto, California
    • Division of Immunology and Rheumatology, Stanford University, 1000 Welch Road, Suite 203, Palo Alto, CA 94304
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    • Drs. Genovese and Kavanaugh have received consulting fees, speaking fees, and/or honoraria from Rigel (less than $10,000).

  • Arthur Kavanaugh,

    1. University of California at San Diego
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    • Drs. Genovese and Kavanaugh have received consulting fees, speaking fees, and/or honoraria from Rigel (less than $10,000).

  • Michael E. Weinblatt,

    1. Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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    • Dr. Weinblatt has received consulting fees, speaking fees, and/or honoraria from Rigel (more than $10,000).

  • Charles Peterfy,

    1. Spire Sciences, San Francisco, California
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    • Dr. Peterfy has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Celgene, Genentech, Eli Lilly, Merck, Novartis, Roche, Servier, Simpirica, and Wyeth (less than $10,000 each), is founder and chief executive officer of Spire Sciences, and owns stock or stock options in Spire Sciences and Synarc.

  • Julie DiCarlo,

    1. Synarc, San Francisco, California
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  • Michael L. White,

    1. Kendle, Cincinnati, Ohio
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    • Dr. White owns stock or stock options in Kendle.

  • Maryann O'Brien,

    1. Rigel, South San Francisco, California
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    • Ms O'Brien and Drs. Grossbard and Magilavy own stock or stock options in Rigel.

  • Elliott B. Grossbard,

    1. Rigel, South San Francisco, California
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    • Ms O'Brien and Drs. Grossbard and Magilavy own stock or stock options in Rigel.

  • Daniel B. Magilavy

    1. Rigel, South San Francisco, California
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    • Ms O'Brien and Drs. Grossbard and Magilavy own stock or stock options in Rigel.


  • ClinicalTrials.gov identifier: NCT00665926.

Abstract

Objective

To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies.

Methods

A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score.

Results

The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level.

Conclusion

Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.

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