期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 363, 期 14, 页码 1303-1312出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1000500
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资金
- Amgen
- Abbott
- Bristol-Myers Squibb
- Biogen Idec
- Crescendo Bioscience
- Genentech
- Astellas
- AstraZeneca
- BioAssets Development
- CalciMedica
- Can-Fite
- Celsion
- Centocor Ortho Biotech
- Cypress Bioscience
- Cytokine PharmaSciences
- DeNovo Pharmaceuticals
- EntreMed
- Ensemble Therapeutics
- Genentech, GlaxoSmithKline
- Hexal-Sandoz
- Horizon Pharma
- Idera Pharmaceuticals
- Johnson Johnson
- KaloBios
- Lexicon Pharmaceuticals
- Lycera
- Lilly
- Medarex
- MedImmune
- Merck
- Novartis
- Pfizer
- Phytomedics
- Portola Pharmaceuticals
- Reata Pharmaceuticals
- Rigel
- Roche
- Sanofi-Aventis
- EMD Serono
- Teva Pharmaceuticals
- Third Rock Ventures
- UCB
- VBL Therapeutics
- Wyeth
- Vertex Pharmaceuticals
- Xiphos Pharmaceuticals
Background: Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy. Methods: We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6. Results: R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy. Conclusions: In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.) N Engl J Med 2010;363:1303-12.
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