An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis.
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.)
Weinblatt
Michael E
ME
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. mweinblatt@partners.org
Kavanaugh
Arthur
A
Genovese
Mark C
MC
Musser
Theresa K
TK
Grossbard
Elliott B
EB
Magilavy
Daniel B
DB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D018709:Statistics, Nonparametric; D000072377:Syk Kinase; D016896:Treatment Outcome
D000631:Aminopyridines; D018501:Antirheumatic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib; D008727:Methotrexate