LB2 - Treatment of Rheumatoid Arthritis (RA) with An Oral Syk Kinase Inhibitor: A 6 Month Randomized Placebo Controlled Phase 2b Study in Patients with Active RA On Chronic Methotrexate

Tuesday, October 20, 2009: 4:45 PM
204 B (Pennsylvania Convention Center)
Michael Weinblatt1, Arthur Kavanaugh2, Mark Genovese3, Elliott Grossbard4 and Daniel Magilavy4, 1Brigham & Women's Hosp, Boston, MA, 2UCSD, San Diego, CA, 3Stanford University, Palo Alto, CA, 4Rigel Pharma, South San Francisco, CA
Presentation Number: LB2

Purpose Syk kinase is an important modulator of immune signaling.  R788, an oral, relatively selective inhibitor of Syk kinase, demonstrated significant clinical efficacy in an earlier dose-ranging 3 month trial in active RA (Arth Rheum 2008.58:3309).  The objective of this study was to confirm the efficacy and safety of R788 in pts with active disease despite chronic methotrexate therapy.

Method 457 patients with active RA on chronic methotrexate enrolled in a 6 month double-blind, placebo-controlled two R788 dose (100 bid, 150 mg qd) , international Phase II trial. The principal endpoint was the ACR 20 response (nonresponder imputation) rate at Month 6.

Results Demographics and baseline clinical characteristics were similar among groups. 85% in the R788 and 79% in the placebo group completed the study. The most common reasons for withdrawal were adverse events in the R788 100 mg bid and 150 mg qd (5%) groups and lack of efficacy in the placebo group (12%). Both R788 dosing regimens were significantly superior to placebo at Month 6 (Table). Clinical effects were noted as early as week one and maximum effect, which was sustained throughout the remainder of the study, by Week 6. Significant improvement in HAQ-DI, FACIT- fatigue, and SF-36 was also noted in the R788 groups. The most common AE, which was reversible and dose-related, was diarrhea (19% in the 100mg bid dose vs 3% in placebo). Transient neutropenia (<1500/mm3) occurred overall in 3% of patients treated with R788 (vs 1% in the placebo).  Elevation of ALT >3 ULN occurred in 4% of both R788 groups and 2% in the placebo. Mean change from baseline in systolic blood pressure at Month 6 was +0.2 mm and +0.6 mm for the 150 mg qd and 100 mg bid groups, respectively, and -1.8 mm for the placebo.  Increase in blood pressure (BP) was observed most frequently in patients with a history of hypertension with BP easily managed with adjustments of conventional antihypertensive medications.

Conclusion Syk inhibition with R788 produced significant clinical benefits with an acceptable safety profile when added to methotrexate in patients with active RA. The onset of clinical effect was rapid with maximum improvement achieved by Week 6  and maintained throughout the trial. 


n (%)
n = 153

R788150 mg qd
n (%)
n = 152

R788 100 mg bid
n (%)
n = 152

ACR 20

53 (35%)

87 (57%)‡

101 (66%) ‡

ACR 50

29 (19%)

49 (32%)*

65   (43%)‡

ACR 70

16 (10%)

21 (14%)

43   (28%)‡


9   (7%) 

26  (21%) +

41   (31%)*

# percent based on pts with available DAS data

‡ p<0.001, * p<0.01, + p<0.05 (compared to placebo)

Keywords: clinical trials, kinase and rheumatoid arthritis, treatment

Disclosure: M. Weinblatt, Rigel Pharma, 5 ; A. Kavanaugh, Rigel Pharma, 5 ; M. Genovese, Rigel Pharma, 2, Rigel Pharma, 5 ; E. Grossbard, Rigel Pharma, 3 ; D. Magilavy, Rigel Pharma, 3 .