Treatment of rheumatoid arthritis with a syk kinase inhibitor: A twelve‐week, randomized, placebo‐controlled trial

Abstract

Objective. Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fc␥-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA).Methods. We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.Results. Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm 3 ), both of which were dose related.Conclusion. These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.Although the mechanism(s) involved in the development of rheumatoid arthritis (RA) has not been definitively established, there is ample evidence to supClinicalTrials.gov identifier: NCT00326339.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…In clinical trials Syk inhibitions was effective in immune thrombocytopenic purpura 54 and rheumatoid arthritis. 19,20 In summary, we demonstrate that pharmacological Syk inhibition targets several key events of GvHD pathogenesis including expansion and migration of Tcs as well as costimulation by and migration of DCs. Importantly, cytolytic effector function of cytotoxic T lymphocyte against leukemia cells and anti-MCMV immunity were preserved despite Syk inhibition.…”

“…18 Recent phase II clinical trials demonstrated that Fostamatinib treatment effectively improved response rates in patients with rheumatoid arthritis. 19,20 Therefore, by using pharmacological inhibitors we aimed to delineate the relevance of Syk with respect to protection from GvHD, graft-versus-leukemia effects and anti-viral immune responses.…”

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

“…The adverse events included diarrhea, increase in systolic blood pressure, and neutropenia (24,39). RA is a disease with complex pathogenic mechanisms involving several inflammatory cascades and recruitment of inflammatory cells.…”

Investigative Drugs for Rheumatoid Arthritis: Novel Targets

“…In that regard, a phase II clinical trial employing the SyK inhibitor, fostamatinib (R406), was shown to improve clinical responses without untoward serious side-effects [15]. From a pathophysiological perspective, R406 also reduced interleukin-6 (IL-6) and matrix metalloproteinase-3 levels in the serum of RA patients compared to the placebo arm [16].…”