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

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, doubleblind, 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.The treatment of rheumatoid arthritis (RA) has traditionally been based on the use of conventional disease-modifying antirheumatic drugs (DMARDs) and, since the late 1990s, on newer, biologically based therapies that inhibit cytokine activity, block T cell-mediated ClinicalTrials.gov identifier: NCT00665926.

Effects of Fostamatinib, an Oral Spleen Tyrosine Kinase Inhibitor, in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate: Results From a Phase III, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study

“…The OSKIRA clinical trial program was initiated after the results of 2 phase II clinical studies demonstrated that treatment with fostamatinib significantly reduced the signs and symptoms of RA (7,8) (a third phase II clinical study in patients who had failed treatment with anti-TNF␣ agents, however, found no significant difference in the proportion of patients achieving an ACR20 improvement response at month 3 [study primary end point] between the fostamatinib and placebo groups [17]). …”

Spleen Tyrosine Kinase: A Novel Target in Autoimmunity

“…Notably, both these studies included a significant proportion of patients who had failed biological therapy with anti-TNF or anti-CD20 agents, and benefit with fostamatinib was seen in these subgroups (although overall response rates were lower than for the whole study population). A subsequent trial designed specifically to examine the efficacy of fostamatinib in this group of patients failing biologic therapy, however, did not achieve its primary endpoint of improved ACR20 in the treatment group (Genovese, Kavanaugh et al 2011). There were, however, significant improvements in radiographic and biochemical markers of inflammation.…”

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

“…Accordingly, several drugs, targeting these kinases have been recently tested in patients suffering from severe auto-inflammation (Grimminger et al, 2010;Laudisi et al, 2014). Meanwhile a promising candidate (PRT062607, Biogen Idec, Cambridge, MA, USA) is under evaluation, previous Syk inhibitors, such as AstraZeneca, R-788, showed low specificity and high toxicity, which forced to abandon their development (Genovese et al, 2011;Flight, 2012). Regardless, Hara and colleagues have showed that specific inhibition of phosphorylated ASC could represent an alternative means to enable suppression of caspase-1 activation and the associated pathological consequences (Laudisi et al, 2014).…”