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

Abstract

Objective. This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy.Methods. Patients taking MTX were randomized(1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS).Results. In this study, 918 patients were randomized and received >1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P ‫؍‬ 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P ‫؍‬ 0.25 and P ‫؍‬ 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (>140/90 mm Hg) occurred at >1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group.Conclusion. With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at ClinicalTrials.gov identifier: NCT01197521.

Fostamatinib for Persistent/Chronic Adult Immune Thrombocytopenia

“…In addition to ITP, fostamatinib has shown activity in clinical studies of patients with rheumatoid arthritis, including those with inadequate responses to TNF-α antagonists or to methotrexate and other disease-modifying antirheumatic drugs [64][65][66][67]. In Phase III studies of fostamatinib in these patients, American College of Rheumatology 20% (ACR20) responses were achieved in a significantly greater proportion of patients when they received fostamatinib 100 mg b.i.d.…”

Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis

“…However, minimal effect on clinical cartilage erosion was observed in the OSKIRA‐1 study 13. This might be due to the concentration of R406 in the cartilage of the patients.…”

“…This subset of patients was used for biomarker analysis, although 5 of the 450 samples did not contain sufficient material to allow measurement of all biomarkers. Baseline clinical and demographic data for this subset of patients for biomarker analysis suggest that these patients were a reasonable representation of the overall intent‐to‐treat population 13. Demographic characteristics of the patients in the OSKIRA‐1 study are summarized in Supplementary Table 1 (available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40527/abstract).…”

“…This study was undertaken to investigate whether a translational model using serum‐based biomarkers in ex vivo and in vitro cultures could have predicted the insufficient clinical effect of fostamatinib on joint structure. In order to investigate this, the clinical data from the OSKIRA‐1 study of fostamatinib in combination with MTX 13, a phase III, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study of RA patients whose illness did not adequately respond to MTX therapy, were used. In vitro human osteoclasts and ex vivo cultures of bovine cartilage and human synovium were used to test the effect of the active metabolite of fostamatinib, R406, on 4 biomarkers of ECM degradation that were also measured in OSKIRA‐1.…”

“…The totality of the OSKIRA phase III program indicated that the profile of this molecule was insufficient to warrant further development for RA 13, 14. As phase III clinical programs require considerable investment from patients, physicians, and sponsors, our goal in the present investigation was to determine whether the lack of structural efficacy in the fostamatinib OSKIRA‐1 study could have been predicted earlier in the clinical development process.…”