Abstract

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, autoimmune and degenerative joint disease leading to disability, reduced life quality, and increased mortality. Although several synthetic and biological disease modifying anti-rheumatic drugs (DMARDs) are available, there is still a medical need for novel drugs controlling disease progression. As only 10% of RA drug candidates that enter phase I trials are eventually FDA registered, there is an immediate requirement for translational drug development tools to facilitate early drug development decision making. We aimed to determine if the failure of fostamatinib, a small molecule inhibitor of Spleen tyrosine kinase (syk), to show sufficient efficacy in phase III could have been predicted earlier in the development process, METHODS: Biomarkers of bone, cartilage and interstitial matrix turnover (CTX-I, C2M, C1M and C3M) were measured in 450 serum samples from OSKIRA-1 (a phase III clinical study testing the efficacy of Fostamatinib in RA) at baseline and follow-up. Additionally, the same biomarkers were subsequently measured in conditioned media from osteoclast, cartilage and synovial membrane cultured with the active metabolite of fostamatinib, R406 to assess the level of suppression induced by fostamatinib.

RESULTS: Fostamatinib suppressed the level of CTX-I and C2M in OSKIRA-1 and in osteoclast and cartilage cultures, fostamatinib mediated no clinical or pre-clinical effect on either C1M or C3M, which have previously associated with disease response and efficacy.

CONCLUSION: These data demonstrate that translational biomarkers are a potential tool for early assessment and decision-making in RA drug development. This article is protected by copyright. All rights reserved.

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