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

Abstract

OBJECTIVE:

Rheumatoid arthritis (RA) is a chronic and degenerative autoimmune joint disease that leads to disability, reduced quality of life, and increased mortality. Although several synthetic and biologic disease-modifying antirheumatic drugs are available, there is still a medical need for novel drugs that control disease progression. As only 10% of experimental drug candidates for treatment of RA that enter phase I trials are eventually registered by the Food and Drug Administration, there is an immediate need for translational tools to facilitate early decision-making in drug development. In this study, we aimed to determine if the inability of fostamatinib (a small molecule inhibitor of Syk) to demonstrate sufficient efficacy in phase III of a previous clinical study could have been predicted earlier in the development process.

METHODS:

Biomarkers of bone, cartilage, and interstitial matrix turnover (C-telopeptide of type I collagen [CTX-I], matrix metalloproteinase-derived types I, II, and III collagen neoepitopes [C1M, C2M, and C3M]) were measured in 450 serum samples from the Oral Syk Inhibition in Rheumatoid Arthritis 1 study (OSKIRA-1, a phase III clinical study of 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 the drug.

RESULTS:

In OSKIRA-1 serum samples and osteoclast and cartilage cultures, fostamatinib suppressed the levels of CTX-I and C2M. In OSKIRA-1 serum samples and synovial membrane cultures, fostamatinib did not mediate any clinical or preclinical effect on either C1M or C3M, which have previously been associated with disease response and efficacy.

CONCLUSION:

These data demonstrate that translational biomarkers are a potential tool for early assessment and decision-making in drug development for RA treatment.

• Authors: Cecilie F Kjelgaard-Petersen, Adam Platt, Martin Braddock, Martin A Jenkins, Kishwar Musa, Emma Graham, Thorbjørn Gantzel, Gillian Slynn, Michael E Weinblatt, Morten A Karsdal, Christian S Thudium, Anne-C Bay-Jensen
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 70 Issue 9 Pg. 1419-1428 (09 2018) ISSN: 2326-5205 [Electronic] United States
• PMID: 29669391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Chemical References

• Aminopyridines
• Antirheumatic Agents
• Biomarkers
• Morpholines
• Oxazines
• Pyridines
• Pyrimidines
• Collagen
• fostamatinib

Topics

• Aminopyridines
• Antirheumatic Agents (pharmacology)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Biomarkers (analysis)
• Cartilage (drug effects, metabolism)
• Collagen (drug effects, metabolism)
• Drug Development (methods)
• Drug Discovery (methods)
• Humans
• Morpholines
• Oxazines (pharmacology)
• Pyridines (pharmacology)
• Pyrimidines
• Synovial Membrane (drug effects, metabolism)
• Translational Research, Biomedical (methods)