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

Abstract

ObjectiveRheumatoid 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.MethodsBiomarkers 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.ResultsIn 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.ConclusionThese data demonstrate that translational biomarkers are a potential tool for early assessment and decision‐making in drug development for RA treatment.

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

“…Although these interstitial collagens type I and III are expressed in multiple tissues throughout the body, preclinical studies have shown a specific association with tissue turnover in synovial membranes. In an ex vivo synovial membrane model, both C1M and C3M are released upon cytokine challenge and synovitis and inhibited by anti-inflammatory inhibitors such as the syk inhibitor fostamatinib [ 20 ]. Type IV collagen is the major constituent of the basement membrane [ 21 ], and C4M has been linked to remodeling of the basement membrane in animal models of liver fibrosis [ 9 ].…”

Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study

“…Kjelgaard-Petersen et al (2018) have previously shown that full-depth bovine articular cartilage explants (BEX) treated with oncostatin M in combination with TNFα (O + T) were a reliable translational model for rheumatoid arthritis by successfully back-translating the serological biomarker results from a phase III clinical study (OSKIRA-1) [32]. Proteomic technologies allow for a large-scale unbiased investigation, making it possible to identify factors involved in joint disease progression and build a library of mediators: previous studies have revealed numerous cytokines, proteases, and matrix fragments in serum, synovial fluid, and articular cartilage of OA patients [33][34][35][36].…”

Characterization of the Interleukin-17 Effect on Articular Cartilage in a Translational Model. An Explorative Study

“…Kjelgaard-Petersen et al (2018) have previously shown that full-depth bovine articular cartilage explants (BEX) treated with oncostatin M in combination with TNFα (O+T) were a reliable translational model for rheumatoid arthritis by successfully back-translating the serological biomarker results from a phase III clinical study (OSKIRA-1) (33). Proteomic technologies allow for a large-scale unbiased investigation, making it possible to identify factors involved in joint disease progression and build a library of mediators: previous studies have revealed numerous cytokines, proteases, and matrix fragments in serum, synovial fluid, and articular cartilage of OA patients (34)(35)(36)(37).…”