Related Experiment Video
Updated: Feb 11, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Translational Biomarkers and Ex Vivo Models of Joint Tissues as a Tool for Drug Development in Rheumatoid Arthritis
Cecilie F Kjelgaard-Petersen1,2, Adam Platt3, Martin Braddock4
1Technical University of Denmark, Kongens Lyngby, Denmark.
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.
Insights
Translational biomarkers can predict rheumatoid arthritis (RA) drug efficacy early. Fostamatinib suppressed bone and cartilage turnover markers but not those linked to RA disease response, indicating potential for early development decisions.
Area of Science:
- Rheumatology
- Pharmacology
- Biomarker Discovery
Background:
- Rheumatoid arthritis (RA) is a debilitating autoimmune disease with unmet needs for effective treatments.
- Current drug development for RA has a high failure rate, necessitating better early assessment tools.
- Fostamatinib, a Syk inhibitor, previously failed to demonstrate sufficient efficacy in Phase III RA trials.
Purpose of the Study:
- To evaluate if translational biomarkers could have predicted fostamatinib's efficacy in rheumatoid arthritis earlier.
- To assess the impact of fostamatinib's active metabolite (R406) on specific matrix turnover biomarkers in vitro.
Main Methods:
- Serum samples from 450 RA patients in the OSKIRA-1 Phase III trial were analyzed for collagen turnover biomarkers (CTX-I, C1M, C2M, C3M).
- Biomarker levels were measured at baseline and follow-up.
- In vitro studies assessed R406's effect on osteoclast, cartilage, and synovial membrane cultures.
Main Results:
- Fostamatinib suppressed levels of CTX-I and C2M in patient serum and in osteoclast/cartilage cultures.
- No suppression of C1M or C3M was observed in patient serum or synovial membrane cultures.
- C1M and C3M are previously associated with RA disease response and drug efficacy.
Conclusions:
- Translational biomarkers (CTX-I, C2M, C1M, C3M) show potential for early efficacy assessment in RA drug development.
- The differential biomarker response suggests why fostamatinib may not have met efficacy endpoints.
- This study highlights the value of biomarkers in guiding early decisions in RA drug development.
More Related Videos
06:31Author Spotlight: Enhancing Rheumatoid Arthritis Research Through HR-pQCT Imaging Analysis
Published on: October 6, 2023
09:31Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients
Published on: October 16, 2016
Related Concept Videos
01:07Development of the Limb Synovial Joints
The mesenchymal stem cells differentiate into chondrocytes that form the hyaline cartilage, and later the cartilaginous model of the bone. This model further transforms into a bone. This process is known as endochondral ossification.
During development, the limbs...
01:31Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
02:33Initiation of Translation
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
01:16Structural Joints: Synovial Joints
01:44Termination of Translation
01:03Structural Joints: Fibrous Joints
Suture
All the bones of the skull, except for the mandible, are joined to each other by a fibrous joint called a suture. The fibrous connective tissue found at a suture strongly unites the adjacent skull bones and thus helps to protect the brain and form the face. In...