Effects of GSK1070806 (anti-IL18 mAb) on biomarkers in synovial tissue and blood of patients with rheumatoid arthritis.

Although the introduction of novel therapies has greatly improved the outlook for patients with rheumatoid arthritis over the years, considerable unmet needs remain. This work will evaluate a potential new mode of action that could be used in early or established rheumatoid arthritis to halt the progression of disease. We will evaluate changes in inflammation observed in the synovial tissue (the membrane around the joint, target of inflammation in arthritis) induced by GSK1070806, a new drug targeting a messenger of inflammation present in the joint. 13 patients will be recruited across 3 centers. Our exploratory objectives will study changes in synovial inflammation evaluated by a range of cutting edge methodologies. Safety and tolerance will also be assessed.

Although the introduction of novel oral and biological therapies has greatly improved the outlook for patients with RA there remains considerable unmet need. The current proposal will evaluate a potential new mode of action that could potentially be used in early or established RA to halt the progression of disease. This proposal is to evaluate changes in synovial inflammation induced by GSK1070806 in subjects with active RA using an open label clinical proof of concept trial. 13 patients with RA according to ACR/EULAR classification criteria with active RA defined by DAS28>3.2 and inadequate responders to at least one bDMARD or tsDMARD (excluding Rituximab) and on a stable dose of csDMARD for at least 6 weeks and off previous biologic for at least 2 half-lives; and at least one joint amenable to synovial biopsy; will be recruited across 3 centers.Our exploratory objectives will comprise a strong experimental focus to study changes in synovial inflammation evaluated by a range of methodologies, as follows: (i) single cell RNA expression analysis of synovial biopsies obtained prior to and after administration of drug. Thereby we will estimate the dependency on IL18 of a variety of cell subsets (myeloid, stromal, lymphocytes) and their molecular signatures. Pending these data we will also apply spatial transcriptomics to determine gene expression and molecular signatures as an exploratory approach to tissue analysis after biologic intervention; (ii) changes in serum biomarkers including inflammatory/anti-inflammatory cytokines through Olink proteomics +/- bone resorption/formation biomarkers and (iii) changes in monocytes expression profile and osteoclastogenesis. Safety and tolerance will also be assessed.