Background Mavrilimumab is a fully human monoclonal antibody targeting granulocyte-macrophage colony-stimulating factor receptor α (GM–CSFR-α). It is the first therapeutic to target this pathway in the treatment of rheumatoid arthritis (RA). A Phase IIb clinical trial (EARTH EXPLORER 1; NCT01706926)1 of patients with moderate to severe RA has demonstrated mavrilimumab to be an efficacious and well-tolerated treatment option for RA.
Objectives We assessed peripheral biomarkers and pathophysiologic pathways modulated by mavrilimumab in association with clinical response through GM–CSFR-α blockade in RA patients.
Methods In a 24-week, randomized controlled study, RA patients received subcutaneous mavrilimumab (30, 100, or 150 mg every other week [eow]) or placebo, both in combination with methotrexate. Serum concentrations of 19 RA-associated proteins, as well as 6 protease-derived protein fragments, from 326 RA patients were measured at baseline and at 5 time points post-administration. Affymetrix HGU133Plus2 arrays were used to measure gene expression changes in whole blood of RA patients receiving mavrilimumab 100 or 150 mg eow, or placebo.
Results Several proteins demonstrated significant down-regulation at Days 8, 15, 29, 85, and 169 after mavrilimumab 100 mg and/or 150 mg eow treatment, compared with placebo, including CRP, SAA, IL-6, macrophage-derived chemokine (CCL22), IL-2RA, MMP3, and VEGF (Mann-Whitney U test, p<0.05). Spearman's correlation analysis indicated significant associations between the suppression of 7 proteins and clinical response (DAS28–CRP reduction) at Day 169 following mavrilimumab administration (p<0.05). While the suppression of CCL22, MMP3, and IL-6 may reflect a direct effect of GM–CSFR blockade on the production of pro-inflammatory mediators by myeloid cells, IL-2RA down-regulation suggests an indirect suppressive effect of mavrilimumab on T-cell activation. Furthermore, mavrilimumab induced significant suppression of MMP-degraded type I collagen (C1M) and citrullinated vimentin (VICM), suggesting a beneficial effect of mavrilimumab on soft tissue damage and auto-antigen formation in RA. Both C1M and VICM down-regulation were more pronounced in ACR20 responders than non-responders at Day 169 (p<0.05). Consistent with serum proteomics results, whole blood gene expression analyses demonstrated suppression of 382 transcripts at Day 196 after mavrilimumab administration (FDR<0.05), which were enriched for macrophage activity in RA and IL-17/IL-22 signaling pathways based on Ingenuity Pathway Analysis. Transcript concentrations of 2 protein citrullination enzymes, MMP9 and MMP25, were down-regulated by mavrilimumab in ACR20 responders, which may be related to suppression of VICM after GM–CSFR blockade.
Conclusions Our analyses indicate that the sustained efficacy of mavrilimumab in RA may result from both direct effects on macrophages and indirect effects on T-cell activation after GM–CSFR blockade. Further, protein citrullination and extracellular matrix degradation were suppressed by mavrilimumab, suggesting tissue damage in RA may be alleviated by mavrilimumab therapy.
Burmester GR, et al. Arthritis Rheum 2014;22(11 Suppl):S1231–S1232.
Disclosure of Interest X. Guo Shareholder of: AstraZeneca, Employee of: MedImmune, D. Sinibaldi Shareholder of: AstraZeneca, Employee of: MedImmune, M. Kuziora Shareholder of: AstraZeneca, Employee of: MedImmune, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, P. Ryan Shareholder of: AstraZeneca, Employee of: MedImmune, A. Bay-Jensen Grant/research support from: MedImmune, M. Karsdal Grant/research support from: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, W. White Shareholder of: AstraZeneca, Employee of: MedImmune
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