Background/Purpose: Treatment of rheumatoid arthritis (RA) patients by anti-tumour necrosis factors (anti-TNFs), such as golimumab, has improved patient outcomes. However, unmet therapeutic needs exist for a substantial proportion of patients. Mavrilimumab is a fully human monoclonal antibody which inhibits the granulocyte-macrophage colony-stimulating factor receptor α (GM–CSFR-α). Recently, a Phase IIb clinical trial has been completed to evaluate the efficacy and safety of mavrilimumab and golimumab in both disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) and anti-tumor necrosis factor-inadequate responders (anti-TNF-IR) patients (EARTH EXPLORER 2, NCT01715896). Our current study aims to assess peripheral biomarkers and pathophysiological pathways modulated by mavrilimumab and golimumab in RA patients.

Methods: The Phase IIb trial enrolled patients with active RA (28-joint Disease Activity Score [DAS28]-C-reactive protein/erythrocyte sedimentation rate ≥3.2), ≥4 swollen joints, and inadequate response to ≥1 DMARDs and/or 1-2 anti-TNFs. Patients were randomized (1:1) to receive subcutaneous mavrilimumab 100 mg (n=70) every other week (Q2W) or golimumab 50 mg (n=68) Q2W alternating with placebo, in combination with methotrexate (7.5-25.0 mg/week) for 24 weeks. Serum levels of 18 RA-associated proteins and 3 protease-derived protein fragments were measured in 71 DMARD-IR and 61 anti-TNF-IR patients at baseline and 4 time points post-administration. Transcriptome sequencing was used to measure gene expression changes in whole blood of RA patients at baseline and day 169 post-administration.

Results: Serum levels of CCL22 (MDC) and CCL17 (TARC) were suppressed by mavrilimumab but not golimumab, while CXCL13 and ICAM1 were suppressed by golimumab but not mavrilimumab. Those four proteins may be specific pharmacodynamic markers for the two biologics respectively. Both mavrilimumab and golimumab induced early and sustained suppression of multiple protein markers in DMARD-IR patients, including CRP, SAA, MMP1, MMP3, IL6, VEGF, IL2R, and CD163. However, golimumab-induced early changes rapidly returned towards baseline levels in anti-TNF-IR patients, while mavrilimumab-induced changes were maintained through day 169. Similarly, mavrilimumab administration was associated with durable suppression of extracellular matrix markers, C1M, C3M, and P4NP7S whilst golimumab only induced a transient change of the three markers in anti-TNF-IR patients. Furthermore, RNA sequencing results demonstrated significant regulation of 1547 transcripts at day 169 after mavrilimumab administration while golimumab had no impact on gene expression in anti-TNF-IR patients. In contrast, significant changes of 1042 and 2058 transcripts were observed in DMARD-IR patients at day 169 post-treatment of mavrilimumab and golimumab respectively.

Conclusion: Our study demonstrated a sustained differential suppression of peripheral disease markers by mavrilimumab but not golimumab in anti-TNF-IR patients, suggesting the potential of greater long-term disease control by mavrilimumab than golimumab in this population of RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sustained-suppression-of-peripheral-biomarkers-by-mavrilimumab-but-not-golimumab-in-anti-tumor-necrosis-factor-inadequate-responders-an-exploratory-analysis-in-the-phase-iib-earth-explorer-2-clinical/