A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis

Abstract

ObjectiveThis 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte–macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF–IR).MethodsPatients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF–IR (1–2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments.ResultsAt week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF–IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28‐CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti‐TNF–IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients. No deaths were reported, and no specific safety signals were identified.ConclusionThe findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

“…GM‐CSF has been implicated in RA pathogenesis and considered as a potential therapeutic target because GM‐CSF is abundant in the synovial fluid of RA patients and associated with activation of synovial macrophages to produce high levels of IL‐6 and TNF‐α in severe inflammation . Several clinical trials using GM‐CSF inhibition therapy for RA patients have indeed succeeded in dampening chronic inflammation with considerably high efficacy …”

“…89,90 Several clinical trials using GM-CSF inhibition therapy for RA patients have indeed succeeded in dampening chronic inflammation with considerably high efficacy. [91][92][93][94] Our recent study with SKG mice has addressed which GM-CSF-producing cells are critical for arthritis development and how GM-CSF production is regulated in each population. Effector…”

A Systems Immunology Approach Identifies Cytokine-Induced STAT Signaling Pathways Critical to Rheumatoid Arthritis Disease Activity and Treatment Response

“…Several interesting differences in monocyte signaling were identified between RA and healthy controls. The observation that there is decreased responsiveness of monocytes to stimulation with GM-CSF, and the bimodal response in this cell population (Figure 3 and 4), are of particular interest given the initial success of anti-GM-CSF mavrilimumab in clinical trials of RA ( 31 ). GM-CSF is an inflammatory cytokine with strong activities cross myeloid cells populations, including DCs, macrophages, and monocytes.…”

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

“…A subsequent phase IIb trial (EARTH EXPLORER 1), demonstrated that mavrilimumab represented a rapid, effective and well‐tolerated potential treatment for RA patients who had previously failed treatment with conventional disease‐modifying anti‐rheumatic drugs (DMARDs), and even biologicals (anti‐cytokine therapies) targeting other inflammatory pathways , and this emphasized an important pathogenic role for the GM‐CSF axis in difficult‐to‐treat RA. Subsequently, results from the EARTH EXPLORER 2 trial confirmed that mavrilimumab was efficacious and well‐tolerated in RA patients who were inadequate responders to both conventional DMARDs and TNF‐inhibitors . Moreover, a subanalysis of the EARTH EXPLORER 2 trial, conducted to dissect whether mavrilimumab and golimumab (TNF inhibitor) in both conventional DMARDs and TNF‐inhibitor inadequate responder RA patients may differ in the modulation of peripheral biomarkers and pathophysiological pathways, showed that serum levels of CCL22 and CCL17 were suppressed selectively by mavrilimumab but not golimumab, while CXCL13 and ICAM1 levels were suppressed by golimumab but not mavrilimumab.…”