Long-term efficacy of eculizumab in refractory generalized myasthenia gravis: responder analyses.

James F Howard,Fanny L O'Brien,Tahseen Mozaffar,Chafic Karam,Marcus Yountz

doi:10.1002/acn3.51376

Abstract

ObjectiveGeneralized myasthenia gravis (gMG) is an autoimmune disease that causes disabling weakness via damage to the neuromuscular junction. In most patients, the disease is mediated by autoantibodies to the acetylcholine receptor, which activate the complement cascade. Our objective was to analyze response profiles in adult patients with anti‐acetylcholine receptor antibody‐positive refractory gMG treated with eculizumab—a terminal complement inhibitor—in the REGAIN study or its open‐label extension (OLE).MethodsWe retrospectively analyzed Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) scores recorded during REGAIN and its OLE. Early/late responses were defined as improvement in MG‐ADL score (≥3 points) or QMG score (≥5 points) at ≤12 or >12 weeks, respectively, after eculizumab initiation.ResultsThe analysis included 98 patients. By Week 12 and conclusion of the OLE, MG‐ADL response had been achieved at some point by 67.3% and 84.7% of patients, respectively, and QMG response by 56.1% and 71.4%, respectively. Response was observed over multiple consecutive assessments for most patients. At Week 130, the least‐squares mean percentage changes (95% CI) from baseline in MG‐ADL score were −61.9% (−69.9%, −53.9%) and −47.5% (−59.0%, −36.0%) in early and late MG‐ADL responders, respectively; the least‐squares mean percentage changes from baseline in QMG score were −40.8% (−48.3%, −33.4%) and −55.5% (−68.4%, −42.7%) in early and late QMG responders, respectively.InterpretationThe findings suggest that, although most patients with refractory gMG will achieve clinical response by Week 12 of eculizumab treatment, first responses can be observed with longer‐term treatment.

Highlights

Generalized myasthenia gravis is a prototypical autoimmune disease resulting from antibody-mediated damage of the neuromuscular junction.[1,2] The majority (~85%) of patients with the disease have antibodies against the acetylcholine receptor (AChR),[3] which cause pathogenic effects at the postsynaptic membrane of the neuromuscular junction via several processes, primarily complement-mediated membrane damage.[4,5,6,7,8,9,10]Treatments for gMG include acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressive therapies (ISTs)
By Week 12 of eculizumab treatment, an Myasthenia Gravis-Activities of Daily Living (MG-ADL) response had been achieved at some point by 66 patients (67.3%) (MG-ADL early responders); a further 17 (17.3%) achieved an MG-ADL response between Week 12 and the end of the open-label extension (OLE) (MG-ADL late responders); and 15 (15.3%) did not achieve the defined MG-ADL response during eculizumab treatment (MG-ADL nonresponders; Table 1)
With regard to Quantitative Myasthenia Gravis (QMG), by Week 12, a response had been achieved at some point by 55 patients (56.1%) (QMG early responders); a further 15 patients (15.3%) had achieved a QMG response between Week 12 and the end of the OLE (QMG late responders); and 28 (28.6%) did not achieve the defined QMG response during eculizumab treatment (QMG nonresponders; Table 2)

Summary

Introduction

Generalized myasthenia gravis (gMG) is a prototypical autoimmune disease resulting from antibody-mediated damage of the neuromuscular junction.[1,2] The majority (~85%) of patients with the disease have antibodies against the acetylcholine receptor (AChR),[3] which cause pathogenic effects at the postsynaptic membrane of the neuromuscular junction via several processes, primarily complement-mediated membrane damage.[4,5,6,7,8,9,10]. Treatments for gMG include acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressive therapies (ISTs). 10–15% of patients do not respond adequately or are unable to tolerate ISTs, and are considered treatment refractory.[11,12] Patients who are treatment refractory continue to have debilitating symptoms and persistent morbidities, and experience frequent exacerbations, hospitalizations, and myasthenic crises that can be life-threatening.[11,13].

Methods

Results

Conclusion