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

OBJECTIVE: Generalized 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). METHODS: We 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. RESULTS: The 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. INTERPRETATION: The 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.

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension.

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Concomitant Immunosuppressive Therapy Use in Eculizumab-Treated Adults With Generalized Myasthenia Gravis During the REGAIN Open-Label Extension Study.

Introduction: Chronic, broad-spectrum immunosuppressive therapy (IST) can be associated with side effects in many people with generalized myasthenia gravis (gMG), and treatment guidelines recommend that the IST dose be tapered once patients achieve a stable treatment response. We therefore examined IST use in eculizumab-treated patients with refractory gMG. Methods: The REGAIN open-label extension (OLE) enrolled 117 adults with refractory anti-acetylcholine receptor antibody-positive gMG who had completed the 6-month, randomized, double-blind, placebo-controlled REGAIN study of eculizumab. Eligible patients had received ≥2 ISTs for ≥1 year or ≥1 IST with intravenous immunoglobulin or plasma exchange ≥4 times in 1 year, without symptom control. During REGAIN, changes in concomitant MG therapies were not permitted; during the OLE, they were permitted at the investigators' discretion. Participants received eculizumab 1,200 mg every 2 weeks for up to 4 years; concomitant prednisone and related corticosteroids (PRED), azathioprine (AZA), and mycophenolate mofetil (MMF) use was recorded. Changes in MG Activities of Daily Living and Quantitative MG total scores, MG exacerbations, and adverse events were also recorded. Results: At last OLE assessment, 88.0% (103/117) of participants were using ≥1 IST vs. 98.3% (115/117) at OLE baseline. During the OLE, 76.9% (90/117) of patients experienced a total of 719 IST changes. Almost half of participants [48.7% (57/117)] stopped or decreased ≥1 IST owing to MG symptom improvement, representing 38.9% (280/719) of all changes. In patients who decreased and/or stopped ≥1 IST, mean daily doses of PRED, AZA, and MMF decreased between OLE baseline and last assessment by 60.8% [standard deviation (SD), 28.07; P < 0.0001], 89.1% (SD, 25.77; P < 0.0001), and 56.0% (SD, 32.99; P < 0.0001), respectively. Improved clinical outcomes were observed with eculizumab regardless of IST changes during the OLE, and eculizumab's safety profile was similar in patients who used PRED, AZA, and MMF. Conclusions: Use of ISTs by patients with previously refractory gMG decreased during eculizumab treatment in the REGAIN OLE. Clinical improvements with eculizumab were maintained by patients in all groups, including those who decreased and/or stopped concomitant ISTs. Trial registration: www.clinicaltrials.gov: NCT01997229, NCT02301624.

Consistent improvement with eculizumab across muscle groups in myasthenia gravis.

OBJECTIVE: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. METHODS: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. RESULTS: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. INTERPRETATION: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.

INTRODUCTION: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. METHODS: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. RESULTS: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). DISCUSSION: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.