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

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Síndrome da pessoa rígida: avaliação de 14 pacientes

Main objective: to describe the characteristics of patients with stiff person syndrome (SPS). Secundary: a) to evaluate clinical and laboratorial findings; b)to identify the best therapeutic responses; c) to identify prognostic factors. Methods: we reviewed medical records and included patients with diagnosis of SPS (January 1989 to May 2015) in Neuromuscular Diseases Section at the Federal University of São Paulo (Unifesp), which had at least: axial stiffness with or without limb involvement; episodic spasms superimposed on the underlying rigidity, precipitated by unexpected external stimuli (tactile stimuli, sudden noises, emotional upset) and absence of any other neurologic disease that could account for rigidity and spasms. This study was approved by the Committee for Ethic in Research of Unifesp and Free and Informed Consent was applied to contactable patients. Compiled data: demographic data; age at symptom onset; time to diagnosis; experts who evaluated the patient and respective diagnosis; examination findings; coexisting diseases, labor capacity.The spasms severity was evaluated based on at Penn scale and a level of disability diagnosis was assigned using the modified Rankin score (RS). Serological (GAD65 antibody), electrophysiological and neuraxial magnetic resonance (nMR) data at the time of initial evaluation were also assessed. Results: Fourteen patients (eight having Classic-SPS; four having Focal-SPS; and two having PLUS-SPS) were GAD65 antibody seropositive; 11 were female(3.6: 1); mean age at symptom onset: 42.57 years; time to diagnosis: on average 43.28 months (Classic-SPS: 46.75 months; Focal-SPS: 15.25 and PLUS-SPS: 85.5). Examination findings: facial hypomimia (28.57%); laryngeal spasms (28.6%); cognitive disorders (50%); increased patellar reflexes (71.43%); muscle stiffness, spasms superimposed on the underlying rigidity, co- contraction of agonist and antagonist muscles (100%); hyperlordosis (50%); impaired gait (100%); pain (78.6%); falls (64.3%); electromyography: involuntary continuous paraspinal motor unity activity (42.85%), co-contraction (28.57%); nMR changes: nodular changes in white matter?s brain (PLUS-SPS with ataxia, one case); accentuation of physiological lumbosacral curvature (two cases). Frequently coexisting diseases: autoimmune diseases: 64.3% (type I diabetes mellitus in 50% and autoimmune thyroid disease in 28.6%) and psychiatric disorders (78.6%). Pharmacologic treatment and the best outcomes: symptomatic benefits: were reported in patients (57,14%) treated with diazepam and baclofen (improvement of RS and subjective symptoms); immunotherapy: nine patients (90%) improved after combination of intravenous immune globulin (IVig) and symptomatic drugs (improvement of RS and subjective symptoms), one patient had improved RS after combination of Ivig and intravenous cyclophosphamide. Conclusion: the study emphasized clinical and laboratory data and has demonstrated the insidious and debilitating clinical evolution ofthis rare syndrome. Patients diagnosed and treated early had better outcomes (reduction of subjective symptoms of muscle stiffness, pain, spasms, andreduction of objective symptoms evaluated by RS). Patients who used diazepam, baclofen and IVig in high doses for longer than six months had betterresponses on motor symptoms.Objetivo principal: descrever pacientes com síndrome da pessoa rígida (SPR). Secundários: a) avaliar características clínicas, laboratoriais e evolução clínica b) identificar e descrever as respostas aos tratamentos sintomáticos e imunomoduladores nos pacientes com SPR. Métodos: incluídos no estudo pacientes com SPR, avaliados entre janeiro de 1989 a maio de 2015 no Setor de Doenças Neuromusculares da Universidade Federal de São Paulo (Unifesp), que apresentaram ao menos três achados: rigidez na musculatura axial, acometendo ou não membro(s) ou rigidez em membro(s); espasmos musculares sobrepostos a rigidez, espontâneos ou desencadeados por estímulos (táteis, sonoros, stress psíquico); ausência de outra doença neurológica que justificasse rigidez e espasmos. Método utilizado: revisão de prontuários. O Comitê de Ética em Pesquisa da Unifesp aprovou o estudo e o termo de consentimento livre e esclarecido foi aplicado aos pacientes contactáveis. Dados compilados: demográficos; idade ao início dos sintomas; tempo diagnóstico; especialistas que avaliaram o paciente e hipóteses diagnósticas; sintomas; alterações neurológicas; enfermidades concomitantes, capacidade laboral. A severidade dos espasmos foi baseada na escala de Penn e a quantificação dos níveis de incapacidade/deficiência foi obtida pelo escore de Rankin (ER). Dosagem sérica de anticorpo anti GAD-65, resultados eletroneuromiográficos e de ressonância magnética contrastada de neuroeixo (RMcn) e tratamentos também foram avaliados. Resultados: quatorze pacientes foram incluídos no estudo, subtipos identificados: SPR-Clássica (oito casos), SPR-Focal (quatro) e SPR-PLUS (dois); dez pacientes eram brancos, três pardos e um negro; gênero mais frequente: feminino (3,6:1); média de idade ao início dos sintomas: 42,57 anos; tempo médio diagnóstico:43,28 meses (SPR-Clássica: 46,75 meses; SPR-Focal: 15,25 e SPR-PLUS:85,5). Alterações clínicas (com o decorrer do tempo) e laboratoriais nos três subtipos: hipomimia facial (28,57%); espasmos laríngeos (28,6%); alterações cognitivas (50%); reflexos patelares aumentados (71,43%); rigidez muscular, espasmos sobrepostos a rigidez, contração simultânea em grupamentos musculares agonistas e antagonistas (100%); hiperlordose (50%); marcha alterada (100%); dor (78,6%); quedas (64,3%) Ac anti-GAD65 positivo (100%); eletroneuromiografia: atividade de unidade motora involuntária e contínua (42,85%), cocontraturas (28,57%); alterações em RMnc: um caso com alterações nodulares de substância branca encefálica (SPR-PLUS com ataxia); dois casos com acentuação da curvatura lombossacra fisiológica. Enfermidades concomitantes mais frequentes: doenças autoimunes em 64,3% (DMI-50% dos casos e doenças tireoidianas (28,6%) e transtornos psiquiátricos (78,6%). Medicações para alívio de sintomas com melhores resultados: diazepam e baclofeno (57,14%) com melhora do ER e sintomas subjetivos. Imunoterapia com melhores resultados: imunoglobulina humana endovenosa (IH-EV) em dez casos, com redução de sintomas e ER em nove. Um paciente usou IH-EV e ciclofosfamida, reduzindo ER. Conclusão: o estudo enfatizou dados descritivos clínicos e laboratoriais da SPR e permitiu observar a evolução clínica insidiosa e debilitante dessa rara síndrome. Pacientes diagnosticados e tratados precocemente tiveram melhores prognósticos (redução dos sintomas subjetivos de rigidez muscular, dor, crises de espasmos e redução de sintomas objetivos avaliados com ER). As melhores respostas terapêuticas foram concernentes aos sintomas motores da síndrome, nos pacientes que fizeram uso de: diazepam, baclofeno e IH-EV em altas doses em períodos superiores a seis meses.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population

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

Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study

Introduction/Aims Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti‐acetylcholine receptor antibody‐positive (AChR+) gMG previously treated with rituximab. Methods This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open‐label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous‐rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no‐previous‐rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous‐rituximab and no‐previous‐rituximab groups (least‐squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least‐squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post‐intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously

Correction to: Eculizumab improves fatigue in refractory generalized myasthenia gravis (Quality of Life Research, (2019), 28, 8, (2247-2254), 10.1007/s11136-019-02148-2)

The article “Eculizumab improves fatigue in refractory generalized myasthenia gravis”, written by “Henning Andersen, Renato Mantegazza, Jing Jing Wang, Fanny O’Brien, Kaushik Patra, James F. Howard Jr. and The REGAIN Study Group” was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 23 March 2019 without open access

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals