See editorial on pages 7–9 in this issue. LONG-TERM SAFETY AND EFFICACY OF ECULIZUMAB IN GENERALIZED MYASTHENIA GRAVIS SRIKANTH MUPPIDI, MD,1 KIMIAKI UTSUGISAWA, MD, PhD,2 MICHAEL BENATAR, MD, PhD,3 HIROYUKI MURAI, MD, PhD,4 RICHARD J. BAROHN, MD,5 ISABEL ILLA, MD, PhD,6,7 SAIJU JACOB, MD, DPhil,8 JOHN VISSING, MD, DMSci,9 TED M. BURNS, MD,10 JOHN T. KISSEL, MD,11 RICHARD J. NOWAK, MD,12 HENNING ANDERSEN, MD, DMSci, PhD,13 CARLOS CASASNOVAS, MD, PhD,7,14 JAN L. DE BLEECKER, MD, PhD,15 TUAN H. VU, MD,16 RENATO MANTEGAZZA, MD,17 FANNY L. O’BRIEN, PhD,18 JING JING WANG, MD,18 KENJI P. FUJITA, MD,18 JAMES F. HOWARD Jr MD ,19 and for the REGAIN STUDY GROUP 1 Department of Neurology and Neurosciences, Stanford University School of Medicine, Stanford, California, USA 2 Department of Neurology, Hanamaki General Hospital, Hanamaki, Japan 3 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA 4 Department of Neurology, International University of Health and Welfare, Narita, Japan 5 Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA 6 Neurology Department, Hospital Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 7 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain 8 Queen Elizabeth Neuroscience Centre and Wellcome Trust Clinical Research Facility, University Hospital Birmingham, Birmingham, United Kingdom 9 Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 10 Department of Neurology, University of Virginia Health System, Charlottesville, Virginia, USA 11 Department of Neurology, The Ohio State University, Columbus, Ohio, USA 12 Department of Neurology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 13 Department of Neurology, Aarhus University Hospital, Aarhus, Denmark 14 Department of Neurology, Bellvitge University Hospital, Barcelona, Spain 15 Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium 16 Department of Neurology, University of South Florida, Tampa, Florida, USA 17 Foundation of the Carlo Besta Neurological Institute, IRCSS, Milan, Italy 18 Alexion Pharmaceuticals, Boston, Massachusetts, USA 19 Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA Accepted 10 February 2019 Additional supporting information may be found in the online version of this article. Abbreviations: AChR+, antiacetylcholine receptor antibody-positive; aHUS, atypical hemolytic uremic syndrome; CI, confidence interval; gMG, generalized myasthenia gravis; IST, immunosuppressive therapy; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; MG-ADL, Myasthe- nia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite scale; MGFA, Myasthenia Gravis Foundation of America; MG-QOL15, Myasthenia Gravis Quality of Life 15; PNH, paroxysmal nocturnal hemoglobinuria; QMG, Quantitative Myasthenia Gravis scale Key words: eculizumab; MG-ADL; MGC; MG-QOL15; myasthenia gravis; QMG Funding: This work was funded by Alexion Pharmaceuticals Conflicts of Interest: S. Muppidi has served as a paid consultant for Alnylam Pharmaceuticals and Alexion Pharmaceuticals. K. Utsugisawa has served as a paid consultant for Alexion Pharmaceuticals. M. Benatar has received support from Eli Lilly and Company and has served as a paid consultant for Alnylam Pharmaceuticals, Ra Pharmaceuticals, Voyager Therapeutics, UCB Pharma, Denali Therapeutics, Mitsubishi Tanabe Pharma, Biogen, and Avexis and as a site investigator for Alexion Pharmaceuticals, Cytokinetics, Neuraltus Pharmaceuticals, and Orphazyme. H. Murai has served as a paid consul- tant for Alexion Pharmaceuticals and has received speaker honoraria from Japan Blood Products Organization. R. J. Barohn has served as a consultant for NuFactor and Momenta Pharmaceuticals and receives research support from PTC Therapeutics, Ra Pharma, Orphazyme, and Sanofi Genzyme. I. Illa has served as a paid consultant for Alexion Pharmaceuticals and UCB Pharma. S. Jacob has served as a paid consultant for Alnylam Pharmaceuticals and Alexion Pharmaceuticals. J. Vissing has received support from and/or served as a paid consultant for Sanofi/Genzyme and Santhera Pharmaceuticals and has served as a paid consultant for Sarepta Therapeutics, Audentes Therapeutics, NOVO Nordisk, Alexion Pharmaceuticals, and Stealth Biotherapeu- tics. T. M. Burns has served as a paid consultant for Argenx and CSL Behring. J. T. Kissel has received support from Alexion Pharmaceuticals, aTyr Pharma, Cytokinetics Novartis, Sanofi Genzyme, BioMarin, Ionis Pharmaceuticals, and AveXis. R. J. Nowak has received support from Alexion Pharma- ceuticals, Genentech, Grifols, and Ra Pharmaceuticals and has served as a paid consultant for Alexion Pharmaceuticals, Momenta, Ra Pharmaceuticals, Shire, and Grifols. H. Andersen has received research and travel support and speaker honoraria and has served as consultant for Octapharma, CSL Beh- ring, NMD Pharma, Pfizer, Eisai, Sanofi Genzyme and UCB Pharma. C. Casasnovas has served as a paid consultant for Alexion Pharmaceuticals, Pharma- next, and CSL Behring. J. L. De Bleecker has served on the scientific advisory boards of Sanofi Genzyme and Pfizer and has received travel funding/speaker honoraria from Sanofi Genzyme and limited research funding from CSL Behring and CAF Belgium. T. H. Vu serves as a site principal investigator and on speaker bureaus for Alexion Pharmaceuticals, on speaker bureaus for CSL Behring, Allergan, and MT Pharma, and is the site principal investigator for clinical trials sponsored by Ra Pharmaceuticals, Argenx, and UCB Pharmaceuticals. R. Mantegazza has received support from Sanofi Genzyme, Teva Pharmaceutical Industries, Bayer and BioMarin and has served as a paid consultant for BioMarin, Alexion Pharmaceuticals, and Argenx BVBA. F. L. O’Brien and K. P. Fujita are employees of and own stock in Alexion Pharmaceuticals. J. J. Wang is a former employee of and owns stock in Alexion Pharmaceuticals. J. F. Howard Jr reports research support from Alexion Pharmaceuticals; grants from Alexion Pharmaceuticals and UCB Pharma; honoraria from Alexion Pharmaceuticals; and nonfinancial support from Alexion Pharmaceuticals, Argenx, Ra Pharmaceuticals, and Toleranzia. Correspondence to: S. Muppidi, Department of Neurology and Neurological Sciences, Stanford Neuroscience Health Center, Palo Alto, California 94304; e-mail: muppidis@stanford.edu © 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc. Published online 14 February 2019 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.26447 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and repro- duction in any medium, provided the original work is properly cited and is not used for commercial purposes. 14 Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 ABSTRACT: Introduction: Eculizumab is effective and well tolerated antibody-positive (AChR+) refractory gMG.14 Eculizumab in patients with antiacetylcholine receptor antibody-positive refractory is approved for the treatment of adults with AChR+ generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, gMG, in addition to paroxysmal nocturnal hemoglo- evaluating eculizumab’s long-term safety and efficacy. Methods: binuria (PNH) and atypical hemolytic uremic syn- Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) drome (aHUS). was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningo- The open-label extension study of the phase coccal infection were reported during the interim analysis period. 3 REGAIN (NCT02301624) was designed to evaluate Myasthenia gravis exacerbation rate was reduced by 75% from the long-term safety and efficacy of eculizumab in the year before REGAIN (P < 0.0001). Improvements with eculi- zumab in activities of daily living, muscle strength, functional abil- patients with AChR+ refractory gMG. Here we report ity, and quality of life in REGAIN were maintained through data from a preplanned interim analysis that was 3 years; 56% of patients achieved minimal manifestations or based on a median duration of almost 2 years of ecu- pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements lizumab treatment. during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained MATERIALS AND METHODS efficacy of eculizumab for refractory gMG. Muscle Nerve 60: 14–24, 2019 Study Design and Participants. Participants who com- pleted the 6-month, double-blind REGAIN study could enter this extension study. Full inclusion and exclusion criteria for Generalized myasthenia gravis (gMG) is a chronic, the REGAIN study have been published previously.14 In brief, rare autoimmune disorder that is characterized by adults (aged ≥18 years) with the following were eligible for severe muscle weakness.1 Autoantibodies to the acetyl- REGAIN: confirmed gMG with positive serology for acetylcho- choline receptor are present in 73%–88% of patients line receptor antibodies, an MG Activities of Daily Living (MG- with gMG.2–7 These autoantibodies initiate accelerated ADL) total score of 6 or higher, and failed treatment with 2 or endocytosis and degradation of acetylcholine receptors more ISTs or at least 1 IST with requirement for chronic IVIg or plasma exchange therapy over the preceding 12 months. and complement-mediated destruction of the neuro- Patients were excluded if they had a history of thymoma or muscular junction, resulting in further reductions in other thymic neoplasm, had undergone thymectomy in the acetylcholine and sodium channel receptors.1,8–13 The 12 months before screening, experienced ocular-only MG complement-mediated pathological membrane changes symptoms (Myasthenia Gravis Foundation of America [MGFA] reduce the efficiency of neurotransmission at the neuro- class I) or myasthenic crisis (MGFA class V) at screening, or muscular junction, resulting in the characteristic muscle required treatment with IVIg or plasma exchange within the 4 weeks before randomization.14 weakness and fatigability that are observed in patients Eligible patients who elected to continue into the open-label with MG.1,14 extension were required to enter it within 2 weeks of complet- Some patients (10%–15%) with MG do not respond ing REGAIN. The first patient was enrolled on November adequately to long-term treatment with corticosteroids 12, 2014, and the last patient was enrolled on March 4, 2016. or multiple steroid-sparing immunosuppressive thera- Participants received open-label eculizumab until it was other- pies (IST), experience intolerable side effects, or require wise available to them, up to a maximum of 4 years in the exten- sion study. The study was completed in January 2019. ongoing treatment with intravenous immunoglobulin All patients provided written, informed consent. Written (IVIg) or plasma exchange.1,15–18 Persistent myasthenic approval for the study protocol and all study amendments was symptoms14–16,18,19 can adversely affect activities of daily obtained from independent ethics committees or institutional living, including breathing, talking, swallowing, walking, review boards at all participating sites. All human studies were and functional muscle strength as well as quality of life.15 approved by the appropriate ethics committee and have been Patients also have increased risks of myasthenic exacer- performed in accordance with the ethical standard laid down bations and crises; an increased requirement for rescue in the 1964 Declaration of Helsinki. therapies; and more frequent inpatient hospitalizations, intensive care unit admissions, and emergency room Dosing and Administration. Patients who received eculi- visits.20,21 zumab in REGAIN continued to receive eculizumab during the open-label study (eculizumab/eculizumab group). Those Eculizumab is a humanized monoclonal antibody that who received placebo in REGAIN started eculizumab treat- specifically binds with high affinity to human terminal ment when they entered the open-label study (placebo/eculi- complement protein C5. This inhibits enzymatic cleav- zumab group). age of C5 to C5a and C5b, thereby preventing C5a- To preserve the blinded nature of REGAIN, patients who induced chemotaxis of proinflammatory cells and entered the open-label study first underwent a 4-week blinded formation of the C5b-induced membrane attack com- induction phase during which investigators, patients, and study plex.22 Eculizumab was shown to have efficacy and was personnel remained blinded to all treatment assignments (Fig. 1). During this phase, patients who had been assigned to well tolerated in the 6-month randomized, double-blind, eculizumab in REGAIN received eculizumab 1,200 mg (4 vials) placebo-controlled REGAIN study (NCT01997229), pro- on day 1 and week 2 and placebo (4 vials) at weeks 1 and ducing clinically meaningful improvements in activities 3. Patients who had been assigned to placebo in REGAIN of daily living, muscle strength, functional ability and received eculizumab (900 mg, 3 vials) and placebo (one vial) quality of life in patients with antiacetylcholine receptor on day 1 and at weeks 1, 2, and 3 (Fig. 1). In the open-label Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 15 REGAIN Open-label study* Eculizumab (n = 62) Randomization Eculizumab/eculizumab 900 mg weekly × 4 then Blinded (n = 56) Safety Screening 1200 mg every 2 weeks induction follow-up 2–4 weeks phase: at 4 weeks 8 weeks‡ Placebo Placebo/eculizumab (n = 63) (n = 61) SOC Study period: 26 weeks Study drug Eculizumab infusion every 2 weeks meningococcal infusion† (1200 mg) vaccination Year 1 Year 2 Year 3 Year 4 Day 1 Week 1 Week 2 Week 3 Week 4 Week 208 FIGURE 1. Study design. *Interim data are reported from the December 31, 2017 data cutoff point. †During the blinded induction phase of the open-label study, patients received eculizumab (1,200 mg; 4 vials) at day 1 and week 2 and received placebo (4 vials) at weeks 1 and 3 (eculizumab/eculizumab group) or placebo (1 vial) plus eculizumab (900 mg; 3 vials) each week (placebo/eculizumab group). ‡ Patients who withdrew or discontinued after receiving any amount of eculizumab were required to complete a safety follow-up visit 8 weeks after their last eculizumab dose. SOC, standard of care. maintenance phase, which started at week 4, all patients ability, and quality of life over time using 4 MG-specific disease received open-label eculizumab (1,200 mg) every 2 weeks. measures (data cutoff December 31, 2017). The primary objective of this open-label study was to evalu- Procedures. To mitigate the increased risk of meningo- ate the long-term safety of eculizumab. Safety was assessed by coccal infection associated with terminal inhibition of the incidences of adverse events, serious adverse events, study dis- complement system,23 all patients in REGAIN were required continuations due to adverse events, exacerbations, hospital to receive Neisseria meningitidis vaccination according to local admissions, and rescue therapy administrations. Adverse guidelines at least 2 weeks before starting blinded study treat- events were coded by preferred term by using the Medical Dic- ment; if they were not vaccinated at the appropriate time, tionary for Regulatory Activities Version 20.1. The number of patients received prophylactic antibiotics until 2 weeks after patients who experienced an adverse event of special interest vaccination. In the open-label study, patients were revacci- (meningococcal infections, aspergillus infections, sepsis, any nated according to local guidelines, which recommend revac- serious infections, infusion-related reactions, serious cutane- cinating patients after 2–5 years to maintain active coverage. ous reactions, cardiac disorders, or angioedema) during each Patients who entered the open-label study were on a stable 3-month study period was determined. For this study, a clinical regimen of concomitant MG therapies, including ISTs that deterioration/exacerbation was defined as 1 of the following: could include but were not limited to corticosteroids, azathio- MG crisis, substantial symptomatic worsening (to a score of prine, mycophenolate mofetil, methotrexate, cyclosporine, 3 or a 2-point worsening on any 1 of the individual MG-ADL tacrolimus, and cyclophosphamide. Adjustment of concomi- items, excluding ocular items), or health in jeopardy if rescue tant MG therapies, including ISTs, was permitted at the discre- therapy was not given, as determined by the treating physi- tion of the study investigator but was not required by the study cian. The exacerbation and hospitalization event rates were protocol. Rescue therapy (e.g., high-dose intravenous cortico- compared with rates during the year before entering REGAIN steroids, IVIg, or plasma exchange) was available at the discre- (collected at REGAIN baseline assessment); the rescue ther- tion of the study investigator for patients who experienced apy event rate was compared with the rate in the placebo disease exacerbation. group during REGAIN. Validated MG assessments of activities of daily living, muscle The primary efficacy endpoint was change in mean MG-ADL strength, functional ability, and quality of life were used to total score from baseline over time. Changes from REGAIN and evaluate the long-term efficacy of eculizumab. These assess- open-label baselines were evaluated. Secondary efficacy end- ments consisted of the MG-ADL scale,24 the Quantitative MG points included changes from baseline in mean QMG, MGC, scale (QMG),25 the MG Composite scale (MGC),26 and the and MG-QOL15 total scores over time and the proportions of 15-item MG Quality of Life questionnaire (MG-QOL15).27 patients achieving clinically meaningful responses to eculizu- MG-ADL, QMG, MGC, and MG-QOL15 assessments were per- mab, prospectively defined as improvements from baseline of at formed on day 1. MG-ADL, QMG, and MGC assessments were least 3 points in MG-ADL total score or at least 5 points in QMG performed weekly from week 1 through week 3. MG-ADL, total score.28–30 Other efficacy endpoints included MGFA postin- QMG, MGC, and MG-QOL15 assessments were then per- terventional status, a disease-specific outcome measure that cap- formed at weeks 4, 8, 12, 16, 20, 26, 40, and 52 in year 1, every tures the physician’s global assessment of the patient’s clinical 6 months thereafter, and at each patient’s end of study visit. status after initiation of MG treatment.31 The same neurologist These same 4 efficacy measures were used in the REGAIN skilled in evaluating patients with MG assessed the MGFA postin- study.14 terventional status throughout the study (at weeks 26 and 40 and then every 26 weeks until end of study/early termina- Outcomes. We report an interim analysis of safety and effi- tion) according to the following categories relative to baseline: cacy data, including the occurrence of adverse events, and improved (a substantial decrease in clinical manifestations or in changes in activities of daily living, muscle strength, functional MG medications), unchanged (no substantial change in clinical 16 Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 manifestations or reduction in MG medications), or worse performed in SAS version 9.4 (SAS Institute, Cary, North Caro- (a substantial increase in clinical manifestations or MG medica- lina). This study did not have a data monitoring committee. tions).31 Patients who had improved were also evaluated for minimal manifestation and pharmacological remission status.31 RESULTS In this interim analysis, 117 of the 118 patients Statistical Analysis. Safety analyses were performed for who completed REGAIN enrolled in the open-label all patients who received at least 1 dose of eculizumab in the open-label study (safety set). Efficacy analyses were conducted study (eculizumab/eculizumab, 56; placebo/eculizu- by using the full analysis set, which comprised all patients who mab, 61) and were included in the safety analysis, received at least 1 dose of eculizumab in the open-label study and 116 patients were included in the efficacy analy- and had at least 1 postdose efficacy assessment. sis (eculizumab/eculizumab, 56; placebo/eculizumab, For exacerbations, hospitalizations, and rescue therapy use, 60); approval for the inclusion of 1 patient in the model-based event rates per 100 patient-years were calculated. interim efficacy analyses was not given by their national This was based on a generalized estimating equation Poisson health authority. regression repeated-measures model with the number of events as the dependent variable, the logarithm of patient-years as the At the time of data cutoff, study participation was ongo- offset variable, and the study phase indicator (prestudy, placebo, ing for 73% of patients. Five patients (eculizumab/eculi- or eculizumab) as the factor assuming a compound symmetry zumab, 2; placebo/eculizumab, 3) had completed the correlation structure. study. Among the 27 patients who discontinued the study, Two baselines were used for the efficacy analyses, REGAIN base- 6 patients discontinued because of 1 or more adverse line, defined as assessment at day 1 in the REGAIN study; and events, and 3 patients died. In addition, study investiga- open-label baseline, defined as the last available assessment tors withdrew 5 patients, 12 patients withdrew consent, before first eculizumab infusion (this was typically the day-1 and 1 patient discontinued for a reason described as assessment in the open-label study; when the day-1 data were “other” (Fig. 2) after a median period of eculizumab ther- missing, the most recent assessment from REGAIN was used as the open-label baseline). Changes from baseline in MG-ADL, apy of 379 days because of various factors including ongo- QMG, MGC, and MG-QOL15 total scores at a particular visit ing comorbidities, perceived lack of clinical benefit, and were based on repeated-measures models. Separate repeated- logistical problems with clinic attendance (Supp. Info. measures models were used for the eculizumab/eculizumab and Table 1). placebo/eculizumab groups because patients in the eculizumab/ Patient demographics for the study population were eculizumab group had already received 6 months of eculizumab in reported for REGAIN.14 Patient characteristics were simi- REGAIN. Assessing the change from the open-label baseline lar between the eculizumab/eculizumab and placebo/ allowed for evaluation of the eculizumab treatment effect in the eculizumab groups (Table 1). In total, 38 patients requir- placebo/eculizumab arm and the effect of continued, long-term treatment in the eculizumab/eculizumab arm. The change from ed revaccination against N meningitidis (eculizumab/ REGAIN baseline allowed for an assessment of all changes from eculizumab, 20; placebo/eculizumab, 18). time of entry to REGAIN. Missing efficacy endpoint assessments The median duration of eculizumab treatment for were not imputed. all 117 patients during the open-label study was The responder analyses measured the proportion of patients 22.7 months (range, 1 day to 37.3 months). Reported with clinically meaningful improvements from REGAIN baseline. data are based on 227 patient-years of open-label eculi- The proportions of patients experiencing this improvement with zumab exposure at the time of data cutoff. and without prior on-study rescue therapy were determined at each visit for both groups. Exact (Clopper–Pearson) 95% confi- The most common adverse events were headache dence intervals (CIs) for the true proportions are presented. and nasopharyngitis, which were experienced by 37.6% Data are presented as least-squares means (changes from and 31.6% of patients, respectively (Table 2). The most open-label baseline) and 95% CIs. All statistical analyses were common serious adverse event was MG worsening, Enrolled (N = 117) Eculizmab/eculizumab Assigned and received Assigned and received Placebo/eculizumab • Completed study (n = 2) eculizumab/eculizumab placebo/eculizumab (n = 56) (n = 61) • Completed study (n = 3) • Discontinued (n = 12) owing to: • Discontinued (n = 15) owing to: – Adverse event (n = 2) – Adverse event (n = 4) – Death (n = 2) – Death (n = 1) – Physician decision (n = 3) – Physician decision (n = 2) – Withdrawal by patient (n = 4) Continuing in study Continuing in study – Withdrawal by patient (n = 8) – Other (n = 1) (n = 42) (n = 43) FIGURE 2. Patient disposition through December 31, 2017. In total, 117 patients enrolled in the open-label study, of whom 56 had received eculizumab and 61 had received placebo during REGAIN. As of December 31, 2017, twenty-seven patients had discontinued, 5 patients had completed the study, and 85 patients were continuing in the study. Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 17 Table 1. Demographics and baseline characteristics of patients Table 2. Safety outcomes in all patients during the open-label entering the open-label study by treatment group (safety set) study Eculizumab/ Placebo/ All Patients eculizumab, eculizumab, patients, Events, experiencing an Events per Variable n = 56 n = 61 N = 117 Event n event, n (%) 100 PY* Mean age (SD), 47.2 (15.5) 47.5 (17.9) 47.4 (16.7) All adverse events 1,816 113 (96.6) 800.0 y* Most common adverse events†,‡, >10% of all patients, N = 117 Sex, n (%) Headache 71 44 (37.6) 31.3 Men 18 (32.1) 20 (32.8) 38 (32.5) Nasopharyngitis 76 37 (31.6) 33.5 Women 38 (67.9) 41 (67.2) 79 (67.5) Diarrhea 40 27 (23.1) 17.6 Race, n (%) Upper respiratory 55 27 (23.1) 24.2 Asian 3 (5.4) 16 (26.2) 19 (16.2) tract infection Black 0 (0.0) 2 (3.3) 2 (1.7) Myasthenia gravis§ 40 23 (19.7) 17.6 White 47 (83.9) 41 (67.2) 88 (75.2) Arthralgia 29 22 (18.8) 12.8 Multiple 1 (1.8) 0 (0.0) 1 (0.9) Nausea 26 21 (17.9) 11.5 Unknown 1 (1.8) 0 (0.0) 1 (0.9) Pain in extremity 21 18 (15.4) 9.3 Other 4 (7.1) 2 (3.3) 6 (5.1) Cough 21 17 (14.5) 9.3 MG duration, 10.7 (7.9) 9.8 (8.5) 10.2 (8.2) Fatigue 21 17 (14.5) 9.3 mean (SD), y† Urinary tract 32 17 (14.5) 14.1 infection MG, myasthenia gravis; SD, standard deviation. Influenza 24 16 (13.7) 10.6 *On day 1 of the open-label extension study. Gastroenteritis 15 14 (12.0) 6.6 † Bronchitis 22 13 (11.1) 9.7 Time from MG diagnosis to first dose date in the open-label extension study. Pyrexia 17 13 (11.1) 7.5 Fall 24 12 (10.3) 10.6 All serious adverse 147 52 (44.4) 64.8 which occurred in 12.8% of patients (Table 2). Three events Most common (≥2 patients) MG- and infection-related serious adverse patients experienced a serious adverse event of MG cri- events†,‡,k sis, which resulted in study discontinuation for 2 of Myasthenia gravis§ 28 15 (12.8) 12.3 them. Six patients withdrew from the study because of Death 3 3 (2.6) 1.3 Myasthenia gravis 3 3 (2.6) 1.3 a serious adverse event. All serious adverse events are crisis listed in Supporting Information Table 2. Pyrexia 3 3 (2.6) 1.3 At the time of this interim analysis, 3 deaths had Gastroenteritis 3 3 (2.6) 1.3 Pneumonia 3 3 (2.6) 1.3 occurred. The death of 1 patient who was concomitantly Sepsis 3 3 (2.6) 1.3 receiving azathioprine was attributed to hemophagocy- Bronchitis 3 2 (1.7) 1.3 tic lymphohistiocytosis associated with cytomegalovirus Influenza 2 2 (1.7) 0.9 Upper respiratory 2 2 (1.7) 0.9 infection of the liver resulting in multiple organ failure. tract infection The second death was attributed to end-stage liver dis- Urinary tract 3 2 (1.7) 1.3 ease in a patient with cryptogenic liver cirrhosis and a infection Aspiration 2 2 (1.7) 0.9 medical history of fatty liver, and the third death was pneumonia due to pulmonary embolism that occurred in a patient who was in the hospital recovering from cardiogenic MedDRA, Medical Dictionary for Regulatory Activities; MG, myasthenia gravis; PY, patient year. shock secondary to sepsis complicated by deep vein *Patient-years is the sum of all years for all patients and observed event thrombosis. rate is the number of events per PY multiplied by 100. † During the open-label study, 22 (18.8%) patients When a patient had more than 1 adverse event for a particular preferred experienced an infectious event of special interest, term, that patient was counted only once for that preferred term. ‡ MedDRA preferred term. including 5 cases of sepsis, septic shock, or pseudo- § Worsening (increased frequency and/or intensity) of a preexisting condi- monas sepsis and 1 case each of aspergillus, cytomeg- tion, including myasthenia gravis, is considered to be an adverse event. alovirus, and pseudomonas infection (Supp. Info. k Serious adverse events are adverse events that are life-threatening or Table 3). The proportion of patients experiencing result in death, hospitalization, or persistent or significant disability or incapacity, are congenital anomalies or birth defects, or are important these infections or other adverse events of special medical events. All serious adverse events in the open-label study are interest (infusion-related reactions, serious cutane- listed in Supporting Information Table 1. ous reactions [urticaria], and cardiac disorders) was in line with that observed during REGAIN. Similar In total, 59 MG exacerbations (including MG crises, proportions of patients in the eculizumab/eculizumab substantial symptomatic worsening, and health in jeop- and placebo/eculizumab groups experienced these ardy if rescue therapy was not given) were experienced adverse events, and rates did not change over time in by 29 patients during the open-label study before data the open-label study (Supp. Info. Table 4). There were cutoff. Compared with the year before REGAIN start, the no cases of meningococcal infection at the interim data exacerbation rate was reduced by 75.2% (prestudy, 102.4 cutoff date; 1 case, which was resolved with antibiotic exacerbations per 100 patient-years; open-label study, treatment, occurred after this date. 25.4 exacerbations per 100 patient-years; P < 0.0001; 18 Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 Fig. 3). The exacerbation rate was also significantly lower REGAIN (P = 0.0105; Fig. 3). The rate of MG-related than in the REGAIN placebo group (73.5 exacerbations hospitalizations was reduced by over 80% compared with per 100 patient-years; P = 0.0061). The rate of rescue the year before REGAIN start (prestudy, 81.3 hospitaliza- therapy use was 23.1 events per 100 patient-years in the tions per 100 patient-years; open-label study, 13.7 hospi- open-label study, compared with 67.5 events per talizations per 100 patient-years; P < 0.0001; Fig. 3). It 100 patient-years in patients receiving placebo during was also lower than in the REGAIN placebo group (48.4 p < 0.0001 hospitalizations per 100 patient-years; P = 0.0228; Fig. 3). A 120 Improvements that had been demonstrated for 75% reduction patients during 6 months of blinded eculizumab in 102.4 100 p = 0.0061 REGAIN were sustained during the open-label study (events per 100 patient-years) 65% reduction for a total maximum eculizumab treatment duration of Model-based event rate 80 73.5 3 years (eculizumab/eculizumab group; Fig. 4). The mean MG-ADL total score from open-label baseline did 60 not change significantly in this group at each assess- ment (−0.8 change from baseline to week 130 [n = 13]; P = 0.0990; Fig. 5A2). This sustained treatment effect 40 was also supported by similar findings with mean total 25.4 scores for QMG (0.1 change from baseline to week 20 136 events 27 events 59 events 130 [n = 13]; P = 0.8949; Fig. 5B2), MGC (−1.3 change 124.8 PY 31.1 PY 227.0 PY n = 125 n = 63 n = 117 from baseline to week 130 [n = 13]; P = 0.1531; 0 Fig. 5C2), and MG-QOL15 (−1.2 change from baseline Pre-study Placebo Eculizumab (1 year prior to (REGAIN)| (open-label study) to week 130 [n = 13]; P = 0.4756; Fig. 5D2). start of REGAIN)* Patients who had received placebo during REGAIN experienced a rapid and significant improvement when B 120 they commenced eculizumab at the start of the open- label extension (Fig. 5A1, B1, C1, D1). Improvements 100 from open-label baseline in mean MG-ADL total score as (events per 100 patient-years) p = 0.0105 well as QMG, MGC, and MG-QOL15 total scores were of Model-based event rate 80 similar magnitude to those experienced by eculizumab- 66% reduction 67.5 treated patients in REGAIN. The mean change from open-label baseline was statistically significant as early as 60 the first visit after eculizumab administration (assessed at week 1 for MG-ADL [−1.6 from baseline], QMG [−2.3 40 from baseline], and MGC [−3.0 from baseline] and at 23.1 week 4 for MG-QOL15 [−5.4 from baseline]; all 20 P < 0.0001; Fig. 5A1, B1, C1, D1), with over half of the 24 events 53 events 31.1 PY n = 63 227.0 PY n = 117 improvement occurring in the first 3 months. These 0 improvements were sustained over 30 months (mean Placebo Eculizumab change in MG-ADL total score from open-label baseline (REGAIN)| (open-label study) to month 30, −3.8; P < 0.0001; n = 15). C 120 At the last assessment for this interim analysis, 55.2% of patients in the open-label study demon- p < 0.0001 strated a clinically meaningful response in activities of 100 (events per 100 patient-years) 83% reduction daily living (at least a 3-point improvement from Model-based event rate 81.3 80 REGAIN baseline in MG-ADL total score without use p = 0.0228 72% reduction FIGURE 3. Treatment effects on event rates for all reported exacer- 60 48.4 bations (A), rescue therapy administration (exacerbation events requiring rescue therapy (B), and MG-related hospitalization (exac- 40 erbation events requiring rescue therapy (C). Model-based event rate per 100 patient-years is based on a generalized estimating equation Poisson regression repeated-measures model with the 20 13.7 number of events as the dependent variable, the logarithm of 107 events 18 events 31 events 124.8 PY 31.1 PY 227.0 PY patient-years as the offset variable, and the study phase indicator n = 125 n = 63 n = 117 (prestudy, placebo, or eculizumab) as the factors assuming a com- 0 Pre-study Placebo Eculizumab pound symmetry correlation structure. *Patient-year for prestudy (1 year prior to (REGAIN)| (open-label study) accounted for a maximum of 365 days for each patient prior to start of REGAIN)* screening. jChanges in event rates in this group reflect the response to placebo that was observed during REGAIN. PY, patient-year. Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 19 Eculizumab Double-blind Eculizumab/eculizumab Placebo Double-blind induction Placebo/eculizumab A Open-label eculizumab 0 mean MG-ADL total score (95% CI) Change from REGAIN baseline in –2 –4 –6 –8 BL 4 8 12 16 20 26 BL 4 8 12 16 20 26 40 52 78 104 130 Patients, n Weeks Eculizumab/eculizumab 53 53 52 49 49 49 47 25 13 Placebo/eculizumab 60 57 57 55 54 54 49 25 15 B 0 Change from REGAIN baseline in mean QMG total score (95% CI) –2 –4 –6 –8 –10 –12 BL 4 8 12 16 20 26 BL 4 8 12 16 20 26 40 52 78 104 130 Patients, n Weeks Eculizumab/eculizumab 52 52 52 48 48 48 46 23 13 Placebo/eculizumab 60 57 57 55 53 53 48 24 15 C 0 Change from REGAIN baseline in mean MGC total score (95% CI) –4 –8 –12 –16 BL 4 8 12 16 20 26 BL 4 8 12 16 20 26 40 52 78 104 130 Patients, n Weeks Eculizumab/eculizumab 52 53 51 49 49 49 47 25 13 Placebo/eculizumab 59 57 57 55 54 54 48 25 15 D 0 mean MG-QOL15 total score (95% CI) Change from REGAIN baseline in –4 –8 –12 –16 –20 –24 –28 BL 4 8 12 16 20 26 BL 4 8 12 16 20 26 40 52 78 104 130 Patients, n Weeks Eculizumab/eculizumab 53 52 52 47 49 49 46 26 13 Placebo/eculizumab 60 57 56 56 54 54 49 25 15 FIGURE 4. Change from REGAIN baseline to week 130 in the open-label extension study in MG-ADL (A), QMG (B), MGC (C), and MG- QOL15 (D) total scores (mean [95% CI]) by treatment arm over time (full analysis set). Patient numbers were not the same for each assessment. BL, baseline; CI, confidence interval; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Com- posite scale; MG-QOL15, Myasthenia Gravis Quality of Life 15; QMG, Quantitative Myasthenia Gravis scale. 20 Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 A1 A2 Double-blind induction Eculizumab/eculizumab baseline in LS mean MG-ADL 2 2 Open-label eculizumab Placebo/eculizumab Change from open-label 0 0 * * total score (95% CI) –2 –2 ‡ ‡ ‡ ‡ ‡ ‡ ‡‡ ‡ ‡ ‡ –4 –4 ‡ ‡ ‡ ‡ ‡ ‡ ‡ –6 –6 –8 –8 BL 1 2 3 4 BL 2 4 8 12 16 20 26 40 52 78 104 130 Weeks Patients, n Weeks Eculizumab/eculizumab 53 53 52 49 49 49 47 25 13 Placebo/eculizumab 60 57 57 55 54 54 49 25 15 B1 B2 2 2 baseline in LS mean QMG Change from open-label 0 0 * total score (95% CI) –2 –2 –4 ‡ ‡ ‡ –4 ‡‡ ‡ ‡ ‡ ‡‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ –6 –6 ‡ –8 –8 BL 1 2 3 4 BL 2 4 8 12 16 20 26 40 52 78 104 130 Weeks Patients, n Weeks Eculizumab/eculizumab 52 52 52 48 48 48 46 23 13 Placebo/eculizumab 60 57 57 55 53 53 48 24 15 C1 C2 2 2 baseline in LS mean MGC * † Change from open-label 0 0 * † total score (95% CI) –2 –2 –4 –4 ‡ ‡ ‡ –6 ‡ –6 ‡ ‡ ‡ ‡ ‡ ‡‡ ‡ ‡ ‡ ‡ –8 –8 ‡ ‡ ‡ –10 –10 BL 1 2 3 4 BL 2 4 8 12 16 20 26 40 52 78 104 130 Weeks Patients, n Weeks Eculizumab/eculizumab 52 53 51 49 49 49 47 25 13 Placebo/eculizumab 59 57 57 55 54 54 48 25 15 D1 D2 MG-QOL15 total score (95% CI) 4 4 Change from open-label † 0 0 baseline in LS mean –4 –4 –8 ‡ –8 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ –12 –12 ‡ –16 –16 BL 1 2 3 4 BL 2 4 8 12 16 20 26 40 52 78 104 130 Weeks Patients, n Weeks Eculizumab/eculizumab 53 52 52 47 49 49 46 26 13 Placebo/eculizumab 60 57 56 56 54 54 49 25 15 FIGURE 5. Legend on next page. Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 21 of rescue therapy). When analysis was performed The rapid response to eculizumab across multiple regardless of rescue therapy, 71.6% of patients experi- disease-specific measures in patients who had previ- enced this improvement. Over one-third (39.7%) of ously received placebo confirms the effect of eculizu- patients experienced a clinically meaningful response mab recorded in REGAIN and exceeded the response in muscle strength (at least a 5-point improvement to placebo that was observed during REGAIN. The from REGAIN baseline in QMG total score without maintenance of this effect in patients who received rescue therapy use), and 48.3% experienced this eculizumab for up to 3 years provides evidence of improvement regardless of rescue therapy use. its durability. The open-label study not only sup- At the final MGFA postinterventional status evalua- ports and extends the body of evidence for the tion before this data cutoff, 74.1% (86/116) of treatment effect of eculizumab but also provides patients were reported by their investigator to have new data regarding its positive impact on clinical clinically improved compared with REGAIN baseline. burden in patients who experience persistent MG In addition, most (65/116 [56.0%]) patients were symptoms despite having a history of using multiple deemed to have achieved minimal manifestations of ISTs. Among such patients, rates of potentially life- MG or pharmacological remission. threatening exacerbations,35 with consequent hos- pitalizations and rescue therapy use, are typically high.20 We have demonstrated that eculizumab DISCUSSION treatment significantly reduces the rates of MG Inhibition of terminal complement activity with eculi- exacerbations and MG-related hospitalizations in com- zumab is a biologically rational approach to prevent dam- parison with the last complete year before entering age at the neuromuscular junction in patients with the study and the rate of rescue therapy requirement AChR+ refractory gMG.22 Eculizumab has been reported compared with placebo-treated patients in REGAIN. to produce rapid and clinically meaningful improve- In addition, most patients were reported by their phy- ments in activities of daily living, muscle strength, func- sicians to have shown global clinical improvements tional ability, and quality of life and is well tolerated in during the open-label study, and over half achieved these patients.14 This interim analysis of the open-label minimal manifestations status or pharmacological extension study provides evidence that the safety and effi- remission according to MGFA postinterventional sta- cacy of eculizumab in this patient population are sus- tus evaluation. These interim results add to the find- tained with long-term treatment. ings of REGAIN in providing evidence of the range of The safety data for eculizumab in this study are in clinical benefits provided by eculizumab and the line with the current safety profile in patients with impact it has on alleviating the burden of disease in refractory gMG and with its well-characterized safety patients with previously refractory gMG. profile (on the basis of >10 years of postmarketing These results add to the evidence that comple- experience) in the other approved indications, PNH ment protein C5 inhibition is a relevant therapeutic and aHUS.14,32–34 Consistent with the mode of action target in AChR+ refractory gMG and provide evi- of eculizumab, infections were the most commonly dence of the long-term benefits of complement inhi- reported events among the adverse events of special bition by eculizumab for patients with this disease. interest. The prevalence of infections and other events Additional investigations into the structural and of special interest did not change with continued eculizu- functional changes at the neuromuscular junction in mab exposure. To mitigate the risk of meningococcal response to eculizumab that correlate with clinical infection, patients were required to receive meningococ- improvement in patients with MG may help to build cal vaccination as described in Materials and Methods. on the current preclinical evidence,36–38 fully charac- There were no occurrences of meningococcal infection terize the pathophysiology of MG including the role by data cutoff; 1 nonfatal case after this date has been of complement inhibition, and elucidate the mecha- reported. Three fatal events were reported in patients nism underlying the rapid response to eculizumab. with important comorbidities that likely contributed to The main limitation of this study is the open-label the clinical outcome. design, which could yield unconscious bias in reporting, FIGURE 5 Change from open-label baseline in MG-ADL to week 4 (double-blind induction phase only; A1), MG-ADL to week 130 (A2), QMG to week 4 (B1), QMG to week 130 (B2), MGC to week 4 (C1), MGC to week 130 (C2), MG-QOL15 to week 4 (D1), and MG-QOL15 to week 130 (D2); total scores (LS mean [95% CI]) by treatment group over time (full analysis set). Patient numbers were not the same for each assessment. The stability of scores during the open-label study in the eculizumab/eculizumab group is evidence of the maintenance of improvements achieved during eculizumab treatment in REGAIN in these patients. The rapid and significant improvements in the placebo/eculizumab group are evidence of these patients’ response to commencing eculizumab at the start of the open-label study, including during the initial 4-week blinded induction phase. *P ≤ 0.05, †P ≤ 0.01, ‡P ≤ 0.0001 compared with open-label baseline, repeated-measures analysis. BL, baseline; CI, confidence interval; LS, least-squares; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite scale; MG-QOL15, Myasthenia Gravis Quality of Life 15; QMG, Quantitative Myasthenia Gravis scale. 22 Long-Term Eculizumab in gMG MUSCLE & NERVE July 2019 particularly of adverse events. The blinded induction 4. Vincent A, McConville J, Farrugia ME, Bowen J, Plested P, Tang T, et al. Antibodies in myasthenia gravis and related disorders. Ann N Y Acad phase was designed to preserve the blinded nature of Sci 2003;998:324–335. REGAIN during the period of potential initial response. 5. Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diag- nostic test for myasthenia gravis: results in 153 validated cases and 2967 Although the lack of a control group may also be con- diagnostic assays. J Neurol Neurosurg Psychiatry 1985;48:1246–1252. sidered a limitation, comparisons can be made with the 6. Oh SJ, Kim DE, Kuruoglu R, Bradley RJ, Dwyer D. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992;15:720–724. placebo group in REGAIN and with pre-REGAIN data 7. Somnier FE. Clinical implementation of anti-acetylcholine receptor for the overall study population. Because over 90% of antibodies. J Neurol Neurosurg Psychiatry 1993;56:496–504. 8. Biesecker G, Gomez CM. Inhibition of acute passive transfer experi- REGAIN participants enrolled in the open-label exten- mental autoimmune myasthenia gravis with Fab antibody to comple- sion study, selection bias based on inclusion in the ment C6. J Immunol 1989;142:2654–2659. 9. Christadoss P. C5 gene influences the development of murine myasthe- open-label study population is unlikely. nia gravis. J Immunol 1988;140:2589–2592. Future analyses of long-term eculizumab data, 10. Karachunski PI, Ostlie NS, Monfardini C, Conti-Fine BM. Absence of IFN-γ or IL-12 has different effects on experimental myasthenia gravis including changes in IST and corticosteroid use dur- in C57BL/6 mice. J Immunol 2000;164:5236–5244. ing eculizumab therapy; the time course of clinical 11. Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble com- plement receptor 1 (sCR1) protects against experimental autoimmune improvements; and achievement of minimal manifes- myasthenia gravis. J Neuroimmunol 1996;71:173–177. tations will be important for understanding the role 12. Fumagalli G, Engel AG, Lindstrom J. Ultrastructural aspects of acetyl- choline receptor turnover at the normal end-plate and in autoimmune of eculizumab in the treatment of individuals with myasthenia gravis. J Neuropathol Exp Neurol 1982;41:567–579. refractory gMG. 13. Conti-Tronconi B, Tzartos S, Lindstrom J. Monoclonal antibodies as probes of acetylcholine receptor structure. 2. Binding to native recep- In conclusion, results of this interim analysis confirm tor. Biochemistry 1981;20:2181–2191. the rapid and robust response to eculizumab that was 14. Howard JF Jr., Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor observed during REGAIN and support the long-term antibody-positive refractory generalised myasthenia gravis (REGAIN): a clinical effectiveness and safety of eculizumab in patients phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol 2017;16:976–986. with AChR+ refractory gMG who previously experienced 15. Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory persistent symptoms and significant morbidities despite myasthenia gravis patients. Yale J Biol Med 2013;86:255–260. 16. Buzzard KA, Meyer NJ, Hardy TA, Riminton DS, Reddel SW. Induction concomitant IST. Improvements in activities of daily liv- intravenous cyclophosphamide followed by maintenance oral immunosup- ing, muscle strength, functional ability, and quality of pression in refractory myasthenia gravis. Muscle Nerve 2015;52:204–210. 17. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin life were maintained through 3 years in patients receiv- Neuromuscul Dis 2014;15:167–178. ing eculizumab. This study also provides new evidence 18. Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. Inter- national consensus guidance for management of myasthenia gravis: for other clinical benefits of eculizumab in these executive summary. Neurology 2016;87:419–425. patients, including reducing the frequency of disease 19. Howard JF Jr. Myasthenia gravis: the role of complement at the neuro- muscular junction. Ann N Y Acad Sci 2018;1412:113–128. exacerbations. The completion of this open-label exten- 20. Engel-Nitz NM, Boscoe AN, Wolbeck R, Johnson J, Silvestri NJ. Burden sion study will provide additional opportunities to con- of illness in patients with treatment refractory myasthenia gravis. Muscle Nerve 2018;58:99–105. tinue studying and understanding the long-term 21. Jani-Acsadi A, Lisak RP. Myasthenic crisis: guidelines for prevention benefits of eculizumab in patients with gMG. and treatment. J Neurol Sci 2007;261:127–133. 22. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treat- ment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 2007; The authors thank the patients who took part in REGAIN and the 25:1256–1264. open-label extension study as well as their families; all of the investiga- 23. McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. 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