ARTICLE OPEN ACCESS CLASS OF EVIDENCE Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension Renato Mantegazza, MD, Gil I. Wolfe, MD, Srikanth Muppidi, MD, Heinz Wiendl, MD, Kenji P. Fujita, MD, Correspondence Fanny L. O’Brien, PhD, Heather D.E. Booth, DPhil, and James F. Howard, Jr., MD, on behalf of the REGAIN Dr. Howard Study Group howardj@neurology.unc.edu ® Neurology 2021;96:e610-e618. doi:10.1212/WNL.0000000000011207 Abstract MORE ONLINE Objective Class of Evidence To evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) Criteria for rating refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America therapeutic and diagnostic (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients’ status studies throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia NPub.org/coe 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. ClinicalTrials.gov 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. From the Fondazione IRCCS Istituto Neurologico Carlo Besta (R.M.), Milan, Italy; Department of Neurology (G.I.W.), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; Department of Neurology and Neurological Sciences (S.M.), Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (H.W.), University of Münster, Germany; Alnylam Pharmaceuticals (K.P.F.), Cambridge, MA; Alexion Pharmaceuticals (F.L.O.), Boston, MA; Oxford PharmaGenesis (H.D.E.B.), UK; and Department of Neurology (J.F.H.), University of North Carolina, Chapel Hill. K.P.F. was formerly affiliated with Alexion Pharmaceuticals, Boston, MA. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. REGAIN study group coinvestigators are listed at links.lww.com/WNL/B275. The Article Processing Charge was funded by Alexion Pharmaceuticals. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. e610 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Glossary AChR+ = anti-acetylcholine receptor-positive; CI = confidence interval; gMG = generalized myasthenia gravis; IST = immunosuppressive therapy; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGFA = Myasthenia Gravis Foundation of America; MM = minimal manifestations; OR = odds ratio; PR = pharmacologic remission; REGAIN = Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis. In most patients with myasthenia gravis (MG), the disease is Study Design and Participants managed using immunosuppressive therapies (ISTs); how- REGAIN was a 6-month, phase 3, randomized, placebo- ever, 10%–15% of patients do not respond adequately to ISTs, controlled study of eculizumab in patients aged 18 years or experience intolerable adverse events, or require maintenance older with AChR+ refractory gMG.8 Patients who completed IV immunoglobulin or plasma exchange treatment.1–3 These REGAIN were eligible for inclusion in the open-label study patients are considered to have refractory MG, which can and were required to enroll within 2 weeks of completing severely affect their health-related quality of life and increase REGAIN.9 Patients were eligible for inclusion in REGAIN if the socioeconomic burden of the disease.4 they had confirmed gMG, AChR+ serology, and a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of at There is a consensus that the treatment goal for patients with least 6, and had received 2 or more ISTs, or at least 1 IST with generalized MG (gMG) should be achievement of a Myas- IV immunoglobulin or plasma exchange treatment at least 4 thenia Gravis Foundation of America (MGFA) post- times in 12 months without symptom control. Patients with intervention status of minimal manifestations (MM), de- ocular MG (MGFA Class I) or myasthenic crisis at screening fined as having no symptoms indicating functional limitations, (MGFA Class V) were excluded from the trial. Full eligibility or better.3,5,6 criteria have been published previously.8 All participants were required to have been vaccinated against Neisseria meningitidis Eculizumab (Soliris, Alexion Pharmaceuticals, Boston, MA) is at least 2 weeks before starting study treatment; individuals a humanized monoclonal antibody that specifically binds and who were not vaccinated at the appropriate time received inhibits cleavage of human terminal complement protein C5.7 prophylactic antibiotics until 2 weeks after vaccination. Dur- The 6-month, phase 3, randomized, placebo-controlled ing the open-label study, patients were revaccinated according REGAIN study (Safety and Efficacy of Eculizumab in Anti- to local guidelines in the country where they were treated, all acetylcholine Receptor-Positive [AChR+] Refractory Gener- of which recommended revaccination after 2–5 years to alized Myasthenia Gravis) demonstrated the efficacy and safety maintain active coverage. During REGAIN, patients who of eculizumab in patients with AChR+ refractory gMG.8 An previously received ISTs were required to maintain their interim analysis of the REGAIN open-label extension results prestudy dose and schedule. During the open-label study, found that eculizumab’s benefits for this population were modifications to IST dose and schedule were permitted at the maintained through 3 years of treatment.9 MGFA post- discretion of the investigator; however, changes were not intervention status was assessed as a tertiary endpoint in these required by the protocol. studies. At the date of the open-label study interim analysis, 74.1% of patients had an MGFA post-intervention status of Dosing of Eculizumab improved, and 56.0% were considered to have achieved MM or In REGAIN, patients randomized to receive eculizumab were pharmacologic remission (PR).9 We report a detailed evalua- given an induction dose of 900 mg on day 1 and at weeks 1, 2, tion of final data from the open-label study on patients’ re- and 3, followed by a maintenance dose of 1,200 mg at week 4 sponse to eculizumab treatment during REGAIN and up to and every 2 weeks thereafter (figure 1).8 Placebo was ad- open-label week 130 using MGFA post-intervention status. ministered on the same schedule. Patients who received eculizumab during REGAIN continued to receive it during the open-label study (eculizumab/eculizumab arm) and those Methods who received placebo during REGAIN started eculizumab Standard Protocol Approvals, Registrations, treatment upon entering the open-label study (placebo/ and Patient Consents eculizumab arm).9 To preserve the blinded nature of All patients provided written, informed consent. Independent REGAIN, patients who continued into the open-label study ethics committees or institutional review boards provided underwent a 4-week blinded induction phase (figure 1). written approval for the study protocols and all amendments. During this phase, patients in the eculizumab/eculizumab The studies were performed in accordance with the ethical group received eculizumab 1,200 mg on day 1 and at week 2, standards laid down in the 1964 Declaration of Helsinki and and placebo at weeks 1 and 3. Patients in the placebo/ are registered with clinicaltrials.gov (identifiers: for REGAIN, eculizumab group received eculizumab 900 mg on day 1 and NCT01997229; for the REGAIN open-label extension, at weeks 1, 2, and 3. All patients were then given open-label NCT02301624). eculizumab 1,200 mg at week 4 and every 2 weeks thereafter Neurology.org/N Neurology | Volume 96, Number 4 | January 26, 2021 e611 Figure 1 Study Design a During the blinded induction phase of the open-label study, patients received eculizumab (1,200 mg; 4 vials) on day 1 and at week 2 and 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). bPatients who withdrew from or discontinued participation in the study after receiving any amount of eculizumab were required to complete a safety follow-up visit 8 weeks after their last eculizumab dose. REGAIN = Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Refractory Generalized Myasthenia Gravis; SOC = standard of care. Figure reproduced with permission (creativecommons.org/licenses/by-nc/4.0/) from Muppidi et al.9 until it was otherwise available to them, for up to a maximum open-label study weeks 26, 40, 52, 78, 104, and 130. PR was of 4 years. The extension study was completed with final achieved if patients had no signs or symptoms of MG for at database lock in January 2019. least 1 year and, upon examination, had no weakness of any muscle, other than isolated weakness of eyelid closure. Assessments The objectives of REGAIN and the open-label study were to Daily doses of corticosteroids, azathioprine, and mycophe- assess the efficacy of eculizumab, as measured by change in nolate mofetil were recorded throughout the open-label MG-ADL total score from baseline, and to evaluate its safety. study. This analysis assessed the tertiary endpoint of MGFA post- intervention status and safety data during REGAIN and the Adverse events were recorded and coded by preferred term open-label study for patients who continued into the open- using the Medical Dictionary for Regulatory Activities Ver- label study. sion 20.1. MG exacerbations, use of rescue therapy, and study discontinuations because of adverse events were also MGFA post-intervention status can be used to evaluate recorded. changes in a patient’s condition following treatment, in- cluding improvement, worsening, or no change of clinical Statistical Analysis manifestations from pretreatment.6 MGFA post-intervention Patients who were not assessed for MGFA post-intervention status following administration of eculizumab or placebo status at a particular time point were not included in the during REGAIN, including achievement of MM, was assessed analysis for that time point. at weeks 4, 12, and 26 of REGAIN and weeks 26, 40, 52, 78, 104, and 130 of the open-label study and was based on The common odds ratio (OR) and the associated 95% con- comparison with patients’ disease state before REGAIN. fidence intervals (CIs) for achievement of improved status or MGFA post-intervention status was reported as improved if a MM at REGAIN week 26 for patients who received eculizu- patient’s pretreatment clinical manifestations were sub- mab compared with those who received placebo were calcu- stantially decreased, worse if they were substantially increased, lated using an ordinal logistic regression model with MGFA or unchanged if they were not substantially changed com- post-intervention status (achieved MM, improved but MM pared with REGAIN baseline. In this analysis, the group of not achieved, unchanged, or worse) as a dependent variable, patients with improved status included patients who achieved and treatment group as an independent variable. MM or PR. In patients with improved status, MM was ach- ieved if they had no symptoms indicating functional limita- For between-group comparisons, 95% CIs of the differences tions from MG but had some weakness on examination of in means were based on the t-distribution for continuous some muscles.6 Subcategories of MM relating to treatment variables. Within a single treatment group, 95% CIs were status were not assessed. Patients were evaluated for PR at calculated using the Clopper-Pearson method. e612 Neurology | Volume 96, Number 4 | January 26, 2021 Neurology.org/N Figure 2 Patient Disposition in REGAIN (Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Re- fractory Generalized Myasthenia Gravis) and the Open-Label Study ECU = eculizumab; PLC = placebo. Figure reproduced with permission (creativecommons.org/licenses/by/4.0/) from Vissing et al.13 All statistical analyses were performed using SAS software research-development. The data request form is available at version 9.4 (SAS Institute, Cary, NC). alexion.com/contact-alexion/medical-information. Classification of Evidence The primary research question of this analysis of data from the Results 6-month, phase 3, randomized, placebo-controlled REGAIN Patient Demographics and Characteristics study and its open-label extension was whether adults with A total of 117 patients who completed REGAIN continued AChR+ refractory gMG could achieve an MGFA post- into the open-label study (eculizumab/eculizumab: 56; intervention status of MM with eculizumab therapy. placebo/eculizumab: 61; figure 2) and were included in the efficacy and safety analysis. Patient demographics and char- This study provides Class II evidence that, in this previously acteristics, published previously, were similar for the difficult-to-treat patient population, after 26 weeks of treat- eculizumab/eculizumab and placebo/eculizumab groups, ment during REGAIN, a greater proportion treated with with the exception that there was a greater proportion of eculizumab than placebo achieved an MGFA post- Asian patients in the placebo/eculizumab group.9 intervention status of MM (25.0% vs 13.3%; common OR 2.3; 95% CI 1.1–4.5). After 130 weeks of eculizumab therapy, The open-label extension study was completed with a final most patients (57.3%) achieved MM status. database lock in January 2019. At study completion, patients had participated in the study for different periods of time. A Data Availability total of 87 patients completed the study (eculizumab/ Alexion will consider requests for disclosure of clinical study eculizumab: 43; placebo/eculizumab: 44; figure 2). Of participant-level data provided that participant privacy is as- these, 71 patients (eculizumab/eculizumab: 35; placebo/ sured through methods like data de-identification, pseudo- eculizumab: 36) had received open-label eculizumab for at nymization, or anonymization (as required by applicable law), least 130 weeks by the end of the study. and if such disclosure was included in the relevant study in- formed consent form or similar documentation. Qualified MGFA Post-intervention Status During REGAIN academic investigators may request participant-level clinical and the Open-Label Study data and supporting documents (statistical analysis plan and During REGAIN, at all time points assessed, a higher pro- protocol) pertaining to Alexion-sponsored studies. Further portion of patients who received eculizumab than of those details regarding data availability and instructions for who were given placebo achieved improved status (table 1 requesting information are available in the Alexion Clinical and figure 3). At week 4, 54.5% of eculizumab-treated patients Trials Disclosure and Transparency Policy at alexion.com/ (30/55) achieved a status of improved compared with 24.6% Neurology.org/N Neurology | Volume 96, Number 4 | January 26, 2021 e613 Table 1 Change in Myasthenia Gravis Foundation of America Post-intervention Status From REGAIN (Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Refractory Generalized Myasthenia Gravis) Baseline During REGAIN and Its Open-Label Extension by Treatment Group Placebo/eculizumab (n = 61) Eculizumab/eculizumab (n = 56) Improved MM Unchanged Worse Improved MM Unchanged Worse n/Nb (%) n/Nb (%) n/Nb (%) n/Nb (%) n/Nb (%) n/Nb (%) n/Nb (%) n/Nb (%) a Study Visit [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI] REGAIN Week 4 15/61 (24.6) 5/61 (8.2) 41/61 (67.2) 5/61 (8.2) 30/55 (54.5) 10/55 (18.2) 25/55 (45.5) 0/55 (0.0) [14.5–37.3] [2.7–18.1] [54.0–78.7] [2.7–18.1] [40.6–68.0] [9.1–30.9] [32.0–59.4] [0.0–6.5] Week 12 22/61 (36.1) 7/61 (11.5) 35/61 (57.4) 4/61 (6.6) 28/53 (52.8) 11/53 (20.8) 24/53 (45.3) 1/53 (1.9) [24.2–49.4] [4.7–22.2] [44.1–70.0] [1.8–15.9] [38.6–66.7] [10.8–34.1] [31.6–59.6] [0.0–10.1] Week 26 25/60 (41.7) 8/60 (13.3) 30/60 (50.0) 5/60 (8.3) 34/56 (60.7) 14/56 (25.0) 21/56 (37.5) 1/56 (1.8) [29.1–55.1] [5.9–24.6] [36.8–63.2] [2.8–18.4] [46.8–73.5] [14.4–38.4] [24.9–51.5] [0.0–9.6] Open- Week 26 40/56 (71.4) 27/56 (48.2) 15/56 (26.8) 1/56 (1.8) 36/48 (75.0) 22/48 (45.8) 12/48 (25.0) 0/48 (0.0) label [57.8–82.7] [34.7–62.0] [15.8–40.3] [0.0–9.6] [60.4–86.4] [31.4–60.8] [13.6–39.6] [0.0–7.4] study Week 40 46/54 (85.2) 34/54 (63.0) 7/54 (13.0) 1/54 (1.9) 37/49 (75.5) 21/49 (42.9) 10/49 (20.4) 2/49 (4.1) [72.9–93.4] [48.7–75.7] [5.4–24.9] [0.0–9.9] [61.1–86.7] [28.8–57.8] [10.2–34.3] [0.5–14.0] Week 52 44/54 (81.5) 31/54 (57.4) 10/54 (18.5) 0/54 (0.0) 41/48 (85.4) 22/48 (45.8) 6/48 (12.5) 1/48 (2.1) [68.6–90.7] [43.2–70.8] [9.3–31.4] [0.0–6.6] [72.2–93.9] [31.4–60.8] [4.7–25.2] [0.1–11.1] Week 78 42/48 (87.5) 29/48 (60.4) 5/48 (10.4) 1/48 (2.1) 37/47 (78.7) 22/47 (46.8) 9/47 (19.1) 1/47 (2.1) [74.8–95.3] [45.3–74.2] [3.5–22.7] [0.1–11.1] [64.3–89.3] [32.1–61.9] [9.1–33.3] [0.1–11.3] Week 104 34/37 (91.9) 22/37 (59.5) 2/37 (5.4) 1/37 (2.7) 33/40 (82.5) 21/40 (52.5) 6/40 (15.0) 1/40 (2.5) [78.1–98.3] [42.1–75.2] [0.7–18.2] [0.1–14.2] [67.2–92.7] [36.1–68.5] [5.7–29.8] [0.1–13.2] Week 130 33/35 (94.3) 22/35 (62.9) 2/35 (5.7) 0/35 (0.0) 28/35 (80.0) 18/35 (51.4) 5/35 (14.3) 2/35 (5.7) [80.8–99.3] [44.9–78.5] [0.7–19.2] [0.0–10.0] [63.1–91.6] [34.0–68.6] [4.8–30.3] [0.7–19.2] Last 47/57 (82.5) 31/57 (54.4) 9/57 (15.8) 1/57 (1.8) 40/56 (71.4) 23/56 (41.1) 13/56 (23.2) 3/56 (5.4) assessment [70.1–91.3] [40.7–67.6] [7.5–27.9] [0.0–9.4] [57.8–82.7] [28.1–55.0] [13.0–36.4] [1.1–14.9] Abbreviations: CI = confidence interval; MM = minimal manifestations. a Weeks are numbered separately for REGAIN (0–26) and the open-label study (0–130). b At the time of study completion, patients had participated for different periods of time. The numbers of patients at each time point reflect this and also account for discontinuations and for patients who did not complete the assessment at the specified time point. of placebo-treated patients (15/61). At week 26, 60.7% of patients were more likely to achieve a status of improved or eculizumab-treated patients (34/56) had achieved a status of MM at REGAIN week 26 than those given placebo (common improved, compared with 41.7% of placebo-treated patients OR 2.3; 95% CI 1.1–4.5). By week 130 of the open-label (25/60). One patient who received eculizumab had a status of study, the proportion of patients achieving MM had increased worse at week 26 compared with 5 individuals who received to 51.4% in the eculizumab/eculizumab group (18/35) and to placebo. By week 130 of the open-label study, most patients in 62.9% in the placebo/eculizumab group (22/35). At last as- both groups had achieved improved status: 80.0% of partici- sessment, MM was achieved by 41.1% of patients in the pants in the eculizumab/eculizumab group (28/35) and eculizumab/eculizumab group (23/56) and 54.4% of patients 94.3% of those in the placebo/eculizumab group (33/35; 1 in the placebo/eculizumab group (31/57). patient did not complete the assessment). Of the 117 patients enrolled in the open-label extension study, 113 were assessed Patients in the eculizumab/eculizumab and placebo/ for MGFA post-intervention status at their last assessment: eculizumab groups received eculizumab for different periods 71.4% of patients in the eculizumab/eculizumab group (40/ of time during REGAIN and its open-label extension; of all 56) and 82.5% of those in the placebo/eculizumab group (47/ patients who received eculizumab for 26 weeks (eculizumab/ 57) achieved improved status. eculizumab group to week 26 of REGAIN and placebo/ eculizumab group to week 26 of the open-label study), most During REGAIN, the proportion of patients receiving eculi- (66.1%; 74/112) achieved improved status and over one-third zumab who achieved MM increased from 18.2% (10/55) at (36.6%; 41/112) achieved MM status (table 2). Almost one- week 4 to 25.0% (14/56) at week 26 (table 1 and figure 3). third of participants (32.1%; 36/112) had a status of un- MM status was achieved by a smaller proportion of the pla- changed and 2 patients had a status of worse after 26 weeks’ cebo group (8.2% [5/61] at week 4 and 13.3% [8/60] at week eculizumab therapy (table 2). The proportions of patients 26) than of the eculizumab group. Eculizumab-treated who achieved improved or MM status increased with e614 Neurology | Volume 96, Number 4 | January 26, 2021 Neurology.org/N Figure 3 Patients Who Achieved Myasthenia Gravis Foundation of America Post-intervention Status of Improved or Minimal Manifestations at REGAIN (Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Refractory Generalized Myasthenia Gravis) Weeks 4, 12, and 26, and Open-Label Study Weeks 26, 52, 78, 104, and 130 a Weeks are numbered separately for REGAIN (0–26) and the open-label study (0–130). bAt the time of study completion, patients had participated for different periods of time. The numbers of patients at each time point reflect this and also account for dis- continuations and for patients who did not complete the assessment at the specified time point. continued eculizumab treatment: 88.0% (66/75) of those achieved improved status and 47.8% (54/113) achieved MM who received eculizumab for 130 weeks achieved improved status (table 2). status and 57.3% (43/75) achieved MM status (table 2). In addition, 2 patients achieved PR after 130 weeks of eculizu- There were no differences in mean age (46.5 vs 47.4 years; dif- mab therapy. At last assessment, 77.0% of patients (87/113) ference −0.9; 95% CI −7.6 to 5.8) or mean disease duration (9.3 vs Table 2 Change in Myasthenia Gravis Foundation of America Post-intervention Status from REGAIN (Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Refractory Generalized Myasthenia Gravis) Baseline by Eculizumab Treatment Duration Duration of eculizumab treatment, wk Improved MM Unchanged Worse 26 74/112 (66.1) [56.5–74.7] 41/112 (36.6) [27.7–46.2] 36/112 (32.1) [23.6–41.6] 2/112 (1.8) [0.2–6.3] 52 80/102 (78.4) [69.2–86.0] 53/102 (52.0) [41.8–62.0] 22/102 (21.6) [14.0–30.8] 0/102 (0.0) [0.0–3.6] 78 83/96 (86.5) [78.0–92.6] 51/96 (53.1) [42.7–63.4] 11/96 (11.5) [5.9–19.6] 2/96 (2.1) [0.3–7.3] 104 71/84 (84.5) [75.0–91.5] 44/84 (52.4) [41.2–63.4] 11/84 (13.1) [6.7–22.2] 2/84 (2.4) [0.3–8.3] 130 66/75 (88.0) [78.4–94.4] 43/75 (57.3) [45.4–68.7] 8/75 (10.7) [4.7–19.9] 1/75 (1.3) [0.0–7.2] Last assessment 87/113 (77.0) [68.1–84.4] 54/113 (47.8) [38.3–57.4] 22/113 (19.5) [12.6–28.0] 4/113 (3.5) [1.0–8.8] Abbreviation: MM = minimal manifestations. At the time of study completion, patients had participated for different periods of time. The numbers of patients listed for each treatment duration reflect this and also account for discontinuations and for patients who did not complete the assessment at the specified time point. Values are n/N (%) [95% confidence interval]. Neurology.org/N Neurology | Volume 96, Number 4 | January 26, 2021 e615 Table 3 Changes in Mean Daily Immunosuppressive Therapy Doses in Patients Who First Achieved Minimal Manifestations (MM) Status During the Open-Label Study No. of patients using IST at open-label Mean (SD) daily dose Last reported mean (SD) daily Percent change in baseline who first achieved MM during the at open-label dose before first achieving mean (SD) daily IST open-label study baseline, mg MM, mg dose Corticosteroids 47 17.0 (11.85) 12.9 (10.29) −18.7 (33.11) Azathioprine 24 163.5 (67.96) 130.2 (92.95) −26.0 (40.77) Mycophenolate 13 2,206.9 (1,139.06) 1,855.0 (1,148.80) −16.0 (30.14) mofetil Abbreviation: IST = immunosuppressive therapy. 10.3 years; difference −1.0; 95% CI −4.2 to 2.2) between and one-third of these patients also achieved MM. By eculizumab-treated patients who achieved MM status up to open- REGAIN week 26, significantly higher proportions of label study week 130 (n = 76) and those who did not (n = 37). eculizumab-treated patients than placebo-treated patients Among the 76 eculizumab-treated patients who achieved MM achieved an MGFA post-intervention status of improved status up to open-label study week 130, 58 (76.3%) were using or MM. corticosteroids, 29 (38.2%) were using azathioprine, and 16 (21.1%) were using mycophenolate mofetil at open-label baseline. Long-term eculizumab treatment was associated with further increases in the proportions of patients who achieved a status of The mean daily doses of ISTs used by patients who first improved or MM. After 130 weeks of eculizumab therapy, al- achieved MM status during the open-label study decreased most 90% of patients remaining in the study had attained a status between open-label baseline and last reported dose before of improved and nearly 60% had achieved MM. Notably, in first achieving MM status. In those using each IST at open- patients who achieved MM status during the open-label study, label baseline, the mean daily doses of corticosteroids, aza- mean daily doses of concomitant ISTs were reduced before they thioprine, and mycophenolate mofetil decreased by 18.7%, first achieved MM. These findings suggest that for some patients 26.0%, and 16.0%, respectively (table 3). with AChR+ refractory gMG, long-term treatment with eculi- zumab is beneficial for optimal disease control. Furthermore, 2 Safety patients achieved PR after 130 weeks of eculizumab treatment, Safety data have previously been published for REGAIN and reflecting long-term maintenance of symptom relief. the interim analysis of the open-label study.8,9 Across these 2 studies, the most common adverse events with eculizumab for The long-term safety profile of eculizumab was consistent patients included in this analysis were headache and naso- with its known profile from over 10 years of clinical use in pharyngitis, which were experienced by 44.4% and 38.5% of other indications,10–12 and no new safety signals were ob- patients, respectively (table 4). Serious adverse events of served during the open-label study. worsening of MG and MG crisis occurred in 15.4% and 3.4% of patients, respectively. MG exacerbations were experienced The main limitation of this analysis is the open-label design of by 29.1% of patients, and 25.6% used rescue therapy. During the extension study, which could yield unconscious bias to- REGAIN and the open-label study, 11 patients discontinued wards reporting of positive outcomes with eculizumab. Be- because of an adverse event, and 3 deaths occurred, which cause over 90% of patients who enrolled in REGAIN were all considered likely to be related to comorbidities continued into the open-label study, selection bias in the (figure 2).9 There were 16 patients who withdrew themselves open-label study population is unlikely. from REGAIN or the open-label study, 6 patients who were withdrawn by their physician, and 1 patient who discontinued The results of this analysis confirm the rapid and sustained clinical for “other” reasons; no further information was collected re- response to eculizumab that was observed during REGAIN and garding the reasons for these discontinuations. the open-label study. Over 50% of patients who were considered to have refractory disease achieved the consensus treatment goal of MM or better after 1 year of eculizumab treatment. These Discussion findings further support the long-term effectiveness of eculizu- mab for use in patients with AChR+ refractory gMG. This analysis found that patients with AChR+ refractory gMG treated with eculizumab experienced rapid improvements in Acknowledgment their clinical condition based on MGFA post-intervention The authors thank REGAIN and extension study participants status. Over 50% of patients achieved a status of improved and their families, investigators, and collaborators; Sivani within 4 weeks of their first dose of eculizumab in REGAIN Paskaradevan (Alexion Pharmaceuticals) for critical review of e616 Neurology | Volume 96, Number 4 | January 26, 2021 Neurology.org/N Table 4 Safety Outcomes for the Study Population During REGAIN (Safety and Efficacy of Eculizumab in Anti-acetylcholine Receptor-Positive Refractory Generalized Myasthenia Gravis) and the Open-Label Study REGAIN and open-label study REGAIN placebo (n = 61, REGAIN eculizumab (n = 56, eculizumab (N = 117, 30.9 PYa) 28.2 PYa) 305.1 PYa) Patients Event rate Patients Event rate Patients Event rate with event, (events/100 with event, (events/100 with event, (events/100 Outcome n (%) PYa) n (%) PYa) n (%) PYa) Exacerbation 13 (21.3) 77.7 4 (7.1) 35.5 34 (29.1) 23.9 Rescue therapy use 10 (16.4) 68.0 4 (7.1) 35.5 30 (25.6) 22.0 b,c Most common adverse events (>15% of all patients) Headache 12 (19.7) 90.6 10 (17.9) 88.7 52 (44.4) 32.8 Nasopharyngitis 10 (16.4) 42.1 9 (16.1) 46.1 45 (38.5) 32.1 Diarrhea 8 (13.1) 29.1 8 (14.3) 35.5 33 (28.2) 17.4 Upper respiratory tract infection 12 (19.7) 45.3 9 (16.1) 46.1 31 (26.5) 25.2 Nausea 9 (14.8) 84.1 7 (12.5) 35.5 27 (23.1) 12.1 d Myasthenia gravis 9 (14.8) 58.3 4 (7.1) 14.2 30 (25.6) 17.4 Arthralgia 5 (8.2) 29.1 1 (1.8) 3.5 24 (20.5) 10.5 Pain in extremity 2 (3.3) 6.5 4 (7.1) 14.2 20 (17.1) 8.5 Urinary tract infection 5 (8.2) 22.7 3 (5.4) 14.2 20 (17.1) 12.5 Most common myasthenia gravis– and infection-related serious adverse eventsb,c (≥2 patients) Myasthenia gravisd 6 (9.8) 45.3 3 (5.4) 10.6 18 (15.4) 10.5 Pyrexia 0 (0.0) 0.0 2 (3.6) 7.1 5 (4.3) 1.6 Myasthenia gravis crisis 0 (0.0) 0.0 0 (0.0) 0.0 4 (3.4) 1.3 Acute respiratory failure 0 (0.0) 0.0 0 (0.0) 0.0 3 (2.6) 1.0 Gastroenteritis 1 (1.6) 9.7 0 (0.0) 0.0 3 (2.6) 1.0 Pneumonia 0 (0.0) 0.0 0 (0.0) 0.0 4 (3.4) 1.6 Sepsis 0 (0.0) 0.0 0 (0.0) 0.0 3 (2.6) 1.0 Bronchitis 0 (0.0) 0.0 0 (0.0) 0.0 2 (1.7) 1.0 Urinary tract infection 0 (0.0) 0.0 0 (0.0) 0.0 2 (1.7) 1.0 Influenza 0 (0.0) 0.0 0 (0.0) 0.0 2 (1.7) 0.7 Upper respiratory tract infection 2 (3.3) 6.5 0 (0.0) 0.0 2 (1.7) 0.7 Pneumonia aspiration 0 (0.0) 0.0 0 (0.0) 0.0 2 (1.7) 0.7 Localized infection 0 (0.0) 0.0 0 (0.0) 0.0 2 (1.7) 0.7 Abbreviation: PY = patient-year. a PY is the sum of all years for all patients and the observed event rate is the number of events per PY multiplied by 100. b Medical Dictionary for Regulatory Activities preferred term. c If a patient had more than 1 adverse event for a particular preferred term, that patient is counted only once for that preferred term. d Worsening (increased frequency and/or intensity) of a preexisting condition, including myasthenia gravis, is considered to be an adverse event. the manuscript; and Cindy Lane (formerly of Alexion Disclosure Pharmaceuticals) for clinical study oversight. R. Mantegazza received funding for research and congress participation from Bayer, BioMarin, Sanofi-Genzyme, and Study Funding Teva, and participated in scientific advisory boards for Alexion This work was funded by Alexion Pharmaceuticals. Pharmaceuticals, argenx, and BioMarin. G.I. Wolfe reports Neurology.org/N Neurology | Volume 96, Number 4 | January 26, 2021 e617 research support from Alexion Pharmaceuticals, CSL Behring, and Ra Pharmaceuticals, and advisory board Appendix 1 (continued) compensation from argenx and Syntimmune. S. Muppidi Name Location Contribution was a consultant for Alexion Pharmaceuticals. H. Wiendl received honoraria for participation in scientific advisory Srikanth Stanford, Major role in data acquisition, data Muppidi, MD CA analysis/interpretation, drafting/revising boards and consultation for Biogen, Evgen, MedDay the manuscript for intellectual content, Pharmaceuticals, Merck Serono, Novartis, Roche Pharma final approval of the manuscript AG, and Sanofi-Genzyme, and speaker honoraria and Heinz Wiendl, Münster, Major role in data acquisition, data travel support from Alexion Pharmaceuticals, Biogen, MD Germany analysis/interpretation, drafting/revising the manuscript for intellectual content, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige final approval of the manuscript Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma Kenji P. Fujita, Boston, Study design/conceptualization, major AG, Sanofi-Genzyme, Teva, and WebMD Global. He has MD MA role in data acquisition, data analysis/ been a paid consultant for AbbVie, Actelion, Biogen, IGES, interpretation, drafting/revising the manuscript for intellectual content, final Novartis, Roche Pharma AG, Sanofi-Genzyme, and the Swiss approval of the manuscript Multiple Sclerosis Society. His research is funded by the Ger- man Ministry for Education and Research (BMBF), Deutsche Fanny L. Boston, Study design/conceptualization, major O’Brien, PhD MA role in data acquisition, data analysis/ Forschungsgesellschaft (DFG), Else Kröner-Fresenius Foun- interpretation, drafting/revising the dation, Hertie Foundation, NRW Ministry of Education and manuscript for intellectual content, final approval of the manuscript Research, Interdisciplinary Center for Clinical Studies (IZKF) Müenster and RE Children’s Foundation, Biogen GmbH, Heather D.E. Oxford, Drafting or revising the manuscript for Booth, DPhil UK intellectual content, final approval of the GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi- manuscript Genzyme. K.P. Fujita was employed by and owns stock in James F. Chapel Study design/conceptualization, major Alexion Pharmaceuticals and is employed by Alnylam Phar- Howard, Jr, Hill, NC role in data acquisition, data analysis/ maceuticals. F.L. O’Brien is employed by and owns stock in MD interpretation, drafting/revising the manuscript for intellectual content, final Alexion Pharmaceuticals. H.D.E. Booth is employed by approval of the manuscript Oxford PharmaGenesis, which received funding from Alex- ion Pharmaceuticals for medical writing support. J.F. Howard received research support from argenx BVBA, Alexion Pharmaceuticals, the Muscular Dystrophy Associa- Appendix 2 Coinvestigators tion, Ra Pharmaceuticals, the Centers for Disease Control and Prevention (Atlanta, GA), and the NIH (including the Coinvestigators are listed at links.lww.com/WNL/B275 National Institute of Neurologic Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases); consulting fees from Alexion Pharmaceuti- References 1. Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis cals; honoraria from Alexion Pharmaceuticals; and non- patients. Yale J Biol Med 2013;86:255–260. financial support from Alexion Pharmaceuticals, argenx 2. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis 2014;15:167–178. BVBA, Ra Pharmaceuticals, and Toleranzia. Go to Neurol- 3. Sanders DB, Wolfe GI, Benatar M, et al. 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Efficacy and safety of eculizumab in atypical final approval of the manuscript hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 2015;87:1061–1073. Gil I. Wolfe, Buffalo, Major role in data acquisition, data 12. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in MD NY analysis/interpretation, drafting/revising paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233–1243. the manuscript for intellectual content, 13. Vissing J, Jacob S, Fujita KP, et al. “Minimal symptom expression” in patients with final approval of the manuscript acetylcholine receptor antibody-positive refractory generalized myasthenia gravis treated with eculizumab. J Neurol 2020;267:1991–2001. e618 Neurology | Volume 96, Number 4 | January 26, 2021 Neurology.org/N Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension Renato Mantegazza, Gil I. Wolfe, Srikanth Muppidi, et al. Neurology 2021;96;e610-e618 Published Online before print November 23, 2020 DOI 10.1212/WNL.0000000000011207 This information is current as of November 23, 2020 Updated Information & including high resolution figures, can be found at: Services http://n.neurology.org/content/96/4/e610.full References This article cites 13 articles, 0 of which you can access for free at: http://n.neurology.org/content/96/4/e610.full#ref-list-1 Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Clinical trials http://n.neurology.org/cgi/collection/all_clinical_trials Autoimmune diseases http://n.neurology.org/cgi/collection/autoimmune_diseases Class II http://n.neurology.org/cgi/collection/class_ii Myasthenia http://n.neurology.org/cgi/collection/myasthenia Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/about/about_the_journal#permissions Reprints Information about ordering reprints can be found online: http://n.neurology.org/subscribers/advertise Neurology ® is the official journal of the American Academy of Neurology. 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