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Tuan Vu,1 Heinz Wiendl,2 Masahisa Katsuno,3 Stephen W Reddel,4 James F Howard Jr5 1Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL, USA; 2Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany; 3Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 4Department of Neurology, Concord Hospital, University of Sydney, Sydney, NSW, Australia; 5Department of Neurology, The University of North Carolina, Chapel Hill, NC, USACorrespondence: Tuan Vu, Department of Neurology, University of South Florida Morsani College of Medicine, 13220 USF Laurel Drive, Tampa, FL, 33612, USA, Tel +1 813 396 2955, Email tvu6@usf.eduAbstract: The terminal complement C5 inhibitor ravulizumab was engineered from the humanized monoclonal antibody eculizumab to have an extended half-life and duration of action. It binds to human terminal complement protein C5, inhibiting its cleavage into C5a and C5b, thus preventing the cascade of events that lead to architectural destruction of the postsynaptic neuromuscular junction membrane by the membrane attack complex, and consequent muscle weakness in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG). The 26-week randomized, placebo-controlled period (RCP) of the phase 3 CHAMPION MG study demonstrated the rapid efficacy of ravulizumab in reducing MG symptoms. Weight-based dosing of ravulizumab every 8 weeks provided sustained efficacy, in terms of patient-reported (Myasthenia Gravis–Activities of Daily Living) and clinician-reported (Quantitative Myasthenia Gravis) endpoints in patients with anti-AChR antibody-positive gMG. Pharmacokinetic and pharmacodynamic analyses showed therapeutic serum ravulizumab concentrations (> 175 μg/mL) were achieved immediately after the first dose and were maintained throughout 26 weeks, irrespective of patient body weight; inhibition of serum free C5 was immediate, complete (< 0.5 μg/mL), and sustained in all patients. Interim results from the open-label extension (OLE) showed that after 60 weeks, efficacy was maintained in patients continuing on ravulizumab. Rapid and sustained improvements in efficacy, similar to those seen in patients initiating ravulizumab in the RCP, were observed after initiation of ravulizumab treatment in patients who switched from placebo in the RCP to ravulizumab in the OLE. The findings from the RCP and OLE support ravulizumab’s favorable safety profile. In conclusion, ravulizumab has a simple weight-based administration and long dosing interval. Its targeted mechanism of action without generalized immunosuppression is reflected in its rapid onset of symptom improvement, sustained efficacy and good safety profile in the treatment of patients with anti-AChR antibody-positive gMG.Plain Language Summary: Ravulizumab in anti-AChR antibody-positive gMGRavulizumab was engineered from eculizumab to have an extended half-life and longer duration of action. It binds to terminal complement protein C5 to inhibit anti-AChR antibody-mediated activation of terminal complement and destruction of the neuromuscular junction.Pharmacokinetic/pharmacodynamic analyses support a simple weight-based administration and long dosing interval and show that therapeutic ravulizumab concentrations and complete inhibition of C5 were achieved immediately after the first dose.The 26-week randomized placebo-controlled period (RCP) of the CHAMPION MG study in patients with anti-AChR antibody-positive gMG showed that ravulizumab has rapid and sustained efficacy with good safety and tolerability across a broad range of patients.Ravulizumab’s efficacy, safety, and tolerability were confirmed in interim analyses of the open-label extension study (including data for up to 60 weeks from the RCP baseline): efficacy was maintained in patients remaining on ravulizumab; rapid and sustained efficacy was established in patients switching from placebo to ravulizumab.Keywords: acetylcholine receptor antibody, complement, membrane attack complex, monoclonal antibody, terminal complement complex

Background and Purpose: The efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG) were demonstrated in the CHAMPION MG study (NCT03920293). This analysis aimed to characterize the latency to onset of a clinically meaningful therapeutic effect for ravulizumab., Methods: Post hoc analysis of data collected for up to 60 weeks from CHAMPION MG was performed to assess the timing of response to ravulizumab. Response was analyzed based on reductions of ≥2 and ≥3 points (minimal clinically important differences [MCIDs]) in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores, respectively, and on more rigorous reductions of ≥3 and ≥5 points, respectively. Time to first response was assessed using the Kaplan-Meier product-limit method., Results: The median (95% confidence interval) time to first response was 2.1 (2.1-2.6) and 4.1 (2.3-10.0) weeks for reductions of ≥2 and ≥3 points in MG-ADL total score, respectively (n = 139), and 4.1 (2.1-10.0) and 18.3 (11.0-33.4) weeks for reductions of ≥3 and ≥5 points in QMG total score, respectively (n = 134). Cumulative response rates at Week 60 (data cut-off) were 88% and 82% for ≥2- and ≥3-point MG-ADL score reductions, respectively, and 86% and 59% for ≥3- and ≥5-point QMG score reductions, respectively., Conclusions: The median times to MCID with ravulizumab treatment in patients with AChR Ab+ gMG were ~2 weeks and ~4 weeks based on MCID MG-ADL and QMG total score reductions, respectively., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available., Objectives: Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks., Design: A model-informed analysis (MIA) within a Bayesian framework., Methods: Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed., Results: At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG., Conclusion: This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies., (© The Author(s), 2024.)

ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 ​mg or efgartigimod IV 10 ​mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 ​mg and efgartigimod IV 10 ​mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG., Competing Interests: Declaration of competing interest This study was sponsored by argenx (Ghent, Belgium), the manufacturer of efgartigimod IV and efgartigimod PH20 SC. Efgartigimod IV has received regulatory approval for the treatment of gMG in multiple countries. Efgartigimod PH20 SC was approved for use in gMG by the US Food and Drug Administration. Medical writing and editorial support were funded by argenx. Li Liu, Fien Gistelinck, Sophie Steeland, Benjamin Van Hoorick, Jana Podhorna, and Filip Borgions are employees of argenx. Jan Noukens is partner at Curare Consulting and is a paid consultant for argenx. James F. Howard, Jr has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the US National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), Patient-Centered Outcomes Research Institute, Ra Pharmaceuticals (now UCB Biosciences), and Millennium Pharmaceuticals/Takeda Pharmaceuticals; honoraria from AcademicCME, Alexion Pharmaceuticals, argenx BV, Biologix Pharma, F. Hoffman-LaRoche Ltd, Horizon Therapeutics plc, Merck EMD Serono, NMD Pharma, Novartis Pharmaceuticals, PeerView CME, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, and Sanofi US; and non-financial support from Alexion Pharmaceuticals, argenx BV, Ra Pharmaceuticals (now UCB Biosciences), Toleranzia AB, and ZaiLab. Tuan Vu serves as site principal investigator for MG clinical trials sponsored by argenx, Alexion, UCB/Ra, Cartesian, Horizon/Viela Bio, Janssen/Momenta, Regeneron, Immunovant, and Sanofi and has served as consultant and/or speaker for argenx, Alexion, and UCB/Ra. George Li has nothing to disclose. Denis Korobko has received speaker honoraria from Roche-Moscow, Novartis Russia, Sanofi, Merck, Janssen (Johnson & Johnson company), BIOCAD; research grants from Novartis Russia, UCB, argenx, Viela Bio Inc. (now Horizon Therapeutics), Sanofi, Bristol Myers Squibb, Hoffman-LaRoche Ltd.; and has served on scientific advisory boards for Novartis Russia, Merck, Janssen (Johnson & Johnson company), and BIOCAD. Marek Smilowski has nothing to report. Yuebing Li has served on advisory boards for argenx, Catalyst, Immunovant, and UCB Pharma and has received grant support from argenx. Kimiaki Utsugisawa has served as a paid consultant for argenx, UCB Pharma, Janssen Pharma, Viela Bio, Chugai Pharma, Merck, and Mitsubishi Tanabe Pharma and has received speaker honoraria from argenx, Alexion Pharmaceuticals, UCB Pharma, and the Japan Blood Products Organization. Heinz Wiendl receives honoraria for acting as a member of scientific advisory boards for AbbVie, Alexion, argenx, Bristol Myers Squibb, Janssen, Merck, Novartis, and Sandoz; has received speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, Genzyme, Merck, Neurodiem, Novartis, Ology, Roche, Teva, and WebMD Global; has received research funding from Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., European Union, Alexion, Amicus Therapeutics, argenx, Biogen, CSL Behring, F. Hoffmann-La Roche, Genzyme, Merck KgaA, Novartis, Roche Pharma, and UCB Biopharma; and is a paid consultant for AbbVie, Actelion, argenx, BD, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, INmune Bio, Syneos Health, Janssen, Merck, NexGen, Novartis, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB, and Worldwide Clinical Trials. Jan L. De Bleecker has served as a paid consultant for or received speaker honoraria from argenx, UCB Pharma, Alexion Pharmaceuticals, Sanofi, CSL Behring, and Roche. Renato Mantegazza has received funding for travel, meeting attendance, or advisory board participation from Alexion, argenx, Biomarin, Catalyst, Sanofi, Regeneron, and UCB., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objectives: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States., Methods: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use., Results: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy., Discussion: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab., (© 2024. The Author(s).)

Background: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG)., Methods: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded., Results: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab., Conclusions: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG., Competing Interests: Declaration of competing interest Dr. Brandsema has received research funding from Alexion, AstraZeneca Rare Disease, Momenta/Janssen, and Argenx; individual consulting fees from Momenta/Janssen and Argenx; and support in attending meetings from Alexion, AstraZeneca Rare Disease. Dr. Ginsberg reports that Alexion, AstraZeneca Rare Disease, sponsored the current research and associated costs including the provision of equipment needed for the conduct of the study. Dr. Rao has received research funding from Alexion, AstraZeneca Rare Disease, and NS Pharma; individual consulting fees from Biogen, AveXis/Novartis, Genentech/Roche, Sarepta Therapeutics, NS Pharma, Scholar Rock, PTC Therapeutics, and Regenxbio; honoraria from Biogen, AveXis/Novartis, Genentech/Roche, PTC therapeutics, France Foundation, and the Muscular Dystrophy Association; travel assistance from Cure SMA, NS Pharma, Biogen, AveXis/Novartis, and France Foundation, Neuropedicon; honoraria for attending advisory boards or data safety meetings from Capricor and Watermark, and expert testimony fees. Dr. Ruzhansky has received research funding from Argenx, Alexion, AstraZeneca Rare Disease, Alnylam, Corbus, UCB/Ra, Momenta Janssen, MGNet, and the Myasthenia Gravis Foundation of America; individual consulting fees from Guidepoint and GLG; honoraria from WebMD; support in attending meetings from MUSC and MGNet; and honoraria for attending advisory boards or data safety meetings from Argenx, Alexion, AstraZeneca Rare Disease, Amylyx, Immunovant, UCB/Ra, and Guidepoint. Dr. Suresh has received payment for speaking from Takeda Pharmaceuticals and for participating in advisory boards or data safety meetings from Alexion, AstraZeneca Rare Disease, and Argenx. Dr. Howard has received research support (paid to his institution) from Alexion, AstraZeneca Rare Disease, Argenx, BVBA, Cartesian Therapeutics, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Pharma), and Takeda Pharmaceuticals; honoraria from Alexion, AstraZeneca Rare Disease, Argenx, BVBA, Immunovant Inc, Ra Pharmaceuticals (now UCB Pharma), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio Inc (now Horizon Therapeutics); and nonfinancial support from Alexion, AstraZeneca Rare Disease, Argenx, BVBA, Ra Pharmaceuticals (now UCB Pharma), and Toleranzia AB. Drs. Frick, Hicks, and Liao are employees of and own stock in Alexion, AstraZeneca Rare Disease. No other disclosures were reported., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction/aims: The CHAMPION MG study demonstrated that ravulizumab significantly improved Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores versus placebo in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG). This post hoc analysis aimed to assess these outcomes by time from MG diagnosis., Methods: Changes from baseline to week 26 in MG-ADL and QMG total scores were analyzed by time from MG diagnosis to study entry (≤2 vs. >2 years). Within each subgroup, least-squares (LS) mean changes for ravulizumab and placebo were compared using mixed models for repeated measures., Results: In ravulizumab-treated patients, differences in LS mean (standard error of the mean) changes from baseline to week 26 were not statistically significant in the ≤2-years subgroup versus the >2-years subgroup for MG-ADL (-4.3 [0.70] vs. -2.9 [0.37]; p = .0511) or QMG (-4.3 [0.94] vs. -2.5 [0.50]; p = .0822) scores. No clear trends were observed in the placebo group. LS mean changes from baseline were significantly greater for ravulizumab versus placebo in both the ≤2 and >2 years from diagnosis subgroups for MG-ADL and QMG scores (all p < .05). The difference in treatment effect between the ≤2-years and >2-years subgroups was not statistically significant. No clinically meaningful between-subgroup differences in treatment-emergent adverse events were observed in ravulizumab-treated patients., Discussion: Ravulizumab treatment improved clinical outcomes for patients with AChR+ gMG regardless of time from diagnosis. A numerical trend was observed favoring greater treatment effect with earlier versus later treatment after diagnosis. Further studies are required for confirmation., (© 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Fatigue is a debilitating symptom of myasthenia gravis (MG). The impact of fatigue on MG can be assessed by Quality of Life in Neurological Disorders (Neuro-QoL) Short Form Fatigue scale. Transformation of raw Neuro-QoL fatigue scores to T-scores is a known approach for facilitating clinical interpretation of clinically meaningful and fatigue severity thresholds., Methods: In the Phase 3, double-blind, placebo-controlled RAISE study (NCT04115293), adults with acetylcholine receptor autoantibody-positive generalised MG (MG Foundation of America Disease Class II-IV) were randomised 1:1 to daily subcutaneous zilucoplan 0.3 mg/kg or placebo for 12 weeks. Patients completing RAISE could opt to receive zilucoplan 0.3 mg/kg in an ongoing, open-label extension study, RAISE-XT (NCT04225871). In this post-hoc analysis, we evaluated the long-term effect of zilucoplan on fatigue in RAISE patients who entered RAISE-XT. We report change in Neuro-QoL Short Form Fatigue T-scores and fatigue severity levels from RAISE baseline to Week 60., Results: Mean Neuro-QoL Short Form Fatigue T-scores improved from baseline to Week 12 in the zilucoplan group (n = 86) with a clinically meaningful difference versus placebo (n = 88; least squares mean difference: - 3.61 (nominal p-value = 0.0060]), and these improvements continued further to Week 60. At Week 12, more patients on zilucoplan (n = 34, 47.2%) experienced improvements in ≥ 1 fatigue severity level from baseline versus placebo (n = 23, 28.4%; p = 0.017). At Week 60, most (n = 55, 65.5%) patients had mild fatigue or none., Conclusion: Treatment with zilucoplan demonstrated statistical and clinically meaningful improvements in fatigue scores and severity versus placebo during RAISE, which were sustained to Week 60 in RAISE-XT., (© 2024. The Author(s).)

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments., Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population., Design: Ongoing, multicenter, phase III open-label extension (OLE) study., Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score., Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening ( n  = 52, 26%) and COVID-19 ( n  = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints., Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses., Trial Registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871)., (© The Author(s), 2024.)

Objective: ADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG)., Methods: ADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores., Results: As of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab-. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab- participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5-7.6])., Conclusion: Results of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG., Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403., Competing Interests: SS, CT’j, and BH are employees of argenx, Ghent, Belgium. AG was an employee of argenx during study execution and at the initiation of this manuscript; he is currently an independent consultant for the biotechnology and pharmaceutical industry. JH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Biosciences), and Millennium Pharmaceuticals/Takeda Pharmaceuticals; honoraria from AcademicCME, Alexion Pharmaceuticals, argenx, Biologix Pharma, F. Hoffman-LaRoche Ltd., Horizon Therapeutics, Immunovant Inc., Medscape CME, Merck EMB Serono, Novartis Pharmaceuticals, PeerView CME, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, Sanofi US, and Zai Laboratories; and non-financial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia AB. VB has participated in scientific advisory boards for CSL Behring, Baxalta, Grifols, argenx, Octapharma, Alpha Technologies, Powell Mansfield Inc., Shire, Akcea, UCB, and Alnylam. She has received funding for travel or speaker honoraria from CSL Behring and has consultancies with CSL Behring, Grifols, BioNevia, Octapharma, Powell Mansfield Inc., argenx, Alpha Technologies, Baxalta, Akcea, UCB, Alnylam, and Pfizer. TV served as site principal investigator for MG clinical trials sponsored by Alexion, argenx, Ra/UCB, Horizon/Viela Bio, Janssen/Momenta, Regeneron, and Cartesian Therapeutics and is a consultant for UCB, Alexion, Dianthus, and argenx. CK has participated in scientific advisory boards for CSL Behring, Takeda, argenx, AstraZeneca, Alexion, Alpine, Corino, Ionis, Sanofi, UCB, and Alnylam. He has received research funding from Ionis. JV has been involved in MG research sponsored by the Prinses Beatrix Spierfonds, Health Holland, and consultancies for argenx, Alexion, and NMD Pharma. Reimbursements were received by the LUMC. He is coinventor on patent applications based on MuSK-related research. He is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). SP has served as site principal investigator for MG clinical trials sponsored by argenx, Ra/UCB, Takeda/Millennium, and Alexion and is a consultant for argenx and Dianthus. JB has served as a paid consultant for or received speaker honoraria from argenx, UCB Pharma, Alexion Pharmaceuticals, Sanofi, and Biogen. HM has served as a paid consultant for Alexion, AstraZeneca Rare Disease, argenx, UCB Pharma, and Roche and has received speaker honoraria from the Japan Blood Products Organization and Chugai Pharmaceutical and research support from the Ministry of Health, Labour and Welfare, Japan. AM has served as advisor, consultant, principal investigator, or speaker and has received research grants (paid to his employer) and honoraria from Alexion, argenx, Axunio, Grifols, Hormosan, Janssen, Merck, Octapharma, and UCB. He serves as chair of the medical advisory board of the German Myasthenia Gravis Society. SB has participated in research studies sponsored by argenx, Sanofi, UCB, Regeneron, Genentech, Janssen, Amylyx, and Healey ALS. He is a paid consultant and speaker for Takeda, Alnylam, Alexion, Grifols, Amylyx, argenx, and CSL. MP has served as a consultant or medical advisor to Terumo BCT, Alexion, CSL Behring, Momenta, Catalyst, UCB, Immunovant, and Janssen. KU has served as a paid consultant for argenx, UCB Pharma, Janssen Pharma, Viela Bio, Chugai Pharma, Merck, and Mitsubishi Tanabe Pharma and has received speaker honoraria from argenx, Alexion Pharmaceuticals, UCB Pharma, and the Japan Blood Products Organization. RM has received funding for travel, meeting attendance, and advisory board participation from Alexion, argenx, Biomarin, Catalyst, Sanofi, Regeneron, and UCB., (Copyright © 2024 Howard, Bril, Vu, Karam, Peric, De Bleecker, Murai, Meisel, Beydoun, Pasnoor, Guglietta, Van Hoorick, Steeland, T’joen, Utsugisawa, Verschuuren, Mantegazza, the ADAPT+ Study Group.)

Background and Purpose: Generalized myasthenia gravis (gMG) is a rare, chronic, neuromuscular autoimmune disease mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Patients with gMG experience debilitating muscle weakness, resulting in impaired mobility, speech, swallowing, vision and respiratory function. Efgartigimod is a human IgG1 antibody Fc fragment engineered for increased binding affinity to neonatal Fc receptor. The neonatal Fc receptor blockade by efgartigimod competitively inhibits endogenous IgG binding, leading to decreased IgG recycling and increased degradation resulting in lower IgG concentration., Methods: The safety and efficacy of efgartigimod were evaluated in the ADAPT study. Key efficacy outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Efgartigimod demonstrated significant improvement in both the MG-ADL and QMG scores. This post hoc analysis aimed to determine whether all subdomains of MG-ADL and QMG improved with efgartigimod treatment. Individual items of MG-ADL and QMG were grouped into four subdomains: bulbar, ocular, limb/gross motor and respiratory. Change from baseline over 10 weeks in each subdomain was calculated for each group., Results: Greater improvements from baseline were seen across MG-ADL subdomains in participants treated with efgartigimod compared with placebo. These improvements were typically observed 1 to 2 weeks after the first infusion and correlated with reductions in IgG. Similar results were observed across most QMG subdomains., Conclusions: These post hoc analyses of MG-ADL and QMG subdomain data from ADAPT suggest that efgartigimod is beneficial in improving muscle function and strength across all muscle groups, leading to the observed efficacy in participants with gMG., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

This article provides a summary of a previously published paper: Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis. The paper reported the results of the CHAMPION-MG trial which investigated the drug ravulizumab in the rare disease, myasthenia gravis. Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis (MP4 594600 KB)., (© 2023. The Author(s).)

Objective: Better understanding the impact of social determinants of health (SDOH) barriers from the patient perspective is crucial to improve holistic patient support in generalized myasthenia gravis (gMG), a rare autoimmune disorder with high disease and treatment burden. The objective of this study was to identify economic challenges experienced by individuals living with gMG and SDOH barriers to better address current unmet needs., Methods: Adults (18-75 years) living with gMG and experiencing SDOH barriers in the United States were recruited to a mixed-methods study including qualitative interviews and a web-based quantitative survey. Quotas were implemented to include a balanced spread of baseline demographic categories including insurance type, living environment, and employment status among the study sample. Direct and indirect economic challenges were identified by degree of concern., Results: The survey was completed by 38 individuals living with gMG, the majority of whom were enrolled in public insurance and not employed. The most commonly reported major economic concerns were managing funds for emergency care (66%), loss of income (61%), and non-medical expenses (58%), highlighting the diversity of economic challenges. Individuals who were using public insurance plans, living in non-urban environments, and unemployed experienced pronounced challenges around managing non-medical costs and accessing government assistance., Conclusion: Both direct and indirect costs were emphasized as major concerns among individuals living with gMG and SDOH barriers. Increasing access to relevant, personalized, and holistic resources, including care management, should be prioritized to improve disease management and outcomes for individuals living with gMG., Competing Interests: TH, JG, and GP are employees of Argenx (Boston, MA, USA). JH has received research support (paid to his institution) from Alexion Pharmaceuticals, Argenx, Cartesian Therapeutics, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Biosciences), and Takeda Pharmaceuticals; and honoraria from Alexion Pharmaceuticals, argenx, F. Hoffman-LaRoche Ltd., Immunovant Inc., Merck EMD Serono, NMD Pharma, Novartis Pharmaceuticals, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, and Sanofi US; and non-financial support from Alexion Pharmaceuticals, argenx, Ra Pharmaceuticals (now UCB Biosciences) and Toleranzia AB. NS consults for argenx, Alexion Pharmaceuticals, UCB Biosciences, and Immunovant Inc. and is a speaker for argenx, Alexion Pharmaceuticals, and UCB Biosciences. AA is a Patient Education Speaker for argenx. MS and SS are employees of ZS Associates (New York, NY, USA) and serve as paid consultants for argenx., (Copyright © 2023 Hughes, Howard, Silvestri, Anderson, Sato, Suchotliff, Guptill and Phillips.)

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects., Methods: Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported., Results: Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was - 4.0 (95% CI: - 4.8, - 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was - 1.7 (95% CI: - 2.7, - 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported., Conclusion: Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis., Clinicaltrials: gov identifier: NCT03920293; EudraCT: 2018-003243-39., (© 2023. The Author(s).)

Background: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells., Methods: MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051., Findings: We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score., Interpretation: In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases., Funding: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health., Competing Interests: Declaration of interests VG has received honoraria as a consultant or advisory board member from Alexion Phermaceuticals, argenx, Immunovant, and Amylyx Pharmaceuticals and is employed by Biohaven Pharmaceuticals. MB received trial support and consulting fees from Alexion, Cartesian, Horizon, Immunovant, Sanofi, Takeda, UCB, and Ra Pharma. MK, MSS, and MVK are employees of and have ownership interest in Cartesian Therapeutics. MDM and CMJ are employees of Cartesian Therapeutics. CMJ is appointed as an employee of the University of Maryland and VA Maryland Health Care System. The views in this paper do not reflect the views of the state of Maryland or the US Government. GS has received research support from Cartesian Therapeutic, Immunovant, and argenx, paid to his institution; received consulting fees from UCB Pharma and Immunovant; received honoraria from argenx and Alexion; received travel support from argenx and Immunovant; and holds unpaid positions at the Myasthenia Gravis Foundation of California and the American Association of Neuromuscular and Electrodiagnostic Medicine. MHF has received honoraria as a consultant or advisory board member from argenx. TV is the University of South Florida site principal investigator for myasthenia gravis clinical trials sponsored by Alexion (now part of AstraZeneca), argenx, (now part of UCB), Horizon (now part of Viela Bio), Janssen (now part of Momenta), Regeneron, and Cartesian Therapeutics, and receives speaking or consulting honoraria relating to myasthenia gravis from Alexion, argenx, and UCB. JFH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), the Patient-Centered Outcomes Research Institute, Ra Pharmaceuticals (now UCB), and Takeda Pharmaceuticals; honoraria from Alexion Pharmaceuticals, argenx, Immunovant, NMD Pharma, Novartis Pharmaceuticals, Ra Pharmaceuticals (now UCB), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio (now Horizon Therapeutics); he has also received non-financial support from Alexion Pharmaceuticals, argenx, Ra Pharmaceuticals (now UCB), and Toleranzia. TM has served in an advisory capacity for Alexion, Amicus, AnnJi, argenx, Arvinas, Ask Bio, Audentes, AvroBio, Horizon Therapeutics, Immunovant, Maze Therapeutics, Momenta (now Janssen), Sanofi-Genzyme, Spark Therapeutics, UCB, and Zogenix; serves on the speaker's bureau for argenx and Sanofi-Genzyme; serves on the medical advisory board for the Myositis Association, Neuromuscular Disease Foundation, Myasthenia Gravis Foundation of California, and Myasthenia Gravis Foundation of America; receives research funding from the Myositis Association, the Muscular Dystrophy Association, the National Institutes for Health, Alexion, Amicus, AnnJi, argenx, Audentes (now part of Astellas) Gene Therapy, Bristol-Myers-Squib, Cartesian Therapeutics, Grifols, ML-Bio, Momenta, Ra Pharmaceuticals, Sanofi-Genzyme, Spark Therapeutics, and Valerion; and serves on the data safety monitoring board for Acceleron, Avexis, Sarepta, and the National Institutes for Health. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The terminal complement C5 inhibitor ravulizumab has a long elimination half-life, allowing maintenance dosing every 8 weeks. In the 26-week, double-blind, randomized, placebo-controlled period (RCP) of the CHAMPION MG study, ravulizumab provided rapid and sustained efficacy and was well tolerated in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). This analysis evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and potential immunogenicity of ravulizumab in adults with AChR Ab+ gMG., Methods: Data were analyzed from 86 patients who received ravulizumab in the CHAMPION MG RCP. Ravulizumab dosing was weight-based: initial loading dose of 2400/2700/3000 mg on Day 1 and maintenance doses of 3000/3300/3600 mg on Day 15 and then every 8 weeks. PK parameters were estimated from serum ravulizumab concentrations determined pre- and post-dose; PD effects of ravulizumab on serum free C5 concentrations were measured; and immunogenicity was assessed using anti-drug antibody and neutralizing-antibody assays., Results: Target serum ravulizumab concentrations (> 175 µg/mL) were achieved immediately after the first ravulizumab dose (within 30 min of infusion completion) and maintained throughout the 26-week treatment period irrespective of patient body weight. Following the final maintenance dose, mean C max was 1548 µg/mL and C trough 587 µg/mL; no meaningful differences were noted among body-weight categories. Inhibition of serum free C5 was immediate, complete (< 0.5 μg/mL), and sustained throughout treatment in all patients. No treatment-emergent anti-drug antibodies were observed., Conclusions: PK/PD evidence supports the use of ravulizumab every 8 weeks for immediate, complete, and sustained inhibition of terminal complement C5 in adults with AChR Ab+ gMG., Trial Registration: ClinicalTrials.gov ID: NCT03920293 (April 18, 2019)., (© 2023. The Author(s).)

Background: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis., Methods: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18-74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II-IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871)., Findings: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change -4·39 [95% CI -5·28 to -3·50] vs -2·30 [-3·17 to -1·43]; least squares mean difference -2·09 [-3·24 to -0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug., Interpretation: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study., Funding: UCB Pharma., Competing Interests: Declaration of interests JFH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx BVBA, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the US National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Biosciences), and Takeda Pharmaceuticals; honoraria from Alexion Pharmaceuticals, argenx BVBA, F Hoffman-LaRoche, Immunovant, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio (now Horizon Therapeutics); and non-financial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia. SB has served as a paid consultant for Sanofi Genzyme, Merck, Alexion, UCB, Biogen, and Bristol Myers Squibb. AG has served as a paid consultant for Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics. CH has received funding for consultancy on scientific or educational advisory boards for UCB Pharma, argenx, Lupin, Roche and Biogen. HJK is a consultant for Roche, Cabaletta Bio, Lincoln Therapeutics, Takeda, and UCB Pharmaceuticals; and is chief executive officer and chief marketing office of ARC Biotechnology, based on US Patent 8,961,98. He is principal investigator of the Rare Disease Network for Myasthenia Gravis National Institute of Neurological Disorders & Stroke, and Targeted Therapy for Myasthenia Gravis. AM received funding for travel, meeting attendance, or advisory board participation from CSL Behring and UCB. RM received funding for travel, meeting attendance, or advisory board participation from Alexion, argenx, BioMarin, Catalyst, Sanofi, Regeneron, and UCB. MM has served as a paid consultant for argenx and Alexion Pharmaceuticals, and has received speaker honoraria from Asahi Kasei Medical, argenx and Alexion Pharmaceuticals. KU has served as a paid consultant for UCB Pharma, argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, and Mitsubishi Tanabe Pharma; and has received speaker honoraria from argenx, Alexion Pharmaceuticals, and the Japan Blood Products Organization. TV is the USF Site Principal Investigator for myasthenia gravis clinical trials sponsored by Alexion/AstraZeneca, argenx, Ra/UCB, Horizon/Viela Bio, Janssen/Momenta, Sanofi, Regeneron, and Cartesian Therapeutics; and has received speaking or consulting honoraria from Alexion, argenx, and UCB. MDW has received honoraria for serving on scientific advisory boards for Alexion, UCB-Ra, argenx, Biogen, Mitsubishi Tanabe Pharma, and Amylyx; consulting honoraria from Cytokinetics and CSL Behring; and speaker honoraria from Soleo Health. He also serves as a special government employee for the US Food and Drug Administration. MZ has served as a paid consultant for Signant Health. MZ was an employee of Medical University of Warsaw, Warsaw, Poland, during the conduct of the study, but is currently employed by MTZ Clinical Research powered by Pratia. BB, Melissa Brock, GdlB, PWD, and MV are employees and shareholders of UCB Pharma. RL was a Veramed consultant for UCB Pharma during the conduct of the study. Veramed are a full-service provider for UCB Pharma. RL is employed by ONO Pharma UK. MIL is funded by the UK National Health Service (Myasthenia and Related Disorders Service and National Specialised Commissioning Group for Neuromyelitis Optica, UK) and by the University of Oxford, Oxford, UK. She has been awarded research grants from the UK association for patients with myasthenia, Myaware, and the University of Oxford. She has received speaker honoraria or travel grants from Biogen Idec, Novartis, argenx, UCB, and the Guthy-Jackson Charitable Foundation. MIL serves on scientific or educational advisory boards for UCB Pharma, argenx, and Viela/Horizon. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To compare the immunopathology of immune checkpoint inhibitor-induced myasthenia gravis (ICI-MG) and idiopathic MG, we profiled the respective AChR autoantibody pathogenic properties. Of three ICI-MG patients with AChR autoantibodies, only one showed complement activation and modulation/blocking potency, resembling idiopathic MG. In contrast, AChR autoantibody-mediated effector functions were not detected in the other two patients, questioning the role of their AChR autoantibodies as key mediators of pathology. The contrasting properties of AChR autoantibodies in these cases challenge the accuracy of serological testing in establishing definite ICI-MG diagnoses and underscore the importance of a thorough clinical assessment when evaluating ICI-related adverse events., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Racial/ethnic differences in diagnostic and treatment services have been identified for a range of health conditions and outcomes. The current study aimed to analyze whether there are racial/ethnic differences in the timing of diagnostic testing and treatments for males with Duchenne muscular dystrophy (DMD)., Methods: Diagnostic and clinical data for male individuals with DMD born during 1990-2010 were analyzed from eight sites (Arizona, Colorado, Georgia, Iowa, Piedmont Region of North Carolina, Western New York, South Carolina, and Utah) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Seven milestones related to diagnosis/treatment experiences were selected as outcomes. Times to each milestone were estimated and compared by four racial/ethnic groups using Kaplan-Meier estimation and Cox proportional-hazards models. Times between initial evaluation or diagnostic testing and later milestones were also compared by race/ethnicity., Results: We identified 682 males with definite or probable DMD of whom 61.7% were non-Hispanic white, 20.5% Hispanic, 10.6% other, and 7.2% non-Hispanic black. Seven milestone events were studied (initial evaluation, first neurology/neuromuscular visit, diagnosis, corticosteroid treatment first offered, corticosteroid treatment started, first electrocardiogram or echocardiogram, and first pulmonary function test). The first five milestone events occurred at an older age for non-Hispanic black individuals compared to non-Hispanic white individuals. Time to first offering of corticosteroids and initiation of corticosteroid therapy was later for Hispanic individuals compared to non-Hispanic white individuals. When accounting for timing of initial evaluation/diagnosis, offering of corticosteroids continued to occur later, but first pulmonary testing occurred earlier, among Hispanic individuals compared to non-Hispanic whites. No significant delays remained for non-Hispanic black individuals after accounting for later initial evaluation/diagnosis., Conclusion: We described racial/ethnic differences in ages at selected diagnostic and treatment milestones. The most notable differences were significant delays for five of seven milestones in non-Hispanic black individuals, which appeared to be attributable to later initial evaluation/diagnosis. Findings for Hispanic individuals were less consistent. Efforts to address barriers to early evaluation and diagnosis for non-Hispanic black children with DMD may promote more timely initiation of recommended disease monitoring and interventions., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: The scratch collapse test (SCT) is a clinical examination maneuver that has been previously reported as a reliable and reproducible test to diagnose carpal tunnel syndrome (CTS). The initial study by Cheng et al in 2008 showed a simple test with high sensitivity. However, subsequent attempts to reproduce those findings have resulted in lower accuracy. Our goal was to evaluate the use of the SCT for patients presenting with symptoms of pain, numbness, or weakness in an upper extremity. Methods: Forty patients were referred to the electrodiagnostic (EDX) lab for evaluation of an upper extremity. One blinded examiner who was familiar with the maneuver performed the SCT on all 40 patients. Another physician or technician performed the nerve conduction study and electromyography. Patient history and accompanying physical examination findings were not revealed to the SCT examiner. Results: The relationship between the SCT performed by a blinded examiner and the EDX performed by blinded examiners was nonsignificant ( P = .676) and showed a sensitivity of 0.48, specificity of 0.59, positive predictive value of 0.61, and negative predictive value of 0.45. Conclusion: Based on this study and previous findings by other authors, we would advise against the use of the SCT in CTS for important patient-care decisions, such as surgical decision-making, until future research is done. It is possible that the SCT, in combination with other physical examination maneuvers, could increase diagnostic accuracy and enhance patient management.

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here we describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera was shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell derived motoneurons. Patient autoantibody binding was sufficient to activate the classical complement pathway resulting in detection of C3b and C5b-9 deposits. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibited reductions in motoneuron action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody had no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 was sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential., Competing Interests: Competing interests: The authors confirm that competing financial interests exist but there has been no financial support for this research that could have influenced its outcome. MJS, MAA, NA and TH are employees of Sanofi and may hold shares and/or stock options in the company.

Abstract: We present the electrodiagnostic findings in a case of a 3-year-old girl presenting with sensory ataxia, gait disturbance, and visual-auditory disturbance with a genetically confirmed diagnosis of riboflavin transporter deficiency type 2 (RTD2). She carries a homozygous mutation in the SLC52A2 gene, c.1016T>C (p.Leu339Pro). Her testing demonstrates a non-length-dependent axonal sensorimotor polyneuropathy affecting predominantly the upper extremities with active denervation of the distal muscles of both arms. It is important to highlight these findings because most genetic neuropathies have a length-dependent pattern of involvement, affecting the distal legs before the arms. The electrodiagnostic findings in RTD2 have not been previously well described. These electrodiagnostic findings are in agreement with the typical clinical phenotype of RTD2, which affects the upper limbs and bulbar muscles more than the lower extremities., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Population-based estimates of survival among individuals with Duchenne muscular dystrophy (DMD) living in the United States are lacking. It is also unclear whether the association between glucocorticoid use and all-cause mortality persists in the context of other common treatments (cardiac medication, cough-assist, bilevel positive airway pressure, and scoliosis surgery) observed to delay mortality. Among 526 individuals identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network, the estimated median survival time from birth was 23.7 years. Current glucocorticoid users had a lower hazard of mortality than non-users. Individuals who ever had scoliosis surgery had a lower hazard of mortality than individuals who did not have scoliosis surgery. Individuals who ever used cough assist had a lower hazard of mortality than individuals who never used cough assist. Non-Hispanic Black individuals had a higher hazard of mortality than non-Hispanic White individuals. No differences in hazards of mortality were observed between ever versus never use of cardiac medication and ever versus never use of bilevel positive airway pressure. The glucocorticoid observation is consistent with the 2018 Care Considerations statement that glucocorticoid use continues in the non-ambulatory phase. Our observations may inform the clinical care of individuals living with DMD., Competing Interests: Declaration of Competing Interest Pangaja Paramsothy, Yinding Wang, Bo Cai, Kristin Conway, Shree Pandya, and Catharine Riley report none. Nicholas Johnson has received grant funding from NINDS (R01NS104010), NCATS (R21TR003184), CDC (U01DD001242) and the FDA (7R01FD006071-02). He receives royalties from the CCMDHI and the CMTHI. He receives research funds from Dyne, AveXis, CSL Behring, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio, Sarepta, and Acceleron Pharma. He has provided consultation for AveXis, AMO Pharma, Strongbridge BioPharma, Acceleron Pharma, Fulcrum Therapeutics, Dyne, Avidity, Arthex, and Vertex Pharmaceuticals. He receives licensing fees from the University of Rochester for the CCMDHI and CMTHI. He has received stock options from ML Bio. Emma Ciafaloni has received personal compensation for serving on advisory boards and/or as a consultant for Viela Bio, Avexis, Inc, Biogen, Medscape, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Ra pharma, Wave, and Strongbridge Biopharma plc. She has received personal compensation for serving on a speaker's bureau for Biogen. She has received research and/or grant support from the Centers for Disease Control and Prevention, CureSMA, Muscular Dystrophy Association, National Institutes of Health, Orphazyme, the Patient-Centered Outcomes Research Institute, Parent Project Muscular Dystrophy, PTC Therapeutics, Santhera, Sarepta Therapeutics, Orphazyme, and the US Food and Drug Administration. She has received royalties from Oxford University Press and compensation from Medlink for editorial duties. Katherine Mathews receives research funding from NIH U54 NS053672 and U24 NS-107181, the Friedreich's Ataxia Research Alliance, the Centers for Disease Control and Prevention (U01 DD001248) and serves as a site PI for clinical research sponsored by PTC Therapeutics Inc, Sarepta Therapeutics Inc, Pfizer Inc, FibroGen Inc, AMO, BMS, Reata, Retrotope, and Italfarmaco. She is an advisory board member for Sarepta Therapeutics Inc and Dyne Therapeutics. Paul Romitti has received support from PTC Therapeutics Inc. for work unrelated to the current study James Howard Jr. has received research support from Alexion Pharmaceuticals, argenx BVBA, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB) and Takeda Pharmaceuticals; Honoraria from Alexion Pharmaceuticals, argenx BVBA, Immunovant Inc., Ra Pharmaceuticals (now UCB), Regeneron Pharmaceuticals, Sanofi US and Viela Bio Inc. and non-financial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals (now UCB) and Toleranzia AB. He receives research support from Research Triangle Institute (the Centers for Disease Control and Prevention (Atlanta, GA, USA)) in support of this study, (Published by Elsevier B.V.)

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage., Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy., Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019)., Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66)., Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017., Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%])., Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy., Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Immune cells infiltrate the peripheral nervous system (PNS) after injury and with autoimmunity, but their net effect is divergent. After injury, immune cells are reparative, while in inflammatory neuropathies (e.g., Guillain Barré Syndrome and chronic inflammatory demyelinating polyneuropathy), immune cells are proinflammatory and promote autoimmune demyelination. An understanding of immune cell phenotypes that distinguish these conditions may, therefore, reveal new therapeutic targets for switching immune cells from an inflammatory role to a reparative state. In an autoimmune regulator (Aire)-deficient mouse model of inflammatory neuropathy, we used single-cell RNA sequencing of sciatic nerves to discover a transcriptionally heterogeneous cellular landscape, including multiple myeloid, innate lymphoid, and lymphoid cell types. Analysis of cell-cell ligand-receptor interactions uncovered a macrophage-mediated tumor necrosis factor-α (TNF-α) signaling axis that is induced by interferon-γ and required for initiation of autoimmune demyelination. Developmental trajectory visualization suggested that TNF-α signaling is associated with metabolic reprogramming of macrophages and polarization of macrophages from a reparative state in injury to a pathogenic, inflammatory state in autoimmunity. Autocrine TNF-α signaling induced macrophage expression of multiple genes ( Clec4e , Marcksl1 , Cxcl1 , and Cxcl10 ) important in immune cell activation and recruitment. Genetic and antibody-based blockade of TNF-α/TNF-α signaling ameliorated clinical neuropathy, peripheral nerve infiltration, and demyelination, which provides preclinical evidence that the TNF-α axis may be effectively targeted to resolve inflammatory neuropathies., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Eculizumab (ECU), a C5 complement inhibitor, is approved to treat acetylcholine receptor autoantibody positive generalized myasthenia gravis (AChR MG). The clinical effect of ECU relies on inhibition of the terminal complement complex; however, the effect of ECU on lymphocytes is largely unknown. We evaluated innate and adaptive immunity among AChR MG patients (N = 3) before ECU and ≥3 months later while on stable therapy, and found reduced activation markers in memory CD4 + T cell subsets, increased regulatory T cell populations, and reduced frequencies of CXCR5 + HLA-DR + CCR7 + Tfh subsets and CD11b + migratory memory B cells. We observed increases within CD8 + T cell subsets that were terminally differentiated and senescent. Our data suggest complement inhibition with ECU modulates the adaptive immunity in patients with MG, consistent with preclinical data showing changes in complement-mediated signaling by T- and antigen-presenting cells. These findings extend our understanding of ECU's mechanism of action when treating patients with MG., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Muscle-specific kinase (MuSK) antibody is seen in 4%-10% of patients with myasthenia gravis (MG), with 40% of these patients reporting bulbar weakness as the initial symptom. We present the case of a 40-year-old woman with MuSK MG whose only presenting symptom was progressive respiratory insufficiency necessitating BiPAP use 16-24 hours daily. She was unresponsive to treatment for cardiac and pulmonary causes and thus referred to neurology. Initial workup directed toward autoimmune and genetic myopathies was unrevealing. MuSK antibodies were positive (60.7 nmol/L, nl 0.00-0.02). Electrodiagnostic studies were unremarkable other than single fiber electromyography which was consistent with a defect in neuromuscular transmission. Treatment with prednisone, plasma exchange, and rituximab led to improvement to reliance on BiPAP only at night. However, her most treatment refractory and quality of life limiting symptom continues to be respiratory insufficiency. Further investigation to better characterize differential response to treatment in this subset of patients with MuSK MG may be needed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction/aims: Telemedicine may be particularly well-suited for myasthenia gravis (MG) due to the disorder's need for specialized care, its hallmark fluctuating muscle weakness, and the potential for increased risk of virus exposure among patients with MG during the coronavirus disease 2019 (COVID-19) pandemic during in-person clinical visits. A disease-specific telemedicine physical examination to reflect myasthenic weakness does not currently exist., Methods: This paper outlines step-by-step guidance on the fundamentals of a telemedicine assessment for MG. The Myasthenia Gravis Core Exam (MG-CE) is introduced as a MG-specific, telemedicine, physical examination, which contains eight components (ptosis, diplopia, facial strength, bulbar strength, dysarthria, single breath count, arm strength, and sit to stand) and takes approximately 10 minutes to complete., Results: Pre-visit preparation, remote ascertainment of patient-reported outcome scales and visit documentation are also addressed., Discussion: Additional knowledge gaps in telemedicine specific to MG care are identified for future investigation., (© 2021 Wiley Periodicals LLC.)

Objective: Generalized myasthenia gravis (gMG) is an autoimmune disease that causes disabling weakness via damage to the neuromuscular junction. In most patients, the disease is mediated by autoantibodies to the acetylcholine receptor, which activate the complement cascade. Our objective was to analyze response profiles in adult patients with anti-acetylcholine receptor antibody-positive refractory gMG treated with eculizumab-a terminal complement inhibitor-in the REGAIN study or its open-label extension (OLE)., Methods: We retrospectively analyzed Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores recorded during REGAIN and its OLE. Early/late responses were defined as improvement in MG-ADL score (≥3 points) or QMG score (≥5 points) at ≤12 or >12 weeks, respectively, after eculizumab initiation., Results: The analysis included 98 patients. By Week 12 and conclusion of the OLE, MG-ADL response had been achieved at some point by 67.3% and 84.7% of patients, respectively, and QMG response by 56.1% and 71.4%, respectively. Response was observed over multiple consecutive assessments for most patients. At Week 130, the least-squares mean percentage changes (95% CI) from baseline in MG-ADL score were -61.9% (-69.9%, -53.9%) and -47.5% (-59.0%, -36.0%) in early and late MG-ADL responders, respectively; the least-squares mean percentage changes from baseline in QMG score were -40.8% (-48.3%, -33.4%) and -55.5% (-68.4%, -42.7%) in early and late QMG responders, respectively., Interpretation: The findings suggest that, although most patients with refractory gMG will achieve clinical response by Week 12 of eculizumab treatment, first responses can be observed with longer-term treatment., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis., Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403)., Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21-11·53, p<0·0001). 65 (77%) of 84 patients in the efgartigimod group and 70 (84%) of 83 in the placebo group had treatment-emergent adverse events, with the most frequent being headache (efgartigimod 24 [29%] vs placebo 23 [28%]) and nasopharyngitis (efgartigimod ten [12%] vs placebo 15 [18%]). Four (5%) efgartigimod-treated patients and seven (8%) patients in the placebo group had a serious adverse event. Three patients in each treatment group (4%) discontinued treatment during the study. There were no deaths., Interpretation: Efgartigimod was well tolerated and efficacious in patients with generalised myasthenia gravis. The individualised dosing based on clinical response was a unique feature of ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further informed by the ongoing open-label extension., Funding: argenx., Competing Interests: Declaration of interests JFH has received research support from Alexion Pharmaceuticals, argenx, the Centers for Disease Control and Prevention (Atlanta, GA, USA), the Muscular Dystrophy Association, the National Institutes of Health (NIH; including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), Patient Centered Outcomes Research Institute, and Ra Pharmaceuticals (now UCB); honoraria from Alexion Pharmaceuticals, argenx, Immunovant, Ra Pharmaceuticals (now UCB), Regeneron Pharmaceuticals, and Viela Bio; and non-financial support from Alexion Pharmaceuticals, argenx, Ra Pharmaceuticals (now UCB), and Toleranzia. VB has received research support from Commonwealth Serum Laboratories, Grifols, UCB, Bionevia, Shire, and Octapharma. TVu has served as a speaker for Alexion; has done consulting work for argenx and UCB; and participated in trials in myasthenia gravis sponsored by NIH, Alexion Pharmaceuticals, argenx, Ra, Viela Bio, UCB, and Grifols. CK has served on advisory boards for Acceleron, Akcea, Alexion, Alnylam, argenx, Biogen, CSL Behring, Cytokinetics, and Sanofi-Genzyme; and received research grants from Genzyme and Akcea. SP reports lecture honoraria from Pfizer, Teva Actavis, Berlin Chemie Menarini, Mylan, Worwag, Adoc, and Salveo; research grants from Kedrion, Octapharma, and Argenx; consultant fees from argenx, Mylan, and Roche; and travel grants from Octapharma, Kedrion, Teva Actavis, Sanofi Genzyme, Pfizer, Roche, Adoc, and Berlin Chemie Menarini, all outside the submitted work. HM has served as a paid consultant for Alexion Pharmaceuticals, argenx, and Ra Pharma; and has received speaker honoraria from the Japan Blood Products Organization and research support from the Ministry of Health, Labor, and Welfare, Japan. AG, PU, and TVa are full-time employees of argenx, Ghent, Belgium. KU has served as a paid consultant for argenx, Ra Pharma, UCB Pharma, Viela Bio, and Regeneron Pharmaceuticals; and has received speaker honoraria from Alexion Pharmaceuticals and the Japan Blood Products Organization. JV receives research support from Target to B consortium, Prinses Beatrix Spierfonds, and argenx; has been involved in trials or consultancies for argenx, Alexion, and Ra pharma; JV is coinventor on patent applications based on MUSK-related research; and is a member of the European Reference Network for Rare Neuromuscular Diseases; and JV's institution received royalties from Immuno-Biological Laboratories. RM has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BioMarin, Catalyst, Alexion Pharmaceuticals, UCB, and argenx. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation., Areas Covered: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex., Expert Opinion: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.

Background: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG., Methods: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG., Results: An increase in CD19 + CD20 - CD38 hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004)., Conclusions: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future., (© 2020 Wiley Periodicals LLC.)

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., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Chronic, broad-spectrum immunosuppressive therapy (IST) can be associated with side effects in many people with generalized myasthenia gravis (gMG), and treatment guidelines recommend that the IST dose be tapered once patients achieve a stable treatment response. We therefore examined IST use in eculizumab-treated patients with refractory gMG. Methods: The REGAIN open-label extension (OLE) enrolled 117 adults with refractory anti-acetylcholine receptor antibody-positive gMG who had completed the 6-month, randomized, double-blind, placebo-controlled REGAIN study of eculizumab. Eligible patients had received ≥2 ISTs for ≥1 year or ≥1 IST with intravenous immunoglobulin or plasma exchange ≥4 times in 1 year, without symptom control. During REGAIN, changes in concomitant MG therapies were not permitted; during the OLE, they were permitted at the investigators' discretion. Participants received eculizumab 1,200 mg every 2 weeks for up to 4 years; concomitant prednisone and related corticosteroids (PRED), azathioprine (AZA), and mycophenolate mofetil (MMF) use was recorded. Changes in MG Activities of Daily Living and Quantitative MG total scores, MG exacerbations, and adverse events were also recorded. Results: At last OLE assessment, 88.0% (103/117) of participants were using ≥1 IST vs. 98.3% (115/117) at OLE baseline. During the OLE, 76.9% (90/117) of patients experienced a total of 719 IST changes. Almost half of participants [48.7% (57/117)] stopped or decreased ≥1 IST owing to MG symptom improvement, representing 38.9% (280/719) of all changes. In patients who decreased and/or stopped ≥1 IST, mean daily doses of PRED, AZA, and MMF decreased between OLE baseline and last assessment by 60.8% [standard deviation (SD), 28.07; P < 0.0001], 89.1% (SD, 25.77; P < 0.0001), and 56.0% (SD, 32.99; P < 0.0001), respectively. Improved clinical outcomes were observed with eculizumab regardless of IST changes during the OLE, and eculizumab's safety profile was similar in patients who used PRED, AZA, and MMF. Conclusions: Use of ISTs by patients with previously refractory gMG decreased during eculizumab treatment in the REGAIN OLE. Clinical improvements with eculizumab were maintained by patients in all groups, including those who decreased and/or stopped concomitant ISTs. Trial registration: www.clinicaltrials.gov: NCT01997229, NCT02301624., (Copyright © 2020 Nowak, Muppidi, Beydoun, O'Brien, Yountz, Howard and for the REGAIN study group.)

Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG)., Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected., Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years., Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status., (© 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Complement activation as a driver of pathology in myasthenia gravis (MG) has been appreciated for decades. The terminal complement component [membrane attack complex (MAC)] is found at the neuromuscular junctions of patients with MG. Animals with experimental autoimmune MG are dependent predominantly on an active complement system to develop weakness. Mice deficient in intrinsic complement regulatory proteins demonstrate a significant increase in the destruction of the neuromuscular junction. As subtypes of MG have been better defined, it has been appreciated that acetylcholine receptor antibody-positive disease is driven by complement activation. Preclinical assessments have confirmed that complement inhibition would be a viable therapeutic approach. Eculizumab, an antibody directed toward the C5 component of complement, was demonstrated to be effective in a Phase 3 trial with subsequent approval by the Federal Drug Administration of the United States and other worldwide regulatory agencies for its use in acetylcholine receptor antibody-positive MG. Second- and third-generation complement inhibitors are in development and approaching pivotal efficacy evaluations. This review will summarize the history and present the state of knowledge of this new therapeutic modality., (Copyright © 2020 Albazli, Kaminski and Howard.)