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Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study., Methods: Vivacity-MG3 was a phase 3, randomised, double-blind, placebo-controlled, phase 3 study conducted at 81 outpatient centres with expertise in myasthenia gravis in 17 countries in Asia-Pacific, Europe, and North America. Adults (aged ≥18 years) with generalised myasthenia gravis inadequately controlled with standard-of-care therapy (MG-ADL score ≥6) were randomly assigned (1:1) to either nipocalimab (30 mg/kg loading dose then 15 mg/kg every 2 weeks for maintenance dosing) or placebo infusions every 2 weeks, added to standard-of-care therapy in both groups, for 24 weeks. Randomisation was stratified by antibody status, day 1 MG-ADL total score, and region. The sponsor, investigators, clinical raters, and participants were masked to treatment assignment. The primary endpoint was the difference between nipocalimab and placebo based on least-squares mean change from baseline in MG-ADL total score averaged over weeks 22, 23, and 24 in the intention-to-treat population of patients who were antibody-positive (for AChR, anti-muscle-specific tyrosine kinase [MuSK], or anti-low-density lipoprotein receptor-related protein 4 [LRP4]). Adverse events were assessed in patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT04951622; the double-blind phase is completed and an open-label extension phase is ongoing., Findings: Between July 15, 2021, and Nov 17, 2023, 199 patients were enrolled, and 196 patients received study drug (98 in the nipocalimab group and 98 in the placebo group); of these, 153 (77 in the nipocalimab group and 76 in the placebo group) were antibody-positive. The least-squares mean change in MG-ADL score from baseline to weeks 22, 23, and 24 was -4·70 (SE 0·329) in the nipocalimab group versus -3·25 (0·335) in the placebo group (difference -1·45 [95% CI -2·38 to -0·52]; p=0·0024). The incidence of adverse events was similar between groups (82 [84%] of 98 in both the nipocalimab and placebo groups), including infections (42 [43%] of 98 in the nipocalimab group and placebo group) and headache (14 [14%] of 98 in the nipocalimab group and 17 [17%] of 98 in the placebo group). Serious adverse events were reported for nine (9%) of 98 patients in the nipocalimab group and 14 (14%) of 98 patients in the placebo group, three of which had a fatal outcome (nipocalimab: myasthenic crisis; placebo: cardiac arrest and myocardial infarction)., Interpretation: Results from the completed double-blind phase of Vivacity-MG3 support the role of nipocalimab, added to standard-of-care therapies, as a safe treatment for sustained disease control over 6 months for a broad population of patients with generalised myasthenia gravis who are antibody-positive. The ongoing open-label extension phase should provide longer term sustained safety and efficacy data with nipocalimab., Funding: Janssen Research & Development, LLC, a Johnson & Johnson company., Competing Interests: Declaration of interests SR, EY, PS, KK, YZ, JJS, and HS are employees of Janssen Research & Development or Janssen Global Services (Johnson & Johnson companies) and might hold stock or stock options in Johnson & Johnson. CA received funding for travel, meeting attendance, and advisory board participation from Alexion, Momenta, Sanofi, argenx, UCB, and Janssen Pharmaceuticals. TV has received research or grant support related to myasthenia gravis from Alexion and AstraZeneca Rare Disease, Amgen, argenx, Cartesians, COUR, Dianthus, Immunovant, Johnson & Johnson, NMD Pharma, Regeneron, and UCB. TV serves as a consultant or on speaker bureaus for Alexion and AstraZeneca Rare Disease, Amgen, argenx, CSL Behring, Dianthus, Johnson & Johnson, and Takeda. RJN has received research support from Alexion, AstraZeneca Rare Disease, argenx, Genentech, Grifols, Immunovant, Momenta Pharmaceuticals (now Janssen), the Myasthenia Gravis Foundation of America, the National Institutes of Health (National Institute of Neurological Disorders and Stroke and National Institute of Allergy and Infectious Diseases), Ra Pharmaceuticals (now UCB), and Viela Bio (Horizon Therapeutics, now Amgen), and has served as consultant or advisor for Alexion, AstraZeneca Rare Disease, argenx, Cour Pharmaceuticals, Immunovant, Momenta Pharmaceuticals (now Janssen), Ra Pharmaceuticals (now UCB), and Viela Bio (Horizon Therapeutics, now Amgen). CF has served as a consultant or advisor for Argenx, Momenta and Janssen, the Muscular Dystrophy Association, and UCB. VB has received research support from AZ-Alexion, Grifols, CSL, UCB, argenx, Takeda, Octapharma, Akcea, Momenta (Johnson & Johnson), Immunovant, Ionis, and Viela. JDB has served on an advisory board for Argenx, Alexion Pharmaceuticals, CSL, UCB Pharma, Janssen Pharmaceuticals, and Sanofi Genzyme. TS has received honoraria for attendance at advisory boards from Argenx, Alnylam, Pfizer, and UCB. SH has received speakers' honoraria from Alexion, Argenx, UCB, Grifols, Roche, and Janssen and honoraria for attendance at advisory boards from Alexion, Argenx, and Roche. SH is member of the medical advisory board of the German Myasthenia Society, DMG. HY, EM, J-SP, MG, MS, KS, and YS report no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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: 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.)