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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.)