Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.

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.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

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.