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

2021; Elsevier BV; Volume: 20; Issue: 7 Linguagem: Inglês

10.1016/s1474-4422(21)00159-9

1474-4465

James F. Howard, Vera Bril, Tuan Vu, Chafic Karam, Stojan Perić, Temur Margania, Hiroyuki Murai, Małgorzata Bilińska, R Shakarishvili, Marek Śmiłowski, Antonio Guglietta, Peter Ulrichts, Tony Vangeneugden, Kimiaki Utsugisawa, Jan J.G.M. Verschuuren, Renato Mantegazza, Jan L. De Bleecker, Kathy de Koning, Katrien De Mey, Annelien De Pue, R. Mercelis, Maren Wyckmans, Caroline Vinck, Linda Wagemaekers, Jonathan Baets, Eduardo Ng, Jafar Shabanpour, Lubna Daniyal, Shabber Mannan, Hans Katzberg, Angela Genge, Zaeem A. Siddiqi, Jana Junkerová, Jana Hořáková, Katerina Reguliova, Michaela Týblová, Ivana Jurajdova, Iveta Nováková, Michala Jakubíková, Jiří Piťha, Stanislav Voháňka, Katerina Havelkova, Tomáš Horák, Josef Bednařík, Mageda Horakova, Andreas Meisel, Dike Remstedt, Claudia Heibutzki, Siegfried Köhler, Lea Gerischer, Sarah Hoffman, Frauke Stascheit, John Vissing, Lizzie Zafirakos, Kuldeep Kumar Khatri, Anne Ostergaard Autzen, Mads Stemmerik, Henning Andersen, Shahram Attarian, Emmanuelle Salort‐Campana, Émilien Delmont, Aude‐Marie Grapperon, Ludivine Kouton, Alexander Tsiskaridze, Csilla Rózsa, Gedeonne Jakab, Szilvia Z. Tóth, G Szabó, David Bors, Enikő Szabó, Angela Campanella, Fiammetta Vanoli, Rita Frangiamore, Carlo Antozzi, Silvia Bonanno, Lorenzo Maggi, Riccardo Giossi, Francesco Saccà, Angela Marsili, Chiara Pane, Giorgia Puorro, Antonio Reia, Giovanni Antonini, Girolamo Alfieri, Stefania Morino, Matteo Garibaldi, Laura Fionda, Luca Leonardi, Shingo Konno, Akiyuki Uzawa, Kaoru Sakuma, Chiho Watanabe, Yukiko Ozawa, Manato Yasuda, Yosuke Onishi, Makoto Samukawa, Tomoko Tsuda, Yasushi Suzuki, Sayaka Ishida, Genya Watanabe, Masanori Takahashi, Hiroko Nakamura, Erina Sugano, Tomoya Kubota, Tomihiro Imai, Mari Hotta Suzuki, Ayako Mori, Daisuke Yamamoto, Kazuna Ikeda, Shin Hisahara, Masayuki Masuda, Miki Takaki, Kanako Minemoto, Nobuhiro Ido, Makiko Naito, Yoshihiko Okubo, Takamichi Sugimoto, Yuka Takematsu, Ayumi Kamei, Mihiro Shimizu, Hiroyuki Naito, Eiichi Nomura, Marjolein Van Heur, Anne-Marie Peters, Martijn R. Tannemaat, Annabel M. Ruiter, Kevin R. Keene, Marek Halas, Andrzej Szczudlik, Marta Pinkosz, Monika Frasinska, G Zwolińska, Anna Kostera‐Pruszczyk, Aleksandra Golenia, Piotr Szczudlik, L Szczechowski, Aneta Paśko, И. Е. Повереннова, Lubov Urtaeva, Nadezhda Kuznetsova, Tatiana Romanova, Nadezhda Malkova, Elena Lapochka, D. S. Korobko, Ilona Vergunova, Anna Melnikova, Ekaterina Bulatova, Е.А. Антипенко, Ivana Basta, Ivo Božović, Dragana Lavrnić, Vidosava Rakočević Stojanović, Said R. Beydoun, Salma Akhter, Ali Malekniazi, Leila Darki, Norianne Pimentel, Victoria Cannon, Manisha Chopra, Rebecca Traub, Tahseen Mozaffar, Isela Hernandez, I C Turner, Ali A. Habib, Namita Goyal, Manisha Kak, Erik Velasquez, Lucy Lam, Niraja Suresh, Jerrica Farias, Sarah Jones, Mary Wagoner, D.J. Eggleston, Tulio E. Bertorini, Cindy Benzel, Robert Henegar, Rekha Pillai, Ratna Bharavaju-Sanka, Carolyn Paiz, Carlayne E. Jackson, Katherine Ruzhansky, Diana Dimitrova, Amy Visser, Nizar Chahin, Todd Levine, Robert P. Lisak, Kelly Jia, Flicia Mada, Evanthia Bernitsas, Mamatha Pasnoor, Katherine Roath, Samantha Colgan, Melissa Currence, Andrew Heim, Richard J. Barohn, Mazen M. Dimachkie, Jeffrey Statland, Omar Jawdat, Duaa Jabari, Constantine Farmakidis, James M. Gilchrist, Yuebing Li, Irys Caristo, Debbie Hastings, John A. Morren, Michael D. Weiss, Srikanth Muppidi, T. M. T. Nguyen, Lesly Welsh, Yuen T. So, Neelam Goyal, Michael Pulley, Cathy S. Bailey, Zubair Quraishi, Alan Ross Berger, Gregory Sahagian, Yasmin Camberos, Benjamin Frishberg,

Antifungal resistance and susceptibility

Summary 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.