Long-term safety and efficacy of eculizumab in generalized myasthenia gravis
Srikanth Muppidi, Kimiaki Utsugisawa, Michael Benatar, Hiroyuki Murai, Richard J Barohn, Isabel Illa, Saiju Jacob, John Vissing, Ted M Burns, John T Kissel, Richard J Nowak, Henning Andersen, Carlos Casasnovas, Jan L de Bleecker, Tuan H Vu, Renato Mantegazza, Fanny L O'Brien, Jing Jing Wang, Kenji P Fujita, James F Howard Jr, Regain Study Group
Abstract
Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy.
Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients.
Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001).
Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.
Keywords: MG-ADL; MG-QOL15; MGC; QMG; eculizumab; myasthenia gravis.
© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.
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References
- Conti‐Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006;116:2843–2854.
- Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976;26:1054–1059.
- Mantegazza R, Pareyson D, Baggi F, Romagnoli P, Peluchetti D, Sghirlanzoni A, et al Anti‐AChR antibody: relevance to diagnosis and clinical aspects of myasthenia gravis. Ital J Neurol Sci 1988;9:141–145.
- Vincent A, McConville J, Farrugia ME, Bowen J, Plested P, Tang T, et al Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 2003;998:324–335.
- Vincent A, Newsom‐Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985;48:1246–1252.
- Oh SJ, Kim DE, Kuruoglu R, Bradley RJ, Dwyer D. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992;15:720–724.
- Somnier FE. Clinical implementation of anti‐acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry 1993;56:496–504.
- Biesecker G, Gomez CM. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J Immunol 1989;142:2654–2659.
- Christadoss P. C5 gene influences the development of murine myasthenia gravis. J Immunol 1988;140:2589–2592.
- Karachunski PI, Ostlie NS, Monfardini C, Conti‐Fine BM. Absence of IFN‐γ or IL‐12 has different effects on experimental myasthenia gravis in C57BL/6 mice. J Immunol 2000;164:5236–5244.
- Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J Neuroimmunol 1996;71:173–177.
- Fumagalli G, Engel AG, Lindstrom J. Ultrastructural aspects of acetylcholine receptor turnover at the normal end‐plate and in autoimmune myasthenia gravis. J Neuropathol Exp Neurol 1982;41:567–579.
- Conti‐Tronconi B, Tzartos S, Lindstrom J. Monoclonal antibodies as probes of acetylcholine receptor structure. 2. Binding to native receptor. Biochemistry 1981;20:2181–2191.
- Howard JF Jr., Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al Safety and efficacy of eculizumab in anti‐acetylcholine receptor antibody‐positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double‐blind, placebo‐controlled, multicentre study. Lancet Neurol 2017;16:976–986.
- Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med 2013;86:255–260.
- Buzzard KA, Meyer NJ, Hardy TA, Riminton DS, Reddel SW. Induction intravenous cyclophosphamide followed by maintenance oral immunosuppression in refractory myasthenia gravis. Muscle Nerve 2015;52:204–210.
- Silvestri NJ, Wolfe GI. Treatment‐refractory myasthenia gravis. J Clin Neuromuscul Dis 2014;15:167–178.
- Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al International consensus guidance for management of myasthenia gravis: executive summary. Neurology 2016;87:419–425.
- Howard JF Jr. Myasthenia gravis: the role of complement at the neuromuscular junction. Ann N Y Acad Sci 2018;1412:113–128.
- Engel‐Nitz NM, Boscoe AN, Wolbeck R, Johnson J, Silvestri NJ. Burden of illness in patients with treatment refractory myasthenia gravis. Muscle Nerve 2018;58:99–105.
- Jani‐Acsadi A, Lisak RP. Myasthenic crisis: guidelines for prevention and treatment. J Neurol Sci 2007;261:127–133.
- Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 2007;25:1256–1264.
- McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. Am J Transplant 2017;17:2481–2484.
- Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology 1999;52:1487–1489.
- Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci 1998;841:769–772.
- Burns TM, Conaway M, Sanders DB; MG‐Qol Study Group . The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010;74:1434–1440.
- Burns TM, Grouse CK, Conaway MR, Sanders DB; MG‐QOL15 Study Group. Construct and concurrent validation of the MG‐QOL15 in the practice setting. Muscle Nerve 2010;41:219–226.
- Muppidi S. The myasthenia gravis–specific activities of daily living profile. Ann N Y Acad Sci 2012;1274:114–119.
- Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve 2014;49:661–665.
- Muppidi S, Wolfe GI, Conaway M, Burns TM, the MG Composite and MG‐QOL15 Study Group. MG‐ADL: still a relevant outcome measure. Muscle Nerve 2011;44:727–731.
- Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55:16–23.
- Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233–1243.
- Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux‐Bacchi V, French Study Group for a HCG . Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643–657.
- Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 2012;12:3337–3354.
- Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, et al Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double‐blind clinical trial. Arch Neurol 2005;62:1689–1693.
- Zhou Y, Gong B, Lin F, Rother RP, Medof ME, Kaminski HJ. Anti‐C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis. J Immunol 2007;179:8562–8567.
- Kusner LL, Satija N, Cheng G, Kaminski HJ. Targeting therapy to the neuromuscular junction: proof of concept. Muscle Nerve 2014;49:749–756.
- Huda R, Tuzun E, Christadoss P. Complement C2 siRNA mediated therapy of myasthenia gravis in mice. J Autoimmun 2013;42:94–104.
Source: PubMed