TY - JOUR
T1 - Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder
T2 - Subgroup analyses of the randomized controlled phase 3 PREVENT trial
AU - on behalf of the PREVENT Study Group
AU - Palace, Jacqueline
AU - Wingerchuk, Dean M.
AU - Fujihara, Kazuo
AU - Berthele, Achim
AU - Oreja-Guevara, Celia
AU - Kim, Ho Jin
AU - Nakashima, Ichiro
AU - Levy, Michael
AU - Terzi, Murat
AU - Totolyan, Natalia
AU - Viswanathan, Shanthi
AU - Wang, Kai Chen
AU - Pace, Amy
AU - Yountz, Marcus
AU - Miller, Larisa
AU - Armstrong, Róisín
AU - Pittock, Sean
N1 - Funding Information:
This work was funded by Alexion Pharmaceuticals. Jacqueline Palace is partly funded by highly specialized services to run a national congenital myasthenia service and a neuromyelitis service. She has received support for scientific meetings and fees for advisory work from Abide Therapeutics, Alexion Pharmaceuticals, argenx, Bayer Schering, Biogen Idec, Chugai Pharma, EuroImmun, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Teva, UCB, and Viela Bio (formerly MedImmune); grants from Abide Therapeutics, Alexion Pharmaceuticals, Bayer Schering, Biogen Idec, Chugai Pharma, Genzyme, MedImmune, Merck Serono, Novartis, and Teva; and grants from Amplo Biotechnology, Eugène Devic European Network, the Grant for Multiple Sclerosis Innovation, the John Fell Fund, the Medical Research Council, the MS Society, Myaware, the UK National Institute for Health Research, Oxford Health Services Research Committee, and The Guthy-Jackson Charitable Foundation for research studies. Dean M. Wingerchuk reports grants from Alexion Pharmaceuticals during the conduct of the study; and personal fees from Biogen, Celgene, Genentech, MedImmune, Novartis, Reistone Biopharma, TG Therapeutics, and Third Rock Ventures. Kazuo Fujihara reports personal fees and other support from Alexion Pharmaceuticals during the conduct of the study. Outside the submitted work, he has received personal fees and other support from Asahi Kasei Medical, Bayer, Biogen, Chugai Pharma, Eisai, Viela Bio (formerly MedImmune), Mitsubishi Tanabe Pharma, Novartis, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Takeda, and Teijin Pharma; and grants from the Ministry of Education, Science and Technology of Japan and the Ministry of Health, Welfare and Labor of Japan. Achim Berthele reports compensation for clinical trials received by his institution from Alexion Pharmaceuticals, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva; and personal fees and non-financial support from Bayer, Biogen, Celgene, Merck Serono, Mylan, Novartis, Roche, and Sanofi Genzyme. Celia Oreja-Guevara has received speaker fees from Biogen Idec, Celgene, Genzyme, Novartis, Roche, Sanofi Merck, and Teva. Ho Jin Kim has received a grant from the National Research Foundation of Korea; reports consultancy/speaker fees from Alexion Pharmaceuticals, Aprilbio, Celltrion, Eisai, HanAll BioPharma, Merck Serono, Novartis, Sanofi Genzyme, Teva-Handok, and Viela Bio (formerly MedImmune); serves on a steering committee for Viela Bio (formerly MedImmune); and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. Ichiro Nakashima reports personal fees from Biogen Japan, Mitsubishi Tanabe Pharma, Novartis, and Takeda; and grants from LSI Medience, the Ministry of Education, Science and Technology of Japan, and the Ministry of Health, Welfare and Labor of Japan. Michael Levy reports research support from Alexion Pharmaceuticals, Alnylam, Apopharma, Sanofi Genzyme, Takeda (formerly Shire), Viela Bio (formerly MedImmune), and ViroPharma; and serves as a consultant for Alexion Pharmaceuticals, ApoPharma, Chugai Pharma, MedImmune, Quest Diagnostics, Sanofi Genzyme, and Takeda (formerly Shire). Murat Terzi, Shanthi Viswanathan, and Kai-Chen Wang report no disclosures. Natalia Totolyan reports personal fees from Bayer, Janssen, Merck, Receptos, Roche, Sanofi Genzyme, and Teva; grants and personal fees from Actelion, BIOCAD (Russia), and Novartis; and grants from GeNeuro. Amy Pace, Marcus Yountz, and Larisa Miller are employees of and hold stock in Alexion Pharmaceuticals. Róisín Armstrong was an employee of and holds stock in Alexion Pharmaceuticals. Sean Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants from Autoimmune Encephalitis Alliance, and Grifols; grants, personal fees, non-financial support, and other support from MedImmune; other support from Astellas; and personal fees from UCB. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia) – issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive) – issued; a patent, GFAP-IgG – pending; a patent, Septin-5-IgG – pending; a patent, MAP1B-IgG – pending; and a patent, KLHL11 – pending.
Publisher Copyright:
© 2020 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - Background: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration: NCT01892345 (ClinicalTrials.gov).
AB - Background: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration: NCT01892345 (ClinicalTrials.gov).
KW - Aquaporin-4 immunoglobulin G-positive
KW - Eculizumab
KW - Neuromyelitis optica spectrum disorder
KW - Relapse
KW - Safety
KW - Subgroups
UR - http://www.scopus.com/inward/record.url?scp=85097469867&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097469867&partnerID=8YFLogxK
U2 - 10.1016/j.msard.2020.102641
DO - 10.1016/j.msard.2020.102641
M3 - Article
C2 - 33310418
AN - SCOPUS:85097469867
VL - 47
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
SN - 2211-0348
M1 - 102641
ER -