Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension

Abstract

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks-5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan-Meier analysis; 95% confidence interval, 75.7-99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.

Keywords: Clinical trial; neuromyelitis optica (NMO).

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.J.P. reports grants, personal fees, and nonfinancial support from Alexion Pharmaceuticals; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, nonfinancial 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. K.F. 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, Mitsubishi Tanabe Pharma, Novartis, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Takeda, Teijin Pharma, and Viela Bio (formerly MedImmune); and grants from the Ministry of Education, Science and Technology of Japan and the Ministry of Health, Welfare and Labor of Japan. J.P. 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; grants from Abide Therapeutics, Alexion Pharmaceuticals, Bayer Schering, Biogen Idec, Chugai Pharma, Genzyme, MedImmune, Merck Serono, Novartis, and Teva; and grants for research studies from Eugène Devic European Network, Grant for Multiple Sclerosis Innovation, Guthy-Jackson Charitable Foundation, John Fell Fund, Medical Research Council, MS Society, Myaware, Oxford Health Services Research Committee, and UK National Institute for Health Research. A.B. 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 nonfinancial support from Alexion Pharmaceuticals, Bayer, Biogen, Celgene, Merck Serono, Mylan, Novartis, Roche, and Sanofi Genzyme. H.J.K. 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; 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. C.O.-G. has received speaker fees from Biogen Idec, Celgene, Genzyme, Novartis, Roche, Sanofi Merck, and Teva. I.N. 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. M.L. 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). S.S., M.Y., and L.M. are employees of and hold stock in Alexion Pharmaceuticals. R.A. was an employee of and holds stock in Alexion Pharmaceuticals. D.M.W. 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.

Figures

Figure 1.

Eculizumab monotherapy efficacy outcomes in patients not using concomitant immunosuppressive therapies. (a) Clinical profiles of patients receiving eculizumab monotherapy during PREVENT and OLE (n = 33). (b) Time to first adjudicated relapse in patients receiving eculizumab monotherapy during PREVENT and OLE. (c) Changes during PREVENT in mean (SD) disability scores by treatment group. (d) Changes during PREVENT in mean (SD) quality of life scores by treatment group. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the PREVENT study period (patients who did not enroll in the OLE) or at the OLE interim cutoff date (patients who enrolled in the OLE). The tick marks indicate censoring of data. Proportions of patients who were relapse-free at week 192 were estimated using the Kaplan–Meier product limit method; 95% CI was based on complementary log–log transformation. Table 1 presents a summary of baseline NMOSD disease characteristics and disease history for this group at eculizumab baseline. One patient in the placebo arm of PREVENT completed the study and did not enroll in the OLE; they were not included in this figure. a0–1 year, black (plain font); ⩾1–5 years, brown (bold font); ⩾5–10 years, green (italic font); ⩾10 years, red (bold italic font). bDuring the 24 months before PREVENT screening. cOne patient receiving eculizumab monotherapy experienced EDSS worsening during PREVENT: this patient’s EDSS score was 7.0 at baseline and 7.5 after 1025 days on study; this patient experienced no relapses (adjudicated or physician-determined) during PREVENT. dAnother patient receiving eculizumab monotherapy experienced HAI worsening during PREVENT: this patient’s HAI score was 8.0 at baseline and 9.0 after 321 days on study; this patient experienced no relapses (adjudicated or physician-determined) during PREVENT. ARR: annualized relapse rate; CI: confidence interval; EDSS: Expanded Disability Status Scale; EQ, EuroQol; EQ-5D-3L: EuroQol five-dimension three-level; HAI: Hauser Ambulation Index; IST: immunosuppressive therapy; mRS: modified Rankin scale; NMOSD: neuromyelitis optica spectrum disorder; OLE: open-label extension; SD: standard deviation; VAS: visual analog scale.