Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

Abstract

BACKGROUND:

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse.

METHODS:

In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death).

RESULTS:

The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval [CI], 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group.

CONCLUSIONS:

Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).

• Authors: Sean J Pittock, Achim Berthele, Kazuo Fujihara, Ho Jin Kim, Michael Levy, Jacqueline Palace, Ichiro Nakashima, Murat Terzi, Natalia Totolyan, Shanthi Viswanathan, Kai-Chen Wang, Amy Pace, Kenji P Fujita, Róisín Armstrong, Dean M Wingerchuk
• Journal: The New England journal of medicine (N Engl J Med) Vol. 381 Issue 7 Pg. 614-625 (08 15 2019) ISSN: 1533-4406 [Electronic] United States
• PMID: 31050279 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Massachusetts Medical Society.

Chemical References

• Antibodies, Monoclonal, Humanized
• Aquaporin 4
• Autoantibodies
• Complement C5
• Complement Inactivating Agents
• Immunoglobulin G
• Immunosuppressive Agents
• eculizumab

Topics

• Adult
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Aquaporin 4 (immunology)
• Autoantibodies (blood)
• Complement C5 (antagonists & inhibitors)
• Complement Inactivating Agents (adverse effects, therapeutic use)
• Disability Evaluation
• Disease Progression
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Headache (chemically induced)
• Humans
• Immunoglobulin G (blood)
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Male
• Neuromyelitis Optica (drug therapy, immunology)
• Quality of Life
• Respiratory Tract Infections (etiology)
• Secondary Prevention