Eculizumab Shows Positives Results in Cutting Relapses of Neuromyelitis Optica Spectrum Disorder


A phase 3 trial of eculizumab found the drug reduced the frequency of relapse neuromyelitis optica spectrum disorder (NMOSD), an autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord.

A phase 3 trial of eculizumab found the drug reduced the frequency of relapse neuromyelitis optica spectrum disorder (NMOSD), an autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord.

Results were published recently in The New England Journal of Medicine and discussed last week at the 2019 American Academy of Neurology Annual Meeting, May 4-10, 2019 in Philadelphia.

Eculizumab (Soliris) is a particularly high-cost biologic that treats rare and ultra-rare diseases, and that faces upcoming biosimilar competition from products in development by numerous manufacturers.

The study was funded by Alexion Pharmaceuticals, which makes the innovator product Soliris; in a statement, the company said the FDA is reviewing the drug under priority review and set a Prescription Drug User Fee Act (PDUFA) action date of June 28, 2019. The drug is also under review by the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency for this indication.

Most cases of NMOSD are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. It affects mostly women and the prevalence is about 0.5 to 10 persons (predominantly women) per 100,000.

Immunosuppressive drugs, such as rituximab, are used off-label to prevent relapses in NMOSD, but 25% to 60% of patients receiving these medications continue to have recurrent attacks, which are frequently associated with complications such as blindness, paralysis, or even death. There is no currently approved treatment for NMOSD.

The randomized, double-blind, time-to-event trial took place at 70 sites in 18 countries. It assigned 143 adults in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first 4 doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or a matched placebo.

The continued use of stable-dose immunosuppressive therapy was permitted, except for rituximab, because of a conflict between its mechanism of action and that of the terminal complement inhibitor in eculizumab.

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).

The trial was stopped after 23 of the 24 prespecified adjudicated relapses, as decided by an independent panel, given that it wasn’t known when the last event would occur.

The patients who completed the trial could enter an extension trial and receive open-label treatment with eculizumab.

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], 0.02-0.20; P <.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, 0.01-0.15; P <.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 1 death from pulmonary empyema in the eculizumab group.

The researchers say there was no significant between-group difference in measures of disability progression.

The study had several limitations, according to the researchers. Among them, since only patients with AQP4-IgG antibodies were included, the findings cannot be generalized to patients without AQP4-IgG antibodies. In addition, no formal inferences could be made about other disability and quality-of-life outcomes overall, because the trial design precluded follow-up beyond 6 weeks after a single relapse and because the confidence interval for the between-group difference in the change from baseline in the EDSS score included zero in hierarchical testing, which implies there was no benefit of the drug on disability progression during the short trial. In addition, treating physicians identified more relapses than the adjudication committee.

However, the study said that was mostly due “to the interpretation of the objective change in the neurologic examination, which we assessed as reflecting concern among treating physicians that relapses should not be overlooked.”

Despite that, the study “a significantly lower risk of relapse with eculizumab than with placebo was apparent in the sensitivity analysis of physician-determined relapses.”


Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4—positive neuromyelitis optica spectrum disorder [published online May 3, 2019]. NEJM. doi: 10.1056/NEJMoa1900866.

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