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Despite off-label treatment with immunosuppressive regimens such as azathioprine and rituximab, many individuals with neuromyelitis optica spectrum disorder (NMOSD) have relapses, which often lead to accumulating permanent disability. Preclinical studies suggest that activation of the complement cascade leads to neuronal injury in NMOSD. Researchers conducted an industry-sponsored, phase 3, randomized, double-blind, placebo-controlled trial of eculizumab, a humanized monoclonal antibody that inhibits cleavage of the complement protein C5, in preventing relapses in aquaporin-4 positive (AQP4+) NMOSD.
Of 143 adults with AQP4+ NMOSD enrolled within 48 hours of a relapse, 96 were randomized to eculizumab and 47 to placebo. Participants could remain on prior immunosuppressive regimens, except for rituximab use in the preceding 3 months. The primary endpoint was first relapse adjudicated by a blinded board. The study lasted until 23 patients had a relapse. Secondary endpoints included first relapse as determined by the treating physician, disability progression, and safety endpoints.
Adjudicated relapse occurred in 3% of eculizumab-treated patients and 43% of placebo-treated patients, a significant difference. Annualized relapse rate and relapses diagnosed by the treating physician were also significantly lower with eculizumab, but measures of disability progression did not differ between treatment groups. Except for upper respiratory tract infections and headache, adverse events were similar between treatment groups.
Pittock SJ et al. Eculizumab in aquaporin-4–positive neuromyelitis optica spectrum disorder. N Engl J Med 2019 May 3; [e-pub]. (https://doi.org/10.1056/NEJMoa1900866)
Comment
In this trial, AQP4+ NMOSD relapses were substantially less frequent with eculizumab than placebo. Most study participants remained on other immunosuppressive medications. Eculizumab may be an effective treatment option to prevent many NMOSD relapses — and potentially their associated accumulating disability. Disability scales showed no differences, but the trial's small size and relatively short follow-up time may have limited detection of a difference. The sponsoring pharmaceutical company controlled the study design, data analysis, and unblinding procedures. Patients with NMOSD who were AQP4-negative and those receiving rituximab were excluded from this study, thus limiting its generalizability to a substantial proportion of patients with NMOSD. Eculizumab is currently FDA-approved for other uses but not for NMOSD.