If you’ve been scratching your myelin-rich heads over how to best treat patients with neuromyelitis optica spectrum disorder (NMOSD), you are not alone.
For many years NMSOD was considered a rare variant of MS. However, a pivotal moment in distinguishing NMOSD as a separate disorder from MS came in 2004 when researchers led by Dr. Vanda Lennon at the Mayo Clinic discovered the NMO-IgG antibody (later identified as targeting aquaporin-4). Over the next few years, it became apparent that the condition included a broader spectrum of presentations than originally thought. This led to the concept of NMO spectrum disorders (NMOSD). In 2015, the International Panel for NMO Diagnosis published new guidelines that formally defined NMOSD and provided criteria for diagnosis in both AQP4 antibody-positive and negative cases.
Before NMOSD was recognized as distinct from MS, patients were often treated with MS-specific therapies, which we now know can be ineffective or even harmful in NMOSD. In the mid to late 2000s, treatment strategies began to shift and by 2019 the first medication specifically for NMOSD was FDA approved. This medication was eculizumab, which is a humanized monoclonal antibody that inhibits terminal complement protein C5. In this Newsletter, we will review the landmark study that led to its approval.
The Prevention of Relapses in Neuromyelitis Optica (PREVENT) trial was a phase 3, randomized, double-blind, placebo-controlled, time-to-event trial published in the New England Journal of Medicine that enrolled patients with AQP4-antibody-positive NMOSD. Eligibility criteria included an Expanded Disability Status Scale (EDSS) score of ≤7 and a history of ≥2 relapses in the previous 12 months or ≥3 in the previous 24 months. Patients on stable immunosuppressive therapies were included, with exceptions for mitoxantrone, rituximab, intravenous immune globulin, or high-dose steroids. The primary endpoint was the first adjudicated relapse.
In a 2:1 randomization, 96 patients received eculizumab and 47 received a placebo. The adjudicated relapse rate was 3% in the eculizumab group versus 43% in the placebo group (hazard ratio, 0.06; 95% CI, 0.02 to 0.20; P<0.001). Secondary endpoints included a reduced annualized relapse rate (0.02 with eculizumab vs. 0.35 with placebo; P<0.001). Notably, the eculizumab group experienced a lower rate of serious adverse events compared to placebo (27 vs. 55 per 100 patient-years). Upper respiratory tract infections and headaches were more frequently reported in the eculizumab group.
While eculizumab was the first medication specifically approved for the treatment of NMOSD, it is now one of several; inebilizumab, a CD19-targeted B-cell depleting therapy, and satralizumab, an IL-6 receptor antagonist, were approved a year after eculizumab (2020). It is crucial for clinicians to familiarize themselves with these newer therapies as they become more prevalent.
So, whether you’re a seasoned NMOSD warrior or a fresh-faced resident still trying to spell ‘neuromyelitis’ correctly, we hope this study has illuminated your path forward. We encourage readers to share their thoughts and experiences with eculizumab in NMOSD treatment.
- Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
- Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189.Â
- Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866
- Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352-1363. doi:10.1016/S0140-6736(19)31817-3
- Yamamura T, Kleiter I, Fujihara K, et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(22):2114-2124. doi:10.1056/NEJMoa1901747
