Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, NewYork-Presbyterian Hospital
Dr. Perumal reports she is a consultant for Genzyme, EMD Serono, and Biogen.
SYNOPSIS: In a randomized, placebo-controlled trial of aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorders, eculizumab demonstrated a decrease in the risk of a relapse. Patients could continue their other stable-dose immune suppressive therapies while enrolled in the trial.
SOURCE: Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med 2019; May 3. doi: 10.1056/NEJMoa1900866. [Epub ahead of print].
Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that preferentially affects the optic nerves and spinal cord. Classic NMO, or Devic’s disease, is characterized by concurrent episodes of optic neuritis (ON) and transverse myelitis (TM). NMO spectrum disorder (NMOSD) is diagnosed in patients with isolated ON or TM who have the NMO IgG aquaporin-4 antibody, which is potentially pathogenic and has high specificity for this group of diseases. The anti-aquaporin-4 test is > 80% sensitive and > 99% specific for NMOSD. This distinction of NMOSD from multiple sclerosis is important as the disease course and treatment options for this disease are different from that of multiple sclerosis.
There are no FDA-approved treatments for NMOSD. Empirically, relapses are treated with a course of intravenous (IV) steroids, and steroid-refractory relapses are treated with IV immunoglobulin (IVIG) or plasma exchange. Long-term disease-modifying treatments that have been used in NMOSD include monthly pulse corticosteroids, repeated IVIG, azathioprine, mycophenolate mofetil, and rituximab.
Eculizumab, a humanized monoclonal antibody, is a complement inhibitor. It binds to complement protein C5, inhibiting its cleavage to C5a and C5b, which cause inflammatory injury. Data suggest that the aquaporin-4 antibody triggers a complement-mediated attack on astrocytes, resulting in injury and neuronal loss. The author of an earlier, small open-label study of 14 NMO patients demonstrated the efficacy of eculizumab in reducing relapses; hence, Pittock et al conducted this larger randomized, placebo-controlled trial.
They enrolled 143 aquaporin-4 antibody-positive patients from 70 international sites. Patients could continue their existing immune-modulating treatment, except for rituximab. Concomitant rituximab use was excluded because of a conflicting mechanism of action; B-cell lysis with rituximab is complement-dependent. The immune-suppressive medications that patients continued included long-term maintenance steroids, azathioprine with or without steroids, and mycophenolate mofetil.
Seventy-six percent of patients in the trial were on other concomitant immune suppressive treatments in addition to the study drug. Patients who had two relapses in the preceding 12 months or three relapses in the preceding 24 months were enrolled. An Expanded Disability Status Scale (EDSS) score of up to 7.0 was inclusive. Patients were randomized in a 2:1 manner to receive either eculizumab or placebo. Eculizumab was administered intravenously over 35 minutes as 900 mg doses every week for four weeks, followed by a maintenance dose of 1,200 mg every two weeks.
The primary endpoint was the first adjudicated relapse. Secondary outcomes included adjudicated relapse rate, quality of life measures, and disability as measured by EDSS. The trial was stopped after 23 of the 24 pre-specified relapses occurred. Adjudicated relapses occurred in three of 96 (3%) patients on eculizumab and 20 of 47 (43%) patients on placebo (hazard ratio, 0.06; 95% confidence interval, 0.02-0.20; P < 0.001). The annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (P < 0.001). Other endpoints, although favoring eculizumab treatment, were not statistically significant. In a prespecified analysis of monotherapy with eculizumab, none of the 21 patients who received eculizumab alone had a relapse, while seven of 13 patients in the corresponding placebo arm had relapses. With regard to adverse events, infections were more common in the eculizumab group compared to placebo, and there was a higher incidence of headaches. One person who was on eculizumab and azathioprine died of pulmonary empyema. Prior to treatment, patients were vaccinated against Neisseria meningitidis because of the potential risk of this specific infection.
Currently, there are no FDA-approved treatments for NMOSD. In a disease that is characterized by severe relapses and where the accrual of disability mainly is through residual deficits from relapses rather than progressive disease course, medications that decreases the risk of a relapse are vital in preventing disability. Based on this study, eculizumab was effective in decreasing the risk of a relapse in aquaporin-4 antibody-positive NMOSD patients. As per the study protocol, patients were allowed to continue their existing treatment, except for rituximab. About three-quarters of the patients were on some other immune-suppressive treatment during the trial. However, patients on eculizumab alone appeared to have a lower risk of a relapse as well.
With regard to co-medications, especially since rituximab is used to treat NMOSD, it is important to keep in mind that eculizumab cannot be combined with rituximab because of a conflicting mechanism of action. In addition to a general infection risk with immune suppression, an important specific issue for clinicians to consider is the potential risk of N. meningitidis infection with eculizumab, requiring vaccination prior to treatment. The dosing regimen for eculizumab would entail weekly IV infusions during the titration phase, followed after four weeks by a maintenance schedule of infusions every two weeks. Eculizumab treatment requires a significant time commitment from patients, but it offers the advantage of not having to take a medication every day once treatment is completed. In this trial, because of the relatively short duration and study design, long-term disability could not be assessed.
In summary, eculizumab was effective in reducing the risk of relapse in patients with NMOSD, three-quarters of whom continued their existing treatment. Given its unique mechanism of action, eculizumab offers a new avenue for the treatment of NMOSD. Further studies elucidating the risks vs. the benefits, long-term efficacy, and the optimal treatment regimen of monotherapy vs. combination therapy are warranted.