Eculizumab cuts relapse risk in NMOSD
The terminal complement inhibitor eculizumab significantly lowered relapse risk in patients with neuromyelitis optical spectrum disorder (NMOSD) who were positive for aquaporin-4 antibodies (AQP4-IgG) compared with placebo, according to the PREVENT* study presented at AAN 2019.
NMOSD is a rare relapsing, inflammatory, autoimmune disorder of the central nervous system that affects 0.5–10 in 100,000 persons. Majority of the cases are associated with AQP4-IgG believed to cause demyelination and axonal damage which primarily affects the spinal cord and optic nerves.
NMOSD is typically characterized by recurrent myelitis and optic neuritis, and recovery is often poor after such attacks. Thus far, no treatment has been approved for relapse prevention and such event is commonly managed with off-label immunosuppressive therapies.
“Among patients with AQP4-IgG–positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo,” the researchers found.
In the global, double-blind, phase III trial, 143 adults (mean age 44.3 years, 91 percent female) with AQP4-IgG–positive NMOSD were randomized 2:1 to receive intravenous eculizumab (900 mg weekly for first 4 weeks followed by 1,200 mg fortnightly as maintenance) or a matching placebo. Concomitant immunosuppressive therapy, except rituximab, was allowed during the study. [AAN 2019, abstract ES.009; N Engl J Med 2019;doi:10.1056/NEJMoa1900866]
At the end of the trial after 23 on-trial relapses, the primary endpoint of the first adjudicated relapse occurred in fewer patients in the eculizumab arm vs the placebo arm (3 percent vs 43 percent), corresponding to a 94 percent reduction in risk of relapse (hazard ratio [HR], 0.06; p<0.001). Most of the relapses were of myelitis.
Eculizumab also significantly reduced the adjudicated annualized relapse rate to 0.02 compared with 0.35 in the placebo arm (rate ratio, 0.04; p<0.001).
However, measures of disability progression were not significantly different between the two groups, as indicated by the change from baseline in the EDSS** score (mean, -0.18 vs 0.12).
In terms of safety, adverse events (AEs) occurred at a rate of 745 per 100 patient-years (PY) in the eculizumab arm compared with 1,127 per 100 PY in the placebo arm. Headache (55 vs 38 events per 100 PY) and upper respiratory tract infection (31 vs 19 events per 100 PY) were more common among patients receiving eculizumab than placebo.
One eculizumab-treated patient died from pulmonary empyema associated with Streptococcus intermedius and Peptostreptococcus micros, which the researchers said were not associated with complement deficiency. There were no reports of meningococcal infection during the trial.
“By blocking the terminal complement system, eculizumab increases the risk of meningococcal and encapsulated bacterial infection. In our trial, all the patients received meningococcal vaccination, and no cases of meningococcal infection were reported,” explained the researchers.
As the trial only included patients who were positive for AQP4-IgG antibodies, the researchers cautioned against extrapolating the findings to patients without the antibodies.
“Since there was no significant between-group difference in measures of disability progression, the long-term effect of eculizumab in patients with NMOSD warrants further study,” they suggested.