Adding the humanized recycling monoclonal antibody satralizumab to standard immunosuppressant therapy for neuromyelitis optica spectrum disorder (NMOSD) reduced relapse risk in a phase 3 study.
Compared to placebo, satralizumab (Chugai Pharmaceuticals) decreased relapses from more than one half to approximately two thirds over a median treatment period of almost 3 years.
Lead author Takashi Yamamura, MD, PhD, director of the Department of Immunology at the National Institute of Neuroscience, National Center of Neurology and Psychiatry in Tokyo, first presented the primary findings at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2018, as previously reported by Medscape Medical News.
The complete double-blind, randomized study findings were published online November 28 in the New England Journal of Medicine.
NMOSD is an autoimmune inflammatory disease that often targets the optic nerve and spinal cord through an aquaporin-4 (AQP4) autoantibody mechanism. Satralizumab could provide a sustained beneficial effect, researchers believe, because it is a recycling monoclonal antibody with a long plasma circulation time. The agent targets interleukin-6 (IL-6) receptors; previous reports showed that during relapses, IL-6 levels were increased in cerebral spinal fluid and in serum.
"Compared with other drugs, it seems that IL-6 receptor blockade may have advantages with regards to its potential to induce regulatory cells," Yamamura said.
In this current trial, a total of 83 patients were enrolled; 41 received active treatment, and 42 received placebo. Median treatment duration with satralizumab in the double-blind period was 107.4 weeks.
Relapse, the primary endpoint, was seen in eight patients (22%) who received active treatment and in 18 (43%) who received placebo (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.16 – 0.88).
The journal report includes new calculations concerning the primary relapse rate outcome that was requested by a reviewer, Yamamura said.
"Analyses with the use of multiple imputations for censored data for the primary endpoint, which excluded patients who were still continuing in the trial at the data cutoff date, resulted in hazard ratios ranging from 0.34 to 0.44, with log rank P values of 0.01 to 0.04," he said.
The full study also includes secondary endpoint results not presented at ECTRIMS. For instance, adjunctive therapy with satrizumab did not significantly alter reported pain or fatigue levels, "key" secondary endpoints, compared with placebo.
Pain and fatigue were measured using the change from baseline to week 24 in the visual analogue scale (VAS) pain score (range, 0 to 100, with higher scores indicating more pain) and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicating more fatigue).
The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, −8.44 to 16.61); the between-group difference in the change in the mean FACIT-F score was −3.10 (95% CI, −8.38 to 2.18).
Rates of serious adverse events and infections did not differ between groups, the authors note.
The new report also continues to support greater efficacy of the agent among participants who are AQP4-IgG positive, although AQP4-negative patients may receive the drug with additional immunosuppressants, Yamamura told Medscape Medical News.
Among the 55 AQP4-IgG–seropositive patients, relapse occurred in 11% of those who received satralizumab and in 43% of those who received placebo (HR, 0.21; 95% CI, 0.06 – 0.75). Of 28 AQP4-IgG–seronegative patients, relapse occurred in 36% of those who received satralizumab and in 43% of those who received placebo (HR, 0.66; 95% CI, 0.20 – 2.24).
Going forward, long-term safety and efficacy of this treatment should be clarified, Yamamura said. In addition, AQP-4–positive patients should be evaluated separately in the future.
"Time Will Tell"
"This is a novel mechanism, with the medication directly targeting a pathway that we know is important to the pathogenesis of the disease," Asaff Harel, MD, a neurologist at Lenox Hill Hospital Northwell Health in New York City, told Medscape Medical News when asked to comment.
This was an "add-on" study, in which satralizumab or placebo was added to azathioprine, mycophenolate, or steroids, and patients taking rituximab were excluded, Harel noted. "As B-cell therapy such as rituximab has started to supplant azathioprine and mycophenolate as the mainstay of treatment for NMO, the generalizability of the present study is somewhat limited.
"However, its mode of administration is appealing, giving patients more freedom by avoiding the need for daily pills or cumbersome infusions.
"Time will tell whether it can be used as a monotherapy in NMO and how it stacks up against current options," Harel said. "As of now, it would provide another option with a unique mechanism in the armamentarium against this severe neurological condition."
Chugai Pharmaceutical Co Ltd funded the study. Yamamura has served on Chugai's scientific advisory board and has received research grants and speaker honoraria from Chugai. Harel has disclosed no relevant financial relationships.
N Engl J Med. Published online November 28, 2019. Abstract
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Cite this: Antibody Cuts NMOSD Relapses but Pain and Fatigue Unaltered - Medscape - Dec 05, 2019.