Satralizumab Slashes Relapse Rate in Neuromyelitis Optica

Damian McNamara

October 17, 2018

BERLIN — Adding an anti-interleukin-6 receptor monoclonal antibody to standard treatment for neuromyelitis optica spectrum disorder (NMOSD) reduced the relapse rate by almost two thirds, a randomized, double-blind, placebo-controlled, phase 3 study found.

"I'm excited to present to you today the primary results of our study of satralizumab," Takashi Yamamura, MD, PhD, said here during a late-breaking abstract session at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018.

"When added to immunosuppressive therapy, satralizumab significantly reduced the risk of protocol-defined relapses by 62% in an intent-to-treat population," added Yamamura, director of the Department of Immunology and the Multiple Sclerosis Center at the National Institute of Neuroscience in Tokyo.

Overcoming a Barrier

NMOSD is an autoimmune-inflammatory disease that often targets the optic nerve and spinal cord through an aquaporin-4 (AQP4) autoantibody mechanism. Satralizumab (Chugai Pharmaceuticals) could provide a sustained beneficial effect because it is a recycling anti-IL-6 receptor monoclonal antibody with a long plasma circulation time, researchers note.

By increasing blood-brain barrier permeability, IL-6 allows the pathologic autoantibodies to penetrate the central nervous system. IL-6 may also work by promoting differentiation of inflammatory Th17 cells and plasmablasts, Yamamura said.

In addition, "elevated IL-6 levels have been described in NMOSD patients in cerebral spinal fluid and serum during relapses."

Yamamura and colleagues designed the phase 3 trial to evaluate the efficacy and safety of adjunctive satralizumab vs placebo.

The primary, double-blind phase of the study lasted 20 weeks. The investigators randomly assigned 41 participants to receive 120 mg subcutaneous satralizumab and another 42 patients to receive placebo. Injections were given at baseline, weeks 2 and 4, and thereafter every 4 weeks.

The mean age of the patients was 42 years (range, 12 to 74 years). Most participants (93%) were women. The multicenter study included researchers in France, Germany, Italy, Poland, the United Kingdom, Spain, Hungary, Taiwan, the United States, and Japan.

The mean duration of NMOSD was almost 5 years. All participants experienced two or more relapses in the 2 years before study enrollment, including at least one in the previous year.

The mean annual relapse rate was 1.44. The median Expanded Disability Status Scale score was 3.5.

Anti-AQP4 Antibodies

The primary endpoint was time to first protocol-defined relapse; evaluation was conducted by a central adjudication committee.

Compared to placebo, satralizumab significantly reduced this risk (hazard ratio [HR], 0.38; 95% confidence interval, 0.16 - 0.88; P = .0184).

Yamamura said that 78% of those patients treated with satralizumab were relapse free.

Fifty-five patients were seropositive for anti-AQP4 antibodies at baseline, which was about two thirds of the study population.

The investigators reported a greater reduction in relapse risk with satralizumab vs placebo in the anti-AQP4-positive group (HR, 0.21, or a 79% risk reduction). Among those who tested negative for anti-AQP4 antibodies, the HR was 0.66, for a 34% reduction.

The investigators also assessed changes in pain and fatigue as secondary outcomes. They compared changes in scores on the visual analogue scale and the Functional Assessment of Chronic Illness Therapy measurement system and found no significant differences with treatment vs placebo.

Three patients in the treatment cohort and 10 patients in the group that received placebo withdrew from treatment.

In the satralizumab group, 37 patients experienced at least one adverse event, as did 40 patients in the group that received placebo. Seven serious events were reported in the treatment arm, vs nine in the placebo arm. No deaths or anaphylactic reactions were reported.

"Satralizumab showed a favorable safety profile. The overall proportion of patients experiencing adverse events or serious adverse events was similar," Yamamura said.

"The study supports the role of IL-6 mediated effects in NMOSD pathophysiology," he added.

Promising Results

"It looks promising, especially for patients who are antibody positive," session comoderator Letizia Leocani, MD, PhD, of the Department of Neurology at the Università Vita-Salute San Raffaele-UniSR in Milan, Italy, told Medscape Medical News when asked to comment on the study.

She added that it would have been useful to know whether there was any difference in disease severity between the active-treatment cohort and the cohort that received placebo or between AQP4-positive and AQP4-negative participants. "It could be the placebo group was not as severely affected," she said.

"I'm not quite sure about the AQP4-negative patients...but overall, it significantly reduced the risk of relapse by 62%," Martin Stangel, MD, of the Department of Clinical Neuroimmunology and Neurochemistry at Hannover Medical School in Germany, said during a review of clinical highlights of the ECTRIMS 2018 conference.

"Clearly there is a reduced risk of relapse when patients are treated with this IL-6 monoclonal antibody," said Stangel, who was not affiliated with the study.

Chugai Pharmaceutical Co Ltd funded the study. Dr Yamamura has served on Chugai's scientific advisory board and has received research grants and speaker honoraria from Chugai. Dr Leocani and Dr Stangel have disclosed no relevant financial relationships.

34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Late Breaking Abstract 323, presented October 12, 2018.

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