KYOTO, Japan — Eculizumab (Soliris, Alexion Pharmaceuticals) is safe for the treatment of patients with severe Guillain-Barré syndrome (GBS), a new phase 2 study shows.
However, although more patients receiving eculizumab in the Japanese Eculizumab Trial for GBS (JET-GBS) were able to walk or run sooner than those receiving placebo, the small number of participants in the trial probably precluded proof that eculizumab was efficacious, the researchers say.
JET-GBS was a prospective, multicenter, placebo-controlled, double-blind, randomized phase 2 trial conducted at 13 tertiary neurology centers in Japan. A primary efficacy endpoint of the trial was the proportion of patients who could walk independently (Hughes functional grade ≤2) at week 4 of treatment.
“Sixty-one percent of the patients in the eculizumab group could walk independently at week 4 whereas 46% in the placebo group could walk independently,” study author Sonoko Misawa, MD, from Chiba University in Japan, told delegates here at the XXIII World Congress of Neurology (WCN).
However, the statistical threshold for efficacy was set at 50%, and the lower limit of the 95% confidence interval for the 61% of patients in the eculizumab group did not exceed this threshold. “So we have to say the primary endpoint cannot show significant efficacy of eculizumab in GBS,” she said.
But, she added, “the difference of 20% between the two groups was sustained throughout the trial.”
Rationale for Eculizumab in GBS
GBS is an immune-mediated neuropathy causing flaccid paralysis. Many patients spontaneously recover over a prolonged period, but a substantial proportion, especially those with severe disease, may have residual weakness persisting for years.
Recent studies have implicated complement activation in the axonal degeneration associated with GBS. Eculizumab is a monoclonal antibody against complement component C5 and may inhibit further complement activation.
Patients (n = 35) with GBS and Hughes functional grade (FG) 3 to 5 (unable to walk independently) 2 weeks from the onset of illness were enrolled in JET-GBS and randomly assigned to receive intravenous (IV) eculizumab 900 mg (n = 23) or placebo (n = 12) once weekly for 4 weeks, with another 20 weeks of observation. All patients received IV immunoglobulin, a current standard treatment for GBS.
The primary endpoints of the trial were safety and the proportion of patients who reached FG2 at 4 weeks. One patient in the placebo group did not receive placebo, so the final placebo population for analysis was 11.
Frequent adverse events (AEs) with eculizumab included insomnia, headache, and constipation. Serious AEs included anaphylaxis, intracranial hemorrhage, brain abscess, and depression. There were no deaths and no meningococcal infections. Meningococcal infections are a known risk with eculizumab, and all patients received prophylactic antibiotics.
At week 4, the proportion of patients able to walk independently (FG ≤ 2) was 60.9% (95% confidence interval [CI], 41.7% to 77.8%) with eculizumab vs 45.5% (95% CI, 20% to 72.9%) with placebo. At week 24, the proportions were 91.6% vs 71.9%, respectively.
Also at 24 weeks, the proportion of patients able to run (FG ≤ 1) was 74% with eculizumab but only 18% with placebo. The curves for eculizumab and placebo began to separate at about 4 weeks. The proportion of patients receiving eculizumab who could run was still rising at 24 weeks, while the proportion of patients receiving placebo who could run plateaued at the 18% level after 8 weeks.
John England, MD, professor and chairman of the Department of Neurology at Louisiana State University School of Medicine, New Orleans, and editor-in-chief of the Journal of Neurological Sciences, told Medscape Medical News that the failure of the study to reach its primary endpoint “is a little bit of discouragement, except it was a small study. It was really a phase 2 study, mainly looking for safety” and was thus not powered to show efficacy. “But I think that there’s enough evidence that it should probably go on to a phase 3.”
Dr England said many patients recover well after GBS. However, at least 20% of patients have persistent, significant deficits that limit their walking and function, and another 10% to 15% have residual fatigue and pain, “so it’s not as benign a disease as we think.”
Most advances in care of patients with GBS have resulted from “assiduous critical care…and ventilating them if they have respiratory failure, and that has actually made the biggest difference,” he said.
Plasma exchange and IV immunoglobulin hasten recovery and increase functional recovery. Both treatments are more than 25 years old, “and we haven’t had a new treatment for GBS, and even with those there’s still about a 5% mortality for GBS.” Patients with severe disease onset do worse, “and we desperately do need another added treatment that would help those patients recover even better,” he said.
He explained that eculizumab “very well could work” in GBS because “antibodies bind to the nerve, and that activates complement, which results in the destruction of membranes in the nerve, and so a complement inhibitor could theoretically help the disease.”
Eculizumab was provided by US-based Alexion Pharmaceuticals Inc under the Global Investigator-Sponsored Research Program. There was no other commercial sponsorship of the study. Dr Misawa has disclosed no other conflicts of interest. Dr England has disclosed no relevant financial relationships.
XXIII World Congress of Neurology (WCN). Abstract 530. Presented September 19, 2017.
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