Three positive phase III trials that could trigger a seismic shift in the therapeutic landscape for neuromyelitis optica spectrum disorder (NMOSD) were presented at the American Academy of Neurology (AAN) Annual Meeting in Philadelphia, USA, at the beginning of May 2019. The three studies were among a number of trials to offer hope to patients with difficult-to-treat neurological diseases.
The first of the NMOSD trials, which has been published in the New England Journal of Medicine, was a phase III study of eculizumab, a monoclonal antibody that targets complement component C5 to inhibit complement activation, which is a major component of CNS inflammation in NMOSD. In a total of 143 patients with anti-aquaporin-4 (AQP4) antibodies, eculizumab reduced the risk of relapse by 94.2% relative to placebo. “This was a dramatic result, providing a significant amount of hope for people with this disease,” said Sean Pittock, the first author of the trial, at the AAN meeting.
The second NMOSD trial, led by Bruce Cree, was a phase III study of the monoclonal antibody inebilizumab, which targets CD19 and leads to depletion of antibody-producing B cells. Against placebo, the antibody reduced the risk of relapse by 77%. Similarly, in the SAkuraSky trial of the anti-IL-6 antibody satralizumab, conducted by Takashi Yamamura and colleagues, treatment reduced the risk of relapse by 79% compared with placebo among patients who were anti-AQP4-antibody-positive, and by 34% among patients who were anti-AQP4-antibody-negative.
The antibodies have yet to receive regulatory approval for their clinical use, but the positive results change the outlook for patients with NMOSD dramatically. “How this will play out for patients is difficult to know,” commented Pittock, who was also involved in the inebilizumab trial. “We now have three drugs, whereas last year we had none. Hopefully, as we continue to work in this area, we can try to identify which patients will suit which drug.”
Continuing the immunological theme was a trial of a novel therapeutic strategy for the treatment of progressive multifocal leukoencephalopathy (PML). This trial, conducted by Irene Cortese and colleagues, involved adoptive transfer of donor-derived T cells that had been engineered to be highly reactive against the JC polyomavirus, which causes PML. A total of 12 patients received T cells, and no serious adverse reactions were seen. Although the study was designed primarily to test the safety of the approach, seven patients survived after the treatment when all were expected to deteriorate rapidly, providing preliminary evidence that the adoptive transfer approach could be effective. Further studies are needed to confirm efficacy, but the results could be a major breakthrough in PML treatment.
Pittock, S. et al. Eculizumab in aquaporin-4–positive neuromyelitis optica spectrum disorder. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1900866 (2019)
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Fyfe, I. Breakthrough neuroimmunology trials impress at AAN meeting. Nat Rev Neurol 15, 368 (2019). https://doi.org/10.1038/s41582-019-0206-0