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  • Review Article
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Hope for patients with neuromyelitis optica spectrum disorders — from mechanisms to trials

Nature Reviews Neurology volume 17, pages 759–773 (2021)Cite this article

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Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.

Key points

  • Improved understanding of the pathophysiological mechanisms of neuromyelitis optica spectrum disorder enabled the development and testing of targeted treatments that have now received regulatory approval.

  • Randomized trials of eculizumab, inebilizumab, satralizumab and rituximab demonstrated that all four reduced the time to protocol-defined first relapse, thereby meeting the primary end points.

  • Differences in the trial designs prevent conclusions about which drug is preferable as first-line treatment. Factors that influence treatment decisions include previous experience with therapy, efficacy, safety, accessibility, cost and convenience.

  • The accessibility and affordability of the newly approved treatments for neuromyelitis optica spectrum disorder will vary between countries and regions and will influence decisions to initiate or switch to these drugs.

  • The RIN-1 trial included too few patients for the quantification of risk reduction; however, the extensive clinical experience with rituximab and its relatively low cost mean that it will remain an important treatment option.

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Fig. 1: Pathogenesis of neuromyelitis optica and pharmacological targets.
Fig. 2: Relapse-free survival in randomized controlled trials in neuromyelitis optica spectrum disorders.

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Acknowledgements

We thank L. Dacy and M. Curtis for technical assistance and S. Lambert for media support.

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Sean J. Pittock, Anastasia Zekeridou & Brian G. Weinshenker

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Sean J. Pittock & Anastasia Zekeridou

  3. Center of Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA

    Sean J. Pittock, Anastasia Zekeridou & Brian G. Weinshenker

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  1. Sean J. Pittock
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Contributions

S.P. wrote the article. S.P. and A.Z. researched data for the article. S.P. and B.G.W. made substantial contributions to discussion of content. All authors reviewed and edited the manuscript before submission.

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Correspondence to Sean J. Pittock.

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Competing interests

S.P. reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants, personal fees, non-financial support and other support from MedImmune/VielaBio; and personal fees for consulting from Genentech/Roche. He is a named inventor on patent 8,889,102 (Application US12/678,350, Neuromyelitis optica autoantibodies as a marker for neoplasia) and a named inventor and assignee on patent 9,891,219B2 (Application US12/573,942, Methods for treating neuromyelitis optica [NMO] by administration of eculizumab to an individual who is aquaporin 4 (AQP4)-IgG autoantibody positive). B.G.W. receives royalties from Hospices Civil de Lyon, MVZ Labour PD Dr. Volkmann und Kollegen GbR, Oxford University, and RSR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders. He has served on adjudication committees for clinical trials in neuromyelitis optica spectrum disorders conducted by Alexion and MedImmune/VielaBio, and has consulted for Chugai/Roche/Genentech and Mitsubishi–Tanabe regarding clinical trial design for neuromyelitis optica spectrum disorders. He has also received honoraria for speaking at internal meetings of Genentech and Novartis and at external meetings for Roche. A.Z. declares no competing interests.

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Nature Reviews Neurology thanks P. Cabre, M.I. Leite, I. Nakashima and D. Sato for their contribution to the peer review of this work.

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Pittock, S.J., Zekeridou, A. & Weinshenker, B.G. Hope for patients with neuromyelitis optica spectrum disorders — from mechanisms to trials. Nat Rev Neurol 17, 759–773 (2021). https://doi.org/10.1038/s41582-021-00568-8

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