Neuromyelitis Optica Spectrum Disorder (NMOSD)

Prior to 2019, there were no US Food and Drug Administration (FDA)-approved therapies for the treatment of neuromyelitis optica spectrum disorder (NMOSD). There has been substantial progress since then, with the approval of Soliris® (eculizumab) in 2019 followed by Uplizna® (inebilizumab-cdon) and Enspryng™ (satralizumab-mwge).1-3 There are also 3 monoclonal antibodies in the experimental phase that may provide breakthroughs in the near future. 


Aquaporumab is a humanized, monoclonal antibody against aquaporin-4 (AQP4). The AQP4 channel plays an important role in regulating the water balance in the central nervous system (CNS), and it appears to regulate neuroinflammation through mechanisms that are not understood. There is speculation that targeted therapy towards AQP4 may have multiple therapeutic properties as well as potential uses in the treatment of ischemic stroke, epilepsy, multiple sclerosis, and Alzheimer’s disease. It may also be beneficial in reducing glial scarring following CNS injury.4 

An innovative approach using aquaporumab to target AQP4 is being developed as a potential treatment for NMOSD. Unlike the pathologic AQP4-immunoglobulin G (IgG) antibody produced by seropositive NMOSD patients, aquaporumab does not activate complement due to modifications at the Fc fragment. In theory, blocking the interaction of pathologic AQP4-IgG antibodies through competitive inhibition with aquaporumab should prevent complement-mediated inflammation in the CNS.5 Research is currently limited to animal models and has not yet been applied to any human patients. 


Bevacizumab (Avastin®) is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). It is FDA-approved for use in certain malignancies and has been evaluated as an experimental, add-on therapy to high-dose corticosteroid treatment for NMOSD. The rationale for using bevacizumab in NMOSD hinges on the observation that during acute attacks, the blood-brain barrier (BBB) is altered, allowing AQP4-IgG to access AQP4 and exert pathologic effects. Increased levels of VEGF are associated with disruptions in the BBB in experimental models and are also observed in glioblastoma multiforme. Targeting VEGF should theoretically improve the integrity of the BBB and improve symptoms during acute NMOSD attacks. A small, open-label phase 1b trial including 10 patients reported that bevacizumab was safe as an add-on therapy to corticosteroids for patients with acute relapses of NMOSD.6 Larger trials are required to establish efficacy. 


Ublituximab is an anti-CD20 monoclonal antibody that targets the specific epitope of the CD20 antigen on mature B lymphocytes and functions as a B-cell-depleting agent. B-cells play an important role in the pathogenesis of NMOSD, serving as antigen-presenting cells and precursors to plasmablasts and plasma cells, which are the producers of AQP4-IgG.7 Rituximab targets CD20+ cells in a similar manner and has been used as a treatment for NMOSD in the past few years.8 A single-center, phase I, class IV, open-label study in seropositive NMOSD patients with acute relapses demonstrated that ublituximab was a safe add-on therapy to corticosteroids.7 Larger studies are required to establish efficacy.

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation

One prospective open-label cohort study of 13 patients with NMOSD, which included 1 seronegative patient and 1 patient with systemic lupus erythematosus (SLE) with neuropsychiatric symptoms, sought to determine if autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) could be a salvage therapy. The median time to follow-up after HSCT was 57 months, and the results demonstrated the following9:

  • The patient with SLE died due to complications from active SLE. 
  • Of the 12 patients with NMOSD without other active coexisting autoimmune diseases, 11 are more than 5 years post-transplant, and 80% are relapse-free of all immunosuppression (P <.001).
  • The Expanded Disability Status Scale score improved from a baseline mean of 4.4 to 3.3 (P <.01) at 5 years after HSCT.
  • Nine of the 11 patients who were initially seropositive became seronegative.
  • There was no documented relapse in the seronegative patient.  

HSCT may be a viable treatment option for both seronegative and seropositive NMOSD patients, and it appears to have curative potential. 


1. FDA approves new therapy for rare disease affecting optic nerve, spinal cord. News release. US Food and Drug Administration; June 11, 2020.

2. FDA approves first treatment for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system. News release. US Food and Drug Administration; June 27, 2019.

3. FDA approves treatment for rare disease affecting optic nerves, spinal cord. News release. US Food and Drug Administration; August 17, 2020.

4. Verkman AS, Smith AJ, Phuan PW, Tradtrantip L, Anderson MO. The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets. 2017;21(12):1161-1170. doi:10.1080/14728222.2017.1398236

5. Duan T, Tradtrantip L, Phuan PW, Bennett JL, Verkman AS. Affinity-matured ‘aquaporumab’ anti-aquaporin-4 antibody for therapy of seropositive neuromyelitis optica spectrum disorders. Neuropharmacology. 2020;162:107827. doi:10.1016/j.neuropharm.2019.107827

6. Mealy MA, Shin K, John G, Levy M. Bevacizumab is safe in acute relapses of neuromyelitis optica. Clin Exp Neuroimmunol. 2015;6(4):413-418. doi:10.1111/cen3.12239

7. Mealy MA, Levy M. A pilot safety study of ublituximab, a monoclonal antibody against CD20, in acute relapses of neuromyelitis optica spectrum disorder. Medicine (Baltimore). 2019;98(25):e15944. doi:10.1097/MD.0000000000015944

8. Jade JD, Bansi S, Singhal B. Rituximab in neuromyelitis optica spectrum disorders: our experience. Ann Indian Acad Neurol. 2017;20(3):229-232. doi:10.4103/aian.AIAN_499_16

9. Burt RK, Balabanov R, Han X, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica. Neurology. 2019;93(18):e1732-e1741. doi:10.1212/WNL.0000000000008394

Reviewed by Harshi Dhingra, MD, on 10/22/2021.