What Is Neuromyelitis Optica?
Neuromyelitis Optica (NMO), or neuromyelitis optica spectrum disorder (NMOSD) aka Devic’s Disease (named after the doctor who initially discovered it), is a rare neurological autoimmune disease- meaning the body’s own immune cells begin to attack components of the nervous system, predominantly the optic nerve and spinal cord. NMOSD can also target areas of the brain. Historically, NMO has been misdiagnosed with multiple sclerosis (MS), another autoimmune disease of the central nervous system (CNS). Misdiagnosis can lead to either delay of appropriate treatment for NMO or inappropriate treatment, which can potentially exacerbate the disease.
NMOSD is a complex neurological autoimmune disease. At the CBJF, we believe that knowledge is power! And with this knowledge, patients and their family/support team can make the best informed shared decisions with their clinical care team. You can listen and learn from NMO healthcare experts from our 2021 patient and caregiver education virtual forum here: NMO Patient Day with the Cleveland Clinic Mellen Center.
NMOSD patients experience optic neuritis (causing eye pain and vision loss), transverse myelitis (leading to limb weakness and paralysis), as well as decreased sensation and loss of bladder and bowel control. Other symptoms can include intractable hiccuping, nausea and vomiting, sexual dysfunction, neuropathic pain, spasticity and chronic fatigue.
Mechanism of Disease
NMOSD is a distinct disease from multiple sclerosis (MS), typically sparing the brain and affecting a higher proportion of females to males (4:1). NMO can specifically lead to the formation of pathogenic (disease-causing) antibodies against aquaporin 4 (AQP4), or NMO-IgG, in the vast majority of patients, which is believed to be a mediator in spinal cord destruction. While nearly 80% of NMO subjects have these antibodies, NMO patients without NMO-IgG have similar spinal inflammation and destruction. Further diverging from MS, in which patients most often have mild attacks with good recovery, NMO attacks lead to severe disability, most often with incomplete recovery. Other subtypes of NMOSD can include MOG-seropositivity. MOG is protein that helps make up the CNS, and antibody formation against this protein can cause damage. Data show that patients can be either AQP4-IgG or MOG-IgG positive, but not both.
Common treatments for acute relapse include high dose intravenouse (IV) steroids, IV immunoglobulin (IVIG), and/or plasmapheresis. (See table below).
To Reduce/Prevent Relapse
There is no cure for NMO, but there are treatments used to reduce relapse.
As of 2020, there are now 3 FDA-approved treatment for NMOSD, in adult patients who are positive for the AQP4 antibody:
Alexion Pharmaceutical's Soliris (eculizumab) is a monoclonal antibody that targets C5, a key component of an inflammatory immune cascade called the complement pathway. The drug was studied in AQP4+ NMOSD patients in the PREVENT clinical trial. The patients who received eculizumab demonstrated a significantly lower risk of NMO relapse compared to those who received placebo, with relapses occurring in 3 of 96 patients (3%) treated with eculizumab group and 20 of 47 (43%) treated with placebo. While there was no significant difference in measures of disability progression between the eculizumab or placebo-treated groups, the mean change in the EDSS score was –0.18 in the eculizumab-treated patients and 0.12 in the placebo-treated patients. Regarding safety outcomes, the clinical trial results show that upper respiratory tract infections and headaches were more common in the eculizumab-treated group, and one patient who had received the immunosuppressant azathioprine died from infectious pleural effusion after 108 weeks in the study. Learn more about the results of the clinical trial in the article published in the New England Journal of Medicine: https://www.nejm.org/doi/full/10.1056/NEJMoa1900866?query=featured_home. Click here for information on the FDA approval: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-neuromyelitis-optica-spectrum-disorder-rare-autoimmune-disease-central?fbclid=IwAR12905cJHuXXwIph-0D4NiVxxB_3SpjytQ7yl7u6aTqMA8d70i2ITl-A8M
You can also access the prescribing information aka label approved by the FDA for Soliris, which provides key safety information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125166s431lbl.pdf
Horizon (formerly Viela Bio)'s FDA-approved treatment inebilizumab (Uplizna), a monoclonal antibody which depletes CD19+ B cells, had exciting results from its clinical trial in NMOSD patients. This trial, called N-MOmentum, is the largest controlled trial in NMOSD ever conducted with participants from 24 countries.
B cells are an immune cell that help make up the adaptive (or more selective, secondary immune response). B cells help activate their adaptive immune system friend T cells, make inflammatory factors, and are the only cell that can make antibody. Keep in mind that many NMOSD patients make an auto-antibody called anti-Aquaporin-4 (or anti-AQP4/NMO IgG/seropositive), and some NMOSD patients make the auto-antibody anti-Myelin Oligodendrocyte Glycoprtoein (or anti-MOG). Both of these auto-antibodies are associated with the targeted destruction of important components of the central nervous system. The thought is by depleting B cells from NMOSD patients, there will be a reduction in the formation of these auto-antibodies, as well as other inflammatory factors, and decreased activation of T cells.
The results of the trial showed a reduction in relapse rate and disability progression in patients treated with inebilizumab comapred to placebo. Although the study included both AQP4 positive and negative patients, most (91%) were seropositive. Inebilizumab reduced the risk of an attack by 77.3% in AQP4-IgG positive patients and 72.8% in the entire treated population. 89% of AQP4-IgG positive patients treated with inebilizumab were relapase free compared to 58% in the placebo group at the end of the controlled study period.
There were similar rates of adverse events and serious adverse events in the inebilizumab and placebo groups. Two deaths occurred in the open-label period- one assocaited with a severe relapse, and the other due to a brain event of unclear origin.
It is unclear what exactly causes NMOSD, but it’s clear that a number of immune-mediated inflammatory mediators are involved, including something called IL-6. IL-6 is an inflammatory cytokine (cell communication signal) that is involved in a number of immune activities that have been implicated in autoimmune diseases, including NMOSD. Chugai Pharmaceutical Co and its partner Roche/Genentech have developed a monoclonal antibody called satralizumab (Enspryng) that targets the IL-6 receptor, thereby helping to inhibit it’s potential inflammatory effect in the disease. Recent phase III study (SAkuraSky) results (from October 2018) demonstrated that satralizumab in addition to immunosuppressive treatment reduced the risk of relapse in NMOSD patients. This efficacy was found in both AQP4 positive AQP4 negative patients. The proportion of satralizumab-treated patients relapse free at weeks 96 was 77.6% compared to 58.7% of patients receiving placebo. With an average treatment duration of about 2 years, results demonstrated overall a favorable safety profile with satralizumab. Read more here: https://www.businesswire.com/news/home/20181014005065/en/Chugai-Presents-Results-Phase-III-Study-Satralizumab
There are a number of immunosuppressive therapies that have been used to help reduce relapse which have not been formally studied in NMOSD and not FDA-approved for NMOSD. Because NMOSD is a rare disease, affecting about 15,000 in the United States, it has been granted Orphan status. An Orphan disease is one that affects less than 200,000 in the United States. For the NMOSD population, orphan drug designation has been granted to a number of immunosuppressive therapies. (See table below).