Multiple Sclerosis Minute: Novel Treatment Options for Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system (CNS). Classically, NMOSD causes relapsing attacks of inflam-mation and demyelination of the optic nerves and/or spinal cord, although cerebral, diencephalic, and brainstem structures can also be affected. Approximately two-thirds of people who meet the most recent revised diagnostic criteria for NMOSD have autoreactive IgG antibodies against the aquaporin-4 (AQP4) water channel present on astrocyte foot processes at the blood-brain barrier.¹ These individuals are termed AQP-IgG “seropositive,” and those with NMOSD in whom these antibodies are not detected are termed “seronegative.” Some seronegative patients may have autoantibodies against other CNS targets such as myelin oligodendrocyte glycoprotein (MOG).

NMOSD relapses are typically clinically severe, and permanent disability from attacks is more common compared with other CNS autoimmune/inflammatory disorders. This has prompted the need for effective therapies to limit or prevent attacks.

Nonapproved Treatments

Before 2019, no medications had been approved by the Food and Drug Administration (FDA) for the treatment of NMOSD. Rituximab (RTX), tocilizumab (TOC), mycophenolate mofetil (MMF), and azathioprine (AZT) have all been used off-label. These medications resulted in NMOSD relapse reduction in open-label studies and case reports/series.² A small observational study that compared the efficacy of AZT, MMF, and RTX showed that 54.5%, 60.0%, and 65.0% of patients, respectively, remained relapse free for more than 24 months.³ More recently, a large meta-analysis of RTX found 62.9% of treated patients achieved an NMOSD relapse-free state with a mean difference in the annualized relapse rate (ARR) ratio of –1.56 after RTX therapy.⁴ TOC has also shown promise in a recent phase 2 trial in which 14% of participants treated with TOC had NMOSD relapses compared with 47% of those treated with AZT after 60 weeks.⁵

Novel Approved Treatments

The observations described above, along with an improved understanding of the pathogenic mechanisms of AQP4-IgG in NMOSD, prompted the pursuit of large, multicenter, placebo-controlled clinical trials for 3 novel NMOSD therapeutics approved in 2019 and 2020 (Table).

Eculizumab

Eculizumab, previously approved for paroxysmal nocturnal hemoglobinuria and myasthenia gravis, is a humanized monoclonal antibody (mAb) that inhibits complement by binding to the C5 component of the complement cascade with high affinity. Binding of eculizumab to C5 prevents formation of the membrane attack complex (MAC) required to induce cell lysis.^6,7 In AQP4-IgG seropositive NMOSD, eculizumab is postulated to disrupt formation of the MAC that forms when AQP4-IgG binds to the AQP4 channel on astrocyte foot processes.^8,9

In a randomized, double-blind, phase 3 clinical trial of eculizumab, 143 adults with AQP4-IgG seropositive NMOSD (based on 2006 or 2007 diagnostic criteria) were assigned to receive eculizumab or placebo in a 2:1 ratio.^10-12 Participants were permitted to continue other immunosuppressive therapies during eculizumab therapy. Eculizumab reduced the relapse rate by 96% (3/96 in eculizumab group vs 20/47 in the placebo group). The adjudicated ARR in those treated with eculizumab was 0.02 compared with 0.35 in those who received placebo.¹⁰ These findings led to eculizumab becoming the first FDA-approved drug for seropositive NMOSD in the US in 2019 and subsequently throughout the world.^13-15

In the clinical trial, there were higher rates of headache and upper respiratory tract infections in those treated with eculizumab vs placebo. Other common adverse effects included nausea, limb pain, back pain, diarrhea, urinary tract infection, and nasopharyngitis.

Although rare, eculizumab is known to increase the risk of infection by meningococci and other encapsulated bacteria. Eculizumab is contraindicated among those who have an unresolved meningococcal infection or have not been vaccinated against Neisseria meningitidis.^15,16 No cases of meningococcal infection occurred in the pivotal trial, but there was 1 case in the pilot open-label study.^10,17 To help mitigate these risks, patients are required to receive meningococcal vaccines at least 2 weeks before their first dose of eculizumab, and providers are required to enroll in the eculizumab Risk Evaluation and Mitigation Strategy (REMS) program to prescribe this medication. If an unvaccinated patient has an emergent medical need for the infusion, providers can consider prophylactic antibiotics for the first 2 weeks of treatment or the duration of therapy.¹⁸

Overall, eculizumab is a highly effective therapy for relapse prevention in AQP4-IgG seropositive NMOSD. Eculizumab is particularly attractive for individuals in whom other therapies have failed because it has a different mechanism of action than any other approved or nonapproved therapy. The primary drawbacks of eculizumab include the route and frequency of administration as well as cost.

Inebilizumab

Inebilizumab is a humanized mAb that binds and depletes CD19-expressing B cells through antibody-dependent, cell-mediated cytotoxicity.¹⁹ The CD19 antigen is expressed on a wider array of B-cell lineages than CD20, including early pro-B cells, late pro-B cells, memory B cells, plasmablasts, and some plasma cells. CD19 functions as an important regulator of specific B-cell activation by antigens.²⁰ Inebilizumab has a unique afucosylated structure among B-cell therapies, which improves binding of the B cell-antibody complex to activating IgG receptors on natural killer cells. Theoretically this improved binding increases cell-mediated cytotoxicity. B cells are thought to play a central role in the pathogenesis of NMOSD through both production of the pathogenic AQP4-IgG autoantibody as well as through promotion of T cell-mediated cytotoxicity.

In the pivotal, randomized, double-blind, placebo-controlled trial of inebilizumab, participants with AQP4-IgG seropositive (n=213) and seronegative (n=17) NMOSD were assigned to receive inebilizumab or placebo in a 3:1 ratio. Inebilizumab significantly reduced the number of relapses, active MRI lesions, and NMOSD-related inpatient hospitalizations.²¹ In seropositive participants, 11% of those treated with inebilizumab experienced a relapse compared with 42% of those who received placebo. Statistically significant conclusions of benefit could not be made in the seronegative group because of limited sample size and no relapses occurring in the placebo group.²¹ These findings led to the FDA approval of inebilizumab for the treatment of AQP4-IgG seropositive NMOSD in June 2020.

During the pivotal trial, inebilizumab was generally well tolerated with a favorable safety profile. The most common adverse events were urinary tract infection, nasopharyngitis, infusion-related reactions, and back pain.²¹ During the open-label extension period, no new safety concerns were identified over an average of 2 years of treatment with inebilizumab.²¹

Before starting treatment with inebilizumab, patients should be screened for hepatitis B and tuberculosis. Immunizations should be given according to guidelines at least 4 weeks prior to starting inebilizumab for live or live-attenuated vaccines and 2 weeks prior for nonlive vaccines. Quantitative levels of serum immunoglobulins should be measured before starting inebilizumab, yearly during treatment, and upon discontinuation until B-cell repletion occurs. Patients should also be monitored for infection and progressive multifocal leukoencephalopathy (PML).²²

Inebilizumab is an important new treatment option for patients with AQP4-IgG seropositive NMOSD. Results of the pivotal trial confirm the benefits of B-cell depletion and the drug has a convenient semiannual dosing schedule. Both targeting a broader range of B cells compared with antiCD20 therapies and the afucosylated structure of inebilizumab could theoretically lead to improved efficacy. However, these characteristics theoretically also could lead to an increased risk of infection, particularly with long-term immunosuppression. Additional long-term safety and efficacy data are needed.

An additional consideration, particularly in the setting of the COVID-19 pandemic, is the effect of B-cell depleting agents on vaccination response. Based on data for ocrelizumab, an antiCD20 mAb approved for treatment of multiple sclerosis, humoral vaccine responses may be reduced by 25% to 50%.²³ Although supporting evidence is very limited, many practitioners recommend obtaining all recommended vaccinations at least 4 weeks prior to starting B-cell depleting agents.

Satralizumab

Satralizumab is a humanized mAb that targets the interleukin-6 (IL-6) receptor. It is hypothesized that dysregulation of IL-6 signaling in NMOSD may 1) aggravate the inflammatory response by promoting peripheral plasmablast survival, AQP4-IgG production, and T-lymphocyte differentiation and activation and 2) disrupt blood-brain barrier integrity by promoting damage to astrocytes, oligodendrocytes, and microglia within the CNS.²⁴ Elevated levels of IL-6 have been identified in both the serum and CSF during NMOSD relapses, supporting this hypothesis.^25,26

In 2 randomized, double-blind, placebo-controlled trials, satralizumab was evaluated for both AQP4-IgG seropositive and seronegative participants who met the 2006 criteria for diagnosis of NMOSD.^12,27,28 In both trials, participants were randomly assigned to receive subcutaneous satralizumab or placebo with a primary endpoint of time to first adjudicated NMOSD relapse. In 1 study, participants (n=95) were not allowed concomitant immunotherapy, and in the other satralizumab was added on to participants’ (n=83) baseline treatment.

In both trials, satralizumab was highly effective in reducing the risk of NMOSD relapse in seropositive patients only. Of seropositive participants who took satralizumab with no other immunotherapy, 23% experienced a relapse compared with 57% of those who took placebo with no other immunotherapy. In those who took adjunctive satralizumab, 11% of seropositive participants had a relapse compared with 43% of those who had placebo in addition to their baseline therapy. No significant benefit was seen in seronegative patients in either study.^27,28 Based on these results, satralizumab was approved in 2020 for the treatment of AQP4-IgG seropositive NMOSD.²⁹

Rates of serious adverse events in the clinical trials were similar between the satralizumab and placebo groups. Mild to moderate infections were slightly more common in participants treated with satralizumab, but serious infection rates were similar to those seen with placebo. The most common adverse reactions were nasopharyngitis, headache, upper respiratory tract infection, cellulitis, rash, arthralgias, fatigue, nausea and gastritis.^27,28

Before starting satralizumab, screening for hepatitis B, tuberculosis, and liver transaminases is required. Immunizations should be given according to guidelines at least 4 weeks prior to starting satralizumab for live or live-attenuated vaccines and 2 weeks prior for nonlive vaccines.³⁰

Monitoring guidelines include checking alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels every 4 weeks for the first 3 months of treatment, then every 3 months for a year, and as clinically indicated thereafter. Neutrophil counts should also be checked 4 to 8 weeks after starting satralizumab and thereafter as needed.³⁰

Satralizumab is an effective treatment option for seropositive NMOSD. Its subcutaneous formulation and favorable safety profile make it an attractive treatment option for many who prefer self-administration over an infusion of medication.

Summary

2019 and 2020 were very exciting years for the treatment of NMOSD with the publication of pivotal trial data and subsequent approval of the 3 new mAb therapies reviewed above. Eculizumab, inebilizumab, and satralizumab are all highly effective for preventing relapses in people with AQP4-IgG seropositive NMOSD. Conclusions regarding relative efficacy are limited owing to significant differences in trial designs. The 3 distinct mechanisms of action of these treatments offer insights into the complex pathophysiology of NMOSD and, importantly, offer critical alternative options for NMOSD failed by other therapies. Further study of alternatives for individuals with AQP4-IgG seronegative NMOSD remains critically needed.