Exploring FDA-Approved Treatments for NMOSD to Manage MOGAD: The METEOROID Study

MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY DISEASE (MOGAD) is an autoimmune disorder characterized by changes in vision and symptoms caused by spinal cord inflammation that present similarly to other demyelinating disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Traditionally, acute attacks of MOGAD have been managed with intravenous (IV) high-dose steroids, IV immunoglobulin, and plasma exchange; however, there are currently no FDA-approved treatments for the condition. This has led clinicians to reach for off-label therapies such as rituximab, azathioprine, or prednisone, among others, to treat their patients.

The discovery of the aquaporin-4 (AQP4) antibody channel led to the first medications to manage NMOSD, beginning with eculizumab (Soliris; Alexion) in June 2019, followed by inebilizumab-cdon (Uplizna; Horizon Therapeutics plc) in June 2020 and satralizumab-mwge (Enspryng; Genentech) in August 2020.¹ All 3 therapies, although different in mechanistic action, are approved only for patients with AQP4-positive NMOSD. Satralizumab, a humanized monoclonal recycling antibody that targets the IL-6 receptor, is currently being assessed in the METEOROID study (NCT05271409), which is the first of its kind in patients with MOGAD (TABLE).

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Previous research has suggested that IL-6 has a role in the pathogenesis of MOGAD, and that IL-6–directed therapy has shown to provide clinical benefit for relapse protection in this patient population.² METEOROID, a phase 3 study, will assesses the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab compared with placebo, either as monotherapy or an add-on to baseline immunosuppressive therapy, in a cohort of 152 individuals with MOGAD.

The design of the study is randomized and double blind in nature. Patients will undergo a 28-day screening period, followed by a 44-month treatment period and concluding with a 24-month open-label extension, with all patients switching or staying on satralizumab.³

Patients in the trial are 12 years or older, are MOG-immunoglobulin (MOG-IgG) seropositive, confirmed by live cell–based assay, and have relapsing MOGAD. The definition for relapsing MOGAD includes those with at least 1 MOGAD relapse in the 12 months prior to screening or at least 2 attacks in the 24 months prior to screening. These individuals have no alternative diagnoses, including MS, N-methyl-D-aspartate receptor autoimmune encephalitis, or NMOSD that is AQP4-IgG positive.

The study’s primary end point is time from randomization of a MOGAD relapse in the double-blind treatment period, as determined by an adjudication committee. Secondary efficacy outcomes include annualized rate of MOGAD relapses, annualized rate of active lesions per neuroaxis MRI, annualized rate of inpatient hospitalization, and proportion of patients receiving rescue therapy. Incidence, seriousness, and severity of adverse events (AEs), as well as changes in vital signs, electrocardiogram parameters, and laboratory testing, will comprise the safety assessments.

METEOROID will recruit patients from approximately 80 sites across 9 countries globally, with 7 sites each in Germany and Italy, and 3 sites in France. The trial will also evaluate serum concentrations of satralizumab, serum levels of IL-6 and soluble IL-6R, and antidrug antibodies in serum. Exploratory end points will include changes in Expanded Disability Status Scale scores, functional system scores, visual acuity, pain, retinal layer thickness by optical coherence tomography, and longitudinal biomarker assessments. Satralizumab’s FDA approval was supported by data from the phase 3 SAkuraStar (NCT02073279) and SAkuraSky (NCT02028884) clinical trials, which included more than 170 patients with NMOSD who were randomly assigned to receive satralizumab 120 mg or placebo.

In SAkuraStar, 30% of patients treated with satralizumab monotherapy experienced relapse compared with 50% of those who received placebo (HR, 0.45; 95% CI, 0.23-0.89; P = .018). Among those who were AQP4-IgG antibody positive, a 74% reduction in relapse risk was observed. In the overall satralizumab-treated population, 76.1% and 72.1% were relapse free at 48 and 96 weeks, respectively, compared with 61.9% and 51.2% with placebo. Data from the AQP4-IgG seropositive subgroup showed that 82.9% and 76.5% were relapse free at 48 and 96 weeks compared with 55.4% and 41.1% with placebo, respectively.⁴

In SAkuraSky, the overall population saw a 62% reduction in the risk of relapse (HR, 0.38; 95% CI, 0.16-0.88; P = .0184), whereas the group of patients who were AQP4-IgG seropositive experienced a 79% reduction in relapse risk (HR, 0.21; 95% CI, 0.06-0.75; P = .0086). Respectively, among the AQP4-IgG seropositive cohort, 91.5% who were treated with satralizumab were relapse free at 48 and 96 weeks compared with 59.9% and 53.3% of patients in the placebo group. The most common AEs observed were upper respiratory tract infection, nasopharyngitis, and headache.⁵

REFERENCES
1. FDA approves Genentech’s Enspryng for neuromyelitis optica spectrum disorder. News release. Genentech. August 15, 2020. Accessed May 1, 2023. https://www.businesswire.com/news/home/20200814005501/en/ADDING-MULTIMEDIA%C2%A0FDA-Approves-Genentech%E2%80%99s-Enspryng-Neuromyelitis-Optica 
2. Ringelstein M, Ayzenberg I, Lindenblatt G, et al. Interleukin-6 receptor blockade in treatment-refractory MOG-IgG-associated disease and neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2021;9(1):e1100. doi:10.1212/NXI.0000000000001100
3. Paul F, Flanagan EP, Kumpfel T, et al. METEOROID: a randomised, double-blind, placebo-controlled,multicentre phase 3 study of satralizumab in patients with MOGAD. Presented at: 38th Congressof the European Committee for Treatment and Research in Multiple Sclerosis; October 26-28, 2022; Amsterdam, Netherlands. EP1040.
4. Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 2020;19(5):402-412. doi:10.1016/S1474-4422(20)30078-8
5. Yamamura T, Kleiter I, Fujihara K, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med. 2019; 381(22):2114-2124. doi:10.1056/NEJMoa1901747