Abstract
Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoantibody-mediated CNS disease. The rs396991 F176V polymorphism of the low-affinity IgG Fc region receptor III-A (FCGR3A) gene affects IgG binding affinity. The V allele is linked to poor outcomes in antibody-mediated autoimmune diseases but enhanced response to monoclonal antibody therapies. Characterize the relationship between rs396991 polymorphism, NMOSD disease activity and treatment response in N–MOmentum trial participants. Material and method: N-MOmentum had a randomized controlled period (RCP; inebilizumab 300 mg or placebo on days 1 and 15) of up to 28 weeks, followed by an open-label period (OLP). 142 participants (104 randomized to inebilizumab, 38 to placebo) consented for polymorphism genotyping via TaqMan qPCR assay. Results: Historical annualized attack rates (AAR) and change in Expanded Disability Status Scale (EDSS) scores from NMOSD onset to enrolment were nominally higher in rs396991 V allele participants (V; V/V or V/F genotype; n=74) than in F/F allele participants (F/F; n=68): mean (±SEM) AAR: V, 1.0 (0.8–1.3); F/F, 0.7 (0.5–0.9); EDSS score change: V, 0.6 (0.5–0.7); F/F, 0.4 (0.3–0.5). In the placebo group, the rates of attacks, new/enlarged T2 MRI lesions and NMOSD-related hospitalizations were higher in V allele (n=22) than in F/F allele participants (n=16), but not statistically significant: mean (±SEM) AAR: V, 1.3 (0.9–1.7); F/F, 0.8 (0.5–1.2); new T2 lesions: V, 4.5 (2.6–6.3); F/F, 2.1 (1.0–3.1); hospitalizations: V, 0.5 (0.2–0.8); F/F, 0.2 (0.0–0.4). At end of RCP, V-allele carriers randomized to inebilizumab (n=52) had greater median (IQR) B-cell, plasma-cell and Ig depletion than F/F homozygotes (n=52): B cells; V, 0.6 (0.1–3.2) vs F/F, 1.3 (0.5–4.2) cells/µl; plasma cells: V, 0.04 (0.02–0.2) vs F/F, 0.05 (0.03–0.2) fold change from control mean; Ig: V, 1050 (867–1284) vs F/F, 1238 (1076–1455) Ig/µl. V allele carriers also had lower attack rates and new/enlarged T2 lesions than F/F homozygotes but differences were not statistically significant: mean (±SEM): AAR: V, 0.1 (0.1–0.2); F/F, 0.3 (0.2–0.4); new T2 lesions: V, 1.4 (0.9–1.8); F/F, 1.7 (1.2–2.2). By dose 4 in the OLP, there was little difference between the subgroups in clinical metrics or B-cell depletion. Conclusion: V allele carriers may have increased NMOSD disease activity but may have greater early pharmacodynamic response to inebilizumab compared with those with the wild F/F genotype.
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