Inebilizumab Reduces Attack Risk Independent of Low Affinity IgG Fc Region Receptor III-A Gene Polymorphisms in Neuromyelitis Optica Spectrum Disorder
Brian Weinshenker1, Jeffrey Bennett2, Bruce Cree3, Friedemann Paul4, Ho Jin Kim5, Hans-Peter Hartung6, Kristina Patterson7, Michael Smith7, William Rees7, Dewei She7, Orhan Aktas8
1University of Virginia Health System, 2University of Colorado School of Medicine, 3UCSF, Multiple Sclerosis Center, 4Charite Universitatsmedizin in Berlin, 5National Cancer Center, 6Heinrich Heine University Medical Faculty Departme, 7Horizon Therapeutics plc, 8Heinrich Heine University Düsseldorf
Objective:
To characterize the relationship between the rs396991 polymorphism and the treatment response in N-MOmentum trial participants.
Background:
Inebilizumab, a humanized, afucosylated IgG1 monoclonal antibody that targets CD19 for B-cell depletion, is approved to treat aquaporin 4 (AQP4) immunoglobulin G positive (IgG+) neuromyelitis optica spectrum disorder (NMOSD). Afucosylated antibodies are engineered to enhance affinity for Fc receptor III-A (FCGR3A) receptors and maximize antibody-dependent cellular cytotoxicity. The F allele of the F176V polymorphism (rs396991) is associated with decreased IgG binding affinity and reduced efficacy of rituximab in NMOSD. Data from participants with different FCGR3A genotypes were compared for disease severity and response to inebilizumab at timepoints up to ≥4 years.
Design/Methods:
N-MOmentum (NCT02200770) was a double-blind, phase 2/3 trial of inebilizumab in adults with NMOSD, with a 28-week randomized controlled period (RCP); (inebilizumab 300 mg or placebo on days 1 and 15) and an optional open-label period (OLP) of ≥2 years. A total of 142 participants (inebilizumab, n=104; placebo, n=38) consented for genotyping via TaqMan qPCR assay.
Results:
V-allele carriers (V-allele genotype [V/V or V/F], n=74) and F/F–allele homozygotes (n=68) did not demonstrate a significant difference in baseline demographics or disease duration. Depletion of CD20+ B-cells was similar in V allele vs F/F allele participants (0.6 (0.1–3.2) vs 1.3 (0.5–4.2) cells/µL at end of RCP) and was sustained in both groups throughout the duration of the study. We did not find any difference in risk of relapse (OR 0.94 (0.39, 2.24)) or Expanded Disability Status Scale worsening (OR: 1.55 (0.54, 4.70)) in V vs F/F allele participants. Annualized attack rates (Standard Error of the Mean [SEM]) for patients on inebilizumab treatment were V/V 0.00 (0.00), V/F 0.10 (0.04), and F/F 0.06 (0.03).
Conclusions:
Inebilizumab treated participants in the N-MOmentum trial did not demonstrate differences in clinical outcomes between those with F and V allele genotypes.