For a presentation at the 2022 European Committee for Treatment and Research in Multiple Sclerosis ECTRIMS meeting, held in Amsterdam, the Netherlands, Dr. Orhan Aktas (University of Düsseldorf, Germany) described how polymorphisms affecting the affinity of the IgG Fc Region Receptor III-A gene FCGR3A do not influence the efficacy of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) [1].


Inebilizumab, a humanized, afucosylated anti-CD19 monoclonal antibody shown to effectively deplete B cells, is approved for the treatment of patients with neuromyelitis optica spectrum disorder (NMOSD) who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG+). Afucosylated monoclonal antibodies are engineered to enhance affinity for the Fc receptor III-A (FCGR3A) receptors. The function of the Fc region of IgG is to increase the stability inebilizumab and prolong the half-life. In addition, the Fc region of IgG1 binds to the Fc-gamma receptors (FCGRs) given rise to a series of immune reactions, such as apoptosis, cytokine release, antibody-dependent cellular cytotoxicity (ADCC), and macrophage-mediated immune complex elimination. For this reason, the FCGRs play a part in innate and acquired immune activation and have been extensively investigated for their role in the pharmacogenetic of biological therapies (BTs). The protein FCGR3A is expressed on monocytes, macrophages, neutrophils, and NK cells, promoting phagocytosis and ADCC mechanisms, and the affinity of FCGR3A for the Fc region of IgG of inebilizumab could vary due to structural changes in extracellular domain of the receptors, which could interfere with the therapeutic response to inebilizumab. The FCGR structural changes could be produced by single-nucleotide polymorphisms (SNPs) located in the genetic coding region of FCGR3A. The low-affinity variants could decrease the binding of inebilizumab to the receptors, and thus its clearance would be lower, increasing the therapeutic effect. Low-affinity receptors could present less binding and clearance of autoimmune complexes, increasing tissue damage in patients carrying low-affinity variants and producing less response to treatment.

Theories about the influence of FCGR2A and FCGR3A SNPs in response to biological therapies are multiple, and the effect of the interaction of these receptors with biologic drugs is unknown. Nevertheless, these SNPs could determine the great interindividual variability in the response to inebilizumab; this was the rationale for this study, according to Dr. Aktas. However, no previous study has evaluated the relationship between the FCGR2A rs1801274 and FCGR3A rs396991 SNPs and inebilizumab response in patients diagnosed with NMOSD. Dr. Aktas noted that the F allele of the F176V polymorphism (rs396991) of FCGR3A is associated with decreased IgG binding affinity and reduced efficacy of rituximab in NMOSD.

To that end, Dr. Aktas and colleagues used data from the randomized, controlled, phase 2/3 N-MOmentum trial, in which patients with NMOSD AQP4+  (n=230) were randomized 3:1 to inebilizumab (300 mg, intravenous, administered at day 1 and 15) or placebo. After 6 months, patients could enter the open-label extension period, during which all enrolled participants received inebilizumab every 6 months. In total, 174 patients completed the open label extension period. The primary outcome was the time to first attack.

The results of the randomized-controlled period showed that inebilizumab outperformed placebo: 87.0% of the patients on inebilizumab were attack-free, compared with 59.9% of placebo recipients (risk reduction, 72.8%; P<0.001) [2,3].

Within this cohort, 142 participants (inebilizumab, N=104; placebo, N=38) consented to be genotyped for the rs396991 polymorphism, which was then correlated with their treatment response in the N-MOmentum trial. Dr. Aktas and colleagues observed that, during the first 6 months of inebilizumab treatment, F/F homozygotes of that allele had modestly slower kinetics of B cell depletion but no difference in risk of attack. 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 the end of the randomized controlled period) and was sustained in both groups throughout the study. There was no 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]).

The authors concluded that Inebilizumab-treated participants in the N-MOmentum trial did not demonstrate differences in clinical outcomes between those with F and V
allele genotypes.

Physician’s Weekly spoke with Friedemann Paul, MD, study author and Head of the Clinical Neuroimmunology Research Group at the NeuroCure Clinical Research Center, Head of Clinical and Experimental Neuroimmunology at the Experimental and Clinical Research Center of Charité–Universitätsmedizin Berlin and the Max Delbrueck Center for Molecular Medicine in Berlin, Germany.

“This is the first and only targeted CD19+ B-cell-depleting monotherapy proven to reduce attacks in adult patients with NMOSD who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+),” said Dr. Paul. “Inebilizumab demonstrated favorable long-term safety and efficacy outcomes for patients with NMOSD, as evidenced in the phase 2/3 N-MOmentum trial. Results showed that the risk of attack in participants with NMOSD who were treated with inebilizumab remained low, no matter whether they had a polymorphism in the FCGR structure affecting affinity. Moreover, long-term use of inebilizumab did not result in the occurrence of unexpected serious adverse events in individuals with FCGR SNPs. People living with NMOSD need novel treatment options that have been shown to reduce attacks that can cause irreversible and debilitating damage, such as vision loss and paralysis. With inebilizumab, physicians have a treatment option that can be given twice a year after initial dosing to help prevent NMOSD attacks by specifically targeting CD19 B-cells, which play a central role in the pathogenesis of the disease. Importantly, this new evidence does not support the need genetic screening of individuals prior to treatment, so that is one less substantial obstacle for the patient.”