BACKGROUND: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770). METHODS: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed. FINDINGS: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4 cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06-0.10] vs 0.14 [0.10-0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes. INTERPRETATION: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years. FUNDING: Horizon Therapeutics (formerly from Viela Bio/MedImmune).

Department of Multiple Sclerosis Therapeutics Fukushima Medical University and Multiple Sclerosis and Neuromyelitis Optica Center Southern Tohoku Research Institute for Neuroscience Koriyama Japan

Department of Neurology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Department of Neurology Mayo Clinic Scottsdale AZ USA

Department of Neurology Research Institute and Hospital of National Cancer Center Goyang South Korea

Experimental and Clinical Research Center Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Horizon Therapeutics plc Gaithersburg MD USA

Mayo Clinic and Center for MS and Autoimmune Neurology Rochester MN USA

Mayo Clinic Rochester MN USA

Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany; Brain and Mind Centre University of Sydney Sydney NSW Australia; Department of Neurology Medical University Vienna Vienna Austria; Department of Neurology Palacky University in Olomouc Olomouc Czech Republic

Service de Neurologie Sclérose en Plaques Pathologies de la Myéline et Neuroinflammation Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon Lyon France

UCSF Weill Institute for Neurosciences Department of Neurology and Department of Ophthalmology University of California San Francisco San Francisco CA USA

UCSF Weill Institute for Neurosciences Department of Neurology University of California San Francisco San Francisco CA USA

University of Alabama at Birmingham Birmingham AL USA

University of Colorado School of Medicine Anschutz Medical Campus University of Colorado Aurora CO USA

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NCT02200770