Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trialResearch in context
Jeffrey L. Bennett,
Orhan Aktas,
William A. Rees,
Michael A. Smith,
Michele Gunsior,
Li Yan,
Dewei She,
Daniel Cimbora,
Sean J. Pittock,
Brian G. Weinshenker,
Friedemann Paul,
Romain Marignier,
Dean Wingerchuk,
Gary Cutter,
Ari Green,
Hans-Peter Hartung,
Ho Jin Kim,
Kazuo Fujihara,
Michael Levy,
Eliezer Katz,
Bruce A.C. Cree
Affiliations
Jeffrey L. Bennett
University of Colorado School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA; Corresponding author.
Orhan Aktas
Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
William A. Rees
Horizon Therapeutics plc, Gaithersburg, MD, USA
Michael A. Smith
Horizon Therapeutics plc, Gaithersburg, MD, USA
Michele Gunsior
Horizon Therapeutics plc, Gaithersburg, MD, USA
Li Yan
Horizon Therapeutics plc, Gaithersburg, MD, USA
Dewei She
Horizon Therapeutics plc, Gaithersburg, MD, USA
Daniel Cimbora
Horizon Therapeutics plc, Gaithersburg, MD, USA
Sean J. Pittock
Mayo Clinic and Center for MS and Autoimmune Neurology, Rochester, MN, USA
Brian G. Weinshenker
Mayo Clinic, Rochester, MN, USA
Friedemann Paul
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
Romain Marignier
Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuroinflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France
Dean Wingerchuk
Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA
Gary Cutter
University of Alabama at Birmingham, Birmingham, AL, USA
Ari Green
UCSF Weill Institute for Neurosciences, Department of Neurology and Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA
Hans-Peter Hartung
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
Ho Jin Kim
Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, South Korea
Kazuo Fujihara
Department of Multiple Sclerosis Therapeutics, Fukushima Medical University and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan
Michael Levy
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Eliezer Katz
Horizon Therapeutics plc, Gaithersburg, MD, USA
Bruce A.C. Cree
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA
Summary: 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).
