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 trial

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; N-MOmentum study investigators

doi:10.1016/j.ebiom.2022.104321

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 trial

EBioMedicine. 2022 Dec:86:104321. doi: 10.1016/j.ebiom.2022.104321. Epub 2022 Nov 10.

Authors

Jeffrey L Bennett¹, Orhan Aktas², William A Rees³, Michael A Smith³, Michele Gunsior³, Li Yan³, Dewei She³, Daniel Cimbora³, Sean J Pittock⁴, Brian G Weinshenker⁵, Friedemann Paul⁶, Romain Marignier⁷, Dean Wingerchuk⁸, Gary Cutter⁹, Ari Green¹⁰, Hans-Peter Hartung¹¹, Ho Jin Kim¹², Kazuo Fujihara¹³, Michael Levy¹⁴, Eliezer Katz³, Bruce A C Cree¹⁵; N-MOmentum study investigators

Affiliations

¹ University of Colorado School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA. Electronic address: [email protected].
² Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
³ Horizon Therapeutics plc, Gaithersburg, MD, USA.
⁴ Mayo Clinic and Center for MS and Autoimmune Neurology, Rochester, MN, USA.
⁵ Mayo Clinic, Rochester, MN, USA.
⁶ 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.
⁷ Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuroinflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France.
⁸ Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
⁹ University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁰ UCSF Weill Institute for Neurosciences, Department of Neurology and Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
¹¹ 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.
¹² Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, South Korea.
¹³ Department of Multiple Sclerosis Therapeutics, Fukushima Medical University and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan.
¹⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Abstract

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).

Keywords: Anti-CD19 monoclonal antibody; Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder; B-cell suppression; Devic disease.

Publication types

Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase II
Clinical Trial, Phase III

MeSH terms

Adult
Antigens, CD19
Autoantibodies
B-Lymphocytes
Double-Blind Method
Humans
Magnetic Resonance Imaging
Neuromyelitis Optica* / drug therapy
Neuromyelitis Optica* / pathology

Substances

Antigens, CD19
Autoantibodies

Associated data

ClinicalTrials.gov/NCT02200770