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

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.

Conflict of interest statement

Declaration of interests J.L.Bennett reports payment for study design/consultation from MedImmune; personal fees from AbbVie, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, Genentech, Genzyme, Reistone Bio, Roche, and TG; grants from Alexion, the National Institutes of Health, and Novartis. In addition, Dr Bennett has a patent ‘Compositions and methods for the treatment of neuromyelitis optica’. O.Aktas reports grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Horizon Therapeutics (formerly from Viela Bio), Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono, and Roche. W.A.Rees, M.A.Smith, D.She, and D.Cimbora are employees of Horizon Therapeutics (formerly Viela Bio) and own stock. L.Yan, M.Gunsior, and E.Katz are former employees of Horizon Therapeutics. S.J.Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals, Inc.; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, non-financial support, and other from Horizon Therapeutics (formerly from Viela Bio) and MedImmune; personal fees for consulting services from Astellas; grants, personal fees, non-financial support and other from Roche/Genentech; personal fees for consulting services from UCB; and has a patent #9,891,219 (Application#12-573942) ’Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody Positive’. B.G.Weinshenker received payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, and Viela Bio/Horizon Therapeutics; has consulted with Chugai, Genentech, Horizon Therapeutics, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr. Volkmann und Kollegen GbR, University of Oxford, and RSR. F.Paul has received research support, speaker honoraria, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Research Council (DFG Exc 257) and the German Competence Network for Multiple Sclerosis; has received travel reimbursement from the Guthy-Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study, sponsored by Novartis. R.Marignier reports personal fees for consulting from Alexion, Horizon Therapeutics (formerly Viela Bio), Roche, and UCB. D.Wingerchuk reports personal fees from Biogen, Celgene, Genentech, MedImmune, Mitsubishi Tanabe, Novartis, Reistone Biopharma, and TG Therapeutics; research support paid to the Mayo Clinic by Alexion and Terumo BCT; and has served on a clinical trial adjudication committee for Horizon Therapeutics (formerly Viela Bio) and MedImmune. G.Cutter has received personal fees for participation on Data and Safety Monitoring Boards from AstraZeneca, Avexis Pharmaceuticals, BioLineRx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obesity Policy Research Unit oversight committee), Galmed Pharmaceuticals, Hisun Pharmaceutical, Horizon Pharmaceuticals (formerly Viela Bio), Mapi Pharma, Merck, Merck/Pfizer, the National Heart, Lung, and Blood Institute (Protocol Review Committee), Neurim Pharmaceuticals, Novartis, OncoImmune, OPKO Biologics, Orphazyme, Reata Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, and Vivus; personal fees for consulting or advisory board participation from BioDelivery Sciences International, Biogen, Click Therapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein Buendel, MedDay, MedImmune, NeuroGenesis, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, AL, USA; and is President of Pythagoras, Inc., a private consulting company based in Birmingham, AL, USA. A.Green reports grants from the Conrad N. Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships (for activities as expert witness, associate editor, advisory board/steering committee participation, and endpoint adjudication) with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Horizon Therapeutics (formerly Viela Bio), Mylan, Synthon, and Trims Pharma; and personal fees from and other financial relationships with Pipeline Therapeutics. H.-P.Hartung has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, Horizon Therapeutics (formerly Viela Bio), MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, and TG Therapeutics with approval by the Rector of Heinrich Heine University Düsseldorf. H.J.Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, Celltrion, Daewoong Pharmaceutical, Eisai, GC Pharma, HanAll Biopharma, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. K.Fujihara has received fees for consulting, speaking, and serving on steering committees from AbbVie, Alexion, Asahi Kasei Kuraray Medical Co., Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi Tanabe Pharma, Novartis, Teijin, Takeda Pharmaceutical Company, and UCB; and a grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan. M.Levy currently receives research support from Acorda Therapeutics, Alexion, Alnylam Pharmaceuticals, ApoPharma, Maryland Technology Development Corporation, the National Institutes of Health, Sanofi Genzyme, and Shire/Takeda; has received personal compensation for consultation with Acorda Therapeutics, Alexion, and Genzyme; and serves on the scientific advisory boards for Acorda Therapeutics, Alexion, and Quest Diagnostics. B.A.C.Cree reports personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn Therapeutics, Avotres Inc., Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini Bio; and has received research support from Genentech.

Copyright © 2022 Horizon Therapeutics plc. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Participant flow in N-MOmentum. For analysis purposes, participants were divided into three groups: “RCP inebilizumab” (participants randomised to inebilizumab during the RCP), “RCP placebo” (participants randomised to placebo during the RCP), and “any inebilizumab” (participants who received inebilizumab at any point during the study, including those from the RCP inebilizumab group and all participants in the OLP; shaded in pink). OLP = open-label period, RCP = randomised controlled period.

Fig. 2

Kinetics of B-cell and immunoglobulin depletion during the study. (a) Total CD20+ B-cell counts. (b) Plasma-cell gene signature normalised to a pool of 10 HDs using the ddCT method. (c) Total immunoglobulin, (d) immunoglobulin G, (e) immunoglobulin M, (f) immunoglobulin A, and (g) immunoglobulin E concentrations over time during the RCP in placebo-treated (in grey) and inebilizumab-treated (in red) participants. Points show medians and shaded regions show IQRs. Dashed black lines show LLOQ of 0.2 cells/μL for FACS assays. Samples with counts below the LLOQ were imputed to 0.05 cells/μL. Mann–Whitney U test between dose groups; p > 0.05 where p not noted. Vertical dashed lines show when participants were transitioned to the OLP and the placebo cohort was administered two inebilizumab doses; the inebilizumab cohort was given an additional maintenance dose. ddCT = delta delta cycle threshold, FACS = fluorescence-activated cell sorting, FC = fold change, HD = healthy donor, IQR = interquartile range, LLOQ = lower limit of quantification, OLP = open-label period, RCP = randomised controlled period.

Fig. 2

Kinetics of B-cell and immunoglobulin depletion during the study. (a) Total CD20+ B-cell counts. (b) Plasma-cell gene signature normalised to a pool of 10 HDs using the ddCT method. (c) Total immunoglobulin, (d) immunoglobulin G, (e) immunoglobulin M, (f) immunoglobulin A, and (g) immunoglobulin E concentrations over time during the RCP in placebo-treated (in grey) and inebilizumab-treated (in red) participants. Points show medians and shaded regions show IQRs. Dashed black lines show LLOQ of 0.2 cells/μL for FACS assays. Samples with counts below the LLOQ were imputed to 0.05 cells/μL. Mann–Whitney U test between dose groups; p > 0.05 where p not noted. Vertical dashed lines show when participants were transitioned to the OLP and the placebo cohort was administered two inebilizumab doses; the inebilizumab cohort was given an additional maintenance dose. ddCT = delta delta cycle threshold, FACS = fluorescence-activated cell sorting, FC = fold change, HD = healthy donor, IQR = interquartile range, LLOQ = lower limit of quantification, OLP = open-label period, RCP = randomised controlled period.

Fig. 2

Kinetics of B-cell and immunoglobulin depletion during the study. (a) Total CD20+ B-cell counts. (b) Plasma-cell gene signature normalised to a pool of 10 HDs using the ddCT method. (c) Total immunoglobulin, (d) immunoglobulin G, (e) immunoglobulin M, (f) immunoglobulin A, and (g) immunoglobulin E concentrations over time during the RCP in placebo-treated (in grey) and inebilizumab-treated (in red) participants. Points show medians and shaded regions show IQRs. Dashed black lines show LLOQ of 0.2 cells/μL for FACS assays. Samples with counts below the LLOQ were imputed to 0.05 cells/μL. Mann–Whitney U test between dose groups; p > 0.05 where p not noted. Vertical dashed lines show when participants were transitioned to the OLP and the placebo cohort was administered two inebilizumab doses; the inebilizumab cohort was given an additional maintenance dose. ddCT = delta delta cycle threshold, FACS = fluorescence-activated cell sorting, FC = fold change, HD = healthy donor, IQR = interquartile range, LLOQ = lower limit of quantification, OLP = open-label period, RCP = randomised controlled period.

Fig. 3

Decreases in NMOSD progression observed with long-term inebilizumab treatment.(a) AAR. (b) Annualised rate of EDSS worsening. (c) Annualised rate of new/enlarging MRI T2 lesions (only participants randomised to inebilizumab are included). (d) Annualised NMOSD-related inpatient hospitalisation rate. Plots show rates in placebo-treated participants during RCP (in grey) and in all participants during the first dosing period of inebilizumab treatment (first dosing interval), and yearly afterwards (in blue). The final bar in each plot displays the combined rate of each endpoint after 2.5 years or more of continued inebilizumab treatment. Mean data with error bars showing 95% CI estimated by negative binomial regression. AAR = annualised attack rate, CI = confidence interval, EDSS = Expanded Disability Status Scale, MRI = magnetic resonance imaging, NMOSD = neuromyelitis optica spectrum disorder, RCP = randomised controlled period.

Fig. 3

Decreases in NMOSD progression observed with long-term inebilizumab treatment.(a) AAR. (b) Annualised rate of EDSS worsening. (c) Annualised rate of new/enlarging MRI T2 lesions (only participants randomised to inebilizumab are included). (d) Annualised NMOSD-related inpatient hospitalisation rate. Plots show rates in placebo-treated participants during RCP (in grey) and in all participants during the first dosing period of inebilizumab treatment (first dosing interval), and yearly afterwards (in blue). The final bar in each plot displays the combined rate of each endpoint after 2.5 years or more of continued inebilizumab treatment. Mean data with error bars showing 95% CI estimated by negative binomial regression. AAR = annualised attack rate, CI = confidence interval, EDSS = Expanded Disability Status Scale, MRI = magnetic resonance imaging, NMOSD = neuromyelitis optica spectrum disorder, RCP = randomised controlled period.

Fig. 4

Temporal relationship between CD20+ B-cell counts and attacks. Box plot of CD20+ B-cell counts in all samples drawn from participants who never experienced attacks, in samples drawn preceding attacks (sample draws 15–115 days preceding attacks), during attack assessment, and after attacks (sample draws 8–200 days after attack). “Other samples” refers to samples that were drawn from participants who experienced attacks, but not directly preceding the attack, directly after the attack, or during the attack. The bold bar shows the median, the box shows the IQR, and the whiskers show the range of data. IQR = interquartile range, LLOQ = lower limit of quantification, WB = whole blood.

Fig. 5

B-cell kinetics in the first dosing interval of inebilizumab predict long-term deep B-cell depletion. (a) Profile plot of CD20+ B-cell counts in individual patients throughout the first dosing interval with inebilizumab. (b) Total CD20+ B-cell counts over 3 years of inebilizumab treatment in patients with B-cell counts >4 cells/μL and ≤4 cells/μL at the end of the first dosing period. Points show medians ± IQR. Mann–Whitney U test was used to calculate p values. IQR = interquartile range, LLOQ = lower limit of quantification.

Fig. 6

Improvement occurs in all participant subgroups over time.(a) AAR. (b) Annualised rate of EDSS worsening. (c) Annualised rate of new/enlarging T2 MRI lesions (only participants randomised to inebilizumab are included). (d) Annualised inpatient hospitalisation rate split by patients with ≤4 cells/μL or >4 cells/μL after the first inebilizumab dosing interval (6 months after treatment). Plot shows rates in placebo-treated participants during the RCP (in grey), then in both inebilizumab-treated participant groups during the first dosing period of inebilizumab treatment (first dosing interval), and yearly afterwards (in blue and red). The final bars in each plot display the combined rate of each endpoint after 2.5 years or more of continued inebilizumab treatment. Mean data with error bars showing 95% CI estimated by negative binomial regression. AAR = annualised attack rate, CI = confidence interval, EDSS = Expanded Disability Status Scale, MRI = magnetic resonance imaging, RCP = randomised controlled period.

Fig. 6

Improvement occurs in all participant subgroups over time.(a) AAR. (b) Annualised rate of EDSS worsening. (c) Annualised rate of new/enlarging T2 MRI lesions (only participants randomised to inebilizumab are included). (d) Annualised inpatient hospitalisation rate split by patients with ≤4 cells/μL or >4 cells/μL after the first inebilizumab dosing interval (6 months after treatment). Plot shows rates in placebo-treated participants during the RCP (in grey), then in both inebilizumab-treated participant groups during the first dosing period of inebilizumab treatment (first dosing interval), and yearly afterwards (in blue and red). The final bars in each plot display the combined rate of each endpoint after 2.5 years or more of continued inebilizumab treatment. Mean data with error bars showing 95% CI estimated by negative binomial regression. AAR = annualised attack rate, CI = confidence interval, EDSS = Expanded Disability Status Scale, MRI = magnetic resonance imaging, RCP = randomised controlled period.