Disability Outcomes in the N-MOmentum Trial of Inebilizumab in Neuromyelitis Optica Spectrum Disorder

Romain Marignier, Jeffrey L Bennett, Ho Jin Kim, Brian G Weinshenker, Sean J Pittock, Dean Wingerchuk, Kazuko Fujihara, Friedemann Paul, Gary R Cutter, Ari J Green, Orhan Aktas, Hans-Peter Hartung, Fred D Lublin, Ian M Williams, Jorn Drappa, Dewei She, Daniel Cimbora, William Rees, Michael Smith, John N Ratchford, Eliezer Katz, Bruce A C Cree, N-MOmentum Study Investigators, Romain Marignier, Jeffrey L Bennett, Ho Jin Kim, Brian G Weinshenker, Sean J Pittock, Dean Wingerchuk, Kazuko Fujihara, Friedemann Paul, Gary R Cutter, Ari J Green, Orhan Aktas, Hans-Peter Hartung, Fred D Lublin, Ian M Williams, Jorn Drappa, Dewei She, Daniel Cimbora, William Rees, Michael Smith, John N Ratchford, Eliezer Katz, Bruce A C Cree, N-MOmentum Study Investigators

Abstract

Objective: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD).

Methods: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach.

Results: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023).

Conclusions: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD.

Classification of evidence: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Post Hoc Analyses of EDSS…
Figure 1. Post Hoc Analyses of EDSS Outcomes
(A) EDSS worsening at the end of the RCP using nonattack visit data. Analysis conducted by using EDSS values from OLP month 3 for those participants who had AC-determined attack at their end of RCP visit (placebo: n = 15; inebilizumab: n = 14). End of the RCP visit data were used for those who did not have attacks (placebo: n = 0; inebilizumab: n = 2). (B) Three-month CDP from the end of the RCP visit. Analysis conducted for the subgroup of patients with EDSS worsening at the last RCP visit irrespective of whether participants had attacks, confirmed at OLP month 3 (placebo: 7/7 had attacks; inebilizumab: 2/6 had attacks). (C) Kaplan-Meier plot of the risk of 3-month CDP from any point in the RCP. None of those randomized to placebo with EDSS worsening at the last RCP visit had a subsequent attack in the first 3 months of OLP. Only 1 participant randomized to inebilizumab with EDSS worsening at the last RCP visit had a subsequent attack within the 3-month OLP window. AC = adjudication committee; CDP = confirmed disability progression; EDSS = Expanded Disability Status Scale; HR = hazard ratio; OLP = open-label period; RCP = randomized controlled period.
Figure 2. Subgroup Analyses of EDSS Outcomes
Figure 2. Subgroup Analyses of EDSS Outcomes
Figure shows the risk of EDSS score worsening from baseline to the end of the RCP. EDSS = Expanded Disability Status Scale; HR = hazard ratio; RCP = randomized controlled period.
Figure 3. Post Hoc Analysis of Change…
Figure 3. Post Hoc Analysis of Change in Mean EDSS Scores During the RCP and OLP
(A) Overall population. (B) Participants with attacks in the RCP. (C) Participants without attacks in the RCP. EDSS = Expanded Disability Status Scale; OLP = open-label period; RCP = randomized controlled period.
Figure 4. mRS Outcomes During the RCP
Figure 4. mRS Outcomes During the RCP
(A) Treatment effect based on the mRS score during the RCP. (B) Distribution of mRS scores at baseline and at the last RCP visit in patients treated with placebo. (C) Distribution of mRS scores at baseline and at the last RCP visit in patients treated with inebilizumab. mRS = modified Rankin Scale; RCP = randomized controlled period; WMWodds = Wilcoxon-Mann-Whitney odds.

References

    1. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–815.
    1. Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol 2014;24:83–97.
    1. Pittock SJ, Lennon VA, Krecke K, Wingerchuk DM, Lucchinetti CF, Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63:390–396.
    1. Jarius S, Wildemann B, Paul F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin Exp Immunol 2014;176:149–164.
    1. Jeong IH, Choi JY, Kim SH, et al. . Normal-appearing white matter demyelination in neuromyelitis optica spectrum disorder. Eur J Neurol 2017;24:652–658.
    1. Ventura RE, Kister I, Chung S, Babb JS, Shepherd TM. Cervical spinal cord atrophy in NMOSD without a history of myelitis or MRI-visible lesions. Neurol Neuroimmunol Neuroinflamm 2016;3:e224.
    1. Jeong IH, Kim HJ, Kim NH, Jeong KS, Park CY. Subclinical primary retinal pathology in neuromyelitis optica spectrum disorder. J Neurol 2016;263:1343–1348.
    1. Ringelstein M, Harmel J, Zimmermann H, et al. . Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders. Neurology 2020;94:e407–e418.
    1. Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol 2016;73:1342–1348.
    1. Espiritu AI, Pasco PMD. Efficacy and tolerability of azathioprine for neuromyelitis optica spectrum disorder: a systematic review and meta-analysis. Mult Scler Relat Disord 2019;33:22–32.
    1. Pittock SJ, Berthele A, Fujihara K, et al. . Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med 2019;381:614–625.
    1. Yamamura T, Kleiter I, Fujihara K, et al. . Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med 2019;381:2114–2124.
    1. Bennett JL, O'Connor KC, Bar-Or A, et al. . B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm 2015;2:e104.
    1. Hausser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol 2019;10:201.
    1. Cree BAC, Bennett JL, Kim HJ, et al. . Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 2019;394:1352–1363.
    1. Cree BA, Bennett JL, Sheehan M, et al. . Placebo-controlled study in neuromyelitis optica-Ethical and design considerations. Mult Scler 2016;22:862–872.
    1. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–1489.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–1452.
    1. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–607.
    1. D'Souza M, Yaldizli O, John R, et al. . Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: a proof of concept study. Mult Scler 2017;23:597–603.
    1. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999;53:1107–1114.
    1. Pittock SJ, Lennon VA, McKeon A, et al. . Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013;12:554–562.
    1. Churilov L, Arnup S, Johns H, et al. . An improved method for simple, assumption-free ordinal analysis of the modified Rankin Scale using generalized odds ratios. Int J Stroke 2014;9:999–1005.
    1. Divine G, Norton HJ, Hunt R, Dienemann J. Statistical grand rounds: a review of analysis and sample size calculation considerations for Wilcoxon tests. Anesth Analg 2013;117:699–710.
    1. Kitley J, Leite MI, Nakashima I, et al. . Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012;135:1834–1849.
    1. Jarius S, Ruprecht K, Wildemann B, et al. . Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 2012;9:14.
    1. Palace J, Lin DY, Zeng D, et al. . Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders. Brain 2019;142:1310–1323.
    1. Kim SH, Mealy MA, Levy M, et al. . Racial differences in neuromyelitis optica spectrum disorder. Neurology 2018;91:e2089–e2099.
    1. Mealy MA, Mossburg SE, Kim SH, et al. . Long-term disability in neuromyelitis optica spectrum disorder with a history of myelitis is associated with age at onset, delay in diagnosis/preventive treatment, MRI lesion length and presence of symptomatic brain lesions. Mult Scler Relat Disord 2019;28:64–68.
    1. Viela Bio. UPLINZA (Inebilizumab): Prescribing Information [online]. Available at: . Accessed August 04, 2020.
    1. Costanzi C, Matiello M, Lucchinetti CF, et al. . Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 2011;77:659–666.
    1. Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 2005;64:1270–1272.
    1. Nikoo Z, Badihian S, Shaygannejad V, Asgari N, Ashtari F. Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. J Neurol 2017;264:2003–2009.
    1. Tahara M, Oeda T, Okada K, et al. . Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2020;19:298–306.
    1. Alexion Pharmaceuticals Inc. SOLIRIS (Eculizumab): Prescribing Information [online]. Available at: . Accessed April 17, 2020.
    1. Alexion Europe S.A.S. SOLIRIS (Eculizumab): Summary of Product Characteristics [online]. Available at: . Accessed April 17, 2020.
    1. Levy M, Fujihara K, Palace J. New therapies for neuromyelitis optica spectrum disorder. Lancet Neurol 2021;20:60–67.
    1. Aktas O, Smith M, Rees W, et al. . Elevated serum glial fibrillary acidic protein (sGFAP) is associated with increased risk of neuromyelitis optica spectrum disorder attacks in the N-MOmentum randomised, masked, placebo-controlled clinical trial of inebilizumab. ECTRIMS Online Libr 2019;278649:P1609.
    1. Oertel FC, Havla J, Roca-Fernandez A, et al. . Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study. J Neurol Neurosurg Psychiatry 2018;89:1259–1265.
    1. Oertel FC, Kuchling J, Zimmermann H, et al. . Microstructural visual system changes in AQP4-antibody-seropositive NMOSD. Neurol Neuroimmunol Neuroinflamm 2017;4:e334.
    1. Ringelstein M, Kleiter I, Ayzenberg I, et al. . Visual evoked potentials in neuromyelitis optica and its spectrum disorders. Mult Scler 2014;20:617–620.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться