Long-term Safety Outcomes with Inebilizumab Treatment in Neuromyelitis Optica Spectrum Disorder: The N-MOmentum Trial - European Medical Journal

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Long-term Safety Outcomes with Inebilizumab Treatment in Neuromyelitis Optica Spectrum Disorder: The N-MOmentum Trial

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Neurology
EMJ Neurology 9.1 2021 Feature Image
Authors:
*Bruce AC Cree, Jeffery L Bennett,2 Brian G Weinshenker,3 Dean M Wingerchuk,4 Friedemann Paul,5 Ho-Jin Kim,6 Sean J Pittock,3 Kazuo Fujihara,7 Gary R Cutter,8 Romain Marignier,9 Orhan Aktas,10 Hans-Peter Hartung,11,12,13 Ari J Green,1,14 Jörn Drappa,15 Dewei She,15 Daniel Cimbora,15 William A Rees,15 John N Ratchford,15 Eliezer Katz15

1. UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, California, USA
2. University of Colorado School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, USA
3. Mayo Clinic, Rochester, Minnesota, USA
4. Mayo Clinic, Scottsdale, Arizona, USA
5. Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Charité–Universitätsmedizin Berlin, Germany
6. Research Institute and Hospital of National Cancer Center, Goyang, South Korea
7. Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan, and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan
8. University of Alabama, Birmingham, Alabama, USA
9. Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France
10. Medical Faculty, Heinrich Heine University Düsseldorf, Germany
11. Department of Neurology, Heinrich Heine University Düsseldorf, Germany
12. Brain and Mind Center, University of Sydney, Australia
13. Department of Neurology, Medical University of Vienna, Austria
14. UCSF Weill Institute for Neurosciences, Department of Ophthalmology, University of California San Francisco, California, USA
15. Horizon Therapeutics, Gaithersburg, Maryland, USA
*Correspondence to [email protected]

Disclosure:

Cree reports personal compensation for consulting from Akili, Alexion, Atara, Autobahn Therapeutics, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini Bio; and has received research support from Genentech. Bennett reports payment for study design/consultation from MedImmune/Horizon Therapeutics; personal fees from AbbVie, Alexion, Chugai, Clene Nanomedicine, Genentech, Genzyme, Mitsubishi Tanabe Pharma, Reistone Biopharma, and Roche; grants and personal fees from EMD Serono and Novartis; grants from the Guthy–Jackson Charitable Foundation, Mallinckrodt, and the National Institutes of Health (NIH); and has a patent for aquaporumab issued. Weinshenker receives payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, Horizon Therapeutics, and MedImmune; has consulted with Chugai, Genentech, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals regarding clinical trial design for NMOSD; 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, RSR, and the University of Oxford. Wingerchuk reports personal fees from Arcus Medica, Biogen, Celgene, Genentech, MedImmune, Novartis, Reistone Biopharma, TG Therapeutics, and Third Rock Ventures; research support paid to the Mayo Clinic by Alexion and Terumo BCT; and serves on a clinical trial adjudication committee for Horizon Therapeutics and MedImmune. Paul has received research support, speaker fees, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study sponsored by Novartis. Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, Celltrion, Eisai, HanAll BioPharma, Horizon Therapeutics, MDimune, Merck Serono, Novartis, Sanofi Genzyme, and Teva-Handok; serves on a steering committee for MedImmune/Horizon Therapeutics; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. Pittock reports grants, personal fees, and non-financial support from Alexion; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, non-financial support, and other from Horizon Therapeutics and MedImmune; consulting support from Astellas; 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’. Fujihara serves on scientific advisory boards for Alexion, Bayer Schering, Biogen Idec, Chugai, Horizon Therapeutics, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, and Ono; has received funding for travel and speaker fees from Asahi Kasei Medical, Astellas, Bayer Schering, Biogen Idec, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, and Takeda; and research support from Asahi Kasei Medical, Bayer Schering, Biogen Idec, Chemo-Sero-Therapeutic Research Institute, Chugai, Genzyme Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Welfare and Labor of Japan, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Ono, Teijin, and Teva. 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, Galmed Pharmaceuticals, Hisun Pharmaceuticals, Horizon Therapeutics, Mapi Pharma, Merck, Merck/Pfizer, Neurim, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), Novartis, OncoImmune, OPKO Biologics, Orphazyme, Reata Pharmaceuticals, Sanofi-Aventis, Teva, and Vivus; personal fees for consulting or advisory board participation from Biodelivery Sciences International, Biogen, Click Therapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, MedDay, MedImmune, Neurogenesis, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham; and is President of Pythagoras, Inc., a private consulting company based in Birmingham, AL, USA. Marignier serves on scientific advisory boards for Horizon Therapeutics and MedImmune; and has received funding for travel and fees from Biogen Idec, Horizon Therapeutics, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. Aktas reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Horizon Therapeutics, Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono, and Roche. 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, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, and TG Therapeutics with approval by the Rector of Heinrich Heine University Düsseldorf. 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, Mylan, Synthon, and Trims Pharma; and personal fees from and other financial relationships with Pipeline Therapeutics. Drappa, She, Cimbora, Rees, and Katz are employees of Horizon Therapeutics. Ratchford was an employee of Horizon Therapeutics at the time of this study. The study was funded by Horizon Therapeutics (formerly Viela Bio) and MedImmune.

Acknowledgements:

The authors would like to thank the participants of the N-MOmentum study. Medical writing support was provided by Ester Baixauli (Oxford PharmaGenesis, Oxford, UK), which was paid for by Horizon Therapeutics.

Support:

This study was supported by the Fondazione Italiana Sclerosi Multipla with a senior research fellowship (FISM2019/BS/009), a research grant from (FISM2018/R/16), and financed or co-financed with the ‘5 per mille’ public funding.

Citation:
EMJ Neurol. ;9[1]:45-48. Abstract Review No. AR6.
Keywords:
Adverse events, B-cell depletion, CD19, inebilizumab, long-term, neuromyelitis optica spectrum disorder (NMOSD), N-MOmentum, safety outcomes.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease characterised by recurrent inflammation of the optic nerve, spinal cord, and/or brain or brainstem.1,2 N-MOmentum was a multi-centre, double-blind, randomised, placebo-controlled Phase II/III study, with an optional open-label period (OLP), of the efficacy and safety of inebilizumab, a humanised anti-CD19 monoclonal antibody, in NMOSD.3 During the randomised controlled period (RCP), inebilizumab showed good tolerability and rates of treatment-emergent adverse events (TEAEs), serious adverse events, and infusion-related reactions (IRRs), similar to placebo.3 The aim is to evaluate the long-term safety of inebilizumab in participants with NMOSD.

MATERIALS AND METHODS

Participants with NMOSD (aged ≥18 years with an Expanded Disability Status Scale [EDSS] score of ≤8 and a recent history of attacks) were randomised 3:1 to inebilizumab or placebo monotherapy in the RCP for 28 weeks or up to attack occurrence, after which they could enter the OLP for a minimum of 2 years. During the OLP, participants received inebilizumab (300 mg intravenous infusion) every 28 weeks for a maximum of 5.5 years. Long-term safety endpoints included TEAEs, adverse events of special interest (including severe and opportunistic infections and IRRs), anti-drug antibodies, and Ig level changes. Participants were grouped into two groups for analysis: ‘any inebilizumab’ (who received inebilizumab at any point during the study) and ‘long-term inebilizumab’ (who received inebilizumab for at least 4 years). Data from participants at the end of the RCP were also used for context.

RESULTS

Overall, 165/174 participants (94.8%) randomised to inebilizumab and 51/56 participants (91.1%) randomised to placebo in the RCP entered the OLP, with a total of 225 participants receiving ‘any inebilizumab’. Mean treatment duration was 3.2 years (standard deviation: ±1.4 years) and 36.8% of participants were treated for more than 4 years; total inebilizumab exposure was 730.36 person-years. During the OLP, there were three deaths: one due to a severe NMOSD attack, one due to a central nervous system event of unclear aetiology, and one related to COVID-19 after 7,224 and 1,225 days of inebilizumab exposure, respectively.

‘Any inebilizumab’ participants did not have higher incidences of the most common TEAEs than those found during the RCP (TEAE rate per person-year: ‘any inebilizumab’, 0.28; RCP inebilizumab, 1.54; RCP placebo, 1.55 Figure 1A). Compared with placebo, inebilizumab did not increase the incidence of adverse events of special interest, including IRRs and opportunistic infections, during the RCP or with multiple dosing in the OLP (Figure 1B).

Figure 1: Rates per person-year.
A) TEAEs occurring in ≥10% of participants in the ‘any inebilizumab’ group. B) AESIs during the N-MOmentum trial. C) IgG level changes during the study in participants who did (‘Yes’) and did not (‘No’) experience an infection. D) Incidence per person-year of treatment-emergent infections in the ‘any inebilizumab’ and ‘long-term inebilizumab’ groups. AESI: adverse event of special interest; CI: confidence interval; IRR: infusion-related reaction; RCP: randomised controlled period; TEAE: treatment-emergent adverse event.

‘Any inebilizumab’ participants had decreased Ig levels, which were 28.8% lower than baseline with long-term treatment. However, Ig depletion did not increase infection rates. There was no correlation between infection and levels of IgG depletion (Fisher exact test, p>0.05 [hl]Figure 1C[/hl]), and rates of infection in participants from the ‘long-term inebilizumab’ group were not higher than in the ‘any inebilizumab’ group (Figure 1D). Moreover, incidence of anti-drug antibody formation remained low during the study and did not increase with inebilizumab treatment or multiple dosing (participants with anti-inebilizumab antibodies: RCP inebilizumab, 2.9% [n=5]; RCP placebo, 7.1% [n=4]; OLP, 6.5% [n=14]).

CONCLUSION

Long-term data from the OLP of N-MOmentum demonstrated that treatment with inebilizumab was generally well tolerated for at least 4 years. No new safety signals were identified and rates of infection or serious infection did not increase with prolonged inebilizumab treatment.

References
Lucchinetti CF et al. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol. 2014;24(1):83-97. Cree BAC et al. Placebo-controlled study in neuromyelitis optica-ethical and design considerations. Mult Scler. 2016;22(7):862-72. Cree BAC 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(10206):1352-63.

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