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2018 年以来获批多发性硬化症药物的疗效和安全性及未来发展

Efficacy and Safety of Multiple Sclerosis Drugs Approved Since 2018 and Future Developments.

机构信息

Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.

出版信息

CNS Drugs. 2022 Aug;36(8):803-817. doi: 10.1007/s40263-022-00939-9. Epub 2022 Jul 22.

DOI:10.1007/s40263-022-00939-9
PMID:35869335
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9307218/
Abstract

Multiple sclerosis treatment made substantial headway during the last two decades with the implementation of therapeutics with new modes of action and routes of application. We are now in the situation that second-generation molecules, approved since 2018, are on the market, characterized by reduced side effects using a more tailored therapeutic approach. Diroximel fumarate is a second-generation fumarate with reduced gastrointestinal side effects. Moreover, several novel, selective, sphingosine-1-phosphate receptor modulators with reduced off-target effects have been developed; namely siponimod, ozanimod, and ponesimod; all oral formulations. B-cell-targeted therapies such as ocrelizumab, given intravenously, and since 2021 ofatumumab, applied subcutaneously, complement the spectrum of novel therapies. The glycoengineered antibody ublituximab is the next anti-CD20 therapy about to be approved. Within the next years, oral inhibitors of Bruton's tyrosine kinase, currently under investigation in several phase III trials, may be licensed for multiple sclerosis. Those developments currently offer an individualized multiple sclerosis therapy, targeting patient needs with substantial effects on relapses, disability progression, and implications for daily life. In this up-to-date review, we provide a holistic overview about novel developments of the therapeutic landscape and upcoming approaches for multiple sclerosis treatment.

摘要

多发性硬化症的治疗在过去二十年取得了重大进展,新作用模式和应用途径的治疗方法已经得到实施。我们现在处于第二代分子的市场环境中,自 2018 年以来已经获得批准,这些分子的副作用较小,采用了更具针对性的治疗方法。富马酸二甲酯是一种第二代富马酸,其胃肠道副作用较小。此外,已经开发出几种新型、选择性、鞘氨醇-1-磷酸受体调节剂,其脱靶效应降低;即西尼莫德、奥扎尼莫德和泊尼莫德;均为口服制剂。B 细胞靶向疗法,如静脉注射用奥瑞珠单抗,以及自 2021 年以来皮下应用的奥法妥木单抗,补充了新型疗法的范围。糖基化工程抗体 ublituximab 是下一种即将获得批准的抗 CD20 疗法。在未来几年,几种正在进行的 III 期临床试验中的布鲁顿酪氨酸激酶口服抑制剂可能会获得多发性硬化症的许可。这些进展目前提供了个体化的多发性硬化症治疗方法,针对患者的需求,对复发、残疾进展和日常生活产生重大影响。在这篇最新的综述中,我们全面概述了治疗领域的新进展和多发性硬化症治疗的新方法。

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Efficacy and Safety of Multiple Sclerosis Drugs Approved Since 2018 and Future Developments.2018 年以来获批多发性硬化症药物的疗效和安全性及未来发展
CNS Drugs. 2022 Aug;36(8):803-817. doi: 10.1007/s40263-022-00939-9. Epub 2022 Jul 22.
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Ozanimod (Zeposia) for multiple sclerosis.奥扎莫德(泽布西)用于治疗多发性硬化症。
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Mult Scler Relat Disord. 2023 Jul;75:104733. doi: 10.1016/j.msard.2023.104733. Epub 2023 Apr 25.

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Towards a biological view of multiple sclerosis from early subtle to clinical progression: an expert opinion.从早期细微变化到临床进展,构建多发性硬化症的生物学视角:专家意见
J Neurol. 2025 Feb 1;272(2):179. doi: 10.1007/s00415-025-12917-4.
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Electrical stimulation of the vagus nerve ameliorates inflammation and disease activity in a rat EAE model of multiple sclerosis.电刺激迷走神经可改善多发性硬化症大鼠 EAE 模型的炎症和疾病活动。
Proc Natl Acad Sci U S A. 2024 Jul 9;121(28):e2322577121. doi: 10.1073/pnas.2322577121. Epub 2024 Jul 5.
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J Inflamm Res. 2024 Jan 9;17:191-210. doi: 10.2147/JIR.S442684. eCollection 2024.
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本文引用的文献

1
Preserved T-cell response in anti-CD20-treated multiple sclerosis patients following SARS-CoV-2 vaccination.抗CD20治疗的多发性硬化症患者在接种SARS-CoV-2疫苗后T细胞反应得以保留。
Ther Adv Neurol Disord. 2022 Dec 9;15:17562864221141505. doi: 10.1177/17562864221141505. eCollection 2022.
2
Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration.皮下或静脉注射后人源化 CD20 小鼠体内奥法妥木单抗和奥瑞珠单抗的分布和疗效。
Front Immunol. 2022 Jul 28;13:814064. doi: 10.3389/fimmu.2022.814064. eCollection 2022.
3
Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies.在复发缓解型多发性硬化症中的长期用ponsimod 治疗:来自随机 2b 期核心和扩展研究的结果。
Neurology. 2022 Aug 23;99(8):e762-e774. doi: 10.1212/WNL.0000000000200606. Epub 2022 Jun 6.
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Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study.在转换为先前的治疗或继续使用 DRF 后,富马酸二甲酯的疗效和安全性结果:来自 3 期 EVOLVE-MS-1 研究的结果。
Adv Ther. 2022 Apr;39(4):1810-1831. doi: 10.1007/s12325-022-02068-7. Epub 2022 Feb 24.
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S1P receptor modulators in Multiple Sclerosis: Detecting a potential skin cancer safety signal.多发性硬化症中的 S1P 受体调节剂:检测潜在的皮肤癌安全性信号。
Mult Scler Relat Disord. 2022 Mar;59:103681. doi: 10.1016/j.msard.2022.103681. Epub 2022 Feb 9.
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Humoral and cellular immunity in convalescent COVID-19 people with multiple sclerosis treated with ofatumumab.恢复期 COVID-19 多发性硬化症患者接受奥法妥木单抗治疗后的体液和细胞免疫。
J Neuroimmunol. 2022 Jan 15;362:577788. doi: 10.1016/j.jneuroim.2021.577788. Epub 2021 Dec 13.
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Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.疾病修正疗法与多发性硬化症中 COVID-19 严重程度的关联。
Neurology. 2021 Nov 9;97(19):e1870-e1885. doi: 10.1212/WNL.0000000000012753. Epub 2021 Oct 5.
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Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.奥法妥木单抗皮下注射快速持久地清除 B 细胞治疗复发型多发性硬化症:APLIOS,一项随机 2 期研究。
Mult Scler. 2022 May;28(6):910-924. doi: 10.1177/13524585211044479. Epub 2021 Oct 4.
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Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.抗 CD20 治疗的多发性硬化症患者接种 SARS-CoV-2 mRNA 疫苗后的细胞和体液免疫反应。
Nat Med. 2021 Nov;27(11):1990-2001. doi: 10.1038/s41591-021-01507-2. Epub 2021 Sep 14.
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Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results.长达 13 年的富马酸二甲酯治疗复发缓解型多发性硬化症患者的长期安全性和疗效:最终 ENDORSE 研究结果。
Mult Scler. 2022 Apr;28(5):801-816. doi: 10.1177/13524585211037909. Epub 2021 Sep 1.