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Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis
CNS Drugs ( IF 7.4 ) Pub Date : 2021-04-02 , DOI: 10.1007/s40263-021-00798-w
Reshmi Roy 1 , Alaa A Alotaibi 1 , Mark S Freedman 1
Affiliation  

Fingolimod (Gilenya) received regulatory approval from the US FDA in 2010 as the first-in-class sphingosine 1-phosphate (S1P) receptor (S1PR) modulator and was the first oral disease-modifying therapy (DMT) used for the treatment of the relapsing forms of multiple sclerosis (MS). Development of this new class of therapeutic compounds has continued to be a pharmacological goal of high interest in clinical trials for treatment of various autoimmune disorders, including MS. S1P is a physiologic signaling molecule that acts as a ligand for a group of cell surface receptors. S1PRs are expressed on various body tissues and regulate diverse physiological and pathological cellular responses involved in innate and adaptive immune, cardiovascular, and neurological functions. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are well known for their major role in MS pathogenesis and play an important regulatory role in the egress of lymphocytes from lymphoid organs to the lymphatic circulation. Thus, S1PR1-directed pharmacological interventions aim to modulate its role in immune cell trafficking through sequestration of autoreactive lymphocytes in the lymphoid organs to reduce their recirculation and subsequent infiltration into the central nervous system. Indeed, receptor subtype selectivity for S1PR1 is theoretically favored to minimize safety concerns related to interaction with other S1PR subtypes. Improved understanding of fingolimod’s mechanism of action has provided strategies for the development of the more selective second-generation S1PR modulators. This selectivity serves to reduce the most important safety concern regarding cardiac-related side effects, such as bradycardia, which requires prolonged first-dose monitoring. It has led to the generation of smaller molecules with shorter half-lives, improved onset of action with no requirement for phosphorylation for activation, and preserved efficacy. The shorter half-lives of the second-generation agents allow for more rapid reversal of their pharmacological effects following treatment discontinuation. This may be beneficial in addressing further treatment-related complications in case of adverse events, managing serious or opportunistic infections such as progressive multifocal leukoencephalopathy, and eliminating the drug in pregnancies. In March 2019, a breakthrough in MS treatment was achieved with the FDA approval for the second S1PR modulator, siponimod (Mayzent), for both active secondary progressive MS and relapsing–remitting MS. This was the first oral DMT specifically approved for active forms of secondary progressive MS. Furthermore, ozanimod received FDA approval in March 2020 for treatment of relapsing forms of MS, followed by subsequent approvals from Health Canada and the European Commission. Other second-generation selective S1PR modulators that have been tested for MS, with statistically significant data from phase II and phase III clinical studies, include ponesimod (ACT-128800), ceralifimod (ONO-4641), and amiselimod (MT-1303). This review covers the available data about the mechanisms of action, pharmacodynamics and kinetics, efficacy, safety, and tolerability of the various S1PR modulators for patients with relapsing–remitting, secondary progressive, and, for fingolimod, primary progressive MS.



中文翻译:

用于多发性硬化症的 1-磷酸鞘氨醇受体调节剂

芬戈莫德 (Gilenya) 于 2010 年获得美国 FDA 的监管批准,作为一流的 1-磷酸鞘氨醇 (S1P) 受体 (S1PR) 调节剂,是第一个用于治疗多发性硬化症(MS)的复发形式。开发这类新的治疗化合物一直是治疗各种自身免疫性疾病(包括 MS)的临床试验中高度关注的药理学目标。S1P 是一种生理信号分子,可作为一组细胞表面受体的配体。S1PRs 在各种身体组织上表达并调节涉及先天性和适应性免疫、心血管和神经功能的各种生理和病理细胞反应。S1PR 亚型 1 (S1PR 1) 表达于淋巴细胞的细胞表面,众所周知,它们在 MS 发病机制中的主要作用,并在淋巴细胞从淋巴器官到淋巴循环的排出中起重要调节作用。因此,S1PR 1导向的药理干预旨在通过隔离淋巴器官中的自身反应性淋巴细胞来调节其在免疫细胞运输中的作用,以减少它们的再循环和随后的中枢神经系统浸润。事实上,S1PR 1 的受体亚型选择性理论上有利于最大限度地减少与其他 S1PR 亚型相互作用相关的安全问题。对芬戈莫德作用机制的深入了解为开发更具选择性的第二代 S1PR 调节剂提供了策略。这种选择性有助于减少有关心脏相关副作用的最重要的安全问题,例如心动过缓,这需要长时间的首剂监测。它导致产生半衰期更短的更小分子,改善了起效,无需磷酸化即可激活,并保留了功效。第二代药物的半衰期较短,可以在停药后更快地逆转其药理作用。这可能有助于在发生不良事件时解决进一步的治疗相关并发症,管理严重或机会性感染,如进行性多灶性白质脑病,以及在妊娠期消除药物。2019 年 3 月,FDA 批准了第二种 S1PR 调节剂 siponimod (Mayzent),用于活跃的继发进展型 MS 和复发缓解型 MS,在 MS 治疗方面取得了突破。这是第一个专门批准用于活性形式的继发进展性 MS 的口服 DMT。此外,ozanimod 于 2020 年 3 月获得 FDA 批准用于治疗复发型 MS,随后获得加拿大卫生部和欧盟委员会的批准。其他已经过 MS 测试的第二代选择性 S1PR 调制器,具有来自 II 期和 III 期临床研究的具有统计学意义的数据,包括波奈莫德 (ACT-128800)、ceralifimod (ONO-4641) 和阿米莫德 (MT-1303)。本综述涵盖了有关各种 S1PR 调节剂对复发缓解型、继发进展型以及芬戈莫德原发进展型 MS 患者的作用机制、药效学和动力学、功效、安全性和耐受性的可用数据。

更新日期:2021-04-02
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