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Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis

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Abstract

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.

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  1. Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

    Reshmi Roy, Alaa A. Alotaibi & Mark S. Freedman

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Mark S. Freedman has received research or educational grants and consultation fees from Sanofi-Genzyme Canada, Hoffmann-La Roche, and EMD Inc. (Canada), Actelion (Janssen/J&J), Alexion, Biogen Idec, Celgene (BMS), Merck Serono, Novartis, and Teva Canada Innovation; is a member of a company advisory board, board of directors, or other similar group for Actelion (Janssen/J&J), Alexion, Atara Biotherapeutics, Bayer Healthcare, Biogen Idec, Celgene (BMS), Clene Nanomedicine, GRI Bio, Hoffman-La Roche, Magenta Therapeutics, Merck Serono, MedDay, Novartis, Sanofi-Genzyme, and Teva Canada Innovation; and has participated in a company-sponsored speaker’s bureau for Sanofi-Genzyme and EMD Serono. Reshmi Roy and Alaa A. Alotaibi have no conflicts of interest that are directly relevant to the content of this article.

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All authors contributed equally to the conception of this work, the interpretation of the literature, and the drafting of the manuscript. The original version of the article was written by Alaa A. Alotaibi and was further edited and expanded upon by Reshmi Roy, who submitted the final draft of the article. All versions were reviewed with Mark S. Freedman. All authors critically revised the review and approved the final manuscript for publication.

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Alaa A. Alotaibi is currently employed at King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

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Roy, R., Alotaibi, A.A. & Freedman, M.S. Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis. CNS Drugs 35, 385–402 (2021). https://doi.org/10.1007/s40263-021-00798-w

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