Review Multiple Sclerosis Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis Patrick Vermersch University of Lille, CHU Lille, INSERM U995 (LIRIC), FHU Imminent, Lille, France DOI: https://doi.org/10.17925/ENR.2018.13.1.25 he introduction of oral disease modifying therapies has transformed the treatment landscape for patients with multiple sclerosis (MS). Fingolimod (Gilenya®, Novartis, Basel, Switzerland), the first oral therapy to be approved, has demonstrated clinical efficacy as a result of modulation of subtype 1 sphingosine-1-phosphate (S1P ) receptors. This leads to retention of lymphocytes in the T 1 lymph nodes, preventing their entry into the central nervous system. However, fingolimod can cause adverse effects as a result of its interaction with other S1P receptor subtypes, which are expressed in numerous tissues, including cardiac myocytes. More selective S1P receptor agents are currently in phase II and III clinical development. Siponimod, ozanimod, ponesimod and amiselimod have demonstrated efficacy with improved safety profiles compared with fingolimod. While more long-term data are needed, these selective S1P receptor modulators appear to be promising options for the treatment of MS and other disorders associated with autoimmunity and inflammation. Keywords In the past decade, a number of novel therapies targeting specific molecules involved in the Multiple sclerosis, oral disease modifying inflammatory or immune system activation cascades have become available, improving the therapies, sphingosine-1-phosphate receptors management of multiple sclerosis (MS).1 However, most new therapies are biological drugs, which need to be injected and are therefore associated with reduced convenience, compliance and Disclosure: Patrick Vermersch has received honoraria and consulting fees from Biogen, Sanofi-Genzyme, injection- or infusion-related adverse effects (AEs).2,3 Most current disease modifying therapies Novartis, Teva, Merck, Roche, Servier, Celgene, Medday (DMTs) for MS primarily target the immunological inflammatory component of the disease without and Almirall. He has also received research support from Biogen, Novartis, Sanofi-Genzyme, Roche and Merck. acting directly on the central nervous system (CNS)4 and have been shown to be only partially Review Process: Double-blind peer review effective. In addition, chronic immunosuppression is associated with mainly opportunistic infections.5 Acknowledgements: Medical writing support was provided by Katrina Mountfort of Touch Medical Another drawback of current DMTs is that, to date, most have shown limited efficacy against Media, and was supported by Touch Medical Media. secondary progressive MS (SPMS),6 although ocrelizumab has been approved for progressive Compliance with Ethics: This article involves a review of the literature and did not involve any studies with MS after showing activity in patients with primary progressive MS.7 A new class of oral targeted human or animal subjects performed by the author. therapies for MS has the potential to overcome these limitations. This review aims to discuss the Authorship: The named author meets the criteria of clinical development of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of the International Committee of Medical Journal Editors for authorship of this manuscript, takes responsibility patients with relapsing forms of MS (RMS) or SPMS. for the integrity of the work as a whole and has given final approval for the version to be published. Mechanism of action of sphingosine-1-phosphate Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which receptor modulators permits any non-commercial use, distribution, adaptation Sphingosine-1-phosphate is an active phospholipid that is produced by the phosphorylation of and reproduction provided the original author and source are given appropriate credit. © The Author 2018. sphingolipids, present in the cell membrane, by sphingosine kinase-1 or -2 (SphK1/2; Figure 1).8 Received: 31 January 2018 It regulates numerous biological processes including immunity, inflammation, angiogenesis, heart Accepted: 21 March 2018 rate, smooth muscle tone, cell differentiation, cell migration and survival, calcium homeostasis Citation: European Neurological and endothelium integrity, and is found in high concentrations in erythrocytes, brain, spleen and Review. 2018;13(1):25–30 eyes.8 Its effects are mediated by S1P receptors, which have seven transmembrane segments and Correspondence: Patrick Vermersch, University of Lille, CHU Lille, INSERM U995 (LIRIC), FHU Imminent, are coupled to G-proteins. There are five known subtypes: S1P1–3 which are broadly distributed in F-59000 Lille, France. E: [email protected] tissues; S1P4, which is expressed mostly in lymphoid tissue and the lungs; and S1P5, which is found in the spleen, skin and oligodendrocytes.8,9 Therefore, S1P receptors are found in multiple organ Support: No funding was received in 9 the publication of this article. systems including the immune, cardiovascular, and respiratory systems, as well as in the CNS. In the CNS, expression of S1P receptors has been reported on oligodendrocytes, astrocytes, 9 neurons and microglia in experimental conditions. Both B- and T-lymphocytes express S1P1 and, 8 to a lesser extent, S1P3 and S1P4. Sphingosine-1-phosphate signalling plays an important role in lymphocyte trafficking, particularly egress from lymph nodes and migration into the blood and target tissues (Figure 1).10,11 In patients with MS, S1P receptors reduce the release of lymphocytes from secondary lymphoid tissues, thymus and bone marrow, resulting in lymphopaenia. The binding of S1P receptor modulators to S1P1 on central memory T-cells (TCM) causes these cells to internalise their own S1P1, resulting in TCM that no longer respond to S1P signals. Any new S1P receptors produced inside the cell remain in an inactive state until S1P receptor modulation is removed.11 TOUCH MEDICAL MEDIA Print Publication Date: 6 June 2018 25 Review Multiple Sclerosis Figure 1: Mechanism of action of sphingosine-1-phosphate receptor modulators A B Lymph node Afferent lymph Lymph node S1P S1P S1P high S1P1 S1P1 S1P low No requirement T TN CM for S1P signal CCR7 CCR7 TEM Blood Efferent lymph Fingolimod inhibits S1P–S1P1-directed lymphocyte egress Blood Efferent lymph C Agent Fingolimod Fingolimod Fingolimod Fingolimod Siponimod Siponimod Ozanimod Ozanimod Ceralimod Ceralimod GSK2018682 GSK2018682 Ponesimod Amiselimoda Receptor S1P1 S1P2 S1P3 S1P4 S1P5 Location Lymphocytes, Central nervous system, Neural cells, Lymphocytes Central nervous system, neural cells, endothelial cells, endothelial cells, oligodendrocytes, endothelial cells, smooth muscle cells smooth muscle cells natural killer cells atrial myocytes, smooth muscle cells Function 1. Egression from 1. Endothelial barrer 1. Neural cell 1. Lymphoid tissue 1. Oligodendrocyte lymph nodes 2. Vascular tone migration/function expression function 2. Neural cell 3. Hearing and 2. Endothelial 2. Dendritic and TH17 2. Natural killer migration/function balance barrier cell modulation cell migration 3. Vasculature formation 3. Vasoconstriction 4. Endothelial barrier 5. Development of CV and nervous system A: Binding of S1P receptor modulators to S1P1 on central memory T-cells. B: Interaction of S1P receptor modulators with S1P receptor subtypes. C: Interaction of fingolimod and selective S1P receptor drugs with S1P receptor subtypes. aAmiselimod is selective, but its selectivity is unknown. CCR7 = C-C chemokine receptor type 7; CV = cardiovascular; S1P = sphingosine-1-phosphate; S1P1–5 = sphingosine-1-phosphate receptor subtypes 1–5; TH17 = T helper cell 17; TCM = central memory T-cell; TEM = effector memory T-cell; 11 54,55 TN = naïve T-cell. Reproduced from Comi et al., 2017 with permission from the original sources. Therefore, TCM do not leave the lymph node in response to S1P signals. and is internalised in the same way as S1P, but the receptor is then As a result, fewer circulating lymphocytes are available to infiltrate the degraded, preventing cell surface signalling.8 Fingolimod is an agonist 8,12,13 14 CNS and mount an autoimmune reaction on the axon myelin sheath. of four S1P receptor subtypes (S1P1, S1P3, S1P4 and S1P5) and induces Modulators of the S1P receptor prevent these autoreactive cells from immunosuppression through inhibition of recirculation of naïve migrating into the CNS. By contrast, the levels of peripheral effector T-cells and the release of antigen-activated T-cells from the draining memory T-cells (TEM) are mostly unaffected by S1P receptor modulators, lymph nodes to lymph and to the blood compartment.15 It crosses the preserving immunosurveillance and the ability to respond to and contain blood-brain barrier and may have direct CNS effects, distinguishing locally invading pathogens.11 it from immunologically targeted MS therapies, although this has not been demonstrated in humans.13 Fingolimod has also been found to Fingolimod (Gilenya®, Novartis, Basel, Switzerland) is a lipophilic attenuate neuroinflammation in rats by regulating the activation and 16,17 sphingosine-like agent that is phosphorylated by SphK1/2 to become neuroprotective effects of microglia, mainly via S1P1. Fingolimod fingolimod-P, an S1P analogue. Fingolimod-P binds to the S1P1 receptor also has direct CNS effects via suppression of pathogenic astrocyte 26 EUROPEAN NEUROLOGICAL REVIEW Sphingosine-1-phosphate Receptor