Ozanimod for the treatment of relapsing forms of multiple sclerosis

Neurodegenerative Disease Management ◽

10.2217/nmt-2021-0005 ◽

2021 ◽

Author(s):

Andrea M Kuczynski ◽

Jiwon Oh

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Side Effects ◽

Receptor Subtypes ◽

Efficacy And Safety ◽

S1p Receptors ◽

Receptor Modulator ◽

Wide Range ◽

Sphingosine 1 Phosphate ◽

S1p Receptor

Multiple sclerosis (MS) is an inflammatory disease that causes chronic neurological disability in young adults. Modulation of sphingosine 1-phosphate (S1P) receptors, a group of receptors that, among other things, regulate egression of lymphocytes from lymph nodes, has proven to be effective in treating relapsing MS. Fingolimod, the first oral S1P receptor modulator, has demonstrated potent efficacy and tolerability, but can cause undesirable side effects due to its interaction with a wide range of S1P receptor subtypes. This review will focus on ozanimod, a more selective S1P receptor modulator, which has recently received approval for relapsing MS. We summarize ozanimod’s mechanism of action, and efficacy and safety from clinical trials that demonstrate its utility as another treatment option for relapsing MS.

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Sphingosine-1-phosphate Receptor Modulators in Multiple Sclerosis

European Neurological Review ◽

10.17925/enr.2018.13.1.25 ◽

2018 ◽

Vol 13 (1) ◽

pp. 25 ◽

Cited By ~ 2

Author(s):

Patrick Vermersch

Keyword(s):

Multiple Sclerosis ◽

Oral Disease ◽

Receptor Subtypes ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System ◽

S1p Receptor ◽

Phase Ii And Iii ◽

Receptor Modulators ◽

Term Data

The 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 (S1P1) receptors. This leads to retention of lymphocytes in the 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.

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FTY720 on the way from the base camp to the summit of the mountain: relevance for remyelination

Multiple Sclerosis Journal ◽

10.1177/1352458512438723 ◽

2012 ◽

Vol 18 (3) ◽

pp. 258-263 ◽

Cited By ~ 24

Author(s):

M Kipp ◽

S Amor

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Therapeutic Potential ◽

Oral Disease ◽

S1p Receptors ◽

Receptor Modulator ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System

FTY720 (fingolimod; Gilenya®), a sphingosine 1-phosphate (S1P) receptor modulator, is the first oral disease-modifying therapy to be approved for the treatment of relapsing–remitting multiple sclerosis. FTY720 is rapidly converted in vivo to the active S-fingolimod-phosphate, which binds to S1P receptors. This action inhibits egress of lymphocytes from the lymph nodes, preventing entry into the blood and thus infiltration into the central nervous system. More recent studies, however, convincingly show that FTY720 crosses the blood–brain barrier, where it is thought to act on S1P receptors on cells within the central nervous system, such as astrocytes, oligodendrocytes or microglia. Here we discuss the evidence showing that FTY720 also plays a role in remyelination and repair within the brain. While the mechanisms of action still require firm elucidation, it is clear that FTY720 could also be reparative, extending its therapeutic potential for multiple sclerosis.

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FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

10.1101/2022.01.10.475450 ◽

2022 ◽

Author(s):

Deepa Jonnalagadda ◽

Yasuyuki Kihara ◽

Aran Groves ◽

Manisha Ray ◽

Arjun Saha ◽

...

Keyword(s):

Multiple Sclerosis ◽

Metabolic Pathways ◽

Type I ◽

Rna Seq ◽

Autoimmune Encephalomyelitis ◽

Altered Expression ◽

Receptor Modulator ◽

Sphingosine 1 Phosphate ◽

Sphingosine Kinases ◽

S1p Receptor

FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P1. Vitamin B12 (B12) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B12 receptor, by S1P1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B12 worsened EAE and eliminated FTY720 efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.

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Does Siponimod Exert Direct Effects in the Central Nervous System?

Cells ◽

10.3390/cells9081771 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1771 ◽

Cited By ~ 1

Author(s):

Markus Kipp

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Direct Interaction ◽

Active Role ◽

Progressive Multiple Sclerosis ◽

Receptor Subtypes ◽

Receptor Modulator ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System

The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

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Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis

Neurological Sciences ◽

10.1007/s10072-021-05049-w ◽

2021 ◽

Author(s):

Jingyi Tong ◽

Qin Zou ◽

Yongmin Chen ◽

Xiaoping Liao ◽

Rong Chen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Relapse Rate ◽

Meta Analysis ◽

Cochrane Library ◽

Disease Modifying Drugs ◽

S1p Receptors ◽

Annualized Relapse Rate ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Mean Differences

Abstract Background and objective Sphingosine-1-phosphate (S1P) receptors are extensively used in the treatment of multiple sclerosis (MS). However, the optimal therapeutic role of S1P in MS patients has still remained elusive. This network meta-analysis (NMA) systematically evaluated the efficacy and acceptability of S1P receptors, as disease-modifying drugs, in the treatment of patients with MS, so as to find out the most appropriate therapeutic strategy and provide a reliable basis for the prescription of S1P drugs for patients with MS. Methods We conducted a systematic review and NMA to compare the efficacy and acceptability of S1P receptors for treating MS patients. Randomized controlled trials (RCTs), which were published until May 2020, were retrieved from the PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases. The primary outcome in this study was the treatment efficacy for the S1P receptor for MS patients, in terms of decrease in annualized relapse rate. The secondary outcomes were adverse events leading to discontinuation of a study, such as an unfavorable or unintended sign/symptom. Outcomes were appraised using a random effects model expressed as standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs), respectively, and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities for hierarchical clustering of interventions. Results A total of 13 RCTS were included, which enrolled 10,554 patients. The results of NMA showed that Fingolimod, Laquinimod, Siponimod, Ozanimod, Amiselimod, and Ponesimod were superior to placebo in terms of reducing the annualized relapse rate of MS patients. Regarding efficacy, the best and worst treatments were Amiselimod (0.4 mg; SUCRA 8.1%) and placebo (SUCRA 90.5%), respectively. As for acceptability, the best and worst interventions were Ozanimod (1 mg; SUCRA 20.4%) and Ponesimod (40 mg; SUCRA 96.0%), respectively. The comparison-adjusted funnel plots of annualized relapse rate and side effects in the included studies revealed that there was no significant funnel plot asymmetry Conclusions This NMA indicated that Amiselimod (0.4 mg) is the most effective treatment strategy as a S1P receptor for MS patients. However, the abovementioned findings need to be further confirmed in the next researches.

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Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Biological Chemistry ◽

10.1515/hsz-2014-0276 ◽

2015 ◽

Vol 396 (6-7) ◽

pp. 783-794 ◽

Cited By ~ 13

Author(s):

Dong Dong Zhang ◽

Bona Linke ◽

Jing Suo ◽

Aleksandra Zivkovic ◽

Yannick Schreiber ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Antinociceptive Effect ◽

Intrathecal Administration ◽

Receptor Subtypes ◽

Nociceptive Behavior ◽

S1p Receptors ◽

Antinociceptive Effects ◽

Sphingosine 1 Phosphate ◽

S1p Receptor

Abstract FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.

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Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

Journal of Biological Chemistry ◽

10.1074/jbc.m311743200 ◽

2004 ◽

Vol 279 (14) ◽

pp. 13839-13848 ◽

Cited By ~ 465

Author(s):

M. Germana Sanna ◽

Jiayu Liao ◽

Euijung Jo ◽

Christopher Alfonso ◽

Min-Young Ahn ◽

...

Keyword(s):

Heart Rate ◽

Receptor Subtypes ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Lymphocyte Recirculation

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COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001104 ◽

2021 ◽

Vol 9 (1) ◽

pp. e1104

Author(s):

Farren Basil Shaw Briggs ◽

Farrah J. Mateen ◽

Hollie Schmidt ◽

Keisha M. Currie ◽

Heather M. Siefers ◽

...

Keyword(s):

Multiple Sclerosis ◽

Injection Site ◽

Safety Information ◽

Vaccine Dose ◽

Research Network ◽

Severe Reaction ◽

Cross Sectional ◽

Convenience Sample ◽

Receptor Modulator ◽

Sphingosine 1 Phosphate

Background and ObjectivesThere are limited data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine reactogenicity in persons with multiple sclerosis (PwMS) and how reactogenicity is affected by disease-modifying therapies (DMTs). The objective of this retrospective cross-sectional study was to generate real-world multiple sclerosis–specific vaccine safety information, particularly in the context of specific DMTs, and provide information to mitigate specific concerns in vaccine hesitant PwMS.MethodsBetween 3/2021 and 6/2021, participants in iConquerMS, an online people-powered research network, reported SARS-CoV-2 vaccines, experiences of local (itch, pain, redness, swelling, or warmth at injection site) and systemic (fever, chills, fatigue, headache, joint pain, malaise, muscle ache, nausea, allergic, and other) reactions within 24 hours (none, mild, moderate, and severe), DMT use, and other attributes. Multivariable models characterized associations between clinical factors and reactogenicity.ResultsIn 719 PwMS, 64% reported experiencing a reaction after their first vaccination shot, and 17% reported a severe reaction. The most common reactions were pain at injection site (54%), fatigue (34%), headache (28%), and malaise (21%). Younger age, being female, prior SARS-CoV-2 infection, and receiving the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vs BNT162b2 (Pfizer-BioNTech) vaccine were associated with experiencing a reaction after the first vaccine dose. Similar relationships were observed for a severe reaction, including higher odds of reactions among PwMS with more physical impairment and lower odds of reactions for PwMS on an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator. In 442 PwMS who received their second vaccination shot, 74% reported experiencing a reaction, whereas 22% reported a severe reaction. Reaction profiles after the second shot were similar to those reported after the first shot. Younger PwMS and those who received the mRNA-1273 (Moderna) vs BNT162b2 vaccine reported higher reactogenicity after the second shot, whereas those on a sphingosine-1-phosphate receptor modulator or fumarate were significantly less likely to report a reaction.DiscussionSARS-CoV-2 vaccine reactogenicity profiles and the associated factors in this convenience sample of PwMS appear similar to those reported in the general population. PwMS on specific DMTs were less likely to report vaccine reactions. Overall, the short-term vaccine reactions experienced in the study population were mostly self-limiting, including pain at the injection site, fatigue, headache, and fever.

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Delayed fingolimod-associated asystole

Multiple Sclerosis Journal ◽

10.1177/1352458511410344 ◽

2011 ◽

Vol 17 (11) ◽

pp. 1387-1389 ◽

Cited By ~ 58

Author(s):

Patricio S Espinosa ◽

Joseph R Berger

Keyword(s):

Multiple Sclerosis ◽

Lymph Nodes ◽

Disability Progression ◽

Receptor Modulator ◽

Sphingosine 1 Phosphate

Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod.

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