Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis

Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA, USA.
Clinical neuropharmacology (Impact Factor: 2.01). 03/2010; 33(2):91-101. DOI: 10.1097/WNF.0b013e3181cbf825
Source: PubMed


Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.

Download full-text


Available from: hans-peter Hartung, Oct 05, 2015
19 Reads
  • Source
    • "S1PRs are needed for the exit of immune cells from lymphoid organs (such as the thymus and lymph nodes) into lymphatic vessels (Kono et al., 2014; Liu et al., 2011). The S1P agonist, fingolimod (FTY720P), acts on most S1PRs (except S1PR2) and provides beneficial effects in multiple sclerosis (Choi et al., 2011; Chun and Hartung, 2010; Lee et al., 2010). Its therapeutical action is generally thought to result from agonistinduced internalization, down-regulation and degradation of S1PR1, a receptor critical for lymphocyte trafficking (Graler and Goetzl, 2004; Mandala et al., 2002; Mullershausen et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine-1-phosphate (S1P) is a ceramide derivative serving not only as a regulator of immune properties but also as a modulator of brain functions. To better understand the mechanism underlying the effects of S1P on brain functions, we investigated the potential impact of S1P receptor (S1PR) activation on NMDA receptor subunits. We used acute rat hippocampal slices as a model system, and determined the effects of the active phosphorylated S1P analogue, fingolimod (FTY720P) on various NMDA receptors. Treatment with FTY720P significantly increased phosphorylation of GluN2B-containing NMDA receptors at Tyr1472. This effect appears rather specific, as treatment with FTY720P did not modify GluN2B-Tyr1336, GluN2B-Ser1480, GluN2A-Tyr1325 or GluN1-Ser897 phosphorylation. Pre-treatment of hippocampal slices with the compounds W146 and PP1 indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 epitopes was dependent on activation of S1PR subunit 1 (S1PR1) and Src/Fyn kinase, respectively. Cell surface biotinylation experiments indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 was also associated with increased levels of GluN1 and GluN2B subunits on membrane surface, whereas no change was observed for GluN2A subunits. We finally demonstrate that FTY720P is inclined to favour Tau and Fyn accumulation on plasma membranes. These results suggest that activation of S1PR1 by FTY720P enhances GluN2B receptor phosphorylation in rat hippocampal slices, resulting in increased levels of GluN1 and GluN2B receptor subunits in neuronal membranes through a mechanism probably involving Fyn and Tau. Copyright © 2015. Published by Elsevier B.V.
    Brain research 08/2015; DOI:10.1016/j.brainres.2015.07.055 · 2.84 Impact Factor
  • Source
    • "Fingolimod (FTY720; Gilenya s ,N o v a r t i sP h a r m aA G )i sa first-in-class sphingosine 1-phosphate receptor (S1PR) modulator (Brinkmann et al., 2010; Chun and Hartung, 2010), approved for relapsing forms of MS as a once-daily oral therapy at a dose of 0.5 mg (European Medicines Agency, 2011; US Food and Drug Administration, 2012b). The efficacy benefits of fingolimod over both placebo and intramuscular interferon β- 1a on key measures of disease activity (relapse rates, disability progression versus placebo, lesion load and brain volume loss) have been established in clinical trials (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya(®), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5mg, -7.5bpm; placebo, 0.0bpm) and those receiving SSRIs (fingolimod 0.5mg, -6.6bpm; placebo, 0.3bpm). In patients treated with fingolimod 0.5mg, the mean change in corrected QT interval from baseline to 6h after treatment initiation was under 10ms, and few patients had absolute corrected QT intervals of over 450ms (men) or 470ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    Multiple Sclerosis and Related Disorders 04/2015; 7(3). DOI:10.1016/j.msard.2015.04.002 · 0.88 Impact Factor
  • Source
    • "Fingolimod is approved as second line disease modifying drug for highly active relapsing remitting multiple sclerosis (MS) patients. In its phosphorylated form it serves as sphingosine-1-phosphat (S1P) receptor analogue, orchestrating relevant mechanisms in the immune system but also cardiovascular system [1]. There are only few reports on S1P-triggered effects on cardiovascular function within systemic or pulmonary circulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Fingolimod is the first oral immunomodulatory therapy approved for highly active relapsing remitting multiple sclerosis. Based on the distribution pattern of fingolimod interacting sphingosine-1-phosphat receptors in organism including immune system and cardiovascular system clinical monitoring of patients and evaluation of adverse events are recommended. Despite extensive data on cardiovascular safety, experience with fingolimod in patients with concomitant cardiological disease, especially within the pulmonary circulation, is rare. Case presentation We report the case of a 46-year-old woman presented with relapsing remitting multiple sclerosis and severe idiopathic pulmonary arterial hypertension. Fingolimod was initiated because of disease activity of multiple sclerosis with two relapses and gadolinium-enhancing lesions in MRI. The patient demonstrated stable disease course of idiopathic pulmonary arterial hypertension when fingolimod was started. Fingolimod therapy did not alter or even worsen the pulmonary or cardiovascular conditions during first dose application as well as follow up of nine months. Conclusion In this report, we present the first case of fingolimod treatment in a patient with highly active multiple sclerosis and severe idiopathic pulmonary arterial hypertension. We suggest an interdisciplinary approach with detailed cardiopulmonary monitoring for safety in such patients.
    BMC Neurology 06/2014; 14(1):126. DOI:10.1186/1471-2377-14-126 · 2.04 Impact Factor
Show more

Similar Publications