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.

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    • "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). "
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    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
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    • "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. "
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    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
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    • "The first session (T0) was performed the day before starting oral fingolimod 0.5 mg/day and the second one (T1) 60 days later. This is a reasonably sufficient time interval for fingolimod to reach its steady state in CNS and exert its actions (Chun and Hartung, 2010; Portaccio, 2011). The left hemisphere was stimulated in all patients. "
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    ABSTRACT: Objective Fingolimod is an effective disease modifying therapy for Multiple Sclerosis (MS). Beyond its main action on peripheral lymphocytes, several noteworthy side effects have been demonstrated in vitro, among which modulation of neural excitability. Our aim was to explore cortical excitability in vivo in patients treated with fingolimod 0.5 mg/day. Methods Paired-pulse TMS was applied on the left primary motor cortex in 13 patients affected by relapsing-remitting MS, the day before the first dose of fingolimod (T0) and 60 days later (T1). Resting motor threshold, baseline motor evoked potentials, short interval intracortical inhibition (at 1, 3, 5 ms) and intracortical facilitation (at 7, 9, 11 and 13 ms) were estimated at T0 and T1. Results Intracortical facilitation was reduced at T1, without any changes in short interval intracortical inhibition. Conclusions Fingolimod selectively reduced intracortical facilitation, which is mainly mediated by glutamate. Significance This is the first in vivo confirmation of the effects of fingolimod on glutamatergic drive in treated humans. Our results suggest a novel neuromodulatory activity of fingolimod with potential effect on glutamate-mediated excitoxicity in vivo, as already seen in animal models.
    Clinical Neurophysiology 06/2014; 126(1). DOI:10.1016/j.clinph.2014.05.031 · 3.10 Impact Factor
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