Journal of Multiple Sclerosis

Fingolimod-An Overview

John^{* *}Correspondence: John, Department of Neurology, Royal Hospital Donnybrook, Iran, Email:

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Introduction

Fingolimod (previously FTY720) is an immunomodulator that's utilized in combination therapy with other immunosuppressant drugs within the prophylaxis of acute rejection after solid organ transplantation and for the treatment of multiple sclerosis. It is phosphorylated intracellularly to fingolimod phosphate, which binds to the sphingosine-1-phosphate receptor, and reduces the recirculation of lymphocytes from lymph nodes to blood and peripheral tissue, including the graft site. This results in reduced infiltration of probably autoaggressive lymphocytes into the central systema nervosum . Preclinical findings also suggest that fingolimod may promote neuroprotective and repair processes within the central systema nervosum by modulating sphingosine-1-phosphate receptors expressed on neural cells.

Mechanism of Action

Fingolimod is a small molecule. This molecule springs from a natural product made by the fungus, Isaria sinclairii. The natural product is myriocin. Fingolimod acts on T cells that reside in lymph nodes, and prevents these T cells from exiting the lymph nodes, where the end-effect is preventing them from migrating to the CNS. In detail, fingolimod acts on a membrane-bound protein of the T cell , namely, the sphingosine-1-phosphate receptor (48,49). The drug induces internalization of the receptor, that is, transfer from the cell surface to the cell’s interior, thereby depriving the T cell of a necessary tool for exiting from the lymph node. Only alittle subset of T cells, not all T cells, becomes trapped within the lymph nodes.

Multiple Sclerosis

Fingolimod’s pharmacologic activity is targeted towards lymphocyte migration out of lymph nodes. This action is highly dependent on the engagement of a Gprotein-coupled receptor, S1P1, present on the surface of the lymphocytes. Fingolimod is structurally almost like S1P and may function as an agonist by engaging four of the five known S1P receptors (S1P1, S1P3, S1P4, S1P5). This results in a discount in activated T cells that are ready to exit the lymph gland and subsequently cross the blood–brain barrier to exert their potential pathogenic effects on perivascular tissue .Studies have indicated the potential for S1P receptors to be present on other cells, including neurons, microglial cells, oligodendrocytes, and astrocytes, suggesting a putative role for fingolimod in influencing myelin repair, modulating survival of oligodendrocyte progenitor cells, and directing astrocyte migration and proliferation.

Pediatric Multiple Sclerosis

Fingolimod, or FTY720, was the primary oral immunosuppressant approved by the FDA for MS. Fingolimod affects the sphingosine-1- phosphate receptor and sequesters lymphocytes in lymph nodes. The TRANSFORMS double-blind, double-dummy randomized controlled trial in adults demonstrated the superior effect of fingolimod as compared to IFNb.65 In patients who received fingolimod, adverse events included cardiac arrhythmias, macular edema, increased liverenzymes, carcinoma , and herpes viral infections. One published retrospective review of pediatric MS patients treated with fingolimod demonstrated reduced relapse rate. No adverse side effects were reported but follow-up time was on average 8.6 months.66 A randomized double-dummy active comparator study of fingolimod to IFN-b-1a is currently underway.