Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis

Abstract

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.

Figures

FIG. 1

Fingolimod is a structural analogue of naturally occurring sphingosine. Fingolimod (molecular weight, 307.47 g/mol), like sphingosine (molecular weight, 299.49 g/mol) is phosphorylated by sphingosine kinases, in particular sphingosine kinase 2, to produced fingolimod phosphate (molecular weight, 387.47 g/mol) while sphingosine undergoes phosphorylation to sphingosine 1-phosphate (molecular weight, 379.47 g/mol).

FIG. 2

Lymphocyte egress from lymph nodes is driven by a sphingosine 1-phosphate (S1P) gradient (40). a) S1P concentrations are higher in body fluids than in lymphoid tissues. Lymphoctyes egress from the lymphoid tissues into the circulation along the S1P gradient. b) Fingolimod downregulates S1P1 on lymphocytes and thereby prevents lymphocyte egress from lymphoid tissues. This in turn reduces the infiltration of autoaggressive cells into the central nervous system. CNS, central nervous system; S1P, sphingosine 1-phosphate; S1P1, sphingosine 1-phosphate receptor subtype 1

FIG. 3

Treatment with oral fingolimod prevents the egress of naïve and central memory T cells (TCM) from lymph nodes into the circulation but spares effector memory T cells (TEM). Percentages of naïve T cells, TCM and TEM cells in peripheral blood in patients with relapsing multiple sclerosis treated with fingolimod and in untreated patients. Adapted from Mehling et al. 2008 (72). MS, multiple sclerosis; naïve, naïve T cells (CCR7+, CD45RA+); TCM cells, central memory T cells (CCR7+, CD45RA−); TEM cells, effector memory T cells (CCR7−, CD45RA−).

FIG. 4

Distribution of sphingosine 1-phosphate (S1P) receptor subtypes on neural cells (4, 39, 46). OLG, oligodendrocyte; OPC, oligodendrocyte progenitor cell; S1P, sphingosine 1-phosphate; S1P1–5, sphingosine 1-phosphate receptor subtypes 1–5.

FIG. 5

Oral fingolimod has prophylactic and therapeutic effects in animal models of multiple sclerosis. Fingolimod was administered at a dose of 0.3 mg/kg on days 0–11 (prophylactic administration), days 12–28 (therapeutic administration) or days 40–53 (rescue therapy) after immunization in a rat experimental autoimmune encephalitis model. (123) Reproduced from with permission from Wiley: Brain Pathology. Foster et al Brain Pathol 2009;19(2):254–66. Copyright 2009. ***p ≤ 0.001. Clinical score was determined from physical and functional signs as follows: 0 = healthy; 1 = flaccid tail; 2 = hind-limb weakness; 3 = paralysis of one or both hind limbs; 4 = forelimb paralysis; 5 = death.