A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya)

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS) through demyelination and neurodegeneration. Until recently, major therapeutic treatments have relied on agents requiring injection delivery. In September 2010, fingolimod/FTY720 (Gilenya, Novartis) was approved by the FDA as the first oral treatment for relapsing forms of MS. Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate (S1P) receptors that are a subset of a larger family of cell-surface, G protein-coupled receptors (GPCRs) mediating the effects of bioactive lipids known as lysophospholipids. Fingolimod's mechanism of action in MS is not completely understood; however, its relevant biology indicates a fundamentally different mechanism compared to all previously approved MS therapies, with evolving research supporting both immunological and nervous system activities. This duality may herald a paradigm shift in the treatment of MS and other neurological disorders.

Figure 1

Model for the role of T cells and astrocytes in the pathology of MS. Recent data suggest a necessary role for Th17 cells and astrocytes in EAE pathology. Activated myelin-specific Th17 cells of the central memory phenotype infiltrate the CNS and are restimulated to produce IL-17 by local dendritic cells to undergo clonal expansion and differentiation into effectors/effector memory T cells. Astrocytes respond via expression of IL-17R to T cell-released IL-17 and produce leukocyte-attracting chemokines in an Act1-dependent manner. Astrocyte-derived chemokines then recruit a second wave of peripheral inflammatory cells, which mediate EAE relapses and progression via Th17 cell-mediated bystander demyelination (adapted from Rodgers et al., 2010).

Figure 2

Fungal source of fingolimod precursors compounds. Fingolimod is a chemical derivative of myriocin/ISP-1, a fungal metabolite that was isolated from Isaria sinclairii, the anamorph stage of the ascomycete species Cordyceps. Along with ginseng and the young antlers of deer, Cordyceps fungi were considered as one of the three oriental medicines that give ‘eternal youth.’ Cordyceps fungi enter into living insects, feed on the insides of the host, and eventually grow onto the surface of the cadaver in the summer. Drugs derived from Cordyceps are Cordycepin (3′ deoxyadenosine) which inhibits tumor growth, Cyclosporin, the classical immunosuppressant used in transplant medicine, and Myriocin (ISP-1), the immunosuppressant that targets serine palmitoyl transferase (SPT). Fingolimod, despite being a chemical derivative of myriocin, has lost activity on SPT but targets the class of G protein-coupled S1P receptors. Isaria sinclairii, photo courtesy of Mr. Clive Shirely; cicada nymph, photo courtesy of Alastair Robertson and Maria Minor; soil bugs, from An Illustrated Guide to New Zealand Soil Invertebrates, http://soilbugs.massey.ac.nz. © Massey University.

Figure 3

Fingolimod-relevant chemical structures. Fingolimod and fingolimod-phosphate (fingolimod-P) are structural analogues of sphingosine and sphingosine 1-phosphate (S1P), respectively. S1P is generated via the intracellular ceramide pathway, and ceramide is formed through de novo biosynthesis or degradation of the cell membrane constituent sphingomyelin. Ceramide is N-deacetylated to yield sphingosine, and both sphingosine and fingolimod are phosphorylated by sphingosine kinases to yield S1P and (S)-fingolimod-P, respectively, whereas (R)-fingolimod-P is not found in vivo. The (S)-fingolimod-P is the biologically active principle of the drug in animal models of autoimmune disease (Albert et al., 2005; Brinkmann et al., 2002).

Figure 4

Modulation of S1P₁ receptors by S1P and fingolimod. To ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, most signalling cascades are tightly regulated. One of the major mechanisms involved in the regulation of G protein-coupled receptors (GPCRs), including S1P receptors, involves their endocytic trafficking. GPCR endocytic trafficking entails the targeting of receptors to discrete endocytic sites at the plasma membrane, followed by receptor internalization and intracellular sorting to terminate the signal. Shown is the fate of S1P- and fingolimod-P-signalling at S1P₁ receptors. S1P produces a signal that is terminated by internalization of the S1P-S1P₁ complex. After dissociation of S1P from S1P₁, the receptor is recycled to the cell membrane. The higher affinity of fingolimod (compared to S1P) to S1P₁ leads to tight binding and less recycling of S1P₁ and, as a consequence, to proteasomal degradation of the drug-receptor complex. This results in termination of an initial agonistic signal, and a “functional antagonism” of S1P₁ receptors that, in models of MS, terminates T cell inflammation and astrogliosis.