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Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis

A Corrigendum to this article was published on 01 December 2010

Key Points

  • Multiple sclerosis (MS) is a chronic, autoimmune disorder of the central nervous system (CNS) that is characterized by inflammation leading to astrogliosis, demyelination and oligodendrocyte and neuronal loss.

  • Current treatment strategies in MS involve management of symptoms and use of disease-modifying drugs, all of which must be injected.

  • Oral fingolimod (FTY720/Gilenya; Novartis) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that, in relapsing–remitting MS, has demonstrated improved efficacy compared to placebo and one of the first-line interferon (IFN) products in terms of relapses and magnetic resonance imaging measures. Fingolimod has also shown an effect on disability and reduces brain atrophy compared to placebo and IFN-β on intent-to-treat analysis over the full duration of the studies.

  • The therapeutic activity of the drug requires phosphorylation in vivo by sphingosine kinases to form the active moiety fingolimod phosphate. Fingolimod phosphate binds to lymphocytic S1P1 receptors, causing internalization and degradation of the receptors. This reduces S1P–S1P1-dependent egress of lymphocytes from lymph nodes and reduces the recirculation of autoaggressive T cells via lymph and blood to the CNS.

  • Fingolimod retains central but not effector memory T cells in lymph nodes; this leads to a preferential reduction of MS-pathogenic immune responses and spares large parts of protective immunity.

  • Based on its lipophilic nature, fingolimod crosses the blood–brain barrier, where the drug may down-modulate S1P receptors on neural cells, particularly astrocytes, to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood–brain barrier.

  • Fingolimod may act through immune-based and central mechanisms to reduce inflammation and to support structural restoration of the CNS parenchyma.

  • In September 2010, 0.5 mg fingolimod was approved by the US Food and Drug Administration as an oral first-line treatment for relapsing–remitting MS.

Abstract

The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod — mediated by the modulation of sphingosine 1-phosphate (S1P) receptors — has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

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Figure 1: A simplified view of the pathophysiology of multiple sclerosis and therapeutic targets.
Figure 2: Fingolimod and sphingolipid metabolism.
Figure 3: T cell subsets in blood of fingolimod-treated patients with multiple sclerosis.

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Acknowledgements

We acknowledge collaborations with the research groups of K. Lynch, University of Virginia, Charlottesville, Virginia, USA; J. Cyster, University of California San Francisco, San Francisco, California, USA; T. Hla, Cornell University, New York, New York, USA; J. Chun, The Scripps Research Institute, La Jolla, California, USA; L. Pott, University of Bochum, Bochum, Germany; S. Kaufmann, Max Planck Institute for Infection Biology, Berlin, Germany; M. Van der Giet, Charite-University Medical Center, Berlin, Germany; D. Pinschewer, University of Geneva, Switzerland; L. Kappos, University Hospital Basel, Switzerland; and G. LeGros, Malaghan Research Institute, Wellington, New Zealand. We also thank D. Pinschewer for critical comments on the manuscript and Oxford PharmaGenesis Ltd for expert editorial support.

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Glossary

Demyelination

Damage of the myelin sheath of axons. A demyelinating disease is any disease of the nervous system in which the myelin sheath is damaged. This impairs the conduction of signals in the affected nerves.

Oligodendrocytes

Brain cells protecting the axons (the long projection of nerve cells) in the central nervous system (the brain and spinal cord) of higher vertebrates. A single oligodendrocyte can extend its processes to more than 50 axons, wrapping around 1 mm of myelin sheath around each axon.

Calcineurin inhibitors

Inhibitors (including cyclosporine and tacrolimus) that bind to the cytosolic protein cyclophilin of immunocompetent lymphocytes, especially T cells, to inhibit the phosphatase calcineurin and, thus, interleukin-2 (IL-2) production and IL-2-dependent proliferation.

Lymph nodes

Small, spherical organs of the immune system that are distributed widely throughout the body and linked by lymphatic vessels. Lymph nodes are garrisons of T, B and other immune cells and act as filters for foreign particles and antigens. These foreign antigens are then presented to T cells by professional antigen-presenting cells (called dendritic cells), and the activated T cells recirculate to blood and initiate protective immunity against infection.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and acute disseminated encephalomyelitis. The most commonly used antigens in rodents are spinal cord homogenate, purified myelin, myelin protein such as myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, or peptides of these proteins, all resulting in distinct models with different disease characteristics regarding both immunology and pathology.

TH17 cell

(T helper 17 cell). A subset of TH cells that produce interleukin-17. They are considered developmentally distinct from TH1 and TH2 cells and are thought to have a key role in autoimmune diseases such as multiple sclerosis, psoriasis, autoimmune uveitis, juvenile diabetes and rheumatoid arthritis.

Astrocytes

Star-shaped glial cells in the brain and spinal cord that provide biochemical support to endothelial cells from the blood–brain barrier and that also provide nutrients to the nervous tissue.

Gadolinium-enhanced lesions

Gadolinium is used as a contrast agent in magnetic resonance imaging (MRI). In multiple sclerosis, gadolinium causes areas of inflammation to be more pronounced than other areas of the brain. This can be seen on the MRI results and indicates where the disease is active.

Magnetic resonance imaging

(MRI). A non-invasive medical diagnostic technique in which the absorption and transmission of high-frequency radio waves are analysed as they irradiate the hydrogen atoms in water molecules and other tissue components placed in a strong magnetic field. This computerized analysis provides a powerful aid to the diagnosis and treatment planning of many diseases, including multiple sclerosis. Image contrast can be further enhanced by 'weighting' the image to capture more of either the longitudinal (termed T1) or transverse (termed T2) relaxation components.

T2-weighted images

The areas of abnormality on transverse (T2)-weighted magnetic resonance imaging (MRI) scans in patients with multiple sclerosis are pathologically nonspecific as they may represent areas of oedema, inflammation, demyelination, gliosis or tissue destruction. Such lesions are usually permanent, although they may decrease in size as acute lesions recover. Counting the number of new, or enlarging, T2 lesions over a period of time is an integral measure of MRI-detected disease activity over that time period.

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Brinkmann, V., Billich, A., Baumruker, T. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9, 883–897 (2010). https://doi.org/10.1038/nrd3248

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