Fingolimod (also known as FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator that has unique and potent immunoregulatory properties. Mechanistic studies indicate that on phosphorylation fingolimod can bind with high affinity to S1P1 receptors. Persistent modulation of lymphocyte S1P1 receptors by fingolimod and the subsequent internalization of these receptors inhibits lymphocyte egress from the lymph nodes, and prevents these cells from infiltrating inflammatory lesions in the CNS. Results of two phase III studies—FREEDOMS and TRANSFORMS—support previous phase II trial observations indicating that fingolimod exerts powerful anti-inflammatory effects in relapsing–remitting multiple sclerosis (MS). Fingolimod might, therefore, be one of the first orally active drug therapies available for the treatment of relapsing–remitting MS. Moreover, results from preclinical studies suggest that fingolimod might promote neural repair in vivo. In this article, we review the background to these findings, present the proposed immunological and neurobiological profile of fingolimod, discuss the data from the FREEDOMS and TRANSFORMS trials, and provide an expert opinion regarding the future of next-generation S1P receptor modulators for MS therapy.
Fingolimod is the first member of a novel class of immunomodulatory compounds that targets the lipid mediator sphingosine-1-phosphate signaling system
Fingolimod induces pronounced lymphopenia by inhibiting the egress of lymphocytes from secondary lymphoid organs into the circulatory system
Fingolimod has direct neuroregenerative effects in vitro
Oral fingolimod reduces relapse rates and disease progression in relapsing–remitting multiple sclerosis; head-to-head comparisons suggest that reduction of relapse rate by this drug exceeds the effect of intramuscular interferon β
Typical adverse events associated with fingolimod use include lymphopenia, respiratory tract infections and transient bradycardia
The causal relationship and possible dose dependency between fingolimod administration and macular edema, skin cancer and reactivation of latent herpes virus infection remains to be established
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We thank J. Chun (Department of Molecular Biology, H. L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA, USA) for critical reading of the manuscript and valuable suggestions. We thank J. Ingwersen (Department of Neurology, Heinrich-Heine-University of Düsseldorf, Germany) for help in creating Supplementary Table 2.
O. Aktas has received honoraria from Bayer HealthCare, Merck Serono, Novartis and Talecris for lectures. B. Kieseier has received honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis, Talecris and Teva for lectures and honoraria from Biogen Idec, Novartis, Sanofi Aventis and Teva for consulting. He has also received research funding from Bayer HealthCare, Biogen Idec, Merck Serono and Teva. H. P. Hartung has received honoraria from Bayer HealthCare, Biogen Idec, BioMS Genzyme, Merck Serono, Novartis, Sanofi Aventis and Teva for lectures. He has also received research funding from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi Aventis and Teva. P. Küry declares no competing interests.
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Aktas, O., Küry, P., Kieseier, B. et al. Fingolimod is a potential novel therapy for multiple sclerosis. Nat Rev Neurol 6, 373–382 (2010). https://doi.org/10.1038/nrneurol.2010.76
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