References
- Papers of special note have been highlighted as:
- • of interest
- •• of considerable interest
- Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol. 2014;122:15–58.
- Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517.
- Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5:158–170.
- Duffy SS, Lees JG, Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;2014:285245.
- US Food and Drug Administration. Gilenya prescribing information. 2010 [ revised 2015 Aug; cited 2015 Aug 20]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022527s019lbl.pdf.
•• Up to date fingolimod prescribing information for the USA.
- European Medicines Agency. Annex I. Summary of product characteristics. Gilenya (fingolimod). 2011 [ revised 2015 Jul; cited 2015 Aug 20]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf.
•• Up to date fingolimod prescribing information for the EU.
- Novartis. Gilenya World Watch. 2014 [cited 2015 Nov 16]. Available from: http://www.gilenyaworldwatch.com/English.html.
- Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–1140.
- Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.
- Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–556.
- Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415.
- Kappos L, Cohen J, Collins W, et al. Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Rel Dis. 2014;3:494–504.
•• Comprehensive safety summary for fingolimod.
- Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PloS One. 2014;9:e88472.
- Bergvall N, Petrilla AA, Karkare SU, et al. Persistence with and adherence to fingolimod compared with other disease-modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis. J Med Econ. 2014;17:696–707.
- He A, Spelman T, Jokubaitis V, et al. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis. JAMA Neurol. 2015;72:405–413.
- Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther. 2007;115:84–105.
- Fujita T, Inoue K, Yamamoto S, et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot (Tokyo). 1994;47:208–215.
- David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet. 2012;51:15–28.
- Hla T, Brinkmann V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology. 2011;76:S3–S8.
- Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33:91–101.
•• Review on the MOA and key preclinical data for fingolimod.
- Turgeon ML. Clinical hematology: theory and procedures. Vol. 936. 4th ed. Wolters Kluwer, Lippincott Williams & Wilkins; 2005.
- Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Ann Rev Immunol. 2004;22:745–763.
- Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355–360.
- 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. 2010;9:883–897.
•• Key paper describing the development and pharmacological characterization of fingolimod.
- Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology. 2008;71:1261–1267.
- Pham TH, Okada T, Matloubian M, et al. S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity. 2008;28:122–133.
- Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–349.
- Francis G, Kappos L, O’Connor P, et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2014;20:471–480.
- Claes N, Dhaeze T, Fraussen J, et al. Compositional changes of B and T cell subtypes during fingolimod treatment in multiple sclerosis patients: a 12-month follow-up study. PloS One. 2014;9:e111115.
- Foster CA, Howard LM, Schweitzer A, et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther. 2007;323:469–475.
- Mullershausen F, Craveiro LM, Shin Y, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem. 2007;102:1151–1161.
- Di Menna L, Molinaro G, Di Nuzzo L, et al. Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol Res. 2013;67:1–9.
- Coelho RP, Payne SG, Bittman R, et al. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther. 2007;323:626–635.
- Miron VE, Jung CG, Kim HJ, et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol. 2008;63:61–71.
- Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011;108:751–756.
- Anthony DC, Sibson NR, Losey P, et al. Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. Neuropharmacol. 2014;79:534–541.
- Miron VE, Ludwin SK, Darlington PJ, et al. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol. 2010;176:2682–2694.
- Balatoni B, Storch MK, Swoboda EM, et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull. 2007;74:307–316.
- Foster CA, Mechtcheriakova D, Storch MK, et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol. 2009;19:254–266.
- Noda H, Takeuchi H, Mizuno T, et al. Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol. 2013;256:13–18.
- Deogracias R, Yazdani M, Dekkers MP, et al. Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2012;109:14230–14235.
- Smith P, Dubost V, Brinkmann V, et al. Fingolimod up-regulates BDNF expression within the CNS and down-regulates tissue pathology in a pre-clinical model of chronic neuroinflammation. Neurology. 2015;84:P1.159.
- De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74:1868–1876.
- De Stefano N, Airas L, Grigoriadis N, et al. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs. 2014;28:147–156.
- Jacobsen C, Hagemeier J, Myhr KM. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry. 2014. DOI:10.1136/jnnp-2013-306906.
- Lublin FD, Miller DH, Freedman M, et al. Oral fingolimod versus placebo in patients with primary progressive multiple sclerosis (PPMS): results of the INFORMS phase III trial. Neurology. 2015;85:e44–e49.
- Pinschewer DD, Brinkmann V, Merkler D. Impact of sphingosine 1-phosphate modulation on immune outcomes. Neurology. 2011;76:S15–19.
- Pinschewer DD, Ochsenbein AF, Odermatt B, et al. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol. 2000;164:5761–5770.
- Mehling M, Hilbert P, Fritz S, et al. Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients. Ann Neurol. 2011;69:408–413.
- Kappos L, Mehling M, Arroyo R, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015;84:872–879.
- Arvin AM, Wolinsky JS, Kappos L, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015;72:31–39.
- Pfender N, Jelcic I, Linnebank M, et al. Reactivation of herpesvirus under fingolimod: a case of severe herpes simplex encephalitis. Neurology. 2015;84:2377–2378.
- Mazurais D, Robert P, Gout B, et al. Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem. 2002;50:661–670.
- DiMarco JP, O’Connor P, Cohen JA, et al. First-dose effects of fingolimod: pooled safety data from three phase 3 studies. Mult Scler Rel Dis. 2014;3:629–638.
• Reference describing the first-dose effects of fingolimod based on data pooled from three pivotal trials.
- Yatani A, Codina J, Brown AM, et al. Direct activation of mammalian atrial muscarinic potassium channels by GTP regulatory protein Gk. Science. 1987;235:207–211.
- Koyrakh L, Roman MI, Brinkmann V, et al. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I. Am J Transplant. 2005;5:529–536.
- Schmouder R, Serra D, Wang Y, et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol. 2006;46:895–904.
- Brodsky M, Wu D, Denes P, et al. Arrhythmias documented by 24-hour continuous electrocardiographic monitoring in 50 male medical students without apparent heart disease. Am J Cardiol. 1977;39:390–395.
- Dickinson DF, Scott O. Ambulatory electrocardiographic monitoring in 100 healthy teenage boys. Br Heart J. 1984;51:179–183.
- US Food and Drug Administration. Gilenya prescribing information. 2012 [cited 2015 Nov 16]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf.
- Gold R, Comi G, Palace J, et al. Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. J Neurol. 2014;261:267–276.
- Hughes B, Cascione M, Freedman MS, et al. First-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Mult Scler Rel Dis. 2014;3:620–628.
- Dantas AP, Igarashi J, Michel T. Sphingosine 1-phosphate and control of vascular tone. Am J Physiol Heart Circ Physiol. 2003;284:H2045–H2052.
- Morales-Ruiz M, Lee MJ, Zollner S, et al. Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. J Biol Chem. 2001;276:19672–19677.
- Nofer JR, van der Giet M, Tolle M, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 2004;113:569–581.
- Taha TA, Argraves KM, Obeid LM. Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochem Biophys Acta. 2004;1682:48–55.
- Coussin F, Scott RH, Wise A, et al. Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles: differential role in vasoconstriction. Circ Res. 2002;91:151–157.
- Hemmings DG, Xu Y, Davidge ST. Sphingosine 1-phosphate-induced vasoconstriction is elevated in mesenteric resistance arteries from aged female rats. Br J Pharmacol. 2004;143:276–284.
- Salomone S, Yoshimura S, Reuter U, et al. S1P3 receptors mediate the potent constriction of cerebral arteries by sphingosine-1-phosphate. Eur J Pharmacol. 2003;469:125–134.
- Hu W, Mahavadi S, Huang J, et al. Characterization of S1P1 and S1P2 receptor function in smooth muscle by receptor silencing and receptor protection. Am J Physiol Gastrointest Liver Physiol. 2006;291:G605–G610.
- Waeber C, Blondeau N, Salomone S. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News Perspect. 2004;17:365–382.
- Zhou H, Murthy KS. Distinctive G protein-dependent signaling in smooth muscle by sphingosine 1-phosphate receptors S1P1 and S1P2. Am J Physiol Cell Physiol. 2004;286:C1130–C1138.
- Lee JF, Gordon S, Estrada R, et al. Balance of S1P1 and S1P2 signaling regulates peripheral microvascular permeability in rat cremaster muscle vasculature. Am J Physiol Heart Circ Physiol. 2009;296:H33–H42.
- Oo ML, Chang SH, Thangada S, et al. Engagement of S1P(1)-degradative mechanisms leads to vascular leak in mice. J Clin Invest. 2011;121:2290–2300.
- Sanna MG, Wang SK, Gonzalez-Cabrera PJ, et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol. 2006;2:434–441.
- Singleton PA, Dudek SM, Ma SF, et al. Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem. 2006;281:34381–34393.
- Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120:1432–1439.
- Nolan R, Gelfand JM, Green AJ. Fingolimod treatment in multiple sclerosis leads to increased macular volume. Neurology. 2013;80:139–144.
- Kume H, Takeda N, Oguma T, et al. Sphingosine 1-phosphate causes airway hyper-reactivity by rho-mediated myosin phosphatase inactivation. J Pharmacol Exp Ther. 2007;320:766–773.
- Rosenfeldt HM, Amrani Y, Watterson KR, et al. Sphingosine-1-phosphate stimulates contraction of human airway smooth muscle cells. FASEB J. 2003;17:1789–1799.
- Roviezzo F, D’Agostino B, Brancaleone V, et al. Systemic administration of sphingosine-1-phosphate increases bronchial hyperresponsiveness in the mouse. Am J Respir Cell Mol Biol. 2010;42:572–577.
- Roviezzo F, Di Lorenzo A, Bucci M, et al. Sphingosine-1-phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness. Am J Respir Cell Mol Biol. 2007;36:757–762.
- Trifilieff A, Fozard JR. Sphingosine-1-phosphate-induced airway hyper-reactivity in rodents is mediated by the sphingosine-1-phosphate type 3 receptor. J Pharmacol Exp Ther. 2012;342:399–406.
- Schmouder R, Hariry S, David OJ. Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur J Clin Pharmacol. 2012;68:355–362.
- Braune S, Lang M, Bergmann A. Second line use of fingolimod is as effective as natalizumab in a German out-patient RRMS-cohort. J Neurol. 2013;260:2981–2985.
- Fox E, Edwards K, Burch G, et al. Outcomes of switching directly to oral fingolimod from injectable therapies: results of the randomized, open-label, multicenter, Evaluate Patient OutComes (EPOC) study in relapsing multiple sclerosis. Mult Scler Rel Dis. 2014;3:607–619.
- Warrender-Sparkes M, Spelman T, Izquierdo G, et al. The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis. Mult Scler. 2015. DOI:10.1177/1352458515594041.
- Radue EW, O’Connor P, Polman CH, et al. Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis. Arch Neurol. 2012;69:1259–1269.
- Brunkhorst R, Vutukuri R, Pfeilschifter W. Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci. 2014;8:283.
- Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord. 2013;6:269–275.
• Guidance for the clinician when initiating fingolimod treatment in MS.
- Camm J, Hla T, Bakshi R, et al. Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J. 2014;168:632–644.
- Marsolais D, Rosen H. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov. 2009;8:297–307.