Fingolimod: A review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis

Expert Review of Neurotherapeutics

Volumn 16, Issue 1, 2016, Pages 31-44

  Jeffery, Douglas R ^a   Rammohan, Kottil W ^b   Hawker, Kathleen ^c   Fox, Edward ^d  

^a Multiple Sclerosis Center   (United States)

^b UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^c NOVARTIS PHARMA AG   (Switzerland)

^d Central Texas Neurology Consultants   (United States)

Author keywords

efficacy; Fingolimod; mechanism of action; multiple sclerosis; non therapeutic effects; safety

Indexed keywords

ALANINE AMINOTRANSFERASE; BETA INTERFERON; FINGOLIMOD; SPHINGOSINE 1 PHOSPHATE RECEPTOR; IMMUNOSUPPRESSIVE AGENT; PROPANEDIOL DERIVATIVE;

ATRIOVENTRICULAR CONDUCTION; BLOOD VESSEL PERMEABILITY; BRADYCARDIA; BRAIN SIZE; BRONCHITIS; CLINICAL PRACTICE; CRYPTOCOCCAL MENINGITIS; CRYPTOCOCCOSIS; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; GERIATRIC PATIENT; HEART RATE; HERPES SIMPLEX ENCEPHALITIS; HERPES ZOSTER; HUMAN; IMMUNE RESPONSE; LOWER RESPIRATORY TRACT INFECTION; LUNG FUNCTION; LYMPHOCYTE; MULTIPLE SCLEROSIS; NERVE CELL; NONHUMAN; PNEUMONIA; RECURRENCE RISK; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SIGNAL TRANSDUCTION; URINARY TRACT INFECTION; VIRUS INFECTION; STANDARDS;

FINGOLIMOD HYDROCHLORIDE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; PROPYLENE GLYCOLS;

EID: 84955334334     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.2016.1123094     Document Type: Review

References (92)

1. Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol. 2014;122:15-58.
2. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502-1517.
3. Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5:158-170.
4. 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.
5. 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.
6. 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.
7. Novartis. Gilenya World Watch. 2014 [cited 2015 Nov 16]. Available from: http://www.gilenyaworldwatch.com/English.html.
8. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124-1140.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet. 2012;51:15-28.
19. Hla T, Brinkmann V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology. 2011;76:S3-S8.
20. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33:91-101.
21. Turgeon ML. Clinical hematology: theory and procedures. Vol. 936. 4th ed. Wolters Kluwer, Lippincott Williams & Wilkins; 2005.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346-349.
28. 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.
29. 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.
30. 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.
31. Mullershausen F, Craveiro LM, Shin Y, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem. 2007;102:1151-1161.
32. Di Menna L, Molinaro G, Di Nuzzo L, et al. Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol Res. 2013;67:1-9.
33. 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.
34. Miron VE, Jung CG, Kim HJ, et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol. 2008;63:61-71.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. Noda H, Takeuchi H, Mizuno T, et al. Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol. 2013;256:13-18.
41. 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.
42. 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.
43. 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.
44. De Stefano N, Airas L, Grigoriadis N, et al. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs. 2014;28:147-156.
45. 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.
46. 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.
47. Pinschewer DD, Brinkmann V, Merkler D. Impact of sphingosine 1-phosphate modulation on immune outcomes. Neurology. 2011;76:S15-19.
48. 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.
49. 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.
50. Kappos L, Mehling M, Arroyo R, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015;84:872-879.
51. 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.
52. 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.
53. Mazurais D, Robert P, Gout B, et al. Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem. 2002;50:661-670.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. Dickinson DF, Scott O. Ambulatory electrocardiographic monitoring in 100 healthy teenage boys. Br Heart J. 1984;51:179-183.
60. 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.
61. 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.
62. 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.
63. Dantas AP, Igarashi J, Michel T. Sphingosine 1-phosphate and control of vascular tone. Am J Physiol Heart Circ Physiol. 2003;284:H2045-H2052.
64. 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.
65. 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.
66. Taha TA, Argraves KM, Obeid LM. Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochem Biophys Acta. 2004;1682:48-55.
67. 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.
68. 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.
69. 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.
70. 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.
71. Waeber C, Blondeau N, Salomone S. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News Perspect. 2004;17:365-382.
72. 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.
73. 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.
74. 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.
75. 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.
76. 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.
77. Zarbin MA, Jampol LM, Jager RD, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120:1432-1439.
78. Nolan R, Gelfand JM, Green AJ. Fingolimod treatment in multiple sclerosis leads to increased macular volume. Neurology. 2013;80:139-144.
79. 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.
80. 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.
81. 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.
82. 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.
83. 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.
84. 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.
85. 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.
86. 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.
87. 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.
88. 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.
89. 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.
90. Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord. 2013;6:269-275.
91. 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.
92. Marsolais D, Rosen H. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov. 2009;8:297-307.