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Orales Fingolimod bei Multipler Sklerose

Therapeutische Modulation des Sphingosin-1-Phosphat-Systems

Oral fingolimod in multiple sclerosis

Therapeutic modulation of the sphingosine-1-phosphate system

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Zusammenfassung

Fingolimod oder FTY720 ist die Leitsubstanz der kürzlich entdeckten Klasse von Sphingosin-1-Phosphat (S1P)-Rezeptor-Modulatoren mit außergewöhnlichen immunregulatorischen Eigenschaften. Mechanistische Studien in Tiermodellen der Multiplen Sklerose (MS) zeigen, dass Fingolimod den Austritt von Immunzellen aus sekundären lymphatischen Organen wie dem Lymphknoten unterbindet und damit die Lymphozytenmigration in entzündetes Zielgewebe verhindert. Tatsächlich belegt eine kürzlich publizierte Phase-III-Studie, dass täglich oral verabreichtes Fingolimod im Vergleich zu Placebo die entzündliche Krankheitsaktivität bei schubförmig-remittierender MS deutlich vermindert und den Verlauf der Erkrankung günstig beeinflusst. Eine weitere Phase-III-Vergleichsstudie zeigt, dass der therapeutische Effekt einer Standardtherapie mit intramuskulär appliziertem Interferon-β1a überlegen ist. Daher ist davon auszugehen, dass Fingolimod in naher Zukunft, möglicherweise zusammen mit Cladribin, als erstes orales Präparat in der MS-Therapie zur Verfügung stehen wird. Zudem legen neueste experimentelle Daten nahe, dass Fingolimod unabhängig von seinen immunmodulatorischen Eigenschaften auch neurale Reparaturmechanismen anstoßen könnte. In dieser Übersicht werden diese rezenten Erkenntnisse zusammengefasst, das immunologische und neurobiologische Profil von Fingolimod dargestellt sowie die vielsprechenden Daten der jüngst veröffentlichten klinischen Studien im Kontext des spezifischen Nebenwirkungsprofils erörtert.

Summary

In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-β1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.

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Literatur

  1. Aktas O, Smorodchenko A, Brocke S et al (2005) Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46:421–432

    Article  PubMed  CAS  Google Scholar 

  2. Aktas O, Ullrich O, Infante-Duarte C et al (2007) Neuronal damage in brain inflammation. Arch Neurol 64:185–189

    Article  PubMed  Google Scholar 

  3. Balatoni B, Storch MK, Swoboda EM et al (2007) FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 74:307–316

    Article  PubMed  CAS  Google Scholar 

  4. Bartholomaus I, Kawakami N, Odoardi F et al (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:94–104

    Article  PubMed  Google Scholar 

  5. Beer MS, Stanton JA, Salim K et al (2000) EDG receptors as a therapeutic target in the nervous system. Lysophospholipids and Eicosanoids Biol Pathophysiol 905:118–131

    CAS  Google Scholar 

  6. Bennun A, Wekerle H, Cohen IR (1981) The Rapid Isolation of Clonable Antigen-Specific Lymphocyte-T Lines Capable of Mediating Autoimmune Encephalomyelitis. Eur J Immunol 11:195–199

    Article  CAS  Google Scholar 

  7. Brinkmann V (2009) FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 158:1173–1182

    Article  PubMed  CAS  Google Scholar 

  8. Brinkmann V, Davis MD, Heise CE et al (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457

    Article  PubMed  CAS  Google Scholar 

  9. Budde K, Schmouder RL, Brunkhorst R et al (2002) First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 13:1073–1083

    PubMed  CAS  Google Scholar 

  10. Coelho RP, Payne SG, Bittman R et al (2007) The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 323:626–635

    Article  PubMed  CAS  Google Scholar 

  11. Cohen JA, Barkhof F, Comi G et al (2010) Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med 362:402–415

    Article  PubMed  CAS  Google Scholar 

  12. Dev KK, Mullershausen F, Mattes H et al (2008) Brain sphingosine-1-phosphate receptors: Implication for FTY720 in the treatment of multiple sclerosis. Pharmacol Ther 117:77–93

    Article  PubMed  CAS  Google Scholar 

  13. Edsall LC, Pirianov GG, Spiegel S (1997) Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 17:6952–6960

    PubMed  CAS  Google Scholar 

  14. Foster CA, Howard LM, Schweitzer A et al (2007) 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 323:469–476

    Article  PubMed  CAS  Google Scholar 

  15. Foster CA, Mechtcheriakova D, Storch MK et al (2009) 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 19:254–266

    Article  PubMed  CAS  Google Scholar 

  16. Fujino M, Funeshima N, Kitazawa Y et al (2003) Amelioration of experimental autoimmune encephalomyelitis in lewis rats by FTY720 treatment. J Pharmacol Exp Ther 305:70–77

    Article  PubMed  CAS  Google Scholar 

  17. Fujita T, Inoue K, Yamamoto S et al (1994) Fungal Metabolites. 11. A Potent Immunosuppressive Activity Found in Isaria-Sinclairii Metabolite. J Antibiot 47:208–215

    PubMed  CAS  Google Scholar 

  18. Fukushima N, Ishii I, Contos JJA et al (2001) Lysophospholipid receptors. Annu Rev Pharmacol Toxicol 41:507–534

    Article  PubMed  CAS  Google Scholar 

  19. Gardell SE, Dubin AE, Chun J (2006) Emerging medicinal roles for lysophospholipid signaling. Trends Mol Med 12:65–75

    Article  PubMed  CAS  Google Scholar 

  20. Gergely P, Wallstrom E, Nuesslein-Hildesheim B et al (2009) Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans. Mult Scler 15:S125–S126

    Google Scholar 

  21. Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971

    Article  PubMed  Google Scholar 

  22. Greter M, Heppner FL, Lemos MP et al (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334

    Article  PubMed  CAS  Google Scholar 

  23. Harada J, Foley M, Moskowitz MA, Weber C (2004) Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J Neurochem 88:1026–1039

    Article  PubMed  CAS  Google Scholar 

  24. Hartung HP (2009) New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 8:28–31

    Article  PubMed  Google Scholar 

  25. Hartung HP, Aktas O (2009) Bleak prospects for primary progressive multiple sclerosis therapy: downs and downs, but a glimmer of hope. Ann Neurol 66:429–432

    Article  PubMed  CAS  Google Scholar 

  26. Hartung HP, Aktas O (2010) Oral therapies for multiple sclerosis: are we there yet? Lancet Neurol 9:454–457

    Article  PubMed  Google Scholar 

  27. Hartung HP, Kieseier BC, Aktas O (2010) Cladribin. Nervenarzt 81:194–202

    Article  PubMed  Google Scholar 

  28. Horga A, Montalban X (2008) FTY720 (fingolimod) for relapsing multiple sclerosis. Expert Rev Neurother 8:699–714

    Article  PubMed  CAS  Google Scholar 

  29. Jung CG, Kim HJ, Miron VE et al (2007) Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 55:1656–1667

    Article  PubMed  CAS  Google Scholar 

  30. Kappos L, Antel J, Comi G et al (2006) Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 355:1124–1140

    Article  PubMed  CAS  Google Scholar 

  31. Kataoka H, Sugahara K, Shimano K et al (2005) FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2:439–448

    PubMed  CAS  Google Scholar 

  32. Kimura A, Ohmori T, Ohkawa R et al (2007) Essential roles of sphingosine 1-phosphate/S1P(1) receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells 25:115–124

    Article  PubMed  CAS  Google Scholar 

  33. Kovarik JM, Schmouder RL, Hartmann S et al (2006) Fingolimod (FTY720) in severe hepatic impairment: Pharmacokinetics and relationship to markers of liver function. J Clin Pharmacol 46:149–156

    Article  PubMed  CAS  Google Scholar 

  34. Kremer D, Heinen A, Jadasz J et al (2009) p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation. Proc Natl Acad Sci U S A 106:9087–9092

    Article  PubMed  CAS  Google Scholar 

  35. Krishnamoorthy G, Saxena A, Mars LT et al (2009) Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 15:626–632

    Article  PubMed  CAS  Google Scholar 

  36. Leypoldt F, Munchau A, Moeller F et al (2009) Hemorrhaging focal encephalitis under fingolimod (Fty720) treatment: a case report. Neurology 72:1022–1024

    Article  PubMed  CAS  Google Scholar 

  37. Mandala S, Hajdu R, Bergstrom J et al (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349

    Article  PubMed  CAS  Google Scholar 

  38. Matloubian M, Lo CG, Cinamon G et al (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360

    Article  PubMed  CAS  Google Scholar 

  39. Mehling M, Brinkmann V, Antel J et al (2008) FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71:1261–1267

    Article  PubMed  CAS  Google Scholar 

  40. Menn B, Garcia-Verdugo JM, Yaschine C et al (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26:7907–7918

    Article  PubMed  CAS  Google Scholar 

  41. Miron VE, Darlington PJ, Ludwin SK et al (2009) The immunomodulator fingolimod (FTY720) increases myelin production following demyelination of organotypic cerebellar slices. Neurology 72:A421

    Google Scholar 

  42. Miron VE, Hall JA, Kennedy TE et al (2008) Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. Am J Pathol 173:1143–1152

    Article  PubMed  CAS  Google Scholar 

  43. Miron VE, Jung CG, Kim HJ et al (2008) FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 63:61–71

    Article  PubMed  CAS  Google Scholar 

  44. Miron VE, Schubart A, Antel JP (2008) Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 274:13–17

    Article  PubMed  CAS  Google Scholar 

  45. Mizugishi K, Yamashita T, Olivera A et al (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25:11113–11121

    Article  PubMed  CAS  Google Scholar 

  46. Moore AN, Kampfl AW, Zhao X et al (1999) Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes. Neuroscience 94:405–415

    Article  PubMed  CAS  Google Scholar 

  47. Mullershausen F, Craveiro LM, Shin Y et al (2007) Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 102:1151–1161

    Article  PubMed  CAS  Google Scholar 

  48. Mullershausen F, Zecri F, Cetin C et al (2009) Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 5:428–434

    Article  PubMed  CAS  Google Scholar 

  49. Novgorodov AS, El-Alwani M, Bielawski J et al (2007) Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J 21:1503–1514

    Article  PubMed  CAS  Google Scholar 

  50. O’Connor P, Comi G, Montalban X et al (2009) Oral fingolimod (FTY720) in multiple sclerosis. Two-year results of a phase II extension study. Neurology 72:73–79

    Article  Google Scholar 

  51. Osinde M, Mullershausen F, Dev KK (2007) Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology 52:1210–1218

    Article  PubMed  CAS  Google Scholar 

  52. Papadopoulos D, Rundle J, Patel R et al (2010) FTY720 Ameliorates MOG-induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses. J Neurosci Res 88:346–359

    Article  PubMed  CAS  Google Scholar 

  53. Pebay A, Toutant M, Premont J et al (2001) Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur J Neurosci 13:2067–2076

    Article  Google Scholar 

  54. Picard-Riera N, Decker L, Delarasse C et al (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A 99:13211–13216

    Article  PubMed  CAS  Google Scholar 

  55. Postma FR, Jalink K, Hengeveld T, Moolenaar WH (1996) Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: Action through a specific cell surface receptor. EMBO J 15:2388–2392

    PubMed  CAS  Google Scholar 

  56. Prozorovski T, Schulze-Topphoff U, Glumm R et al (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10:385–394

    Article  PubMed  CAS  Google Scholar 

  57. Ransohoff RM (2006) EAE: pitfalls outweigh virtues of screening potential treatments for multiple sclerosis. Trends Immunol 27:167–168

    Article  PubMed  CAS  Google Scholar 

  58. Rausch M, Hiestand P, Foster CA et al (2004) Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: Clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging 20:16–24

    Article  PubMed  Google Scholar 

  59. Rouach N, Pebay A, Meme W et al (2006) S1P inhibits gap junctions in astrocytes: involvement of G(i) and Rho GTPase/ROCK. Eur J Neurosci 23:1453–1464

    Article  PubMed  Google Scholar 

  60. Sanna MG, Liao JY, Jo EJ et al (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P(1) and S1P(3), respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279:13839–13848

    Article  PubMed  CAS  Google Scholar 

  61. Schmouder R, Serra D, Wang YB et al (2006) FTY720: Placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol 46:895–904

    Article  PubMed  CAS  Google Scholar 

  62. Schulze-Topphoff U, Prat A, Prozorovski T et al (2009) Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system. Nat Med 15:788–793

    Article  PubMed  CAS  Google Scholar 

  63. Schwab SR, Cyster JG (2007) Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 8:1295–1301

    Article  PubMed  CAS  Google Scholar 

  64. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647

    Article  PubMed  CAS  Google Scholar 

  65. Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: An enigmatic signalling lipid. Nat Rev Mol Cell Biol 4:397–407

    Article  PubMed  CAS  Google Scholar 

  66. Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26:565–571

    Article  PubMed  CAS  Google Scholar 

  67. Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1:1810–1819

    Article  PubMed  CAS  Google Scholar 

  68. Takabe K, Paugh SW, Milstien S, Spiegel S (2008) „Inside-Out“ signaling of sphingosine-1-phosphate: Therapeutic targets. Pharmacol Rev 60:181–195

    Article  PubMed  CAS  Google Scholar 

  69. Teshima K, Imayoshi T, Matsura M (1995) FTY720, a novel immunosuppressant, possessing unique mechanisms. III. Pharmacological activities in several autoimmune and inflammatory models. Abstracts of the 9th International Congress of Immunology, San Fransisco 5172

  70. Toman RE, Payne SG, Watterson KR et al (2004) Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension. J Cell Biol 166:381–392

    Article  PubMed  CAS  Google Scholar 

  71. Webb M, Tharn CS, Lin FF et al (2004) Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153:108–121

    Article  PubMed  CAS  Google Scholar 

  72. Yanagawa Y, Sugahara K, Kataoka H et al (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol 160:5493–5499

    PubMed  CAS  Google Scholar 

  73. McDonald et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127

    Article  PubMed  CAS  Google Scholar 

  74. Polman CH, Reingold SC, Edan G et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the“McDonald Criteria”. Ann Neurol 58: 840–846

    Article  PubMed  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: OA erklärt, Honorare und Reiseunterstützungen von BayerSchering, MerckSorono, Novartis und Teva erhalten zu haben. RH erklärt, Forschungsmittel und Honorare von Novartis, BayerSchering, BiogenIdec, Teva, Sanofi-Aventis, und MerkSerono erhalten zu haben. HPH und BK erklären, mit Genehmigung des Rektors der HHU Honorare für Beratung, Vorträge und Tätigkeit in Steering Committees von folgenden Firmen erhalten zu haben: BayerSchering, BiogenIdec, BioMS, Genzyme, MerckSerono, Novartis, Teva, SanofiAventis.

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  1. Neurologische Universitätsklinik, Heinrich-Heine-Universität, Düsseldorf, Deutschland

    O. Aktas, J. Ingwersen, B. Kieseier, P. Küry &  H.-P. Hartung

  2. Institut für Klinische Neuroimmunologie, Ludwig-Maximilians-Universität, München, Deutschland

    R. Hohlfeld

  3. Max-Planck-Institut für Neurologie, Martinsried, München, Deutschland

    R. Hohlfeld

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  1. O. Aktas
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Aktas, O., Ingwersen, J., Kieseier, B. et al. Orales Fingolimod bei Multipler Sklerose. Nervenarzt 82, 215–225 (2011). https://doi.org/10.1007/s00115-010-3075-8

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