Recent trials for FTY720 (Fingolimod): A new generation of immunomodulators structurally similar to sphingosine

Reviews on Recent Clinical Trials

Volumn 3, Issue 1, 2008, Pages 62-69

  Mansoor, Moizza ^a   Melendez, Alirio J ^a,b  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Clinical trials; FTY720; Lymphocyte migration; Multiple sclerosis; Rena1 transplant; S1P 1 agonist

Indexed keywords

CHEMOKINE RECEPTOR CCR7; CYCLOSPORIN A; CYTOCHROME P450; CYTOCHROME P450 4F; DRUG METABOLIZING ENZYME; EVEROLIMUS; FINGOLIMOD; IMMUNOMODULATING AGENT; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PLACEBO; RAPAMYCIN; SERINE PALMITOYLTRANSFERASE; SPHINGOSINE; TACROLIMUS; UNCLASSIFIED DRUG;

ACUTE GRAFT REJECTION; ALLERGIC DISEASE; ASTHMA; ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; BRADYCARDIA; BRAIN DISEASE; CHRONIC GRAFT REJECTION; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONCENTRATION RESPONSE; CYTOMEGALOVIRUS INFECTION; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MEGADOSE; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; ENZYME INHIBITION; GRAFT FAILURE; GRAFT SURVIVAL; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; ISCHEMIA; KIDNEY TRANSPLANTATION; LIVER TRANSPLANTATION; LUNG INSUFFICIENCY; LYMPHOCYTE COUNT; LYMPHOCYTE MIGRATION; LYMPHOCYTOPENIA; MONOTHERAPY; MULTIPLE SCLEROSIS; NONHUMAN; PHARMACODYNAMICS; POSTOPERATIVE CARE; PREOPERATIVE CARE; PRIORITY JOURNAL; REPERFUSION INJURY; RETINA MACULA EDEMA; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SINGLE DRUG DOSE; SURVIVAL TIME;

ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; IMMUNE SYSTEM DISEASES; IMMUNOSUPPRESSIVE AGENTS; PROPYLENE GLYCOLS; SPHINGOSINE;

EID: 39449109861     PISSN: 15748871     EISSN: None     Source Type: Journal    
DOI: 10.2174/157488708783330486     Document Type: Review

References (91)

1. Kee TH, Vit P, Melendez AJ. Sphingosine kinase signalling in immune cells. Clin Exp Pharmacol Physiol 2005; 32:153-161.
2. Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005; 118: 4605-4612.
3. Melendez AJ, Ibrahim FB. Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2+ signals, enzyme release, cytokine production, and chemotaxis. J Immunol 2004; 173: 1596-1603.
4. Zhi L, Leung BP, Melendez AJ. Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNFa1pha in primary human monocytes. J Cell Physiol 2006; 208: 109-115.
5. Chun J, Goetzl EJ, Hla T, et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 2002; 54: 265-269.
6. Takuwa Y, Takuwa N, Sugimoto N. The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities. J Biochem (Tokyo) 2002; 131: 767-771.
7. Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 2005; 5: 560-570.
8. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346-349.
9. Suzuki S, Enosawa S, Kakefuda T, et al. A novel immunosuppressant, FTY720, with a unique mechanism of action, induces longterm graft acceptance in rat and dog allotransplantation. Transplantation 1996; 61: 200-205.
10. Chiba K, Yanagawa Y, Masubuchi Y, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immumol 1998; 160: 5037-5044.
11. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, Zinkernagel RM. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 2000; 164: 5761-5770.
12. Kunzendorf U, Ziegler E, Kabelitz D. FTY720-the first compound of a new promising class of immunosuppressive drugs. Nephrol Dial Transplant 2004; 19: 1677-1681.
13. Troncoso P, Kahan BD. Preclinical evaluation of a new immunosuppressive agent, FTY720. Clin Biochem 1998; 31: 369-373.
14. Wei SH, Rosen H, Matheu MP, et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat Immunol 2005; 6: 1228-1235.
15. 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.
16. Brinkmann V, Pinschewer D, Chiba K, Feng L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci 2000; 21: 49-52.
17. Bromley SK, Thomas SY, Luster AD. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol 2005; 6: 895-901.
18. Henning G, Ohl L, Junt T, et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med 2001; 194: 1875-1881.
19. Yopp AC, Fu S, Honig SM, et al. FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. J Immunol 2004; 173: 855-865.
20. Pabst O, Herbrand H, Willenzon S, et al. Enhanced FTY720-mediated lymphocyte homing requires G alpha i signaling and depends on beta 2 and beta 7 integrin. J Immunol 2006; 176: 1474-1480.
21. Halin C, Scimone ML, Bonasio R, et al. The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches. Blood 2005; 106: 1314-1322.
22. Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 2003; 554: 189-193.
23. Kharel Y, Lee S, Snyder AH, et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 2005; 280: 36865-36872.
24. Graler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J 2004; 18: 551-553.
25. Sanchez T, Estrada-Hernandez T, Paik JH, et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem 2003; 278: 47281-47290.
26. Suzuki S, Li XK, Shinomiya T, et al. Induction of lymphocyte apoptosis and prolongation of allograft survival by FTY720. Transplant Proc 1996; 28: 2049-2050.
27. Bohler T, Waiser J, Schutz M, et al. FTY 720A mediates reduction of lymphocyte counts in human renal allograft recipients by an apoptosis-independent mechanism. Transpl Int 2000; 13 (Suppl 1): S311-313.
28. Bohler T, Budde K, Neumayer HH, Waiser J. Novel mediators of FTY720 in human lymphocytes. Transplantation 2005; 79: 492-495.
29. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001; 2: 816-822.
30. Sawicka E, Dubois G, Jarai G, et al. The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/ CD25+ T-regulatory cells and enhances their functional activity. J Immunol 2005; 175: 7973-7980.
31. Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD2+ regulatory T cells. J Immunol 2007; 178: 2458-2468.
32. Idzko M, Hammad H, van Nimwegen M, et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 2006; 116: 2935-2944.
33. Lan YY, De Creus A, Colvin BL, et al. The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am J Transplant 2005; 5: 2649-2659.
34. Muller H, Hofer S, Kaneider N, et al. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol 2005; 35: 533-545.
35. Sawicka E, Zuany-Amorim C, Manlius C, et al. Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. J Immunol 200; 171: 6206-6214.
36. Payne SG, Oskeritzian CA, Griffiths R, et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 2007; 109: 1077-1085.
37. Budde K, Schmouder RL, Brunkhorst R, et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 2002: 13: 1073-1083.
38. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 2003; 76: 1079-1084.
39. Kovarik JM, Schmouder RL, Slade AJ. Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther Drug Monit 2004; 26: 585-587.
40. Skerjanec A, Tedesco H, Neumayer HH, et al. FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship. J Clin Pharmacol 2005; 45: 1268-1278.
41. Kovarik JM, Slade A, Voss B, et al. Ethnic sensitivity study of fingolimod in white and Asian subjects. Int J Clin Pharmacol Ther 2007; 45:98-109.
42. Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 2004; 57:586-591.
43. Kovarik JM, Schmouder RL, Hartmann S, et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J Clin Pharmacol 2006; 46: 149-156.
44. Kovarik JM, Tedesco-Silva H, Lorber MI, Foster C. Exposure-efficacy relationships of a fingolimod-everolimus regimen in kidney transplant patients at risk for delayed graft function. Transplant Proc 2006; 38: 3479-3482.
45. Kovarik JM, Hartmann S, Bartlett M, et al. Oral-intravenous cross-over study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm Drug Dispos 2007; 28: 97-104.
46. Budde K, R LS, Nashan B, et al. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 2003; 3: 846-854.
47. Oppenheimer F, Mulgaonkar S, Ferguson R, et al. Impact of long-term therapy with FTY720 or mycophenolate mofetil on cardiac conduction and rhythm in stable adult renal transplant patients. Transplantation 2007; 83: 645-648.
48. Chiba K, Hoshino Y, Ohtsuki M, et al. Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: I. Prevention of allograft rejection in rats and dogs by FTY720 and FTY720-phosphate. Transplant Proc 2005; 37: 102-106.
49. Suzuki T, Jin MB, Shimamura T, et al. A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments. Transpl Int 2004; 17: 574-584.
50. Yan, S, Rodriguez-Barbosa JI, Pabst O, et al. Protection of mouse small bowel allografts by FTY720 and costimulation blockade. Transplantation 2005; 79: 1703-1710.
51. Suzuki K, Kazui T, Kawabe A, et al. Immunosuppressive effect of FTY720 on rat pancreas allograft. Transplant Proc 1998; 30: 3417-3418.
52. Quesniaux V, Menninger K, Audet M, Gaschen L, Schuurman HJ. FTY-720 is efficacious in monkey kidney transplantation. Transplant Proc 2001; 33: 2374-2375.
53. Kunikata S, Nagano T, Nishioka T, Akiyama T, Kurita T. Immuno-suppressive action of FTY720 for renal allograft a rat model. Transplant Proc 1999; 31: 1157-1159.
54. Suzuki S, Enosawa S, Kakefuda T, Amemiya H, Hoshino Y, Chiba K. Long-term graft acceptance in allografted rats and dogs by treatment with a novel immunosuppressant, FTY720. Transplant Proc 1996; 28: 1375-1376.
55. Wang ME, Tejpal N, Qu X, et al. Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus. Transplantation 1998; 65: 899-905.
56. Silva FR, Silva LB, Cury PM, Burdmann EA, Bueno V. FTY720 in combination with cyclosporine-an analysis of skin allograft survival and renal function. Int Immunopharmacol 2006; 6: 1911-1918.
57. Xu M, Pirenne J, Antoniou EA, Afford SC, D'Silva M, McMaster P. Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation. Transpl Int 1998; 11: 288-294.
58. Tamura A, Li XK, Funeshima N, et al. Immunosuppressive therapy using FTY720 combined with tacrolimus in rat liver transplantation. Surgery 2000; 127: 47-54.
59. Nikolova Z, Hof A, Baumlin Y, Hof RP. Efficacy of SDZ RAD compared with CsA monotherapyand combined Rad/FTY720 treatment in a murine cardiac allotransplantation model. Transpl Immunol 2001; 9: 43-49.
60. Schuurman HJ, Menninger K, Audet M, et al. Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD. Transplantation 2002; 74: 951-960.
61. Kim YM, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J Clin Invest 2003; 111: 659-669.
62. Taylor PA, Ehrhardt MJ, Lees CJ, et al. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood 2007; 110(9):3480-8.
63. Hashimoto D, Asakura S, Matsuoka K, et al. FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease. Eur J Immunol 2007; 37: 271-281.
64. Kataoka H, Ohtsuki M, Shimano K, et al. Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: II. Effect of FTY720 and FTY720-phosphate on host-versus-graft and graft-versus-host reaction in mice. Transplant Proc 2005; 37: 107-109.
65. Lee RS, Kuhr CS, Sale GE, et al. FTY720 does not abrogate acute graft-versus-host disease in the dog leukocyte antigen-nonidentical unrelated canine model. Transplantation 2003; 76: 1155-1158.
66. Song J, Ito T, Matsuda C, et al. Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation. Clin Exp Immunol 2006; 146: 85-92.
67. Song J, Ito T, Matsuda C, et al. Regulation of donor T cells in the tolerant rats to graft-versus-host disease by FTY720 following small bowel transplantation. Transplant Proc 2006; 38: 3181-3183.
68. Ysebaert DK, De Greef KE, De Beuf A, et al. T cells as mediators in renal ischemia/reperfusion injury. Kidney Int 2004; 66:491-496.
69. Dragun D, Bohler T, Nieminen-Kelha M, et al. FTY720-induced lymphocyte homing modulates post-transplant preservation/reperfusion injury. Kidney Int 2004; 65: 1076-1083.
70. Troncoso P, Ortiz M, Martinez L, Kahan BD. FTY 720 prevents ischemic reperfusion damage in rat kidneys. Transplant Proc 2001; 33: 857-859.
71. Kaudel CP, Schmiddem U, Frink M, et al. FTY720 for treatment of ischemia-reperfusion injury following complete renal ischemia in C57/BL6 mice. Transplant Proc 2006; 38: 679-681.
72. Suleiman M, Cury PM, Pestana JO, Burdmann EA, Bueno V. FTY720 prevents renal T-cell infiltration after ischemia/reperfusion injury. Transplant Proc 2005; 37: 373-374.
73. Man K, Ng KT, Lee TK, et al. FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers. Am J Transplant 2005; 5: 40-49.
74. Mulgaonkar S, Tedesco H, Oppenheimer F, et al. FTY720/cyclosporine regimens in de novo renal transplantation: a 1 -year dose-finding study. Am J Transplant 2006; 6: 1848-1857.
75. Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomedulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 2005; 79: 1553-1560.
76. Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 2006, 82: 1689-1697.
77. Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant 2006; 6: 2912-2921.
78. Matsuura M, Imayoshi T, Gkumoto T. Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats; Int J Immunopharmacol 2000, 22: 323-331.
79. Fujii R, Kanai T, Nemoto Y, et al. FTY720 sappresses CD4+CD44 highCD62L- effector memory T cell-mediated colitis. Am J Physiol Gastrointest Liver Physiol 2006; 291: G267-274.
80. Kitabayashi H, Isobe M, Watanabe N, Suzuki J, Yazaki Y, Sekiguchi M. FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes. J Cardiovasc Pharmacol 200; 35: 410-416.
81. Kohno T, Tsuji T, Hirayama K, et al. A novel immunomodulator, FTY720, prevents development of experimental autoimmune my-asthenia gravis in C57BL/6 mice. Biol Pharm Bull 2005; 28: 736-739.
82. Okazaki H, Hirata D, Kamimura T, et al. Effects of FTY720 in MRL-1pr/1pr mice: therapeutic potential in systemic lupus erythematosus. J Rheumatol 2002; 29: 707-716.
83. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453-21457.
84. Fujino M, Funeshima N, Kitazawa Y, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003; 305: 70-77.
85. Webb M, Tham CS, Lin FF, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153: 108-121.
86. Kataoka H, Sugahara K, Shimano K, et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2005; 2: 439-448.
87. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124-1140.
88. Tolle M, Levkau B, Keul P, et al. Immunomodulator FTY720 Induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circ Res 2005; 96: 913-920.
89. Keul P, Tolle M, Lucke S, et al. The sphingosine-1-phosphate analogue FTY720 reduces atherosclerosis in apoliprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 607-613.
90. Koyrakh L, Roman MI, Brinkman V, Wickman K. 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.
91. Kieseier BC, Wiendl H, Hemmer B, Hartung HP. Treatment and treatment trials in multiple sclerosis. Curr Opin Neurol 2007; 20 286-293.