Fingolimod

Fingolimod
Clinical data
Trade names Gilenya
AHFS/Drugs.com Monograph
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  • AU: D
  • US: C (Risk not ruled out)
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    administration    		 By mouth (capsules)
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    Chemical and physical data
    Formula C19H33NO2
    Molar mass 307.471 g/mol
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    Fingolimod (INN, trade name Gilenya, Novartis) is an immunomodulating drug, mostly used for treating multiple sclerosis (MS).[1] It has reduced the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period.[2] Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

    Medical uses

    Fingolimod is used in the treatment of the relapsing form of multiple sclerosis. Its effect in those with primary progressive MS is not clear. It may also be used in chronic inflammatory demyelinating polyneuropathy.[1]

    Adverse effects

    The most common side effects of fingolimod have been head colds, headache, and fatigue. A few cases of skin cancer have been reported, which has also been reported in patients taking natalizumab (Tysabri), an approved MS drug.[3] Fingolimod has also been associated with potentially fatal infections, bradycardia and, recently, a case of hemorrhaging focal encephalitis, an inflammation of the brain with bleeding.[4] Two people died: one due to brain herpes infection, and a second one due to herpes zoster. It is unclear whether the drug was responsible for the events.[5] At least three cases of progressive multifocal leukoencephalopathy had also occurred as of 2015.[6]

    Fingolimod has also been known to cause macular edema, resulting in decreased vision.[7][8] Therefore, frequent surveillance eye examinations are required while taking this medication.

    The European Medicines Agency has advised doctors to increase their level of monitoring of people after the first dose of the medicine. This includes electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour.[9]

    Structure and mechanism

    It is derived from myriocin (ISP-1), a metabolite of the fungus Isaria sinclairii. It is a structural analogue of sphingosine and is phosphorylated by sphingosine kinases in the cell (most importantly sphingosine kinase 2).[10][11][12] The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1.[13] Phospho-fingolimod causes the internalization of S1P receptors, which sequesters lymphocytes in lymph nodes, preventing them from moving to the central nervous system and cause a relapse in multiple sclerosis.

    The unphosphorylated moiety of fingolimod, which is the predominant form of the drug in the body, is also an active molecule. Unphosphorylated fingolimod impairs the ability of cytotoxic CD8 T cells to kill their target cells by a different mechanism that involves the arachidonic acid pathway, which is unrelated to sphigosine phosphate receptors.[14] This has implications to both increasing susceptibility to viral infections as well as enhancing its therapeutic efficacy in multiple sclerosis.[14]

    Additionally, fingolimod shifts macrophages to an anti-inflammatory M2 phenotype. It modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7 (TRPM7).[15]

    Finally, fingolimod has been also found to have other molecular targets and functions. Fingolimod has been reported to be a cannabinoid receptor antagonist,[16] a cPLA2 inhibitor [17] and a ceramide synthase inhibitor.[18][19] It has also been reported to stimulate the repair process of glial cells and precursor cells after injury.[20]

    History

    First synthesized in 1992 by Yoshitomi Pharmaceuticals, fingolimod was derived from an immunosuppressive natural product, myriocin (ISP-I) through chemical modification. Myriocin was isolated from the culture broth a type of entomopathogenic fungus (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine.[21] Showing positive results in both in vitro (mixed lymphocyte reaction) and in vivo screening (prolonging rat skin graft survival time), myriocin was modified through a series of steps to yield fingolimod, code named at the time FTY720.[22]. A recent review highlights the synthetic methods, mode of action and potential applications of this molecule.[23] Structure activity relationship (SAR) studies on myriocin homologs and partially synthetic derivatives showed that the configuration at the carbon bearing the 3-hydroxy group or the 14-ketone, the 6-double bond, and the 4-hydroxy group were not important for its activity and simplification of the structure of ISP-I was done in an attempt to reduce toxicity and improve drugability.[21]

    Elimination of side chain functionalities and removal of chiral centers was part of the simplification process and an intermediate compound (ISP-I-28) with the carboxylic acid of myriocin transformed to a hydroxymethyl group was generated. ISP-I-28 was found to be less toxic and more effective at lengthening rat skin allograft time than ISP-1.

    In September 2010, fingolimod became the first oral disease-modifying drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis.[24] In April 2011 Novartis said that the drug would be available in Canadian pharmacies.[25][26] In March 2011, the European Medicines Agency approved the drug for use in the European Union.[27]

    In 2015, after a challenge at the US Patent and Trademark Office by a generic competitor, the patent office quashed Novartis's patent claims stating they were obvious. Novartis appealed and the federal circuit upheld the patent office decision in April 2017, leaving a high likelihood of generics coming to market by 2019.[28]

    See also

    References

    1. 1 2 "Fingolimod Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Aug 9, 2015.
    2. ↑ Sanford, M (August 2014). "Fingolimod: a review of its use in relapsing-remitting multiple sclerosis". Drugs. 74 (12): 1411–33. doi:10.1007/s40265-014-0264-y. PMID 25063048.
    3. ↑ "Good News for Oral MS Drug Fingolimod". Webmd.com. 2008-04-16. Retrieved 2013-09-30.
    4. ↑ Leypoldt F, Münchau A, Moeller F, Bester M, Gerloff C, Heesen C (2009). "Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report". Neurology. 72 (11): 1022–4. doi:10.1212/01.wnl.0000344567.51394.e3. PMID 19289744.
    5. ↑ http://www.ms-uk.org/dmd?flap=6#6
    6. ↑ Brooks, Megan (2015-08-18). "Third Case of PML With Fingolimod (Gilenya) in MS". Medscape. Retrieved 2015-08-20.
    7. ↑ Jain N, Bhatti MT (2012). "Fingolimod-associated macular edema: incidence, detection, and management". Neurology. 78 (9): 672–80. doi:10.1212/WNL.0b013e318248deea. PMID 22371414.
    8. ↑ Jain N, Bhatti MT (April 2012). "Macular Edema Associated With Fingolimod" (PDF). EyeNet.
    9. ↑ "European Medicines Agency - News and Events - European Medicines Agency starts review of Gilenya (fingolimod)". Ema.europa.eu. 2012-01-20. Retrieved 2013-09-30.
    10. ↑ Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003). "The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2". FEBS Lett. 554 (1–2): 189–93. doi:10.1016/S0014-5793(03)01168-2. PMID 14596938.
    11. ↑ Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T (2003). "Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases". J Biol Chem. 278 (48): 47408–15. doi:10.1074/jbc.M307687200. PMID 13129923. Free full text
    12. ↑ Sanchez, T; Estrada-Hernandez, T; Paik, JH; Wu, MT; Venkataraman, K; Brinkmann, V; Claffey, K; Hla, T (2003). "Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability". The Journal of Biological Chemistry. 278 (47): 47281–90. doi:10.1074/jbc.M306896200. PMID 12954648.
    13. ↑ Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001). "Lysophospholipids--receptor revelations". Science. 294 (5548): 1875–8. doi:10.1126/science.1065323. PMID 11729304.
    14. 1 2 Ntranos, Achilles; Hall, Olivia; Robinson, Dionne P.; Grishkan, Inna V.; Schott, Jason T.; Tosi, Dominique M.; Klein, Sabra L.; Calabresi, Peter A.; Gocke, Anne R. "FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway". Journal of Neuroimmunology. 270 (1–2): 13–21. doi:10.1016/j.jneuroim.2014.03.007.
    15. ↑ Schilling, Tom; Miralles, Francesc; Eder, Claudia (2014-11-01). "TRPM7 regulates proliferation and polarisation of macrophages". J Cell Sci. 127 (21): 4561–4566. doi:10.1242/jcs.151068. ISSN 0021-9533. PMID 25205764.
    16. ↑ Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006). "Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor". Mol. Pharmacol. 70 (1): 41–50. doi:10.1124/mol.105.020552. PMID 16571654.
    17. ↑ Payne SG; Oskeritzian CA; Griffiths R; Subramanian P; Barbour SE; Chalfant CE; Milstien S; Spiegel S. (2007). "The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors". Blood. 109 (3): 1077–85. doi:10.1182/blood-2006-03-011437. PMC 1785128. PMID 17008548.
    18. ↑ Berdyshev EV, Gorshkova I, Skobeleva A, Bittman R, Lu X, Dudek SM, Mirzapoiazova T, Garcia JG, Natarajan V (2009). "FTY720 Inhibits Ceramide Synthases and Up-regulates Dihydrosphingosine 1-Phosphate Formation in Human Lung Endothelial Cells". Journal of Biological Chemistry. 284 (24): 16090–8. doi:10.1074/jbc.M805186200. PMC 2645812. PMID 19119142.
    19. ↑ Sujoy Lahiri; Park H; Laviad EL; Lu X; Bittman R; Futerman AH. (2009). "Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner". Journal of Biological Chemistry. 284 (9): 5467–77. doi:10.1074/jbc.M807438200. PMC 2713526. PMID 19357080.
    20. ↑ FTY720 (Fingolimod) for Relapsing Multiple Sclerosis, Expert Review of Neurotherapeutics, Alejandro Horga; Xavier Montalban 06/04/2008; Expert Rev Neurother. 2008;8(5):699-714
    21. 1 2 Adachi, K; Chiba, K (2007). "FTY720 Story. Its Discovery and the Following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology". Perspectives in medicinal chemistry. 1: 11–23. PMC 2754916. PMID 19812733.
    22. ↑ Fujita T, Yoneta M, Hirose R, Sasaki S, Inoue K, Kiuchi M, Hirase S, Adachi K, Arita M, Chiba K (1995). "Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity". Bioorg. Med. Chem. Lett. 5 (8): 847–52. doi:10.1016/0960-894X(95)00126-E.
    23. ↑ Balasubramaniam, Sivaraman; Sankaran, Ganapathy Subramanian; Badle, Sanjay Sneh. "Perspective on FTY720, an Immunosuppressant". Synthesis. 50 (5): 968–83. doi:10.1055/s-0036-1591877.
    24. ↑ FDA press release on approval of Gilenya
    25. ↑ First oral MS treatment approved for Canada http://www.vancouversun.com/health/First+oral+treatment+approved+Canada+says+drug+company/4420028/story.html
    26. ↑ "Novartis new MS treatment receives Notice of Compliance in Canada". NewsMedical.net. 10 March 2011.
    27. ↑ EMA approval information about Gilenya
    28. ↑ Sagonowsky, Eric (April 13, 2017). "Novartis' Gilenya patent loss sets MS market up for battle with early generics". FiercePharma.
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