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Krasnov V.S.

Pavlov First St. Petersburg State Medical University

Kolontareva Yu.M.

Novartis Pharma LLC

Siponimod: a new view at the therapy of secondary progressive multiple sclerosis

Authors:

Krasnov V.S., Kolontareva Yu.M.

More about the authors

Journal: S.S. Korsakov Journal of Neurology and Psychiatry. 2021;121(7): 124‑129

DOI: 10.17116/jnevro2021121071124

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SIPONIMOD: A NEW VIEW AT THE THERAPY OF SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS
SIPONIMOD: A NEW VIEW AT THE THERAPY OF SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS

To cite this article:

Krasnov VS, Kolontareva YuM. Siponimod: a new view at the therapy of secondary progressive multiple sclerosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2021;121(7):124‑129. (In Russ.)
https://doi.org/10.17116/jnevro2021121071124

Подписка 2025-2 (S.S. Korsakov Journal of Neurology and Psychiatry)
 
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Siponimod is a selective modulator of sphingosine-1-phosphate (S1P) receptors of types 1 and 5, registered in the Russian Federation for the treatment of patients with secondary progressive multiple sclerosis (SPMS), regardless of the presence or absence of exacerbations. The effectiveness of the drug in comparison with placebo was demonstrated in patients with SPMS in the international clinical trial EXPAND (phase III). This review devotes actual problems in the treatment of patients with SPMS, discusses the pathophysiology of multiple sclerosis progression, describes the peripheral and central mechanisms of siponimod action and its differences from fingolimod. According to analysis of scientific literature experimental, clinical and neuroimaging data are presented, which could explain the reasons for the successful use of siponimod in patients with SPMS, taking into account the pathophysiological mechanisms of the development of progression and the mechanisms of drug action.

Keywords:

secondary progressive multiple sclerosis
siponimod
neurodegeneration
remyelination

Authors:

Krasnov V.S.

Pavlov First St. Petersburg State Medical University

Kolontareva Yu.M.

Novartis Pharma LLC

Received:

20.04.2021

Accepted:

04.06.2021

List of references:

  1. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O’Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014; 83(3): 278-286.  https://doi.org/10.1212/WNL.0000000000000560
  2. Khachanova NV, Boyko AN, Bakhtiyarova KZ, Vlasov YV, Evdoshenko EP, Sivertseva SA, Schmidt TE, Shumilina MV. Recommendations from the Expert Meeting «Secondary progressive multiple sclerosis: unresolved issues and prospects». Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2019;11(4):172—175. (In Russ.). https://doi.org/10.14412/2074-2711-2019-4-172-175
  3. Sand IK , Krieger S, Farrell C, Miller AE. Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult Scler. 2014; 20(12):1654-1657. https://doi.org/10.1177/1352458514521517
  4. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet. 2017; 389(10076):1357-1366. https://doi.org/10.1016/S0140-6736(16)31320-4
  5. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, Clanet M, Comi G, Derfuss T, Fazekas F, Hartung HP, Havrdova E, Hemmer B, Kappos L, Liblau R, Lubetzki C, Marcus E, Miller DH, Olsson T, Pilling S, Selmaj K, Siva A, Sorensen PS, Sormani MP, Thalheim C, Wiendl H, Zipp F. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2018; 24(2):96-120.  https://doi.org/10.1177/1352458517751049
  6. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, Haboubi M, Halper J, Hosey JP, Jones DE, Lisak R, Pelletier D, Potrebic S, Sitcov C, Sommers R, Stachowiak J, Getchius TSD, Merillat SA, Pringsheim T. Comprehensive systematic review summary: disease-modifying therapies for adults with multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2018; 90(17):789- 800.  https://doi.org/10.1212/WNL.0000000000005345
  7. Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, Polman C, McFarland H., European (EU-SPMS). Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology. 2004; 63(10):1779-1787. https://doi.org/10.1212/01.wnl.0000145561.08973.4f
  8. European Study Group on interferon beta-1b in secondary progressive MS Placebocontrolled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet. 1998; 352(9139):1491-1497.
  9. Panitch H, Miller A, Paty D, Weinshenker B. North American Study Group. Interferon beta-1b in secondary progressive MS: Results from a 3-year controlled study. Neurology. 2004; 63(10):1788-95.  https://doi.org/10.1212/01.wnl.0000146958.77317.3e
  10. Wiendl H., Meuth SG Pharmacological approaches to delaying disability progression in patient with multiple sclerosis. Drugs. 2015;75(9):947-977.  https://doi.org/10.1007/s40265-015-0411-0
  11. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017; 376(3):221-234.  https://doi.org/10.1056/NEJMoa1601277
  12. Menge T, Dubey D, Warnke C, Hartung HP, Stüve O. Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2016;16 (10):1131-1139. https://doi.org/10.1080/14737175.2016.1227242
  13. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3):209-220.  https://doi.org/10.1056/NEJMoa1606468
  14. Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdová EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, doubleblind, placebo-controlled trial with an open label extension. Lancet Neurol. 2018;17(5):405-415.  https://doi.org/10.1016/S1474-4422(18)30069-3
  15. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, Wolf C, Wallström E, Dahlke F; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a doubleblind, randomised, phase 3 study. Lancet. 2018; 391(10127):1263-1273. https://doi.org/10.1016/S0140-6736(18)30475-6
  16. Novartis Europharm Ltd. Siponimod (Mayzent®): EU summary of product characteristics. 2020. Accessed 9 Jul 2020. https://www.ema.europa.eu/
  17. Novartis Pharamceuticals Corporation. MAYZENT® (siponimod) tablets, for oral use: US prescribing information. 2019. Accessed 9 Jul 2020. https://www.fda.gov/
  18. https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=0215f434-7648-4432-852b-6b085166381f&t=
  19. Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140(3): 527-546.  https://doi.org/10.1093/brain/aww258
  20. Uccelli A, Aloisi F, Pistoia V. Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol. 2005;26(5):254-259.  https://doi.org/10.1016/j.it.2005.02.009
  21. Franciotta D, Salvetti M, Lolli F, Serafini B, Aloisi F. B cells and multiple sclerosis. Lancet Neurol. 2008;7(9):852-85.  https://doi.org/10.1016/S1474-4422(08)70192-3
  22. Pérez-Cerdá F, Sánchez-Gómez MV, Matute C. The link of inflammation and neurodegeneration in progressive multiple sclerosis multiple sclerosis and demyelinating disorders. Multiple Sclerosis and Demyelinating Disorders .2016; 1:9.  https://doi.org/10.1186/s40893-016-0012-0
  23. Dusaban SS, Chun J, Rosen H, Purcell NH, Brown JH. Sphingosine 1-phosphate receptor 3 and Rho. A signaling mediate inflammatory gene expression in astrocytes Brown J Neuroinflamm 2017; 14:111.  https://doi.org/10.1186/s12974-017-0882-x
  24. Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O’Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014; 6(248):248ra107. https://doi.org/10.1126/scitranslmed.3008879
  25. Wicken C, Nguyen J, Karna R, Bhargava P. Leptomeningeal inflamation in multiple sclerosis: insights from animal and human studies . Multiple Sclerosis and Related Disoders. 2018; 26: 173-182.  https://doi.org/10.1016/j.msard.2018.09.025
  26. Milstein JL, Barbour CR, Jackson K, Kosa P, Bielekova B. Intrathecal, not systemic inflammation is correlated with multiple sclerosis severity, especially in progressive multiple sclerosis. Front Neurol. 2019;10:1232. https://doi.org/10.3389/fneur.2019.01232
  27. Lehmann-Horn K., Kinzel S, Feldmann L, Radelfahr F, Hemmer B, Traffehn S, Bernard CCA, Stadelmann C, Brück W, Weber MS. Intrathecal anti-CD20 efficiently depletes meningeal B cells in CNS autoimmunity. Ann Clin Transl Neurol. 2014; 1(7):490-496.  https://doi.org/10.1002/acn3.71
  28. Lehmann-Horn K, Wang S, Sagan SA, Zamvil SS, von Büdingen H-C. B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. JCI Insight. 2016; 1(20):e87234. https://doi.org/10.1172/jci.insight.87234
  29. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1): 61-76.  https://doi.org/10.1016/j.neuron.2006.09.011
  30. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-558.  https://doi.org/10.1038/nri3871
  31. Geurts JJ, Roosendaal SD, Calabrese M, Ciccarelli O, Agosta F, Chard DT, Gass A, Huerga E, Moraal B, Pareto D, Rocca MA, Wattjes MP, Yousry TA, Uitdehaag BM, Barkhof F; MAGNIMS Study Group. Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI. Neurology. 2011;76(5):418-424.  https://doi.org/10.1212/WNL.0b013e31820a0cc4
  32. Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M, Huitinga I. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathologica.2018; 135(4):511-528.  https://doi.org/10.1007/s00401-018-1818-y
  33. Witte ME, Mahad DJ, Lassmann H, van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med. 2014; 20(3):179-187.  https://doi.org/10.1016/j.molmed.2013.11.007
  34. Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, Sepman H, Marfia GA, Centonze D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015;11(12):711-724.  https://doi.org/10.1038/nrneurol.2015.222
  35. Hackney AC, Evans ES. Doping, Performance Enhancing Drugs, and Hormones in Sport. Hormone and Metabolic Modulators (Chapter 7). 2018: 77-89.  https://doi.org/10.1016/B978-0-12-813442-9.00007-9
  36. Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y, Chu A, Hinterding K, Gardin A, End P, Heining P, Bruns C, Cooke NG, Nuesslein-Hildesheim B. Discovery of BAF312 (Siponimod), a potent and selective S1P receptor modulator. ACS Med Chem Lett. 2013;4(3):333-337.  https://doi.org/10.1021/ml300396r
  37. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A. Metabolism and disposition of siponimod, a novel selective S1P1/S1P5 agonist, in healthy volunteers and in vitro identification of human cytochrome P450 enzymes involved in its oxidative metabolism. Drug Metab Dispos. 2018;46(7):1001-1013. https://doi.org/10.1124/dmd.117.079574
  38. Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, Lubetzki C, Hartung HP, Montalban X, Uitdehaag BMJ, Merschhemke M, Li B, Putzki N, Liu FC, Häring DA, Kappos L; INFORMS study investigators. Oral fingolimod in primary progressive multiple sclerosis (INFORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016; 387:1075-1084. https://doi.org/10.1016/S0140-6736(15)01314-8
  39. Legangneux E, Gardin A, Johns D. Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. Br J Clin Pharmacol. 2013;75(3):831-841.  https://doi.org/10.1111/j.1365-2125.2012.04400.x
  40. Lesley J. Scott1 Siponimod: A Review in Secondary Progressive Multiple Sclerosis. CNS Drugs.2020; 34:1191—1200. https://doi.org/10.1007/s40263-020-00771-z
  41. Bigaud M, Rudolph B, Briard E, Beerli C, Schubart A, Gardin A. Siponimod penetrates, distributes and acts on the central nervous system: translational insights [abstract no. 3973]. Neurology. 2020;94(15 Suppl).
  42. O’Sullivan C, Schubart A, Mir AK, Dev KK. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016 ;13:31.  https://doi.org/10.1186/s12974-016-0494-x
  43. Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, Pan S, Gray NS, Hinterding K, Cooke NG, Groenewegen A, Vitaliti A, Sing T, Luttringer O, Yang J, Gardin A, Wang N, Crumb WJ Jr, Saltzman M, Rosenberg M, Wallström E. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species — specific effects on heart rate. Br J Pharmacol. 2012;167(5):1035-1047. https://doi.org/10.1111/j.1476-5381.2012.02061.x
  44. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L, Schubart A, Mandolesi G, Centonze D. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016; 13(1):207.  https://doi.org/10.1186/s12974-016-0686-4
  45. Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F, Osinde M, Wishart WL, Guerini D, Thallmair M, Schwab ME, Sivasankaran R, Seuwen K, Dev KK. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem. 2007;102(4):1151-1161. https://doi.org/10.1111/j.1471-4159.2007.04629.x
  46. Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010;58(12):1465-1476. https://doi.org/10.1002/glia.21021
  47. Kim HJ, Miron VE, Dukala D, Proia RL, Ludwin SK, Traka M, Antel JP, Soliven B. Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. FASEB J. 2011;25(5):1509-1518. https://doi.org/10.1096/fj.10-173203
  48. Roggeri A, Schepers M, Tiane A, Rombaut B, van Veggel L, Hellings N, Prickaerts J, Pittaluga A, Vanmierlo T. Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation. Int J Mol Sci. 2020;21(20):7537. https://doi.org/10.3390/ijms21207537
  49. Jackson SJ, Giovannoni G, Baker D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation. 2011;8:76.  https://doi.org/10.1186/1742-2094-8-76
  50. Mannioui A, Vauzanges Q, Fini JB, Henriet E, Sekizar S, Azoyan L, Thomas JL, Pasquier DD, Giovannangeli C, Demeneix B, Lubetzki C, Zalc B. The Xenopus tadpole: an in vivo model to screen drugs favoring remyelination. Mult Scler J. 2018; 24(11):1421—32. Mult Scler. 2018; 24(11):1421—1432. https://doi.org/10.1177/1352458517721355
  51. Arnold DL, Vermersch P, Cree BAC Evidence for improved myelination in patients treated with siponimod: results from the phase 3 EXPAND MRI substudy [abstract no.EPR1147]. Eur J Neurol. 2020; 27(Suppl 1):194—195. 
  52. Cree BA, Magnusson B, Rouyrre N, Fox RJ, Giovannoni G, Vermersch P, Bar-Or A, Gold R, Piani Meier D, Karlsson G, Tomic D, Wolf C, Dahlke F, Kappos L. Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis. Mult Scler. 2020; 1-13.  https://doi.org/10.1177/1352458520971819

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