Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights

1. Arnold, DL, Bar-Or, A, Cree, BAC, et al. Impact of siponimod on myelination as assessed by MTR across SPMS subgroups: post hoc analysis from the EXPAND MRI substudy. Mult Scler J 2020; 26: 397–659.
Google Scholar | Medline2. Fox, R, Arnold, D, Giovannoni, G, et al. Siponimod reduces grey matter atrophy in patients with secondary progressive multiple sclerosis: subgroup analyses from the EXPAND study (1130). Neurology. 2020; 94: 1130.
Google Scholar3. Kappos, L, Bar-Or, A, Cree, BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018; 391: 1263–1273.
Google Scholar | Crossref | Medline4. Behrangi, N, Fischbach, F, Kipp, M. Mechanism of siponimod: anti-inflammatory and neuroprotective mode of action. Cells. 2019; 8: 24.
Google Scholar5. Gergely, P, Nuesslein-Hildesheim, B, Guerini, D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012; 167: 1035–1047.
Google Scholar | Crossref | Medline | ISI6. Mannioui, A, Vauzanges, Q, Fini, JB, et al. The Xenopus tadpole: an in vivo model to screen drugs favoring remyelination. Mult Scler. 2018; 24: 1421–1432.
Google Scholar | SAGE Journals | ISI7. Pan, S, Gray, NS, Gao, W, et al. Discovery of BAF312 (siponimod), a potent and selective S1P receptor modulator. ACS Med Chem Lett. 2013; 4: 333–337.
Google Scholar | Crossref | Medline8. Mayzent® US Prescribing Information 2019. East Hanover, NJ: Novartis Pharmaceuticals Corporation.
Google Scholar9. Mayzent® summary of product characteristic 2020. Novartis Pharma AG.
Google Scholar10. Brinkmann, V, Cyster, JG, Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant. 2004; 4: 1019–1025.
Google Scholar | Crossref | Medline | ISI11. Zecri, FJ . From natural product to the first oral treatment for multiple sclerosis: the discovery of FTY720 (gilenya)? Curr Opin Chem Biol. 2016; 32: 60–66.
Google Scholar | Crossref | Medline12. Huwiler, A, Zangemeister-Wittke, U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives. Pharmacol Ther. 2018; 185: 34–49.
Google Scholar | Crossref | Medline13. Juif, PE, Kraehenbuehl, S, Dingemanse, J. Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators. Expert Opin Drug Metab Toxicol. 2016; 12: 879–895.
Google Scholar | Crossref | Medline | ISI14. Cui, QL, Fang, J, Almazan, G, et al. Sphingosine 1-phosphate receptor agonists promote axonal ensheathment by human fetal oligodendrocyte progenitors. Multi Scler J. 2011; 17: S366 [P823].
Google Scholar15. Jackson, SJ, Giovannoni, G, Baker, D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation. 2011; 8: 76.
Google Scholar | Crossref | Medline | ISI16. O’Sullivan, C, Schubart, A, Mir, AK, et al. The dual S1PR1/S1PR5 drug BAF312 (siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016; 13: 31.
Google Scholar | Crossref | Medline17. Briard, E, Rudolph, B, Desrayaud, S, et al. MS565: a SPECT tracer for evaluating the brain penetration of BAF312 (siponimod). ChemMedChem. 2015; 10: 1008–1018.
Google Scholar | Crossref | Medline18. Di, L, Rong, H, Feng, B. Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J Med Chem. 2013; 56: 2–12.
Google Scholar | Crossref | Medline19. Feng, B, Doran, AC, Di, L, et al. Prediction of human brain penetration of P-glycoprotein and breast cancer resistance protein substrates using In vitro transporter studies and animal models. J Pharm Sci. 2018; 107: 2225–2235.
Google Scholar | Crossref | Medline20. Tavares, A, Barret, O, Alagille, D, et al. Brain distribution of MS565, an imaging analogue of siponimod (BAF312), in non-human primates (P1.168). Neurology. 2014; 82: P1.168. https://n.neurology.org/content/82/10_Supplement/P1.168.short
Google Scholar21. Liu, X, Smith, BJ, Chen, C, et al. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab Dispos. 2006; 34: 1443–1447.
Google Scholar | Crossref | Medline22. Choi, JW, Gardella, SE, Herra, 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. 2011; 108: 751–756.
Google Scholar | Crossref | Medline | ISI23. Hunter, SF, Bowen, JD, Reder, AT. The direct effects of fingolimod in the central nervous system: implications for relapsing multiple sclerosis. CNS Drugs. 2016; 30: 135–147.
Google Scholar | Crossref | Medline24. Mullershausen, F, Craveiro, LM, Shin, Y, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem. 2007; 102: 1151–61.
Google Scholar | Crossref | Medline | ISI25. Healy, LM, Sheridan, GK, Pritchard, AJ, et al. Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes. Brit J Pharmacol. 2013; 169: 1114–1129.
Google Scholar | Crossref | Medline26. Colombo, E, Bassani, C, Angelis, AD, et al. Siponimod (BAF312) activates Nrf2 while hampering NFκB in human astrocytes, and protects from astrocyte-induced neurodegeneration. Frontiers Immunol. 2020; 11: 635.
Google Scholar | Crossref | Medline27. Dietrich, M, Hecker, C, Beerli, C, et al. Optimising siponimod (BAF312) oral administration for long-term experimental studies in mice. ECTRIMS On Line Library 2018; 229455: ePoster EP1618. https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/229455/philipp.albrecht.optimising.siponimod.28baf31229.oral.administration.for.html?f=menu=6*ce_id=1428*ot_id=20024*media=3*browseby=8
Google Scholar28. Ben Yacoub, N, Uffelmann, T, Tisserand, S, et al. Mouse astrocytes exhibit agonist-induced functional S1P1 receptor antagonism. ECTRIMS On Line Library 2020; Poster P0357. https://library.msvirtual2020.org/virtual-library-search?product_id=7
Google Scholar29. Kim, S, Bielawski, J, Yang, H, et al. Functional antagonism of sphingosine-1-phosphate receptor 1 prevents cuprizone-induced demyelination. Glia. 2018; 66: 654–669.
Google Scholar | Crossref | Medline30. Brinkmann, V, Streiff, M, Bigaud, M, et al. Fingolimod treatment is associated with a down-modulation of S1P1 receptor protein in the CNS. Neurology. 2012; 78(Suppl 1): P02.107. https://n.neurology.org/content/78/1_Supplement/P02.107.short
Google Scholar31. Gräler, MH, Goetzl, EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G protein-coupled receptor. FASEB J. 2004; 18: 551-3.
Google Scholar | Crossref | Medline32. Bigaud, M, Tisserand, S, Fuchs-Loesle, P, et al. The S1P5 receptor is not down-modulated in response to selective agonists. Mult Scler. 2018; 24(S2): 913 (EPoster 1617).
Google Scholar33. Van Doorn, R, Van Horssen, J, Verzijl, D, et al. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010; 58: 1465–1476.
Google Scholar | Crossref | Medline | ISI34. Colombo, E, Di Dario, M, Capitolo, E, et al. Fingolimod may supportnNeuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014; 76: 325–337.
Google Scholar | Crossref | Medline35. Briard, E, Orain, D, Beerli, C, et al. BZM055, An iodinated radiotracer candidate for PET and SPECT imaging of myelin and FTY720 brain distribution. ChemMedChem. 2011; 6: 667–677.
Google Scholar | Crossref | Medline36. Tamagnan, G, Tavares, A, Barret, O, et al. Brain distribution of BZM055, an analog of fingolimod (FTY720), in human. Mult Scler J. 2012; 18: 379.
Google Scholar37. Gardin, A, Dodman, A, Kalluri, S, et al. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther. 2017; 55: 54–65.
Google Scholar | Crossref | Medline38. 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.
Google Scholar | Crossref | Medline | ISI39. Bigaud, M, Tisserand, S, Ramseier, P, et al. Differentiated pharmacokinetic/pharmacodynamic (PK/PD) profiles for siponimod vs fingolimod. ECTRIMS On Line Library 2019; 278982: Poster P622. https://onlinelibrary.ectrimscongress.eu/ectrims/2019/stockholm/278982/marc.bigaud.differentiated.pharmacokinetic.pharmacodynamic.%28pk.pd%29.profiles.html
Google Scholar40. Scott, FL, Clemons, B, Brooks, J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016; 173: 1778–1792.
Google Scholar | Crossref | Medline | ISI41. Bigaud, M, Tisserand, S, Albrecht, P, et al. Siponimod: from understanding mode of action to differentiation versus fingolimod (1536). Neurology. 2020; 94: 1536.
Google Scholar42. Bigaud, MDF, Hach, T, Piani Meier, D, et al. Dual mode of action of siponimod in secondary progressive multiple sclerosis: a hypothesis based on the relevance of pharmacological properties. Mult Scler J 2020; 26: 272–659.
Google Scholar | Medline43. Cuzzocrea, S, Doyle, T, Campolo, M, et al. Sphingosine 1-phosphate receptor subtype 1 as a therapeutic target for brain trauma. J Neurotrauma. 2018; 35: 1452–1466.
Google Scholar | Crossref | Medline44. 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.
Google Scholar | Crossref | Medline | ISI

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