, Volume 79, Issue 9, pp 1009–1015 | Cite as

Siponimod: First Global Approval

  • Zaina T. Al-SalamaEmail author
AdisInsight Report


Siponimod (Mayzent®) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR1,5) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.


Compliance with Ethical Standards


The preparation of this review was not supported by any external funding.

Conflict of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Zaina T. Al-Salama is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.


  1. 1.
    Baldassari LE, Fox RJ. Therapeutic advances and challenges in the treatment of progressive multiple sclerosis. Drugs. 2018;78(15):1549–66.CrossRefGoogle Scholar
  2. 2.
    De Angelis F, Plantone D, Chataway J. Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs. 2018;32(6):499–526.CrossRefGoogle Scholar
  3. 3.
    Novartis Pharmaceuticals Corporation. MAYZENT® (siponimod): US prescribing information. 2019. Accessed 20 May 2019.
  4. 4.
    Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics. 2017;14(4):859–73.CrossRefGoogle Scholar
  5. 5.
    O’Sullivan C, Schubart A, Mir AK, et al. The dual S1PR1/S1PR5 drug BAF312 (siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflamm. 2016;13:31.CrossRefGoogle Scholar
  6. 6.
    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(5):1035–47.CrossRefGoogle Scholar
  7. 7.
    Lewis ND, Haxhinasto SA, Anderson SM, et al. Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3. J Immunol. 2013;190(7):3533–40.CrossRefGoogle Scholar
  8. 8.
    Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflamm. 2016;13(1):207.CrossRefGoogle Scholar
  9. 9.
    Mao-Draayer Y, Wu Q, Wang Q, et al. Basic immunological profile changes of SPMS patients treated with BAF312 [abstract no. P1.384]. Neurology. 2017;88(16 Suppl.).Google Scholar
  10. 10.
    Bar-Or A, Derfuss T, Vermersch P, et al. Longitudinal changes in lymphocyte subsets of siponimod treated patients with SPMS [abstract no. P1238]. Mult Scler J. 2017;23(Suppl. 3):660.Google Scholar
  11. 11.
    Kuhle J, Kropshofer H, Barro C, et al. Siponimod reduces neurofilament light chain blood levels in secondary progressive multiple sclerosis patients [abstract no. S8.006]. Neurology. 2018;90(15 Suppl.).Google Scholar
  12. 12.
    Biswal S, Polus F, Pal P, et al. Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects. Int J Clin Pharmacol Ther. 2015;53(10):855–65.CrossRefGoogle Scholar
  13. 13.
    Shakeri-Nejad K, Aslanis V, Veldandi UK, et al. Effects of therapeutic and supratherapeutic doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. Clin Ther. 2015;37(11):2489–2505.e2.CrossRefGoogle Scholar
  14. 14.
    Glaenzel U, Jin Y, Nufer R, et al. 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):1001–13.CrossRefGoogle Scholar
  15. 15.
    Gardin A, Shakeri-Nejad K, Gray C, et al. Absolute bioavailability of single, oral dose of siponimod in healthy subjects [abstract no. P3.402]. Neurology. 2018;90(15 Suppl.).Google Scholar
  16. 16.
    Gardin A, Ufer M, Legangneux E, et al. Effect of fluconazole coadministration and CYP2C9 genetic polymorphism on siponimod pharmacokinetics in healthy subjects. Clin Pharmacokinet. 2019;58(3):349–61.CrossRefGoogle Scholar
  17. 17.
    Gardin A, Gray C, Neelakantham S, et al. Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects. Eur J Clin Pharmacol. 2018;74(12):1593–604.CrossRefGoogle Scholar
  18. 18.
    Huth F, Gardin A, Umehara K-I, et al. Prediction of the impact of CYP2C9 genotypes on the drug-drug interaction potential of siponimod with PBPK modeling:a comprehensive approach for drug label recommendations. Clin Pharmacol Ther (in press).Google Scholar
  19. 19.
    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(1):54–65.CrossRefGoogle Scholar
  20. 20.
    Shakeri-Nejad K, Aslanis V, Veldandi UK, et al. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther. 2017;55(1):41–53.CrossRefGoogle Scholar
  21. 21.
    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(10127):1263–73.CrossRefGoogle Scholar
  22. 22.
    Cree B, Fox R, Giovannoni G, et al. Siponimod affects disability progression in SPMS patients independent of relapse activity: results from the phase III EXPAND study [abstract no. O330]. Eur J Neurol. 2018;25(Suppl. 2):70–1.Google Scholar
  23. 23.
    Cree B, Fox R, Giovannoni G, et al. Uncoupling the impact on relapses and disability progression: siponimod in relapsing and non-relapsing patients with secondary progressive multiple sclerosis in the phase III EXPAND study [abstract no. S8.005]. Neurology. 2018;90(15 Suppl.).Google Scholar
  24. 24.
    Benedict RHB, Cree B, Tomic D, et al. Impact of siponimod on cognition in patients with secondary progressive multiple sclerosis: results from phase 3 EXPAND study [abstract no. S44.004]. Neurology. 2018;90(15 Suppl.).Google Scholar
  25. 25.
    Benedict RH, Cree B, Tomic D, et al. Siponimod improves cognitive processing speed in patients with SPMS: results from Phase 3 EXPAND Study [abstract no. EPR2103]. Eur J Neurol. 2018;25(Suppl. 2):432.Google Scholar
  26. 26.
    Benedict R, Fox R, Tomic D, et al. Effect of siponimod on cognition in patients with secondary progressive multiple sclerosis (SPMS): phase 3 EXPAND study subgroup analysis [abstract no. P3.2-051]. Neurology. 2019;92(15 Suppl).Google Scholar
  27. 27.
    Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756–67.CrossRefGoogle Scholar
  28. 28.
    Kappos L, Li DK, Stuve O, et al. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol. 2016;73(9):1089–98.CrossRefGoogle Scholar
  29. 29.
    Kappos L, Vermersch P, Fox R, et al. Longer-term safety with siponimod treatment in multiple sclerosis: pooled analysis of data from the BOLD and EXPAND trials and their extensions [abstract no. P911]. Mult Scler J. 2018;24(Suppl. 2):491–2.Google Scholar
  30. 30.
    US Food & Drug Administration. FDA approves new oral drug to treat multiple sclerosis [media release]. Mar 26 2019.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Springer NatureAucklandNew Zealand

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