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Siponimod: First Global Approval

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Abstract

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.

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References

  1. Baldassari LE, Fox RJ. Therapeutic advances and challenges in the treatment of progressive multiple sclerosis. Drugs. 2018;78(15):1549–66.

    Article  CAS  PubMed  Google Scholar 

  2. De Angelis F, Plantone D, Chataway J. Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs. 2018;32(6):499–526.

    Article  CAS  PubMed  Google Scholar 

  3. Novartis Pharmaceuticals Corporation. MAYZENT® (siponimod): US prescribing information. 2019. http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf. Accessed 20 May 2019.

  4. Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics. 2017;14(4):859–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  8. Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflamm. 2016;13(1):207.

    Article  CAS  Google Scholar 

  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.).

  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.

  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.).

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.).

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.).

  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.).

  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.

  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).

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

  30. US Food & Drug Administration. FDA approves new oral drug to treat multiple sclerosis [media release]. Mar 26 2019. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634469.htm.

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    Zaina T. Al-Salama

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  1. Zaina T. Al-Salama
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Correspondence to Zaina T. Al-Salama.

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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.

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This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch and beyond.

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Al-Salama, Z.T. Siponimod: First Global Approval. Drugs 79, 1009–1015 (2019). https://doi.org/10.1007/s40265-019-01140-x

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  • DOI: https://doi.org/10.1007/s40265-019-01140-x

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