Skip to main content
Erschienen in: Drugs 9/2019

01.06.2019 | AdisInsight Report

Siponimod: First Global Approval

verfasst von: Zaina T. Al-Salama

Erschienen in: Drugs | Ausgabe 9/2019

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Baldassari LE, Fox RJ. Therapeutic advances and challenges in the treatment of progressive multiple sclerosis. Drugs. 2018;78(15):1549–66.CrossRefPubMed Baldassari LE, Fox RJ. Therapeutic advances and challenges in the treatment of progressive multiple sclerosis. Drugs. 2018;78(15):1549–66.CrossRefPubMed
2.
Zurück zum Zitat De Angelis F, Plantone D, Chataway J. Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs. 2018;32(6):499–526.CrossRefPubMed De Angelis F, Plantone D, Chataway J. Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs. 2018;32(6):499–526.CrossRefPubMed
4.
Zurück zum Zitat Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics. 2017;14(4):859–73.CrossRefPubMedPubMedCentral Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics. 2017;14(4):859–73.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat 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.CrossRef 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.CrossRef
6.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
8.
Zurück zum Zitat Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflamm. 2016;13(1):207.CrossRef Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflamm. 2016;13(1):207.CrossRef
9.
Zurück zum Zitat 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.). 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.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.). 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.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
13.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
14.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
15.
Zurück zum Zitat 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.). 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.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
17.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
18.
Zurück zum Zitat 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). 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.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
20.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
21.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
22.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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.). 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.
Zurück zum Zitat 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.). 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.
Zurück zum Zitat 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. 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.
Zurück zum Zitat 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). 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.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
28.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
29.
Zurück zum Zitat 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. 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.
Metadaten
Titel
Siponimod: First Global Approval
verfasst von
Zaina T. Al-Salama
Publikationsdatum
01.06.2019
Verlag
Springer International Publishing
Erschienen in
Drugs / Ausgabe 9/2019
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-019-01140-x

Weitere Artikel der Ausgabe 9/2019

Drugs 9/2019 Zur Ausgabe