Siponimod
{{Short description|Chemical compound}}
{{Use dmy dates|date=November 2019}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image = Siponimod.svg
| width = 275
| alt =
| caption =
| pronounce =
| Drugs.com = {{drugs.com|monograph|siponimod-fumarate}}
| MedlinePlus = a619027
| DailyMedID = Siponimod
| pregnancy_AU = D
| pregnancy_AU_comment = {{cite web | title=Mayzent Australian prescription medicine decision summary | website=Therapeutic Goods Administration (TGA) | date=13 December 2019 | url=https://www.tga.gov.au/resources/auspmd/mayzent | access-date=23 August 2020}}
| pregnancy_category =
| routes_of_administration = By mouth
| class =
| ATCvet =
| ATC_prefix = L04
| ATC_suffix = AE03
| ATC_supplemental =
| legal_AU = S4
| legal_AU_comment = {{cite web | title=Summary for ARTG Entry:310499 Mayzent siponimod 2 mg film-coated tablet blister pack | website=Therapeutic Goods Administration (TGA) | url=http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=0D2452FF253B9A85CA2585880030C9BA&agid=(PrintDetailsPublic)&actionid=1 | format=PDF | access-date=23 August 2020 }}{{Dead link|date=August 2021 |bot=InternetArchiveBot |fix-attempted=yes }}{{cite web | url=https://www.tga.gov.au/sites/default/files/auspar-siponimod-191211.pdf | title= Australian Public Assessment Report for Siponimod | website=Therapeutic Goods Administration (TGA) }}
| legal_BR =
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = {{cite web | title=Mayzent Product information | website=Health Canada | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98630 | access-date=29 May 2022}}{{cite web | title=Summary Basis of Decision (SBD) for Mayzent | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00471&lang=en | access-date=29 May 2022}}
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| legal_UK = POM
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_UN =
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| legal_status = Rx-only
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| index2_label = as salt
| CAS_number = 1230487-00-9
| CAS_supplemental =
| PubChem = 44599207
| IUPHAR_ligand =
| DrugBank = DB12371
| ChemSpiderID = 29315058
| UNII = RR6P8L282I
| KEGG = D11460
| KEGG2 = D11072
| ChEBI =
| ChEMBL = 2336071
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = BAF-312
| IUPAC_name = 1-({4-[(1E)-1-({[4-Cyclohexyl- 3-(trifluoromethyl)phenyl]methoxy}imino)ethyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid
| C=29 | H=35 | F=3 | N=2 | O=3
| SMILES = CCC1=C(C=CC(=C1)C(=NOCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)C)CN4CC(C4)C(=O)O
| StdInChI = 1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)/b33-19+
| StdInChI_comment =
| StdInChIKey = KIHYPELVXPAIDH-HNSNBQBZSA-N
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Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS).{{cite web | title=Mayzent- siponimod tablet, film coated | website=DailyMed | date=26 March 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=44492772-5aed-4627-bd85-e8e89f308bb3 | access-date=22 January 2020}} It is intended for once-daily oral administration.{{cite journal | vauthors=Kappos L, Bar-Or A, Cree B, Fox R, Giovannoni G, Gold R, Vermersch P, Lam E, Pohlmann H, Wallström E | title=Siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis: Design of the phase 3 EXPAND trial | journal=Multiple Sclerosis and Related Disorders | volume=3 | issue=6 | year=2014 | issn=2211-0348 | doi=10.1016/j.msard.2014.09.185 | page=752}}
In March 2019, it was approved in the United States to treat adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.{{cite press release | title=FDA approves new oral drug to treat multiple sclerosis | website=U.S. Food and Drug Administration (FDA) | date=26 March 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-drug-treat-multiple-sclerosis | archive-url=https://web.archive.org/web/20191127022957/https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-drug-treat-multiple-sclerosis | archive-date=27 November 2019 | url-status=live | access-date=24 November 2019}}{{PD-notice}}
Medical uses
Siponimod is indicated for the treatment of secondary progressive multiple sclerosis, which is the progressive neurological decline of multiple sclerosis that happens independent of acute relapses. In active secondary progressive multiple sclerosis, siponimod decreases the risk of disability and multiple sclerosis relapses.
Adverse effects
In clinical trials of siponimod, the most common adverse effects were headache, high blood pressure, and liver function test abnormalities.
Pharmacology
=Mechanism of action=
File:Cells-08-00024-g004-550.webp
Siponimod binds selectively to some of the sphingosine-1-phosphate receptor forms—including sphingosine-1-phosphate receptor 1—found on lymphocytes and other cell types.{{cite journal | vauthors = 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, Saltzman M, Rosenberg M, Wallström E | title = The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate | journal = British Journal of Pharmacology | volume = 167 | issue = 5 | pages = 1035–47 | date = November 2012 | pmid = 22646698 | pmc = 3485666 | doi = 10.1111/j.1476-5381.2012.02061.x }}
Siponimod may be very similar to fingolimod but preventing lymphopenia, one of its main side effects, by preventing egress of lymphocytes from lymph nodes. Siponimod may be more selective in the particular sphingosine-1-phosphate receptors (five in number) that it modulates.{{cite patent|country=WO|number=2008000419|title=S1P Receptor modulators for treating multiple sclerosis |inventor1-first=Peter C|inventor1-last=Hiestand |inventor2-first=Christian|inventor2-last=Schnell |assign=Novartis|pubdate=2008-01-03}} It is selective for the -1 and -5 SIP receptors.
History
In March 2019, siponimod was approved in the United States to treat adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.{{cite web | title=Drug Approval Package: Mayzent (siponimod) | website=U.S. Food and Drug Administration (FDA) | date=3 May 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000TOC.cfm | access-date=22 January 2020}} {{PD-notice}}
The efficacy of siponimod was shown in a clinical trial{{ClinicalTrialsGov|NCT01665144|Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)}} of 1,651 patients that compared siponimod to placebo in people with secondary progressive multiple sclerosis who had evidence of disability progression in the prior two years and no relapses in the three months prior to enrollment.{{cite web | title=Drug Trials Snapshots: Mayzent | website=U.S. Food and Drug Administration (FDA) | date=19 April 2019 | url=https://www.fda.gov/drugs/drug-safety-and-availability/drug-trials-snapshots-mayzent | archive-url=https://web.archive.org/web/20190928001701/https://www.fda.gov/drugs/drug-safety-and-availability/drug-trials-snapshots-mayzent | archive-date=28 September 2019 | url-status=live | access-date=24 November 2019 }}{{PD-notice}} The primary endpoint of the study was the time to three-month confirmed progression in disability. The trial was conducted at 294 centers in Asia, Australia, Canada, Europe, South America, and the United States.
The U.S. Food and Drug Administration (FDA) granted approval of Mayzent to Novartis.
Siponimod was approved for medical use in Australia in October 2019.
In January 2020, siponimod was approved in the European Union for the treatment of adults with secondary progressive multiple sclerosis with active disease evidenced by relapses or imaging features of inflammatory activity.{{cite press release |title=Novartis announces EU approval of Mayzent (siponimod) for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease |url=https://www.novartis.com/news/media-releases/novartis-announces-eu-approval-mayzent-siponimod-adult-patients-secondary-progressive-multiple-sclerosis-spms-active-disease |website=Novartis |access-date=23 January 2020 |date=20 January 2020}}{{cite web | title=Mayzent EPAR | website=European Medicines Agency (EMA) | date=12 November 2019 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/mayzent | access-date=3 May 2020}}
References
{{Reflist}}
{{Demyelinating diseases of CNS}}
{{Immunosuppressants}}
{{Sphingolipids}}
{{Lysophospholipid signaling}}
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Category:Drugs developed by Novartis
Category:Trifluoromethyl compounds