Ponesimod

Ponesimod
Names
Trade namesPonvory
Other namesACT-128800
IUPAC name
  • (2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
Clinical data
Main usesMultiple sclerosis (MS)[1]
Side effectsUpper respiratory tract infection, liver inflammation, high blood pressure[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
    Routes of
    use    		By mouth
    Typical dose20 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    Metabolism2 main metabolites
    Elimination half-life31–34 hrs[5]
    ExcretionFeces (57–80%, 26% unchanged), urine (10–18%)[6]
    Chemical and physical data
    FormulaC23H25ClN2O4S
    Molar mass460.97 g·mol−1
    3D model (JSmol)
    SMILES
    • CCC/N=C\1/N(C(=O)/C(=C/C2=CC(=C(C=C2)OC[C@@H](CO)O)Cl)/S1)C3=CC=CC=C3C
    InChI
    • InChI=1S/C23H25ClN2O4S/c1-3-10-25-23-26(19-7-5-4-6-15(19)2)22(29)21(31-23)12-16-8-9-20(18(24)11-16)30-14-17(28)13-27/h4-9,11-12,17,27-28H,3,10,13-14H2,1-2H3/b21-12-,25-23-/t17-/m1/s1
    • Key:LPAUOXUZGSBGDU-STDDISTJSA-N

    Ponesimod, sold under the brand name Ponvory, is a medication used to treat multiple sclerosis (MS).[1] Specifically it is used for the relapsing forms including clinically isolated syndrome, relapsing-remitting disease, and secondary progressive disease.[7][1] It is taken by mouth.[1]

    Common side effects include upper respiratory tract infection, liver inflammation, and high blood pressure.[1] Other side effects may include infection, slow heart rate, breathing problems, and skin cancer.[1] Use during pregnancy may harm the baby.[1] It is a [[sphingosine 1-phosphate receptor modulator which decreases the activity of T and B cells.[1][7]

    Ponesimod was approved for medical use in the United States and Europe in 2021.[1][7] In the United Kingdom 4 weeks of treatment costs the NHS about £1100 as of 2022.[8] In the United States this amount costs about 7,900 USD.[9]

    Medical uses

    During two years of treatment it decreases the number of flairs to 0.2 compared to 0.3 with teriflunomide.[7]

    Dosage

    It is generally started at 2 mg per day and increased to 10 mg per day over two weeks.[7] The typical long term dose is 20 mg once per day.[1]

    Side effects

    Common side effects are temporary bradycardia (slow heartbeat), usually at the beginning of the treatment, dyspnoea (breathing difficulties), and increased liver enzymes (without symptoms). No significant increase of infections was observed under ponesimod therapy.[10] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.[11]

    Mechanism of action

    Like fingolimod, which is already approved for the treatment of MS, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.[10] Ponesimod is selective for subtype 1 of this receptor, S1P1.[12]

    Society and culture

    On 25 March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Ponvory, intended for the treatment of active relapsing forms of multiple sclerosis.[13] The applicant for this medicinal product is Janssen-Cilag International N.V.[13] Ponesimod was approved for medical use in the European Union in May 2021.[4]

    Research

    In a 2009–2011 Phase II clinical trial including 464 MS patients, ponesimod treatment resulted in fewer new active brain lesions than placebo, measured during the course of 24 weeks.[10][14]

    In a 2010–2012 Phase II clinical trial including 326 patients with psoriasis, 46 or 48% of patients (depending on dosage) had a reduction of at least 75% Psoriasis Area and Severity Index (PASI) score compared to placebo in 16 weeks.[10][15] The approval is already applied for in 2020.[16]

    In a 2015–2019 Phase III randomised, double-blind clinical trial of 1133 adult patients with relapsing MS, those under ponesimod treatment showed a 30% reduction in annual relapse rate and a significantly reduced number of new inflammatory lesions on brain MRI by 56% compared to those taking teriflunomide.[17]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Ponvory- ponesimod tablet, film coated Ponvory- ponesimod kit". DailyMed. Archived from the original on 21 January 2022. Retrieved 31 March 2021.
    2. 1 2 "Ponvory APMDS". Therapeutic Goods Administration (TGA). 24 March 2022. Retrieved 4 April 2022.{{cite web}}: CS1 maint: url-status (link)
    3. ↑ "Summary Basis of Decision (SBD) for Ponvory". Health Canada. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
    4. 1 2 "Ponvory EPAR". European Medicines Agency (EMA). 24 March 2021. Archived from the original on 19 March 2022. Retrieved 18 December 2021.
    5. ↑ Brossard P, Scherz M, Halabi A, Maatouk H, Krause A, Dingemanse J (February 2014). "Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: favorable impact of dose up-titration". Journal of Clinical Pharmacology. 54 (2): 179–88. doi:10.1002/jcph.244. PMID 24408162. S2CID 38041837.
    6. ↑ Reyes M, Hoch M, Brossard P, Wagner-Redeker W, Miraval T, Dingemanse J (February 2015). "Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 45 (2): 139–49. doi:10.3109/00498254.2014.955832. PMID 25188442. S2CID 23905158.
    7. 1 2 3 4 5 "European Medicines Agency Approval of Ponesimod". Archived from the original on 2021-08-04. Retrieved 2021-08-04.
    8. ↑ "Ponesimod". SPS - Specialist Pharmacy Service. 12 January 2016. Archived from the original on 20 January 2022. Retrieved 31 October 2022.
    9. ↑ "Ponvory". Archived from the original on 31 October 2022. Retrieved 31 October 2022.
    10. 1 2 3 4 Spreitzer H (29 September 2014). "Neue Wirkstoffe – Ponesimod". Österreichische Apothekerzeitung (in German) (20/2014): 42.{{cite journal}}: CS1 maint: unrecognized language (link)
    11. ↑ Hoch M, Darpo B, Brossard P, Zhou M, Stoltz R, Dingemanse J (May 2015). "Effect of ponesimod, a selective S1P1 receptor modulator, on the QT interval in healthy individuals". Basic & Clinical Pharmacology & Toxicology. 116 (5): 429–37. doi:10.1111/bcpt.12336. PMID 25287214.
    12. ↑ "Ponesimod". Actelion. Archived from the original on 3 December 2011. Retrieved 31 October 2014.
    13. 1 2 "Ponvory: Pending EC decision". European Medicines Agency (EMA). 25 March 2021. Archived from the original on 26 March 2021. Retrieved 27 March 2021.
    14. ↑ Olsson T, Boster A, Fernández Ó, Freedman MS, Pozzilli C, Bach D, et al. (November 2014). "Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial". Journal of Neurology, Neurosurgery, and Psychiatry. 85 (11): 1198–208. doi:10.1136/jnnp-2013-307282. PMC 4215282. PMID 24659797.
    15. ↑ Vaclavkova A, Chimenti S, Arenberger P, Holló P, Sator PG, Burcklen M, et al. (December 2014). "Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial". Lancet. 384 (9959): 2036–45. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208. S2CID 20452934.
    16. ↑ "Ozanimod bei schubförmiger MS zugelassen". Multiple Sklerose News – AMSEL (in Deutsch). 2020-07-06. Archived from the original on 2020-10-26. Retrieved 2020-10-03.
    17. ↑ "Europe Approves Ponvory Ponesimod for Multiple Sclerosis". Archived from the original on 2021-08-04. Retrieved 2021-08-04.
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