Ponesimod

Ponesimod, sold under the brand name Ponvory, is a medication for the treatment of multiple sclerosis.^[4][9] It is a sphingosine-1-phosphate receptor modulator.^[4]

Ponesimod

Clinical data
Trade names	Ponvory
Other names	ACT-128800
AHFS/Drugs.com	Micromedex Detailed Consumer Information
License data	US DailyMed: Ponesimod
Pregnancy category	AU: D[1][2]
Routes of administration	By mouth
ATC code	L04AE04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only[3] US: ℞-only[4] EU: Rx-only[5][6]
Pharmacokinetic data
Metabolism	2 main metabolites
Elimination half-life	31–34 hrs[7]
Excretion	Feces (57–80%, 26% unchanged), urine (10–18%)[8]
Identifiers
IUPAC name (2Z,5Z)-5-{3-Chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one
CAS Number	854107-55-4
PubChem CID	11363176
DrugBank	DB12016
ChemSpider	9538103
UNII	5G7AKV2MKP
KEGG	D11215
ChEMBL	ChEMBL1096146
CompTox Dashboard (EPA)	DTXSID50234631
Chemical and physical data
Formula	C23H25ClN2O4S
Molar mass	460.97 g·mol−1
3D model (JSmol)	Interactive image
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

The most common side effects include upper respiratory tract infection, hepatic transaminase elevation, and hypertension.^[4][5][9]

Ponesimod was approved for medical use in the United States in March 2021,^[4][9] and in the European Union in June 2021.^[10]

Medical uses

Ponesimod is indicated for the treatment of relapsing forms of multiple sclerosis including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.^[4][5]

Adverse effects

Common adverse effects in studies were 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.^[11] QT prolongation is detectable but was considered to be too low to be of clinical importance in a study.^[12]

Mechanism of action

Like fingolimod, which is already approved for the treatment of multiple sclerosis, ponesimod blocks the sphingosine-1-phosphate receptor. This mechanism prevents lymphocytes (a type of white blood cells) from leaving lymph nodes.^[11] Ponesimod is selective for subtype 1 of this receptor, S1P₁.^[13]

History

Clinical trials

In a 2009–2011 Phase II clinical trial including 464 multiple sclerosis patients, ponesimod treatment resulted in fewer new active brain lesions than placebo, measured during the course of 24 weeks.^[11][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.^[11][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 multiple sclerosis, 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]

In October 2020, Janseen-Cilag International NV submitted an application for the modification of agreed pediatric investigation plan (PIP) to European Medicines Agency (including deferral and waiver criteria). This application was launched for the amendments of proposed changes against the European Medicines Agency’s decisions issued in November 2012 and April 2018. The approved procedure has already started in December 2022. To evaluate pharmacodynamics and pharmacokinetics efficacy of ponesimod in pediatric patients with relapsing-remitting multiple sclerosis (RRMS); a multicenter, randomized, double blind clinical study of duration of 108 weeks treatment for age group 10 to less than 18 years, is in progress. The clinical trial will end in November 2027.^[18][19]

Society and culture

Legal status

In 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.^[20] The applicant for this medicinal product is Janssen-Cilag International N.V.^[20] Ponesimod was approved for medical use in the European Union in May 2021.^[5]

References

1. "Ponvory APMDS". Therapeutic Goods Administration (TGA). 24 March 2022. Retrieved 4 April 2022.
2. "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Retrieved 2 January 2023.
3. "Summary Basis of Decision (SBD) for Ponvory". Health Canada. 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
4. "Ponvory- ponesimod tablet, film coated Ponvory- ponesimod kit". DailyMed. Archived from the original on 21 January 2022. Retrieved 31 March 2021.
5. "Ponvory EPAR". European Medicines Agency (EMA). 24 March 2021. Archived from the original on 19 March 2022. Retrieved 18 December 2021.
6. "Ponvory Product information". Union Register of medicinal products. Retrieved 3 March 2023.
7. 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): 179–188. doi:10.1002/jcph.244. PMID 24408162. S2CID 38041837.
8. 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): 139–149. doi:10.3109/00498254.2014.955832. PMID 25188442. S2CID 23905158.
9. "Janssen Announces U.S. FDA Approval of Ponvory (ponesimod), an Oral Treatment for Adults with Relapsing Multiple Sclerosis Proven Superior to Aubagio (teriflunomide) in Reducing Annual Relapses and Brain Lesions" (Press release). Janssen. 19 March 2021. Archived from the original on 19 March 2021. Retrieved 19 March 2021 – via PR Newswire.
10. "European Medicines Agency Approval of Ponesimod". 24 March 2021. Archived from the original on 4 August 2021. Retrieved 4 August 2021.
11. Spreitzer H (29 September 2014). "Neue Wirkstoffe – Ponesimod". Österreichische Apothekerzeitung (in German) (20/2014): 42.
12. 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): 429–437. doi:10.1111/bcpt.12336. PMID 25287214. S2CID 10426898.
13. "Ponesimod". Actelion. Archived from the original on 3 December 2011. Retrieved 31 October 2014.
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): 1198–1208. 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): 2036–2045. doi:10.1016/S0140-6736(14)60803-5. PMID 25127208. S2CID 20452934.
16. "Ozanimod bei schubförmiger MS zugelassen". Multiple Sklerose News – AMSEL (in German). 6 July 2020. Archived from the original on 26 October 2020. Retrieved 3 October 2020.
17. "Europe Approves Ponvory Ponesimod for Multiple Sclerosis". Archived from the original on 4 August 2021. Retrieved 4 August 2021.
18. EMA (17 September 2018). "EMEA-000798-PIP01-09-M03". European Medicines Agency. Retrieved 12 June 2023.
19. Rose K, Müller T (September 2016). "Children with multiple sclerosis should not become therapeutic hostages". Therapeutic Advances in Neurological Disorders. 9 (5): 389–395. doi:10.1177/1756285616656592. PMC 4994785. PMID 27582894.
20. "Ponvory: Pending EC decision". European Medicines Agency (EMA). 25 March 2021. Archived from the original on 26 March 2021. Retrieved 27 March 2021.