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Palovarotene

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Palovarotene
Clinical data
Trade namesSohonos
Other namesR-667, RG-667
AHFS/Drugs.comMonograph
MedlinePlusa623038
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth
Drug classRetinoic acid receptor gamma agonist
ATC code
Legal status
Legal status
Identifiers
  • 4-[(E)-2-[5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]ethenyl]benzoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H30N2O2
Molar mass414.549 g·mol−1
3D model (JSmol)
  • CC1(CCC(C2=C1C=C(C(=C2)/C=C/C3=CC=C(C=C3)C(=O)O)CN4C=CC=N4)(C)C)C
  • InChI=1S/C27H30N2O2/c1-26(2)12-13-27(3,4)24-17-22(18-29-15-5-14-28-29)21(16-23(24)26)11-8-19-6-9-20(10-7-19)25(30)31/h5-11,14-17H,12-13,18H2,1-4H3,(H,30,31)/b11-8+
  • Key:YTFHCXIPDIHOIA-DHZHZOJOSA-N

Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[6][7] It is a highly selective retinoic acid receptor gamma (RARγ) agonist.[8] It is taken by mouth.[7]

It was approved for medical use in Canada in June 2022,[6] and in the United States in August 2023.[7] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[9]

Medical uses

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Palovarotene is indicated for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[6][7]

History

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Palovarotene is a retinoic acid receptor gamma (RARγ) agonist licensed to Clementia Pharmaceuticals from Roche Pharmaceuticals. At Roche, palovarotene was evaluated in more than 800 individuals including healthy volunteers and patients with chronic obstructive pulmonary disease (COPD).[10] A one-year trial did not demonstrate a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.[11]

In 2011, animal studies demonstrated that RARγ agonists, including palovarotene, blocked new bone formation in both an injury-induced mouse model of heterotopic ossification (HO) and a genetically modified biological mouse model of fibrodysplasia ossificans progressiva containing a continuously active ACVR1/ALK2 receptor in a dose-dependent manner.[12][13] A 2016 study demonstrated that palovarotene also inhibited spontaneous heterotopic ossification, maintained limb mobility and functioning, and restored skeletal growth in fibrodysplasia ossificans progressiva mouse models.[14]

Society and culture

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Palovarotene is being developed by Ipsen Biopharmaceuticals and was granted priority review and orphan drug designations by the United States Food and Drug Administration (FDA) for the treatment of fibrodysplasia ossificans progressiva[15][16] and orphan medicinal product designation by the European Medicines Agency (EMA) in 2014.[17][18][19][20] Phase II clinical studies failed to show a significant change in heterotopic bone volume, the main outcome measure, but prompted further investigation in a phase III clinical trial.[21] In December 2022, the FDA declined to approve palovarotene for the fibrodysplasia ossificans progressiva without additional clinical trial data.[22] In January 2023, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for palovarotene for the treatment of fibrodysplasia ossificans progressiva.[23] In May 2023, the European Medicines Agency confirmed its recommendation to refuse marketing authorization for Sohonos.[24]

Research

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Phase II

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Clementia submitted a new drug application for palovarotene for the treatment of fibrodysplasia ossificans progressiva after observing positive phase II results.[25]

Phase III

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In December 2019, Ipsen issued a partial clinical hold for people under the age of 14, due to reports of early fusion of growth plates.[26] Ipsen acquired Clementia in 2019.[27]

References

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  1. ^ a b "Sohonos APMDS". Therapeutic Goods Administration (TGA). 11 December 2023. Archived from the original on 2 January 2024. Retrieved 7 March 2024.
  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  3. ^ "Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]". Health Canada. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022.
  4. ^ "Summary Basis of Decision - Sohonos". Health Canada. 23 October 2014. Archived from the original on 6 August 2022. Retrieved 6 August 2022.
  5. ^ "Sohonos product information". Health Canada. 20 June 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
  6. ^ a b c d "Sohonos Product Information". Health Canada. 22 October 2009. Archived from the original on 18 August 2023. Retrieved 17 August 2023.
  7. ^ a b c d e "Sohonos- palovarotene capsule". DailyMed. 24 August 2023. Retrieved 6 October 2023.
  8. ^ "Health Canada Approves Ipsen's Sohonos (palovarotene capsules) as the First Approved Treatment for Fibrodysplasia Ossificans Progressiva" (Press release). Ipsen. 24 January 2022. Archived from the original on 29 May 2022. Retrieved 28 May 2022 – via Business Wire.
  9. ^ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
  10. ^ Hind M, Stinchcombe S (November 2009). "Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema". Current Opinion in Investigational Drugs. 10 (11): 1243–50. PMID 19876792.
  11. ^ Stolk J, Stockley RA, Stoel BC, Cooper BG, Piitulainen E, Seersholm N, et al. (August 2012). "Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor". The European Respiratory Journal. 40 (2): 306–12. doi:10.1183/09031936.00161911. PMID 22282548.
  12. ^ Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, et al. (April 2011). "Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists". Nature Medicine. 17 (4): 454–60. doi:10.1038/nm.2334. PMC 3073031. PMID 21460849.
  13. ^ Kaplan FS, Shore EM (April 2011). "Derailing heterotopic ossification and RARing to go". Nature Medicine. 17 (4): 420–1. doi:10.1038/nm0411-420. PMC 4913781. PMID 21475232.
  14. ^ Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, et al. (September 2016). "Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1(R206H) Fibrodysplasia Ossificans Progressiva (FOP) Mutation". Journal of Bone and Mineral Research. 31 (9): 1666–75. doi:10.1002/jbmr.2820. PMC 4992469. PMID 26896819.
  15. ^ "Ipsen announces FDA Priority Review for NDA in patients with FOP". Ipsen (Press release). 24 August 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
  16. ^ "Palovarotene Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 1 January 2013. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
  17. ^ "EU/3/14/1368". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
  18. ^ "Public summary of opinion on orphan designation. Palovarotene for the treatment of fibrodysplasia ossificans progressiva" (PDF). European Medicines Agency (EMA). Archived (PDF) from the original on 22 April 2016. Retrieved 11 April 2016.
  19. ^ "Clementia Pharmaceuticals Receives Fast Track Designation for Palovarotene for Treatment of Fibrodysplasia Ossificans Progressiva (FOP)" (Press release). Clementia Pharmaceuticals. 1 December 2014. Archived from the original on 23 April 2016. Retrieved 11 April 2016 – via PR Newswire.
  20. ^ "Clementia Pharmaceuticals Receives EMA Orphan Medicinal Product Designation for Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva" (Press release). Clementia Pharmaceuticals. 21 November 2014. Archived from the original on 23 April 2016. Retrieved 11 April 2016 – via PR Newswire.
  21. ^ Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, et al. (October 2022). "Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial". Journal of Bone and Mineral Research. 37 (10): 1891–1902. doi:10.1002/jbmr.4655. PMC 9804935. PMID 35854638. S2CID 250697248.
  22. ^ "FDA Tells Ipsen It Won't Approve Palovarotene for FOP". Global Genes. 27 December 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
  23. ^ "Sohonos: Pending EC decision". European Medicines Agency (EMA). 26 January 2023. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
  24. ^ "Sohonos EPAR". European Medicines Agency. 27 July 2023. Archived from the original on 25 August 2023. Retrieved 25 August 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  25. ^ "Clementia Announces Plan to Submit a New Drug Application for Palovarotene for the Treatment of FOP Based on Positive Phase 2 Results" (Press release). 23 October 2018. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
  26. ^ "Ipsen Initiates Partial Clinical Hold for Palovarotene IND120181 and IND135403 Studies". Archived from the original on 15 December 2019. Retrieved 15 December 2019.
  27. ^ "Ipsen Completes Acquisition of Clementia Pharmaceuticals". Archived from the original on 15 December 2019. Retrieved 15 December 2019.
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Clinical trial number NCT03312634 for "An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva. (MOVE)" at ClinicalTrials.gov

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