Chemistry:Palovarotene

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Short description: Chemical compound
Palovarotene
Palovarotene2DACS.svg
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
FormulaC27H30N2O2
Molar mass414.549 g·mol−1
3D model (JSmol)

Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[5][6] It is a highly selective retinoic acid receptor gamma (RARγ) agonist.[7] It is taken by mouth.[6]

It was approved for medical use in Canada in June 2022,[5] and in the United States in August 2023.[6] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[8]

Medical uses

Palovarotene is indicated for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[5][6]

History

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).[9] 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.[10]

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.[11][12] 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.[13]

Society and culture

Legal status

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[14][15] and orphan medicinal product designation by the European Medicines Agency (EMA) in 2014.[16][17][18][19] 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.[20] In December 2022, the FDA declined to approve palovarotene for the fibrodysplasia ossificans progressive without additional clinical trial data.[21] In January 2023, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for palovarotene for the treatment of fibrodysplasia ossificans progressiva.[22] In May 2023, the European Medicines Agency confirmed its recommendation to refuse marketing authorization for Sohonos.[23]

Research

Phase II

Clementia submitted a new drug application for palovarotene for the treatment of fibrodysplasia ossificans progressiva after observing positive phase II results.[24]

Phase III

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.[25] Ipsen acquired Clementia in 2019.[26]

References

  1. ↑ 1.0 1.1 https://www.tga.gov.au/resources/auspmd/sohonos
  2. ↑ "Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24"]. 24 January 2022. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2022-01-24.html. 
  3. ↑ "Summary Basis of Decision - Sohonos". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00593&lang=en. 
  4. ↑ "Sohonos product information". 20 June 2022. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=101365. 
  5. ↑ 5.0 5.1 5.2 5.3 "Sohonos Product Information". 22 October 2009. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=101365. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Sohonos- palovarotene capsule". 24 August 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=67dce406-7cc4-4d66-92de-ad18b6df0625. 
  7. ↑ "Health Canada Approves Ipsen's Sohonos (palovarotene capsules) as the First Approved Treatment for Fibrodysplasia Ossificans Progressiva" (Press release). Ipsen. 24 January 2022. Retrieved 28 May 2022 – via Business Wire.
  8. ↑ (PDF) New Drug Therapy Approvals 2023 (Report). January 2024. https://www.fda.gov/media/175253/download. Retrieved 9 January 2024. 
  9. ↑ "Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema". Current Opinion in Investigational Drugs 10 (11): 1243–50. November 2009. PMID 19876792. 
  10. ↑ "Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor". The European Respiratory Journal 40 (2): 306–12. August 2012. doi:10.1183/09031936.00161911. PMID 22282548. 
  11. ↑ "Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists". Nature Medicine 17 (4): 454–60. April 2011. doi:10.1038/nm.2334. PMID 21460849. 
  12. ↑ "Derailing heterotopic ossification and RARing to go". Nature Medicine 17 (4): 420–1. April 2011. doi:10.1038/nm0411-420. PMID 21475232. 
  13. ↑ "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. September 2016. doi:10.1002/jbmr.2820. PMID 26896819. 
  14. ↑ "Ipsen announces FDA Priority Review for NDA in patients with FOP". Ipsen (Press release). 24 August 2022. Retrieved 28 January 2023.
  15. ↑ "Palovarotene Orphan Drug Designations and Approvals". 1 January 2013. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=438714. 
  16. ↑ "EU/3/14/1368". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-14-1368. 
  17. ↑ "Public summary of opinion on orphan designation. Palovarotene for the treatment of fibrodysplasia ossificans progressiva.". http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2015/01/WC500180398.pdf. 
  18. ↑ "Clementia Pharmaceuticals Receives Fast Track Designation for Palovarotene for Treatment of Fibrodysplasia Ossificans Progressiva (FOP)" (Press release). Clementia Pharmaceuticals. 1 December 2014. Retrieved 11 April 2016 – via PR Newswire.
  19. ↑ "Clementia Pharmaceuticals Receives EMA Orphan Medicinal Product Designation for Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva" (Press release). Clementia Pharmaceuticals. 21 November 2014. Retrieved 11 April 2016 – via PR Newswire.
  20. ↑ "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. October 2022. doi:10.1002/jbmr.4655. PMID 35854638. 
  21. ↑ "FDA Tells Ipsen It Won't Approve Palovarotene for FOP". 27 December 2022. https://globalgenes.org/2022/12/27/fda-tells-ipsen-it-wont-approve-palovarotene-for-fop/. 
  22. ↑ "Sohonos: Pending EC decision". 26 January 2023. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/sohonos. 
  23. ↑ "Sohonos EPAR". 27 July 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/sohonos.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  24. ↑ "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.
  25. ↑ "Ipsen Initiates Partial Clinical Hold for Palovarotene IND120181 and IND135403 Studies". https://www.ipsen.com/press-releases/ipsen-initiates-partial-clinical-hold-for-palovarotene-ind120181-and-ind135403-studies/. 
  26. ↑ "Ipsen Completes Acquisition of Clementia Pharmaceuticals". https://apnews.com/Business%20Wire/567afd38b3974e72879bca7862d64c03. 

External links

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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