Palovarotene

Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP). It is a highly selective retinoic acid receptor gamma (RARγ) agonist.[4][5]

Palovarotene
Clinical data
Trade namesSohonos
Routes of
administration		By mouth
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
ChemSpider
UNII
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 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[6][7] and orphan medicinal product designation by the European Medicines Agency (EMA) in 2014.[8][9][10][11] 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.[12] In December 2022, the FDA declined to approve palovarotene for the fibrodysplasia ossificans progressive without additional clinical trial data.[13] In January 2023, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for Sohonos for the treatment of fibrodysplasia ossificans progressiva.[14]

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).[15] 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.[16]

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.[17][18] 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.[19]

Research

Phase II

Clementia submitted a new drug application for palovarotene for the treatment of fibrodysplasia ossificans progressiva after observing positive phase II results.[20]

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.[21] Ipsen acquired Clementia in 2019.[22]

References
  1. "Notice: Multiple Additions to the Prescription Drug List (PDL) [2022-01-24]". Health Canada. 24 January 2022. Retrieved 28 May 2022.
  2. "Summary Basis of Decision - Sohonos". Health Canada. 23 October 2014. Retrieved 6 August 2022.
  3. "Sohonos product information". Health Canada. 20 June 2022. Retrieved 28 January 2023.
  4. "FOP Fact Sheets". www.ifopa.org. Archived from the original on 4 April 2016. Retrieved 11 April 2016.
  5. "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.
  6. "Ipsen announces FDA Priority Review for NDA in patients with FOP". Ipsen (Press release). 24 August 2022. Retrieved 28 January 2023.
  7. "Palovarotene Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 1 January 2013. Retrieved 28 January 2023.
  8. "EU/3/14/1368". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 January 2023.
  9. "Public summary of opinion on orphan designation. Palovarotene for the treatment of fibrodysplasia ossificans progressiva" (PDF). European Medicines Agency (EMA). Retrieved 11 April 2016.
  10. "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.
  11. "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.
  12. 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.
  13. "FDA Tells Ipsen It Won't Approve Palovarotene for FOP". Global Genes. 27 December 2022. Retrieved 28 January 2023.
  14. "Sohonos: Pending EC decision". European Medicines Agency (EMA). 26 January 2023. Retrieved 28 January 2023.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. "Clementia Announces Plan to Submit a New Drug Application for Palovarotene for the Treatment of FOP Based on Positive Phase 2 Results". 23 October 2018.
  21. "Ipsen Initiates Partial Clinical Hold for Palovarotene IND120181 and IND135403 Studies".
  22. "Ipsen Completes Acquisition of Clementia Pharmaceuticals".
  • "Palovarotene". Drug Information Portal. U.S. National Library of Medicine.


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