Palovarotene

Palovarotene is a highly selective retinoic acid receptor gamma (RAR-γ) agonist that is under investigation as a potential treatment for fibrodysplasia ossificans progressiva (FOP), an ultra-rare and severely disabling genetic disease characterized by extra-skeletal bone formation (heterotopic ossification or HO) in muscle and soft tissues.[1]

Palovarotene
Clinical data
Routes of
administration		By mouth
ATC code
Identifiers
PubChem CID
ChemSpider
Chemical and physical data
FormulaC27H30N2O2
Molar mass414.549 g·mol−1
3D model (JSmol)

Palovarotene is being developed by Clementia Pharmaceuticals and was granted Fast Track and orphan drug designations by the United States Food and Drug Administration for the treatment of FOP and Orphan Medicinal Product Designation by the European Medicines Agency (EMA) in 2014.[2][3][4] Phase II clinical studies yielded positive results.[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).[7] 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.[8]

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 FOP containing a continuously active ACVR1/ALK2 receptor in a dose-dependent manner.[9][10] A 2016 study demonstrated that palovarotene also inhibited spontaneous heterotopic ossification, maintained limb mobility and functioning, and restored skeletal growth in FOP mouse models.[11]

Clinical trials

Phase 2

Clementia submitted a new drug application for palovarotene for the treatment of FOP after observing positive phase 2 results.[12]

Phase 3

On the 6th of December 2019, Ipsen issued a partial clinical hold for patients under the age of 14, due to reports of early fusion of growth plates. [13] Ipsen acquired Clementia in 2019.[14]

References
  1. "FOP Fact Sheets". www.ifopa.org. Retrieved 11 April 2016.
  2. "Public summary of opinion on orphan designation. Palovarotene for the treatment of fibrodysplasia ossificans progressiva" (PDF). www.ema.europa.eu. Committee for Orphan Medicinal Products. Retrieved 11 April 2016.
  3. "Clementia Pharmaceuticals Receives Fast Track Designation for Palovarotene for Treatment of Fibrodysplasia Ossificans Progressiva (FOP)". PRNewswise. 1 December 2014. Retrieved 11 April 2016.
  4. "Clementia Pharmaceuticals Receives EMA Orphan Medicinal Product Designation for Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva". PRNewswire. 21 November 2014. Retrieved 11 April 2016.
  5. "Clementia Pharmaceuticals Initiates Phase 2 Study of Palovarotene in Patients With Fibrodysplasia Ossificans Progressiva (FOP)". Marketwired. 14 July 2014. Retrieved 11 April 2016.
  6. Marriott N (October 16, 2016). "Success for Clementia's Phase II Fibrodysplasia Ossificans Progressiva trial". European Pharmaceutical Review.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. https://www.globenewswire.com/news-release/2018/10/23/1625817/0/en/Clementia-Announces-Plan-to-Submit-a-New-Drug-Application-for-Palovarotene-for-the-Treatment-of-FOP-Based-on-Positive-Phase-2-Results.html
  13. https://www.ipsen.com/press-releases/ipsen-initiates-partial-clinical-hold-for-palovarotene-ind120181-and-ind135403-studies/
  14. "Ipsen Completes Acquisition of Clementia Pharmaceuticals".
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