Palovarotene

Palovarotene
Systematic (IUPAC) name
4-[(E)-2-[5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]ethenyl]benzoic acid
Clinical data
Routes of
administration		 Oral
Legal status
Legal status
  • Investigational
Identifiers
ATC code None
PubChem CID 10295295
ChemSpider 8470763
Chemical data
Formula C27H30N2O2
Molar mass 414.5393 g/mol

Palovarotene (R-667, RO-3300074) 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 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 are currently underway.[5]

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).[6] 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.[7]

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.[8][9] A 2016 study demonstrated that palovarotene also inhibited spontaneous heterotopic ossification, maintained limb mobility and functioning, and restored skeletal growth in FOP mouse models.[10]

Palovarotene is currently being investigated as a potential therapy for FOP, a disorder of heterotopic ossification, in humans.[11]


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. ↑ Hind, M; Stinchcombe, S (November 2009). "Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema". Current Opinion in Investigation Drugs 10 (11): 1243–1250. PMID 19876792.
  7. ↑ Stolk, J; Stockley, RA; Stoel, BC; Cooper, BG; Piitulainen, E; Seersholm, N; Chapman, KR; Burdon, JG; Decramer, M; Abboud, RT; Mannes, GP; Wouters, EF; Garrett, JE; Barros-Tizon, JC; Russi, EW; Lomas, DA; MacNee, WA; Rames, A (August 2012). "Randomised controlled trial for emphysema with a selective agonist of the c-type retinoic acid receptor". European Respiratory Journal 40 (2): 306–312. doi:10.1183/09031936.00161911. PMID 22282548.
  8. ↑ Shimono; et al. (2011). "Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-y agonists". Nature Medicine. Vol 17 (No.4): 454–460. doi:10.1038/nm.2334.
  9. ↑ Kaplan FS and Shore EM (2011). "Derailing heterotopic ossification and RARing to go". Nature Medicine. Vol 17 (No.4): 420. doi:10.1038/nm0411-420.
  10. ↑ Chakkalakal; et al. (2016). "Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation". J Bone Miner Res. doi:10.1002/jbmr.2820.
  11. ↑ Radke, James (1 December 2014). "Failed COPD Drug Being Tested for Fibrodysplasia Ossificans Progressiva". Rare Disease Report. Retrieved 11 April 2016.


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