Palovarotene

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Palovarotene

CAS 410528-02-8

4-[(E)-2-[5,5,8,8-tetramethyl-3-(pyrazol-1-ylmethyl)-6,7-dihydronaphthalen-2-yl]ethenyl]benzoic acid

FDA 8/16/2023

To reduce the volume of new heterotopic ossification in adults and pediatric patients (aged 8 years and older for females and 10 years and older for males) with fibrodysplasia ossificans progressiva

  • RG-667
  • RO-3300074

Palovarotene.png

Palovarotene, sold under the brand name Sohonos, is a medication used for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[4][5] It is a highly selective retinoic acid receptor gamma (RARγ) agonist.[6]

It was approved for medical use in Canada in June 2022,[4] and in the United States in August 2023.[5]

Medical uses

Palovarotene is indicated for the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.[4][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).[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 fibrodysplasia ossificans progressiva 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 fibrodysplasia ossificans progressiva mouse models.[11]

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[12][13] and orphan medicinal product designation by the European Medicines Agency (EMA) in 2014.[14][15][16][17] 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.[18] In December 2022, the FDA declined to approve palovarotene for the fibrodysplasia ossificans progressive without additional clinical trial data.[19] In January 2023, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for palovarotene for the treatment of fibrodysplasia ossificans progressiva.[20]

Research

Phase II

Clementia submitted a new drug application for palovarotene for the treatment of fibrodysplasia ossificans progressiva after observing positive phase II results.[21]

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.[22] Ipsen acquired Clementia in 2019.[23]

syn

J. Med. Chem. 2025, 68, 2147−2182

Palovarotene (Sohonos). Palovarotene (7) is a selective retinoic acid receptor γ (RARγ) agonist that was developed for the treatment of fibrodysplasia ossificans progressiva (FOP), a very rare autosomal dominant disorder, impacting ∼1 in2million individuals worldwide. 54,55 This orally bioavailable agonist reduces the incidence of heterotopic ossification in patients with FOP and was developed by the French biopharmaceutical company Ipsen. 56 The small Molecule agonist was originally developed by Roche for a different indication, and was later licensed to Clementia Pharmaceuticals, which was ultimately acquired by Ipsen. AlthoughapprovedbytheUSFDAinAugust2023,palovarotene was first approved by Health Canada in January 2022 for patients with FOP inadults andchildren aged 10 years and older for males and aged 8 years and older for females. With respect to pharmacodynamics, the agonist binds to RARγ and thus inhibits bone morphogenetic protein and Smad 1/5/8 signaling.57 This signaling inhibition permits normal muscle tissue repair and ultimately reduces the incidence of heterotopic ossification. A robust kilogram-scale synthesis of palovarotene has been disclosed in a patent by Roche and is depicted in Scheme 11.58 Starting from 2,5-dimethyl-2,5-hexanediol (7.1), the two tertiary alcohols were chlorinated with concentrated hydro chloric acid in toluene. Without isolation, the resulting

(54) Wentworth, K. L.; Masharani, U.; Hsiao, E. C. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br. J. Clin. Pharmacol. 2019, 85, 1180−1187. (55) Semler, O.; Rehberg, M.; Mehdiani, N.; Jackels, M.; Hoyer Kuhn, H. Current and emerging therapeutic options for the management of rare skeletal diseases. Paediatr. Drugs 2019, 21, 95− 106. (56) Hoy, S. M. Palovarotene: first approval. Drugs 2022, 82, 711− 716. (57) Pignolo, R. J.; Pacifici, M. Retinoid agonists in the targeting of heterotopic ossification. Cells 2021, 10, 3245. (58) Martin, M. Process for preparing retinoid compounds. US 20070232810, 2007.

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SYN

Desjardins, C., Grogan, D. R., Packman, J. N., & Harnett, M. (2017). Methods for treating heterotopic ossification (WO2017210792A1). World Intellectual Property Organization. https://patents.google.com/patent/WO2017210792A1

Chemical Communications (Cambridge, United Kingdom) (2019), 55(38), 5420-5422

WO2014105446

US20070232810

Patent

https://patents.google.com/patent/WO2002028810A3/en

WO2002028810

STR1

XAMPLE 12: PREPARATION OF 4-r(E)-2-(5,5.8.8-TETRAMETHYL-3-PYRAZOL-l-YLMETHYL -5.6.7.8-TETRAHYDRO-NAPHTHALEN-2-YL VINYLl BENZOIC ACID (6)

A mixture of 2.0 g (4.5 mmol) of (E)- methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 0.65 g (9.5 mmol) of pyrazole in 15 mL of N-methyl pyrrolidine was heated at 100°. After 2 hours, the reaction mixture was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with hexane and the product was filtered off, washed with hexane and dried to give 1.6 g (83%) of methyl-4-[2-(5,5,8,8-Tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+ = 429).
A mixture of 27.6 g (64.4 mmol) of methyl-4-[2-(5,5,8,8-tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 97 mL (193 mmol) of 2 N sodium hydroxide in 300 mL of ethyl alcohol was heated at reflux. After 1 hour, the reaction mixture was cooled to room temperature and diluted with 900 mL of water. The reaction mixture was acidified with 2 N HCl and the product was isolated by filtration, washed with water and pentane and dried to give 25.9 g (97%) of 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid (m.p. = 246.5-248 °C) 6.
Proceeding as described in the example above but substituting pyrazole with pyrrole, 4-methylpyrazole, 1,2,4-triazole, moφholine, 2-pyrrohdone, 3,5-dimethylpyrzole,
δ – valerolactone, 2-methyhmidazole and 4-methylimidzole gave 4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrrol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 7, 4-{(E)-2-[5,5,8,8-Tetramemyl-3-(4-methylpyrazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 20, 4-[(E)-2-(5,5,8,8-Tetxamethyl-3-[l,2,4]triazol-l-ylmethyl-5,6,7,8Jetrahydro-naphthalen-2-yl]vinyl}benzoic acid 39, 4-[(E)-2-(5,5,8,8-tetramethyl-3-moφhohn-4-ylmethyl- 5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 138, 4-[(E)-2-(5,5,8,8-tetramethyl-3- (2-oxo-pyrrohdin-l-yl-methyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 139, 4-{(E)-2-[5,5,8,8-Tetramet yl-3-(3,5-mmemylpyτazol-l-yhnethyl-5,6,7,8-tetrahydro-napn^ 2-yl)vinyl]benzoic acid 143, 4-[(E)-2-(5,5,8,8-tetramethyl-3-(2-oxo-piperidin-l-yl-methyl-5,6,7,8-tetrahydro-naρhthalen-2-yl)vinyl]benzoic acid 146 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(2-methyhmidazol-l-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 149and 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(4-methyhmidazol-l-ylmethyl-5,6,7,8-tettahydro-naphthalen-2-yl)vinyl]benzoic acid 150 respectively.

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Palovarotene
Clinical data
Trade names Sohonos
Other names R-667, RG-667
License data
Routes of
administration		 By mouth
Drug class Retinoic acid receptor gamma agonist
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C27H30N2O2
Molar mass 414.549 g·mol−1
3D model (JSmol)

References[

  1. ^ “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.
  2. ^ “Summary Basis of Decision – Sohonos”. Health Canada. 23 October 2014. Archived from the original on 6 August 2022. Retrieved 6 August 2022.
  3. ^ “Sohonos product information”. Health Canada. 20 June 2022. Archived from the original on 29 January 2023. Retrieved 28 January 2023.
  4. ^ Jump up to:a b c d “Sohonos Product Information”. Health Canada. 22 October 2009. Archived from the original on 18 August 2023. Retrieved 17 August 2023.
  5. ^ Jump up to:a b c d “Archived copy” (PDF). Archived (PDF) from the original on 18 August 2023. Retrieved 18 August 2023.
  6. ^ “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.
  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. ^ “Ipsen announces FDA Priority Review for NDA in patients with FOP”. Ipsen (Press release). 24 August 2022. Retrieved 28 January 2023.
  13. ^ “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.
  14. ^ “EU/3/14/1368”. European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
  15. ^ “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.
  16. ^ “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.
  17. ^ “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.
  18. ^ 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.
  19. ^ “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.
  20. ^ “Sohonos: Pending EC decision”. European Medicines Agency (EMA). 26 January 2023. Archived from the original on 27 January 2023. Retrieved 28 January 2023.
  21. ^ “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. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
  22. ^ “Ipsen Initiates Partial Clinical Hold for Palovarotene IND120181 and IND135403 Studies”. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
  23. ^ “Ipsen Completes Acquisition of Clementia Pharmaceuticals”. Archived from the original on 15 December 2019. Retrieved 15 December 2019.

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

 
 

/////////FDA 2023, APPROVALS 2023, Palovarotene, Sohonos, RG-667, RO-3300074

syn


European Journal of Medicinal Chemistry 265 (2024) 116124

Palovarotene (Sohonos) 
On February 17, 2022, the FDA granted approval to Palovarotene for the treatment of heterotopic ossification (HO) linked to fibrodysplasia ossificans progressiva (FOP) [64]. FOP, or myositis ossificans pro
gressiva (MOP), is an uncommon hereditary condition marked by atypical bone growth in regions beyond the usual skeletal structure. It is commonly accompanied by recurring episodes of discomfort and abrupt
swelling of soft tissues. This disorder causes restricted mobility and fusion of joints, leading to deformities, limited movement, and premature mortality [65]. Palovarotene is an orally available retinoic acid receptor γ (RARγ) agonist [66]. Palovarotene specifically attaches to RARγ and hinders the phosphorylation process of mothers against decapentaplegic homolog (SMAD)1/5/8. This action results in the suppression of the bone morphogenetic protein (BMP)/ALK2 downstream signaling pathway, leading to a decrease in ALK2/SMAD-dependent chondrogenesis and osteoblast differentiation. Consequently, the over all effect is a reduction in endochondral ossification [67].
The preparation of Palovarotene is shown in Scheme 18 [68].Starting with 2,5-dimethylhexane-2,5-diol (PALO-001), a nucleophilic substitution reaction with HCl, followed by AlClpromoted Friedel-Crafts alkylation with 1-bromo-2-methylbenzene (PALO-003), gave PALO-004. PALO-005 was obtained by substitution with CuCN.The cyano group of PALO-005 was reduced to aldehyde by diisobutylalumium hydride (DIBAL-H) to obtain PALO-006. PALO-006 was subjected to Wittig-Horner reaction with methyl 4-((dimethoxyphosphoryl)methyl)benzoate PALO-007 to obtain olefin PALO-008.
PALO-008 was brominated with N-bromosuccinimide (NBS) to obtain PALO-009. PALO-009 was nucleophilic substituted with 1H-pyrazole (PALO-010) to obtain PALO-011, which was hydrolyzed under alkaline conditions to obtain the final product Palovarotene.

[64] S.M. Hoy, Palovarotene: first approval, Drugs 82 (2022) 711–716.
[65] R.J. Pignolo, E.M. Shore, F.S. Kaplan, Fibrodysplasia ossificans progressiva:
diagnosis, management, and therapeutic horizons, Pediatr. Endocrinol. Rev. 2
(2013) 437–448.
[66] G.J. Pavey, A.T. Qureshi, A.M. Tomasino, C.L. Honnold, D.K. Bishop, S. Agarwal,
S. Loder, B. Levi, M. Pacifici, M. Iwamoto, B.K. Potter, T.A. Davis, J.A. Forsberg,
Targeted stimulation of retinoic acid receptor-γ mitigates the formation of
heterotopic ossification in an established blast-related traumatic injury model,
Bone 90 (2016) 159–167.
[67] H. Kitoh, Clinical aspects and current therapeutic approaches for FOP,
Biomedicines 8 (2020) 325.
[68] J.-M. Lapierre, D.M. Rotstein, E.B. Sjogren, Preparation of New Retinoids for the
Treatment of Emphysema, Cancer and Dermatological Disorders, 2002.
WO2002028810.

 

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