palovarotene   Click here for help

GtoPdb Ligand ID: 8276

Synonyms: CLM-001 | IPN-60120 | IPN60120 | R-667 | R667 | RG-667 | Ro-3300074 | Sohonos®
Approved drug
palovarotene is an approved drug (Canada (2022))
Compound class: Synthetic organic
Comment: Palovarotene is an orally bioavailable, retinoic acid receptor gamma (RAR-γ) agonist. This compound was originally investegated for its potential to repair alveolar damage in emphysema and COPD [1,7], but it failed to demonstrate significant clinical efficacy. Ipsen acquired palovarotene when it purchased Clementia Pharmaceuticals in 2019, and they repurposed palovarotene for potential to reduce heterotopic ossification in patients with fibrodysplasia ossificans progressiva (FOP) [5,8].
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 55.12
Molecular weight 414.23
XLogP 7.85
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
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Canonical SMILES OC(=O)c1ccc(cc1)C=Cc1cc2c(cc1Cn1cccn1)C(C)(C)CCC2(C)C
Isomeric SMILES OC(=O)c1ccc(cc1)/C=C/c1cc2c(cc1Cn1cccn1)C(C)(C)CCC2(C)C
InChI 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+
InChI Key YTFHCXIPDIHOIA-DHZHZOJOSA-N
No information available.
Summary of Clinical Use Click here for help
The EMA and FDA have granted palovarotene orphan drug designation for the rare disease fibrodysplasia ossificans progressiva (FOP). Phase 2 clinical trials for the treatment of preosseous flare-ups in FOP patients are underway (see NCT02190747 and NCT02279095).
FOP is a rare, severely disabling disease characterised by painful, recurrent episodes of soft tissue swelling (flare-ups) that result in abnormal bone formation (heterotopic ossification) in muscles, tendons, and ligaments.
In January 2022 Canada was the first jurisdiction to approve palovarotene [2]; it is indicated to reduce the formation of heterotopic ossification in adults and children with FOP.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
FOP is commonly driven by gain-of-function missense mutation in the ACVR1 (ALK2) gene that encodes the bone morphogenetic protein (BMP) type I receptor, ACVR1 (which is a receptor serine/threonine kinase that is essential for controlling bone and muscle growth/ development pre- and postnatally). Retinoids inhibit differentiation of mesenchymal tissue into cartilage and bone [9], and this may be the mechanism by which palovarotene suppresses ectopic bone formation (heterotopic ossification) within the soft tissues of FOP patients [6], i.e. reducing the impact of the overactive ACVR1/BMP/SMAD 1/5/8 pathway. Palovarotene also appears to inhibit NF-κB signalling in models of heterotopic ossification [4]. This action on NF-κB signalling may be synergistic with its action on ACVR1/BMP/SMAD signalling [3].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02190747 An Efficacy and Safety Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects Phase 2 Interventional Clementia Pharmaceuticals Inc.
NCT02279095 An Open-Label Extension Study of Palovarotene Treatment in FOP Phase 2 Interventional Clementia Pharmaceuticals Inc.
NCT03312634 An Efficacy and Safety Study of Palovarotene for the Treatment of Fibrodysplasia Ossificans Progressiva. Phase 3 Interventional Ipsen In early 2020 Ipsen announced that an interim analysis indicated that this clinical trial was unlikely to meet its primary endpoint (preventing new bone formation outside of the normal skeletal system), but that the drug did reduce the total annual mean amount of new bone formed.