Identification
- Summary
Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ) used to reduce heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva (FOP).
- Generic Name
- Palovarotene
- DrugBank Accession Number
- DB05467
- Background
Fibrodysplasia Ossificans Progressiva (FOP), with an estimated worldwide prevalence of one in 2 million individuals,3 is an exceptionally rare genetic disorder. FOP is caused by a gain-of-function mutation in the ACVR1/ALK2 gene which results in progressive heterotopic ossification, a process wherein connective tissues (e.g. skeletal muscle, ligaments, tendons) are replaced with bone.3 The ossification occurring as a result of FOP is insidious and cumulative, and is provoked during flare-ups or in response to injury. Treatment options for patients with FOP are extremely limited, although there has been substantial recent interest in novel treatments for this disease.3
Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ) belonging to a class of medications known as retinoids, similar in mechanism to drugs like tazarotene or trifarotene, which are derivatives of vitamin A. It first garnered interest as a potential treatment for emphysema,1,2 but was eventually recognized as a potential novel therapy for patients with FOP.3 Agonists for retinoic acid receptors have been shown to inhibit chondrogenesis of heterotopic ossification in a transgenic mice model of FOP, with selective RARγ agonists (e.g. palovarotene) demonstrating the greatest efficacy.3
Palovarotene was approved for use in Canada in January 2022 for the management of heterotopic ossification in patients with FOP,4 representing the first global approval for any FOP therapy.6 It has been granted rare pediatric disease and breakthrough therapy designations from the US FDA, although a previously submitted NDA was withdrawn in August 2021 pending the resubmission of additional data analyses.5
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Palovarotene (DB05467)
- Weight
- Average: 414.549
Monoisotopic: 414.230728214 - Chemical Formula
- C27H30N2O2
- Synonyms
- Palovarotene
- External IDs
- R-667
- R667
- RG-667
- RO3300074
Pharmacology
- Indication
Palovarotene is indicated in Canada to reduce the formation of heterotopic ossification in adults and children (≥8 years old for females and ≥10 years old for males) with Fibrodysplasia Ossificans Progressiva (FOP).4
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Palovarotene exerts its pharmacologic effects by inhibiting the pathway(s) responsible for heterotopic ossification in patients with FOP.4 It is orally bioavailable and can be administered once daily, with allowances for short-term increases in dosage in the event of a flare-up.4
As with other retinoids, palovarotene can cause birth defects, and it should not be used by patients who are, or intend to become, pregnant. Palovarotene is contraindicated in patients of childbearing potential unless a number of pregnancy prevention strategies are met (e.g. effective contraception, regular pregnancy testing).4
Palovarotene may also cause a premature physeal closure in growing children. Physeal growth plates should be monitored every 3 months throughout therapy, or more frequently if evidence of adverse effects on growth are observed.4
- Mechanism of action
The pathogenesis of FOP is driven by a gain-of-function mutation in the ACVR1/ALK2 gene encoding activin A receptor type 1 (ACVR1)/activin-like kinase 2 (ALK2), a bone morphogenetic protein type 1 receptor (BMPR-I).3 BMP signaling begins with the complexation of BMPR-II and BMPR-I, which initiates an intracellular signaling pathway mediated by phosphorylated SMAD proteins. The sustained and aberrant signaling caused by the gain-of-function mutation in ACVR1/ALK2 results in an overactivation of the downstream SMAD1/5/8 signaling pathway, which in turn is thought to trigger the formation of ectopic chondrogenesis, osteogenesis, and joint fusion characteristic of FOP.3
Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ), a receptor expressed in chondrogenic cells and chondrocytes that acts as a transcriptional repressor.4 In binding to RARγ, palovarotene decreases BMP signaling and subsequently inhibits the SMAD1/5/8 signaling pathway. Palovarotene's interference with these pathways inhibits chondrogenesis and allows for normal muscle tissue repair to take place, ultimately reducing damage to muscle tissue.4
Target Actions Organism ARetinoic acid receptor gamma agonistHumans - Absorption
Following oral administration of 20mg once daily in healthy adult subjects, the median Tmax was 4.6 hours, the mean Cmax was 140 ng/mL, and the mean AUC(0-τ) was 942 ng*hr/mL.4 At steady-state, the mean trough concentration of palovarotene was 3.5 ng/mL.4
The administration of palovarotene with a high-fat, high-calorie meal resulted in an approximate 40% increase in AUC, an approximate 16% increase in Cmax, and a delay in Tmax by approximately 2 hours when compared to its administration under fasting conditions.4
- Volume of distribution
The mean apparent volume of distribution of palovarotene at steady-state is 319 L.4
- Protein binding
Palovarotene is 99% protein-bound in vitro, although the specific proteins to which it binds are unclear.4
- Metabolism
Palovarotene undergoes extensive metabolism by CYP3A4 and, to a lesser extent, CYP2C8 and CYP2C19.4 Five metabolites have been observed in plasma: M1 (6,7-dihydroxy), M2 (6-hydroxy), M3 (7-hydroxy), M4a (6-oxo), and M4b (7-oxo).4 Following oral administration of palovarotene, the parent drug and its four main metabolites (M2, M3, M4a, and M4b) account for approximately 40% of total plasma exposure.4
The metabolites of palovarotene are functionally inactive, with M3 and M4b carrying 1.7% and 4.2% of the activity of their parent compound, respectively.4
- Route of elimination
Following the administration of a 1mg radiolabeled dose of palovarotene in healthy subjects, approximately 97.1% of the administered radioactivity was recovered in the feces, with only 3.2% recovered in the urine.4
- Half-life
The mean elimination half-life of palovarotene at steady-state is 8.7 hours.4
- Clearance
The apparent total body clearance of palovarotene is approximately 19.9 L/h.4
- Adverse Effects
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Clinical data regarding overdosage with palovarotene is unavailable. A single incident in which a patient was administered a supratherapeutic dose of 50mg resulted in no apparent effects to the patient.4 If an overdosage is suspected, patients should be treated with supportive care as clinically indicated.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Palovarotene can be increased when it is combined with Abametapir. Acitretin The risk or severity of adverse effects can be increased when Acitretin is combined with Palovarotene. Alitretinoin The risk or severity of adverse effects can be increased when Alitretinoin is combined with Palovarotene. Amiodarone The serum concentration of Palovarotene can be increased when it is combined with Amiodarone. Amprenavir The serum concentration of Palovarotene can be increased when it is combined with Amprenavir. Apalutamide The serum concentration of Palovarotene can be decreased when it is combined with Apalutamide. Aprepitant The metabolism of Palovarotene can be decreased when combined with Aprepitant. Atazanavir The serum concentration of Palovarotene can be increased when it is combined with Atazanavir. Berotralstat The metabolism of Palovarotene can be decreased when combined with Berotralstat. Bexarotene The risk or severity of adverse effects can be increased when Bexarotene is combined with Palovarotene. 
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- Avoid grapefruit products. Grapefruit-containing products may inhibit the CYP3A4 activity responsible for palovarotene metabolism.
- Avoid St. John's Wort. The significant induction of CYP3A4 metabolism caused by St. John's wort may decrease the effectiveness of palovarotene.
- Take with food. Co-administration with food increases the oral absorption of palovarotene.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Sohonos Capsule 10 mg Oral Ipsen Biopharmaceuticals Canada Inc 2022-06-20 Not applicable Canada 
Sohonos Capsule 1.5 mg Oral Ipsen Biopharmaceuticals Canada Inc 2022-06-20 Not applicable Canada Sohonos Capsule 5 mg Oral Ipsen Biopharmaceuticals Canada Inc 2022-06-20 Not applicable Canada Sohonos Capsule 1 mg Oral Ipsen Biopharmaceuticals Canada Inc 2022-06-20 Not applicable Canada Sohonos Capsule 2.5 mg Oral Ipsen Biopharmaceuticals Canada Inc 2022-06-20 Not applicable Canada
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Stilbenes
- Sub Class
- Not Available
- Direct Parent
- Stilbenes
- Alternative Parents
- Tetralins / Benzoic acids / Styrenes / Benzoyl derivatives / Pyrazoles / Heteroaromatic compounds / Carboxylic acids / Azacyclic compounds / Organooxygen compounds / Organonitrogen compounds show 2 more
- Substituents
- Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzoic acid / Benzoic acid or derivatives / Benzoyl / Carboxylic acid / Carboxylic acid derivative / Heteroaromatic compound show 12 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 28K6I5M16G
- CAS number
- 410528-02-8
- InChI Key
- YTFHCXIPDIHOIA-DHZHZOJOSA-N
- 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+
- IUPAC Name
- 4-[(1E)-2-{5,5,8,8-tetramethyl-3-[(1H-pyrazol-1-yl)methyl]-5,6,7,8-tetrahydronaphthalen-2-yl}ethenyl]benzoic acid
- SMILES
- CC1(C)CCC(C)(C)C2=C1C=C(CN1C=CC=N1)C(\C=C\C1=CC=C(C=C1)C(O)=O)=C2
References
- Synthesis Reference
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
- General References
- Chiu YY, Roth MD, Kolis S, Rogovitz D, Davies B: Pharmacokinetics of a novel agent, R667, in patients with emphysema. Br J Clin Pharmacol. 2007 May;63(5):527-33. Epub 2007 Feb 23. [Article]
- Brennan B, Chiu Y, Berthelon L, Kolis S, Davies B: Effect of age and gender on the pharmacokinetics of R667, a novel agent for the treatment of emphysema, in healthy volunteers. J Pharm Pharm Sci. 2007;10(1):9-16. [Article]
- Kitoh H: Clinical Aspects and Current Therapeutic Approaches for FOP. Biomedicines. 2020 Sep 2;8(9). pii: biomedicines8090325. doi: 10.3390/biomedicines8090325. [Article]
- Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
- Ipsen: Ipsen announces withdrawal of palovarotene NDA, confirming intention to re-submit following additional data analyses [Link]
- Ipsen Press Release: Health Canada approves Ipsen’s Sohonos (palovarotene capsules) as the first approved treatment for fibrodysplasia ossificans progressiva [Link]
- External Links
- ChemSpider
- 8470763
- ChEMBL
- CHEMBL2105648
- ZINC
- ZINC000038467831
- Wikipedia
- Palovarotene
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Fibrodysplasia Ossificans Progressiva (FOP) 1 3 Recruiting Treatment Fibrodysplasia Ossificans Progressiva (FOP) 1 2 Active Not Recruiting Treatment Fibrodysplasia Ossificans Progressiva (FOP) 1 2 Completed Treatment Fibrodysplasia Ossificans Progressiva (FOP) 2 2 Terminated Treatment Exostoses, Multiple Hereditary 1 2 Terminated Treatment Fibrodysplasia Ossificans Progressiva (FOP) 1 1 Completed Treatment Dry Eye Syndrome (DES) 1 1 Completed Treatment Fibrodysplasia Ossificans Progressiva (FOP) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 1 mg Capsule Oral 1.5 mg Capsule Oral 10 mg Capsule Oral 2.5 mg Capsule Oral 5 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 0.04 μg/mL https://pdf.hres.ca/dpd_pm/00064435.PDF - Predicted Properties
Property Value Source Water Solubility 0.000344 mg/mL ALOGPS logP 6.94 ALOGPS logP 6.75 ChemAxon logS -6.1 ALOGPS pKa (Strongest Acidic) 4.13 ChemAxon pKa (Strongest Basic) 2.07 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 55.12 Å2 ChemAxon Rotatable Bond Count 5 ChemAxon Refractivity 137.81 m3·mol-1 ChemAxon Polarizability 47.96 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Zinc ion binding
- Specific Function
- Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
- Gene Name
- RARG
- Uniprot ID
- P13631
- Uniprot Name
- Retinoic acid receptor gamma
- Molecular Weight
- 50341.405 Da
References
- Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
Drug created at January 31, 2022 20:47 / Updated at February 03, 2022 06:25