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rare pediatric disease and breakthrough therapy designations from the US FDA, although a previously submitted NDA was withdrawn in August 2021 pending the resubmission of additional data analyses.5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
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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Associated Conditions
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
ARetinoic acid receptor gamma
agonist
Humans
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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Toxicity

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.
DrugInteraction
AbametapirThe serum concentration of Palovarotene can be increased when it is combined with Abametapir.
AcitretinThe risk or severity of adverse effects can be increased when Acitretin is combined with Palovarotene.
AlitretinoinThe risk or severity of adverse effects can be increased when Alitretinoin is combined with Palovarotene.
AmiodaroneThe serum concentration of Palovarotene can be increased when it is combined with Amiodarone.
AmprenavirThe serum concentration of Palovarotene can be increased when it is combined with Amprenavir.
ApalutamideThe serum concentration of Palovarotene can be decreased when it is combined with Apalutamide.
AprepitantThe metabolism of Palovarotene can be decreased when combined with Aprepitant.
AtazanavirThe serum concentration of Palovarotene can be increased when it is combined with Atazanavir.
BerotralstatThe metabolism of Palovarotene can be decreased when combined with Berotralstat.
BexaroteneThe risk or severity of adverse effects can be increased when Bexarotene is combined with Palovarotene.
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Food Interactions
  • 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

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SohonosCapsule10 mgOralIpsen Biopharmaceuticals Canada Inc2022-06-20Not applicableCanada flag
SohonosCapsule1.5 mgOralIpsen Biopharmaceuticals Canada Inc2022-06-20Not applicableCanada flag
SohonosCapsule5 mgOralIpsen Biopharmaceuticals Canada Inc2022-06-20Not applicableCanada flag
SohonosCapsule1 mgOralIpsen Biopharmaceuticals Canada Inc2022-06-20Not applicableCanada flag
SohonosCapsule2.5 mgOralIpsen Biopharmaceuticals Canada Inc2022-06-20Not applicableCanada flag

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
  1. 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]
  2. 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]
  3. Kitoh H: Clinical Aspects and Current Therapeutic Approaches for FOP. Biomedicines. 2020 Sep 2;8(9). pii: biomedicines8090325. doi: 10.3390/biomedicines8090325. [Article]
  4. Health Canada Product Monograph: Sohonos (palovarotene) capsules for oral use [Link]
  5. Ipsen: Ipsen announces withdrawal of palovarotene NDA, confirming intention to re-submit following additional data analyses [Link]
  6. Ipsen Press Release: Health Canada approves Ipsen’s Sohonos (palovarotene capsules) as the first approved treatment for fibrodysplasia ossificans progressiva [Link]
ChemSpider
8470763
ChEMBL
CHEMBL2105648
ZINC
ZINC000038467831
Wikipedia
Palovarotene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
3RecruitingTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
2Active Not RecruitingTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
2CompletedTreatmentFibrodysplasia Ossificans Progressiva (FOP)2
2TerminatedTreatmentExostoses, Multiple Hereditary1
2TerminatedTreatmentFibrodysplasia Ossificans Progressiva (FOP)1
1CompletedTreatmentDry Eye Syndrome (DES)1
1CompletedTreatmentFibrodysplasia Ossificans Progressiva (FOP)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral1 mg
CapsuleOral1.5 mg
CapsuleOral10 mg
CapsuleOral2.5 mg
CapsuleOral5 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility0.04 μg/mLhttps://pdf.hres.ca/dpd_pm/00064435.PDF
Predicted Properties
PropertyValueSource
Water Solubility0.000344 mg/mLALOGPS
logP6.94ALOGPS
logP6.75ChemAxon
logS-6.1ALOGPS
pKa (Strongest Acidic)4.13ChemAxon
pKa (Strongest Basic)2.07ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area55.12 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity137.81 m3·mol-1ChemAxon
Polarizability47.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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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
  1. 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
  1. 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
  1. 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
  1. 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