Palovarotene

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, is an exceptionally rare genetic disorder.³ 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 but was eventually recognized as a potential novel therapy for patients with FOP.^1,2,3 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 (HO) in patients with FOP, representing the first global approval for any FOP therapy.^4,6 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rare pediatric disease and breakthrough therapy designations from the US FDA, although a previously submitted NDA was withdrawn in August 2021 pending the resubmission of additional data analyses.⁵ On August 16, 2023, palovarotene was also approved by the FDA for the management of HO associated with FOP.⁹

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Palovarotene (DB05467)

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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) by Health Canada and FDA.^4,7

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Associated Conditions

• Heterotopic Ossification (HO)

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

At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent.⁷

Palovarotene binds to retinoic acid receptor gamma (RARγ) with a 10-fold greater affinity compared to retinoic acid receptor alpha or beta. In animal models of Fibrodysplasia Ossificans Progressiva (BMP implant in WT mouse, Q207D mouse model, R206H mouse model), palovarotene decreased heterotopic ossification (HO) in a dose-dependent manner as well as inflammatory and fibroproliferative responses at the sites of injury. Additionally, palovarotene also outperformed corticosteroids in preventing HO, with a dexamethasone treatment of 4.4 mg/kg/day for 4 days demonstrating no clinical efficacy on heterotropic bone volume.⁸

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 signalling begins with the complexation of BMPR-II and BMPR-I, which initiates an intracellular signalling pathway mediated by phosphorylated SMAD proteins. The sustained and aberrant signalling caused by the gain-of-function mutation in ACVR1/ALK2 results in overactivation of the downstream SMAD1/5/8 signalling 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 signalling and subsequently inhibits the SMAD1/5/8 signalling 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	agonist	Humans

Absorption

Following oral administration of 20mg once daily in healthy adult subjects, the median T_max was 4.6 hours, the mean C_max 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 C_max, and a delay in T_max by approximately 2 hours when compared to its administration under fasting conditions.⁴

Volume of distribution

The mean (SD) apparent volume of distribution (Vd/F) is 237 (± 90.1) L following the administration of a single 20 mg dose with food.⁷

Protein binding

The protein binding of palovarotene is 97.9% to 99.6% in vitro.⁷

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

Palovarotene is contraindicated during pregnancy. Based on the findings in animal studies and class effects of retinoids, SOHONOS can cause fetal harm when administered during pregnancy. In animal reproduction studies, oral administration of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal malformations typical of retinoids (e.g., cleft palate, malformed skull bone, shortening of the long bones) at doses ≥0.25 mg/kg/day (less than the clinical exposure). There are no available human data on palovarotene use in pregnant women. If pregnancy occurs during treatment with palovarotene, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling.⁷

No clinical experience with an overdose of palovarotene has been reported. Palovarotene is a derivative of vitamin A. In case of accidental overdose, signs of hypervitaminosis A could appear, including severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. Any overdose should be treated with supportive care according to the signs and symptoms exhibited by the patient. If an overdose is suspected, patients should be treated with supportive care as clinically indicated.⁷

Long-term studies to assess the carcinogenic potential of palovarotene have not been conducted. Palovarotene and its metabolites were negative in the vitro bacterial reverse mutation (Ames) assay and an in vitro micronucleus assay in primary human lymphocyte. Palovarotene did not have any clastogenic effect in the in vivo mouse micronucleus study.⁷

Palovarotene effects on fertility and reproductive function were assessed in male and female rats. In a female rat fertility study, palovarotene was orally administered to females for 14 days prior to mating with drug naïve males and up to GD 7 at the dose levels of 0.3, 1, and 3 mg/kg/day. Palovarotene caused prolonged periods of diestrous and reduced ovulation rate, resulting in lower numbers of implantation sites and live embryos at 3 mg/kg/day, a dose associated with maternal toxicity.⁷

In a male rat fertility study, palovarotene was orally administered prior to mating, during mating, and up to scheduled euthanasia (approximately 11 weeks in total) at 0.3, 1, and 3 mg/kg/day. Palovarotene did not cause adverse effects on mating, fertility indices, conception rate, reproductive organ weights, or sperm parameters up to 1 mg/kg/day (less than the clinical exposure). Males did not tolerate 3 mg/kg/day, as it produced severe systemic toxicity including deaths, adverse skin and hair coat clinical signs, and substantially reduced body weight.⁷

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Palovarotene can be increased when it is combined with Abametapir.
Abemaciclib	The metabolism of Abemaciclib can be increased when combined with Palovarotene.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Palovarotene.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Palovarotene.
Acitretin	The risk or severity of adverse effects can be increased when Acitretin is combined with Palovarotene.
Albendazole	The metabolism of Albendazole can be increased when combined with Palovarotene.
Alectinib	The metabolism of Alectinib can be increased when combined with Palovarotene.
Alitretinoin	The risk or severity of adverse effects can be increased when Alitretinoin is combined with Palovarotene.
Alpelisib	The metabolism of Alpelisib can be increased when combined with Palovarotene.
Aminophylline	The metabolism of Aminophylline can be increased when 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.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Sohonos	Capsule	10 mg/1	Oral	Ipsen Biopharmaceuticals, Inc.	2023-08-16	Not applicable
Sohonos	Capsule	1.5 mg/1	Oral	Ipsen Biopharmaceuticals, Inc.	2023-08-16	Not applicable
Sohonos	Capsule	5 mg	Oral	Ipsen Biopharmaceuticals Canada Inc	2022-06-20	Not applicable
Sohonos	Capsule	5 mg/1	Oral	Ipsen Biopharmaceuticals, Inc.	2023-08-16	Not applicable
Sohonos	Capsule	1 mg	Oral	Ipsen Biopharmaceuticals Canada Inc	2022-06-20	Not applicable
Sohonos	Capsule	1 mg/1	Oral	Ipsen Biopharmaceuticals, Inc.	2023-08-16	Not applicable
Sohonos	Capsule	2.5 mg	Oral	Ipsen Biopharmaceuticals Canada Inc	2022-06-20	Not applicable
Sohonos	Capsule	2.5 mg/1	Oral	Ipsen Biopharmaceuticals, Inc.	2023-08-16	Not applicable
Sohonos	Capsule	10 mg	Oral	Ipsen Biopharmaceuticals Canada Inc	2022-06-20	Not applicable
Sohonos	Capsule	1.5 mg	Oral	Ipsen Biopharmaceuticals Canada Inc	2022-06-20	Not applicable

Categories

ATC Codes

M09AX11 — Palovarotene

• M09AX — Other drugs for disorders of the musculo-skeletal system
• M09A — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M09 — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M — MUSCULO-SKELETAL SYSTEM

Drug Categories

• BCRP/ABCG2 Inhibitors
• Benzene Derivatives
• Benzylidene Compounds
• BSEP/ABCB11 Inhibitors
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Substrates
• Musculo-Skeletal System
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B3 inhibitors
• OCT1 inhibitors
• Retinoids

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 / Organic oxides / Hydrocarbon derivatives

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Substituents

Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzoic acid / Benzoic acid or derivatives / Benzoyl / Carboxylic acid / Carboxylic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Monocyclic benzene moiety / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Pyrazole / Stilbene / Styrene / Tetralin

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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]
7. FDA Approved Drug Products: SOHONOS (palovarotene) capsules, for oral use [Link]
8. PALOVAROTENE FOR THE PREVENTION OF HETEROTOPIC OSSIFICATION IN ADULTS AND CHILDREN (≥ 8 YEARS OF AGE FOR FEMALES AND ≥ 10 YEARS OF AGE FOR MALES) WITH FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP) [Link]
9. US FDA approves Ipsen’s SohonosTM (palovarotene) capsules, the first and only treatment for people with fibrodysplasia ossificans progressiva [Link]

External Links

ChemSpider

8470763

ChEBI

188559

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	Completed	Treatment	Fibrodysplasia Ossificans Progressiva (FOP)	1
2	Completed	Treatment	Fibrodysplasia Ossificans Progressiva (FOP)	3
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/1
Capsule	Oral	1 mg
Capsule	Oral	1.5 mg/1
Capsule	Oral	1.5 mg
Capsule	Oral	10 mg/1
Capsule	Oral	10 mg
Capsule	Oral	2.5 mg/1
Capsule	Oral	2.5 mg
Capsule	Oral	5 mg
Capsule	Oral	5 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11622959	No	2017-06-08	2037-06-08
US10864194	No	2017-06-08	2037-06-08
US10292954	No	2011-08-31	2031-08-31
US9789074	No	2011-08-31	2031-08-31
US9314439	No	2011-08-31	2031-08-31

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	0.04 μg/mL	L39990

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

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Details1. Retinoic acid receptor gamma

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]
2. FDA Approved Drug Products: SOHONOS (palovarotene) capsules, for oral use [Link]

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Drug created at January 31, 2022 20:47 / Updated at August 23, 2023 22:19