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Palovarotene | CAS No: 410528-02-8 | GMP-certified suppliers

A medication that reduces heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva, supporting management of this rare genetic musculoskeletal disorder.

Therapeutic categories

BCRP/ABCG2 InhibitorsBenzene DerivativesBenzylidene CompoundsBSEP/ABCB11 InhibitorsCytochrome P-450 CYP2B6 InducersCytochrome P-450 CYP2B6 Inducers (strength unknown)

Generic name

Palovarotene

Molecule type

small molecule

CAS number

410528-02-8

DrugBank ID

DB05467

Approval status

Approved drug, Investigational drug

ATC code

M09AX11

Primary indications

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

Product Snapshot

Palovarotene is an oral small molecule available in capsule formulation
It is primarily used to reduce heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva (FOP)
The product is approved in Canada and the US, with regulatory authorization from Health Canada and the FDA

Clinical Overview

Palovarotene (CAS Number 410528-02-8) is a selective retinoic acid receptor gamma (RARγ) agonist indicated for the reduction of heterotopic ossification (HO) formation in patients with Fibrodysplasia Ossificans Progressiva (FOP). FOP is a rare genetic disorder with a global prevalence estimated at one in two million. It is characterized by progressive heterotopic ossification, wherein connective tissues such as skeletal muscle, ligaments, and tendons are pathologically replaced by bone during flare-ups or following injury. This process results from a gain-of-function mutation in the ACVR1/ALK2 gene, leading to aberrant activation of bone morphogenetic protein (BMP) signaling and ectopic chondrogenesis and osteogenesis.

Palovarotene’s mechanism of action involves high-affinity binding to RARγ, a receptor predominantly expressed on chondrogenic cells. Activation of RARγ by palovarotene exerts transcriptional repression that downregulates BMP-induced SMAD1/5/8 signaling, thereby inhibiting inappropriate cartilage and bone formation. In preclinical models, palovarotene dose-dependently reduced heterotopic ossification and associated inflammatory responses. Clinically, it is administered orally once daily, with dosage adjustments permitted for acute flare management.

Pharmacokinetic data indicate oral bioavailability and a metabolic profile involving cytochrome P-450 enzymes, including CYP3A4 and CYP2C19 substrates and inducers. Palovarotene exhibits no clinically significant QT prolongation at doses up to 2.5 times the recommended maximum. Safety considerations include teratogenicity consistent with retinoids; the drug is contraindicated in pregnancy and requires effective contraception and pregnancy testing in individuals of childbearing potential. In pediatric patients, monitoring of physeal growth plates is mandated due to the risk of premature closure.

Palovarotene received regulatory approval in Canada in January 2022 and in the United States in August 2023 for the management of HO in FOP patients aged 8 years or older (females) and 10 years or older (males). Its approval marks the first authorized treatment specifically for FOP globally.

When sourcing palovarotene API, stringent quality control is essential given the compound’s potent biological activity and safety profile. Suppliers should ensure compliance with pharmacopeial standards, maintain batch consistency, and provide comprehensive analytical documentation, including impurity profiles and stability data. Due to the rarity of FOP and the specialized nature of palovarotene therapy, reliable supply chain management is critical for uninterrupted clinical use.

Identification & chemistry

Generic name	Palovarotene
Molecule type	Small molecule
CAS	410528-02-8
UNII	28K6I5M16G
DrugBank ID	DB05467

Pharmacology

Summary	Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ) that modulates transcriptional activity in chondrogenic cells to reduce abnormal bone morphogenetic protein (BMP) signalling. By inhibiting the downstream SMAD1/5/8 pathway, palovarotene suppresses aberrant chondrogenesis and heterotopic ossification associated with gain-of-function mutations in the ACVR1/ALK2 gene in Fibrodysplasia Ossificans Progressiva (FOP). Its pharmacodynamic profile includes the reduction of ectopic bone formation and fibroproliferative responses at injury sites.
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). 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. 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. 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.
Pharmacodynamics	Palovarotene exerts its pharmacologic effects by inhibiting the pathway(s) responsible for heterotopic ossification in patients with FOP. 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. 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). 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. At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent. 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.

Targets

Target	Organism	Actions
Retinoic acid receptor gamma	Humans	agonist

ADME / PK

Absorption	Following oral administration of 20mg once daily in healthy adult subjects, the median T<sub>max</sub> was 4.6 hours, the mean C<sub>max</sub> was 140 ng/mL, and the mean AUC<sub>(0-τ)</sub> was 942 ng*hr/mL. At steady-state, the mean trough concentration of palovarotene was 3.5 ng/mL. 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<sub>max</sub>, and a delay in T<sub>max</sub> by approximately 2 hours when compared to its administration under fasting conditions.
Half-life	The mean elimination half-life of palovarotene at steady-state is 8.7 hours.
Protein binding	The protein binding of palovarotene is 97.9% to 99.6% in vitro.
Metabolism	Palovarotene undergoes extensive metabolism by CYP3A4 and, to a lesser extent, CYP2C8 and CYP2C19. Five metabolites have been observed in plasma: M1 (6,7-dihydroxy), M2 (6-hydroxy), M3 (7-hydroxy), M4a (6-oxo), and M4b (7-oxo). 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. 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.
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.
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.
Clearance	The apparent total body clearance of palovarotene is approximately 19.9 L/h.

Formulation & handling

Palovarotene is a lipophilic small molecule intended for oral administration in capsule form due to low water solubility.
Co-administration with food enhances oral absorption, while grapefruit and St. John's Wort should be avoided due to CYP3A4 interactions affecting metabolism.
Formulation considerations should focus on stabilizing the solid form and optimizing bioavailability given its high LogP and sensitivity to metabolic enzyme modulation.

Regulatory status

Lifecycle	The API is currently under patent protection in the United States through 2031 and 2037, with marketed products available in the US and Canada. The market remains in a proprietary phase with generics expected to enter post-patent expiry.

Markets	Canada, US

Supply Chain

Supply chain summary	Palovarotene is currently supplied by a limited number of originator companies with branded products primarily marketed in the US and Canada under the name Sohonos. Patent protection for these products extends through at least 2031, with key US patents expiring between 2031 and 2037, indicating that generic competition is not imminent. The manufacturing and supply landscape is therefore characterized by established branded exclusivity within North American markets.

Supply chain summary

Palovarotene is currently supplied by a limited number of originator companies with branded products primarily marketed in the US and Canada under the name Sohonos. Patent protection for these products extends through at least 2031, with key US patents expiring between 2031 and 2037, indicating that generic competition is not imminent. The manufacturing and supply landscape is therefore characterized by established branded exclusivity within North American markets.

Safety

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. 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. 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. 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. 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.

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. 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. 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. 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. 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.

High Level Warnings:

Palovarotene is contraindicated in pregnancy due to teratogenic effects observed in animal studies, including fetal malformations at doses below clinical exposure levels
No clinical data on overdose exist
However, palovarotene may induce symptoms consistent with hypervitaminosis A, necessitating supportive care upon suspected overdose

Palovarotene is a type of Antimetabolites

Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.

One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.

Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.

Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.

In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.