Omaveloxolone

Identification

Summary

Omaveloxoloneis a semisynthetic triterpenoid used to treat Friedreich’s ataxia in adults and adolescents 16 years and older.

Brand Names

Skyclarys

Generic Name

Omaveloxolone

DrugBank Accession Number

DB12513

Background

Omaveloxolone (RTA-408) is a semisynthetic oleanane triterpenoid with antioxidant and anti-inflammatory properties.^2,4Omaveloxolone acts as an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that mitigates oxidative stress. In patients with Friedreich's ataxia, a genetic disease involving mitochondrial dysfunction, the Nrf2 pathway is impaired, and Nrf2 activity is lower. Therefore, the use of Nrf2 activators such as omaveloxolone represents a therapeutic advantage in this group of patients.¹In February 2023, omaveloxolone was approved by the FDA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.⁷The use of omaveloxolone for the treatment of conditions involving mitochondrial dysfunction and oxidative stress has also been evaluated.^2,6

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOL SDF 3D-SDF PDB SMILES InChI

Similar Structures

Structure for Omaveloxolone (DB12513)

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Weight

Average: 554.723
Monoisotopic: 554.331999611

Chemical Formula

C₃₃H₄₄F₂N₂O₃

Synonyms

• Omaveloxolone
• Propanamide, N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2,2-difluoro-

External IDs

• RTA 408
• RTA-408

Pharmacology

Indication

Omaveloxolone is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.⁷

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Associated Conditions

• Friedreich's Ataxia

Contraindications & Blackbox Warnings

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Pharmacodynamics

The MOXIe study showed that after 4 weeks of administration, the use of omaveloxolone led to robust dose‐dependent changes at 80 ‐300 mg/day.⁵. The effect of omaveloxolone on QTc interval has yet to be defined.⁷The use of omaveloxolone can lead to an elevation in hepatic transaminases (both aspartate transaminase and alanine transaminase) and an increase in B-type natriuretic peptide (BNP), a marker of cardiac function. It can also cause changes in cholesterol.⁷

Mechanism of action

The mechanism of action of omaveloxolone has not been fully elucidated; however, its therapeutic effect in patients with Friedreich's ataxia may be linked to its ability to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.⁷Nrf2 is a transcription factor that mitigates oxidative stress. In normal conditions, Nrf2 levels are regulated by Kelch-like ECH-associated protein 1 (KEAP1), which binds to Nrf2, prevents Nrf2 translocation to the nucleus, and degrades it by ubiquitination. In the presence of oxidative stress, the ubiquitination system is disrupted. Nrf2 accumulates and translocates to the nucleus, where it promotes the expression of genes against oxidative stress. In patients with Friedreich's ataxia, the Nrf2 signaling pathway is dysfunctional. In Friedreich's ataxia models, Nrf2 has a lower activity; therefore, Nrf2 activators such as omaveloxolone represent a therapeutic opportunity.¹A study has shown that omaveloxolone binds to KEAP1, inhibiting its interaction with Nrf2 and promoting the translocation of Nrf2 to the nucleus.³Aside from activating Nrf2, omaveloxolone also inhibits the NF-κB signalling pathway, promoting antioxidative, anti-inflammatory, and antiapoptotic mechanisms.^2,4

Target	Actions	Organism
UKelch-like ECH-associated protein 1	inhibitor	Humans

Absorption

Between 50 mg (0.33 times the recommended dosage) and 150 mg, the AUC of omaveloxolone increased in a dose-dependent and dose-proportional manner. However, at the same dose range, the C_maxincreased in a less than dose-proportional manner in healthy fasted subjects. The median time to achieve peak plasma concentration was 7 to 14 hours. Compared to fasted conditions, the AUC_0-infand C_maxof omaveloxolone were 350% and 15% higher with a high-fat meal (800 to 1000 calories, with 150, 250, and 500 to 600 calories coming from protein, carbohydrate, and fat, respectively).⁷

Volume of distribution

Omaveloxolone has an apparent volume of distribution of 7361 L.⁷

Protein binding

The protein binding of omaveloxolone is 97%.⁷

Metabolism

Omaveloxolone is mainly metabolized by CYP3A, although CYP2C8 and CYP2J2 play also a minor role.⁷

Route of elimination

Omaveloxolone is mainly excreted in feces. In healthy subjects given a single oral dose of radiolabeled omaveloxolone (150 mg), about 92% and 0.1% of the dose were recovered in feces and urine, respectively. Approximately 91% of the omaveloxolone found in feces was recovered within 96 hours after administration.⁷

Half-life

Omaveloxolone has a terminal half-life of 57 hours.⁷

Clearance

Omaveloxolone has an apparent plasma clearance of 109 L/hr.⁷

Adverse Effects

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Toxicity

Toxicity information regarding omaveloxolone is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as elevation in hepatic transaminases and B-Type natriuretic peptide (BNP), as well as lipid abnormalities.⁷Symptomatic and supportive measures are recommended.

The carcinogenicity of omaveloxolone has not been evaluated. In a bacterial reverse mutation (Ames) assay, omaveloxolone showed negative results, while a chromosomal aberration assay in human peripheral blood lymphocytes showed positive results. Rats given 0, 1, 3, and 10 mg/kg/day of oral omaveloxolone had a higher incidence of pre- and post-implantation loss and resorptions, leading to a decrease in viable embryos at the highest dose. The no-effect dose (3 mg/kg/day) of omaveloxolone for fertility and reproductive function adverse effects was equivalent to an AUC of approximately 2 times the recommended human dose(150 mg/day).⁷

Pathways

Not Available

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Interactions

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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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1,2-Benzodiazepine	The serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Omaveloxolone.
Abametapir	The serum concentration of Omaveloxolone can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Omaveloxolone.
Abiraterone	The serum concentration of Abiraterone can be decreased when it is combined with Omaveloxolone.
Acalabrutinib	The serum concentration of Acalabrutinib can be decreased when it is combined with Omaveloxolone.
Acenocoumarol	The serum concentration of Acenocoumarol can be decreased when it is combined with Omaveloxolone.
Acetaminophen	The serum concentration of Acetaminophen can be decreased when it is combined with Omaveloxolone.
Adagrasib	The serum concentration of Adagrasib can be decreased when it is combined with Omaveloxolone.
Albendazole	The serum concentration of Albendazole can be decreased when it is combined with Omaveloxolone.
Alectinib	The metabolism of Alectinib can be increased when combined with Omaveloxolone.

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Food Interactions

• Take on an empty stomach. Take omaveloxolone capsules on an empty stomach at least 1 hour before eating. Compared to fasting conditions, a high-fat meal increased the Cmax and AUC by approximately 350% and 15%, respectively.

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International/Other Brands

Skyclarys (Reata Pharmaceuticals)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Skyclarys	Capsule	50 mg/1	Oral	Reata Pharmaceuticals, Inc	2023-02-28	Not applicable

Categories

Drug Categories

• Anti-Inflammatory Agents
• Antioxidants
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (weak)
• 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 (weak)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Substrates
• OAT1/SLC22A6 inhibitors
• Oxidation-Reduction Agent
• Terpenes
• Triterpenes

Chemical TaxonomyProvided byClassyfire

Description

This compound belongs to the class of organic compounds known as cyclohexenones. These are compounds containing a cylohexenone moiety, which is a six-membered aliphatic ring that carries a ketone and has one endocyclic double bond.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbonyl compounds

Direct Parent

Cyclohexenones

Alternative Parents

Secondary carboxylic acid amides/Nitriles/Organofluorides/Organic oxides/Hydrocarbon derivatives/Alkyl fluorides

Substituents

Aliphatic homopolycyclic compound/Alkyl fluoride/Alkyl halide/Carbonitrile/Carboxamide group/Carboxylic acid derivative/Cyanide/Cyclohexenone/Hydrocarbon derivative/Nitrile

Molecular Framework

Aliphatic homopolycyclic compounds

External Descriptors

Not Available

Affected organisms

Not Available

Chemical Identifiers

UNII

G69Z98951Q

CAS number

1474034-05-3

InChI Key

RJCWBNBKOKFWNY-IDPLTSGASA-N

InChI

InChI=1S/C33H44F2N2O3/c1-27(2)11-13-33(37-26(40)32(8,34)35)14-12-31(7)24(20(33)17-27)21(38)15-23-29(5)16-19(18-36)25(39)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3,(H,37,40)/t20-,22-,24-,29-,30+,31+,33-/m0/s1

IUPAC Name

N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-4a-yl]-2,2-difluoropropanamide

SMILES

CC(F)(F)C(=O)N[C@]12CCC(C)(C)C[C@H]1[C@H]1C(=O)C=C3[C@@]4(C)C=C(C#N)C(=O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2

References

Synthesis Reference

Sheikh, AY et al. (2018). Bardoxolonmethyl-2,2-difluoropropionamide derivatives, polymorphe forms and procedures for use thereof. DK/EP 2989114 T3. Danish Patent and Trademark Office. Available at https://patentimages.storage.googleapis.com/51/87/43/97d0fb3e69ee73/DK2989114T3.pdf

General References

1. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J: Emerging therapies in Friedreich's Ataxia. Expert Rev Neurother. 2020 Dec;20(12):1215-1228. doi: 10.1080/14737175.2020.1821654. Epub 2020 Sep 21. [Article]
2. Jiang Z, Qi G, Lu W, Wang H, Li D, Chen W, Ding L, Yang X, Yuan H, Zeng Q: Omaveloxolone inhibits IL-1beta-induced chondrocyte apoptosis through the Nrf2/ARE and NF-kappaB signalling pathways in vitro and attenuates osteoarthritis in vivo. Front Pharmacol. 2022 Sep 27;13:952950. doi: 10.3389/fphar.2022.952950. eCollection 2022. [Article]
3. Shekh-Ahmad T,埃克尔R, Dayalan Naidu年代,希金斯M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May 1;141(5):1390-1403. doi: 10.1093/brain/awy071. [Article]
4. Probst提单,Trevino我,麦考利L, Bumeister R, Dulubova I, Wigley WC, Ferguson DA: RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity. PLoS One. 2015 Apr 21;10(4):e0122942. doi: 10.1371/journal.pone.0122942. eCollection 2015. [Article]
5. Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C: Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018 Nov 10;6(1):15-26. doi: 10.1002/acn3.660. eCollection 2019 Jan. [Article]
6. Zighan M, Arkadir D, Douiev L, Keller G, Miller C, Saada A: Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects. Front Mol Biosci. 2022 Aug 12;9:890653. doi: 10.3389/fmolb.2022.890653. eCollection 2022. [Article]
7. FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]

External Links

PubChem Compound

71811910

PubChem Substance

347828744

ChemSpider

34980948

RxNav

2631931

ChEMBL

CHEMBL4303525

ZINC

ZINC000144682962

Wikipedia

Omaveloxolone

Clinical Trials

Clinical TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
2	Active Not Recruiting	Treatment	Friedreich's Ataxia	1
2	Completed	Prevention	Breast Cancer	1
2	Completed	Prevention	Cataract Surgery/Endothelial Cell Loss, Corneal/Eye Pain/Ocular Inflammation	1
2	Completed	Treatment	Mitochondrial Myopathies	1
1	Completed	Treatment	Healthy Adult Subjects	1
1	Completed	Treatment	Healthy Male Subjects	1
1	Completed	Treatment	Healthy Subjects (HS)	2
1	Completed	Treatment	Hepatic Impairment	1
1	Completed	Treatment	Metastatic or Incurable Non-small Cell Lung Cancer/Relapsed, Refractory Melanoma	1
1, 2	Completed	Treatment	Melanoma/Metastatic Melanoma/Unresectable (Stage III) Melanoma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	50 mg/1

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Practically insoluble	FDA label
pKa	7.26	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.00119 mg/mL	ALOGPS
logP	5.64	ALOGPS
logP	6.28	Chemaxon
logS	-5.7	ALOGPS
pKa (Strongest Acidic)	10.11	Chemaxon
pKa (Strongest Basic)	-5.3	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	87.03 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	151.25 m3·mol-1	Chemaxon
Polarizability	60.76 Å3	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	0	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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Details 1.Kelch-like ECH-associated protein 1

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Curator comments

By binding and inhibiting KEAP1, omaveloxolone activates nuclear factor erythroid 2-related factor 2 (Nrf2).

General Function

Transcription factor binding

Specific Function

Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the s...

Gene Name

KEAP1

Uniprot ID

Q14145

Uniprot Name

Kelch-like ECH-associated protein 1

Molecular Weight

69665.765 Da

References

1. Shekh-Ahmad T,埃克尔R, Dayalan Naidu年代,希金斯M, Yamamoto M, Dinkova-Kostova AT, Kovac S, Abramov AY, Walker MC: KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain. 2018 May 1;141(5):1390-1403. doi: 10.1093/brain/awy071. [Article]
2. Parsons ALM, Bucknor EMV, Castroflorio E, Soares TR, Oliver PL, Rial D: The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy. Antioxidants (Basel). 2022 Jan 14;11(1):157. doi: 10.3390/antiox11010157. [Article]

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Drug created at October 20, 2016 22:40 / Updated at March 22, 2023 02:02