NAV

Omaveloxolone

Identification

Summary

Omaveloxolone is 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.2,4 Omaveloxolone 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.1 In February 2023, omaveloxolone was approved by the FDA for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.7 The 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
Similar Structures
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
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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
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofFriedreich'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.7 The 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.7 Nrf2 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.1 A study has shown that omaveloxolone binds to KEAP1, inhibiting its interaction with Nrf2 and promoting the translocation of Nrf2 to the nucleus.3 Aside from activating Nrf2, omaveloxolone also inhibits the NF-κB signalling pathway, promoting antioxidative, anti-inflammatory, and antiapoptotic mechanisms.2,4

TargetActionsOrganism
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 Cmax increased 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 AUC0-inf and Cmax of 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.7 Symptomatic 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
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
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interactions in your software
1,2-BenzodiazepineThe serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Omaveloxolone.
AbametapirThe serum concentration of Omaveloxolone can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Omaveloxolone.
AbirateroneThe serum concentration of Abiraterone can be decreased when it is combined with Omaveloxolone.
AcalabrutinibThe serum concentration of Acalabrutinib can be decreased when it is combined with Omaveloxolone.
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
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SkyclarysCapsule50 mg/1OralReata Pharmaceuticals, Inc.2023-02-28Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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, Eckel R, Dayalan Naidu S, Higgins 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 BL, Trevino I, McCauley 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]
PubChem Compound
71811910
PubChem Substance
347828744
ChemSpider
34980948
RxNav
2631931
ChEMBL
CHEMBL4303525
ZINC
ZINC000144682962
Wikipedia
Omaveloxolone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentFriedreich's Ataxia1
2CompletedPreventionBreast Cancer1
2CompletedPreventionCataract Surgery / Endothelial Cell Loss, Corneal / Eye Pain / Ocular Inflammation1
2CompletedTreatmentInflammation and Pain Following Ocular Surgery1
2CompletedTreatmentMitochondrial Myopathies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8993640No2015-03-312033-04-24US flag
US9670147No2017-06-062029-04-20US flag
US8440854No2013-05-142029-04-20US flag
US8124799No2012-02-282029-12-03US flag
US9701709No2017-07-112033-04-24US flag
US11091430No2021-08-172029-04-20US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleFDA label
pKa7.26FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00119 mg/mLALOGPS
logP5.64ALOGPS
logP6.28Chemaxon
logS-5.7ALOGPS
pKa (Strongest Acidic)10.11Chemaxon
pKa (Strongest Basic)-5.3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area87.03 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity151.25 m3·mol-1Chemaxon
Polarizability60.76 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
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/MSsplash10-0a4i-0000090000-2edbdd9bf2b41dacacd5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0000090000-c6fa2124a5ca2a5ac319
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0540-4252790000-f1768a2b6d1bed9201ee
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-8100090000-3110aa426a44ac3e9a31
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0r6r-2000950000-e40e4528608ba18ce2e2
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01x0-2277910000-991dabeda5c72de7f6be
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-230.69868
predicted
DeepCCS 1.0 (2019)
[M+H]+232.52602
predicted
DeepCCS 1.0 (2019)
[M+Na]+238.58678
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. 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, Eckel R, Dayalan Naidu S, Higgins 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]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
Details2. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]
Details3. Cytochrome P450 2J2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da
References
  1. FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]

Transporters

Details1. Solute carrier family 22 member 6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. FDA Approved Drug Products: SKYCLARYS (omaveloxolone) capsules for oral use (February 2023) [Link]

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