Omaveloxolone

CAS
1474034-05-3

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

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

FDA 2023, 2/28/2023, To treat Friedrich’s ataxia
Drug Trials Snapshot

WeightAverage: 554.723
Monoisotopic: 554.331999611

Chemical FormulaC₃₃H₄₄F₂N₂O₃

• RTA 408
• RTA-408

• OriginatorDartmouth College; University of Texas M. D. Anderson Cancer Center
• DeveloperBiogen
• ClassAnalgesics; Anti-inflammatories; Antineoplastics; Eye disorder therapies; Neuroprotectants; Small molecules; Triterpenes
• Mechanism of ActionNF-E2-related factor 2 stimulants
• Orphan Drug StatusYes – Friedreich’s ataxia; Malignant melanoma

• MarketedFriedreich’s ataxia
• Phase IIMitochondrial disorders; Ocular inflammation; Ocular pain
• Phase I/IIMalignant melanoma
• PreclinicalBrain disorders
• DiscontinuedDuchenne muscular dystrophy; Non-small cell lung cancer; Radiation-induced skin damage

• 08 Apr 2025Biogen completes a phase I pharmacokinetics trial (In volunteers) in USA (PO) (NCT06612879)
• 17 Mar 2025Registered for Friedreich’s ataxia (In adolescents, In adults) in Canada (PO)
• 18 Oct 2024Biogen initiates enrolment in a phase I pharmacokinetics trial (In volunteers) in USA (PO) (NCT06612879)

Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich’s ataxia.^[2][5] It is taken by mouth.^[2]

The most common side effects include an increase in alanine transaminase and an increase of aspartate aminotransferase, which can be signs of liver damage, headache, nausea, abdominal pain, fatigue, diarrhea and musculoskeletal pain.^[5]

Omaveloxolone was approved for medical use in the United States in February 2023,^{[2][5][6][7][8]} and in the European Union in February 2024.^[3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[9]

SYNTHESIS

PATENT
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

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP159939262&_cid=P21-MAKI10-93498-1

[0164]  Reagents and conditions: (a) (PhO) ₂PON ₃ (DPPA), triethylamine, toluene, 0 °C for 5 minutes, then ambient temperature overnight, ∼94%; (b) benzene, 80 °C for 2 hours; (c) HCl, CH ₃CN, ambient temperature for 1 hour; (d) CH ₃CF ₂CO ₂H, dicyclohexylcarbodiimide, 4-(dimethylamino)pyridine, CH ₂Cl ₂, ambient temperature overnight, 73% from RTA 401 (4 steps).

[0165]Compound 1: RTA 401 (20.0 g, 40.6 mmol), triethylamine (17.0 mL, 122.0 mmol), and toluene (400 mL) were added into a reactor and cooled to 0 °C with stirring. Diphenyl phosphoryl azide (DPPA) (13.2 mL, 61.0 mmol) was added with stirring at 0 °C over 5 minutes, and the mixture was continually stirred at room temperature overnight (HPLC-MS check shows no RTA 401 left). The reaction mixture was directly loaded on a silica gel column and purified by column chromatography (silica gel, 0% to 5% ethyl acetate in CH ₂Cl ₂) to give compound 1 (19.7 g, ∼94%, partially converted into compound 2) as a white foam.

[0166]Compound 2: Compound 1 (19.7 g, ∼38.1 mmol) and benzene (250 mL) were added into a reactor and heated to 80 °C with stirring for 2 hours (HPLC-MS check shows no compound 1 left). The reaction mixture was concentrated at reduced pressure to afford crude compound 2 as a solid residue, which was used for the next step without purification.

[0167]Compound 3: Crude compound 2 (≤38.1 mmol) and CH ₃CN (200 mL) were added into a reactor and cooled to 0 °C with stirring. HCl (12 N, 90 mL) was added at 0 °C over 1 minute, and the mixture was continually stirred at room temperature for 1 hour (HPLC-MS check shows no compound 2 left). The reaction mixture was cooled to 0 °C and 10% NaOH (∼500 mL) was added with stirring. Then, saturated NaHCO ₃ (1 L) was added with stirring. The aqueous phase was extracted by ethyl acetate (2×500 mL). The combined organic phase was washed by H ₂O (200 mL), saturated NaCl (200 mL), dried over Na ₂SO ₄, and concentrated to afford crude compound 3 (16.62 g) as a light yellow foam, which was used for the next step without purification.

[0168]RTA 408: Crude amine 3 (16.62 g, 35.9 mmol), CH ₃CF ₂CO ₂H (4.7388 g, 43.1 mmol), and CH ₂Cl ₂ (360 mL) were added into a reactor with stirring at room temperature. Then, dicyclohexylcarbodiimide (DCC) (11.129 g, 53.9 mmol) and 4-(dimethylamino)pyridine (DMAP) (1.65 g, 13.64 mmol) were added and the mixture was continually stirred at room temperature overnight (HPLC-MS check shows no compound 3 left). The reaction mixture was filtered to remove solid by-products, and the filtrate was directly loaded on a silica gel column and purified by column chromatography (silica gel, 0% to 20% ethyl acetate in hexanes) twice to give compound RTA 408 (16.347 g, 73% from RTA 401 over 4 steps) as a white foam: ¹H NMR (400 MHz, CD ₃Cl) δ ppm 8.04 (s, 1H), 6.00 (s, 1H), 5.94 (s, br, 1H), 3.01 (d, 1H, J = 4.8 Hz), 2.75-2.82 (m, 1H), 1.92-2.18 (m, 4H), 1.69-1.85 (m, 7H), 1.53-1.64 (m, 1H), 1.60 (s, 3H), 1.50 (s, 3H), 1.42 (s, 3H), 1.11-1.38 (m, 3H), 1.27 (s, 3H), 1.18 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.92 (s, 3H); m/z 555 (M+1).

SYNTHESIS
J. Med. Chem. 2025, 68, 2147−2182

Omaveloxolone (Skyclarys). Omaveloxolone (6) was approved in February 2023 for the treatment of Friedreich’s Ataxia (FRDA), a genetic, neurodegenerative disease. Patients with FRDA have lowered activity of the frataxin gene (FXN), attributed to an expansion of a guanine-adenine-adenine (GAA)
triplet. The resulting decrease in frataxin limits the production of iron−sulfur clusters, leading to accumulation of iron in the mitochondria and oxidative stress which in turn leads to cell damageanddeath.49
Omaveloxoloneactivates the nuclear factor erythroid 2-related factor 2 (Nrf2), an important pathway in
oxidative stress. It acts by preventing ubiquitination and subsequent degradation of Nrf2, keeping levels high enough to counteract the oxidative stress associated with FRDA. 50
Omaveloxolone was developed by Reata Pharmaceuticals (which was acquired by Biogen in September 2023) and was granted orphan drug, fast track, priority review, and rare pediatric disease designations. 51Omaveloxolone (6) is a semisynthetic triterpenoid based on the oleanolic acid scaffold.52
advanced intermediate 6.1,The synthesis started from the53also known as CDDO orbardoxolone, which has individually been investigated fortherapeutic benefits from Nrf2 activation (Scheme 10).
Treatment of acid 6.1 with DPPA produced the azide, and subsequent heating in benzene generated isocyanate 6.2 via aCurtius rearrangement. Hydrolysis with aqueous acid generated amine 6.3, and an amidation with 2,2-difluoropropanoic acid produced omaveloxolone (6). A yield of 73% over the sequence was reported, and intermediates were used crude with no purification between steps.

(49) Ghanekar, S. D.; Miller, W. W.; Meyer, C. J.; Fenelon, K. J.;
Lacdao, A.; Zesiewicz, T. A. Orphan drugs in development for the
treatment of Friedreich’s ataxia: focus on omaveloxolone. Degener.
Neurol. Neuromuscular Dis. 2019, 9, 103−107.
(50) Abeti, R.; Baccaro, A.; Esteras, N.; Giunti, P. Novel Nrf2-inducer
prevents mitochondrial defects and oxidative stress in Friedreich’s
ataxia models. Front. Cell. Neurosci. 2018, 12, 188.
(51) Lee,A.Omaveloxolone:first approval. Drugs 2023, 83, 725−729.
(52) Anderson, E.; Decker, A.; Liu, X. Synthesis, pharmaceutical use,
and characterization of crystalline forms of 2,2-difluoropropionamide
derivatives of bardoxolone methyl. WO 2013163344, 2013.
(53) Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang, Y.;
Sporn, M. B. Design and synthesis of 2-cyano-3,12-dioxoolean-1,9
dien-28-oic acid, a novel and highly active inhibitor of nitric oxide
production in mouse macrophages. Bioorg. Med. Chem. Lett. 1998, 8,
2711−2714.

SYN

European Journal of Medicinal Chemistry 265 (2024) 116124

Omaveloxolone (Skyclarys)
Omaveloxolone was granted FDA approval on February 28, 2023, to treat Friedrich’s ataxia in individuals aged 16 and older [2]. Omaveloxolone possesses antioxidant and anti-inflammatory properties, making it a semi-synthetic triterpenoid compound. It has the ability to function as a stimulator of nuclear factor-erythroid 2 related factor 2(Nrf2), a transcription factor that reduces oxidative stress. In individuals
suffering from FA, a genetic disorder characterized by mitochondrial dysfunction, the Nrf2 pathway is compromised, leading to a decrease in Nrf2 activity. Hence, Omaveloxolone, an Nrf2 activator, can be
employed as a therapeutic option for the management of these in dividuals [23].The process route of Omaveloxolone is described below in Scheme 724]. The substitution reaction of carboxylic acid OMAV-001 with diphenylphosphoryl azide (DPPA) gave the acyl azide OMAV-002,which underwent Curtius-rearrangement under heating conditions to produce isocyanate OMAV-003. The amine OMAV-004 was obtained under acidic conditions. OMAV-004 was condensed with 2,2-difluoro propionic acid to obtain the final product Omaveloxolone.

[23] B.L. Probst, I. Trevino, L. McCauley, R. Bumeister, I. Dulubova, W.C. Wigley, D.
A. Ferguson, RTA 408, A novel synthetic triterpenoid with broad anticancer and
anti-inflammatory activity, PLoS One 10 (2015) e0122942.
[24] E. Anderson, A. Decker, X. Liu Synthesis, Pharmaceutical Use, and
Characterization of Crystalline Forms of 2,2-difluoropropionamide Derivatives of
Bardoxolone Methyl, 2013. WO2013163344.

.

Medical uses

Omaveloxolone is indicated for the treatment of Friedreich’s ataxia.^[2][5]

Friedreich’s ataxia causes progressive damage to the spinal cord, peripheral nerves, and the brain, resulting in uncoordinated muscle movement, poor balance, difficulty walking, changes in speech and swallowing, and a shortened lifespan.^[5] The condition can also cause heart disease.^[5] This disease tends to develop in children and teenagers and gradually worsens over time.^[5]

Although rare, Friedreich’s ataxia is the most common form of hereditary ataxia in the United States, affecting about one in every 50,000 people.^[5]

Mechanism of action

The mechanism of action of omaveloxolone and its related compounds has been demonstrated to be through a combination of activation of the antioxidative transcription factor Nrf2 and inhibition of the pro-inflammatory transcription factor NF-κB.^[10]

Nrf2 transcriptionally regulates multiple genes that play both direct and indirect roles in producing antioxidative potential and the production of cellular energy (i.e., adenosine triphosphate or ATP) within the mitochondria. Consequently, unlike exogenously administered antioxidants (e.g., vitamin E or Coenzyme Q10), which provide a specific and finite antioxidative potential, omaveloxolone, through Nrf2, broadly activates intracellular and mitochondrial antioxidative pathways, in addition to pathways that may directly increase mitochondrial biogenesis (such as PGC1α) and bioenergetics.^[11]

History

Omaveloxolone is a second generation member of the synthetic oleanane triterpenoid compounds and in clinical development by Reata Pharmaceuticals. Preclinical studies have demonstrated that omaveloxolone possesses antioxidative and anti-inflammatory activities^[10][12] and the ability to improve mitochondrial bioenergetics.^[11] Omaveloxolone is under clinical investigation for a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies, immunooncology, and prevention of corneal endothelial cell loss following cataract surgery.

The efficacy and safety of omaveloxolone was evaluated in a 48-week randomized, placebo-controlled, and double-blind study [Study 1 (NCT02255435)] and an open-label extension.^[5] Study 1 enrolled 103 individuals with Friedreich’s ataxia who received placebo (52 individuals) or omaveloxolone 150 mg (51 individuals) for 48 weeks.^[5] Of the research participants, 53% were male, 97% were white, and the mean age was 24 years at study entry.^[5] Nine (18%) patients were younger than age 18.^[5] The primary objective was to evaluate the change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score compared to placebo at week 48.^[5] The mFARS is a clinical assessment that measures disease progression, namely swallowing and speech (bulbar), upper limb coordination, lower limb coordination, and upright stability.^[5] Individuals receiving omaveloxolone performed better on the mFARS than people receiving placebo.^[5]

The US Food and Drug Administration (FDA) granted the application for omaveloxolone orphan drug, fast track, priority review, and rare pediatric disease designations.^[5][9]

Society and culture

Legal status

Omaveloxolone was approved for medical use in the United States in February 2023.^[2][5]

In December 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Skyclarys, intended for the treatment of Friedreich’s ataxia.^[3] The applicant for this medicinal product is Reata Ireland Limited.^[3] Omaveloxolone was approved for medical use in the European Union in February 2024.^[3][4]

References

1. ^ “Register of Innovative Drugs”. Health Canada. 3 November 2006. Retrieved 17 April 2025.
2. ^ Jump up to:^{a b c d e f} “Skyclarys- omaveloxolone capsule”. DailyMed. 12 May 2023. Archived from the original on 1 July 2023. Retrieved 16 December 2023.
3. ^ Jump up to:^{a b c d e} “Skyclarys EPAR”. European Medicines Agency (EMA). 14 December 2023. Archived from the original on 15 December 2023. Retrieved 16 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
4. ^ Jump up to:^a b “Skyclarys product information”. Union Register of medicinal products. 12 February 2024. Retrieved 19 February 2024.
5. ^ Jump up to:^{a b c d e f g h i j k l m n o p q} “FDA approves first treatment for Friedreich’s ataxia”. U.S. Food and Drug Administration (FDA). 28 February 2023. Archived from the original on 1 March 2023. Retrieved 28 February 2023.  This article incorporates text from this source, which is in the public domain.
6. ^ “Reata Pharmaceuticals Announces FDA Approval of Skyclarys (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia”. Reata Pharmaceuticals Inc. (Press release). 28 February 2023. Archived from the original on 1 March 2023. Retrieved 28 February 2023.
7. ^ Lee A (June 2023). “Omaveloxolone: First Approval”. Drugs. 83 (8): 725–729. doi:10.1007/s40265-023-01874-9. PMID 37155124. S2CID 258567442. Archived from the original on 9 December 2023. Retrieved 16 December 2023.
8. ^ Subramony SH, Lynch DL (May 2023). “A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia”. Cerebellum. 23 (2): 775–777. doi:10.1007/s12311-023-01568-8. PMID 37219716. S2CID 258843532.
9. ^ Jump up to:^a b New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
10. ^ Jump up to:^a b Reisman SA, Lee CY, Meyer CJ, Proksch JW, Ward KW (July 2014). “Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin”. Archives of Dermatological Research. 306 (5): 447–454. doi:10.1007/s00403-013-1433-7. PMID 24362512. S2CID 25733020.
11. ^ Jump up to:^a b Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, et al. (July 2011). “Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis”. Free Radical Biology & Medicine. 51 (1): 88–96. doi:10.1016/j.freeradbiomed.2011.03.027. PMC 3109235. PMID 21457778.
12. ^ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW (May 2014). “Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis”. Radiation Research. 181 (5): 512–520. Bibcode:2014RadR..181..512R. doi:10.1667/RR13578.1. PMID 24720753. S2CID 23906747.

External links

Clinical trial number NCT02255435 for “RTA 408 Capsules in Patients With Friedreich’s Ataxia – MOXIe” at ClinicalTrials.gov

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]
8. EMA Approved Drug Products: Skyclarys (omaveloxolone) Oral Capsules [Link]
9. Health Canada Approved Drug Products: SKYCLARYS (Omaveloxolone) Capsules For Oral Use [Link]

///////////Omaveloxolone, Skyclarys, Friedrich’s ataxia, FDA 2023, APPROVALS 2023, RTA 408, RTA-408, omaveloxolona, RTA 408, 63415, PP415, orphan drug, fast track, priority review, rare pediatric disease

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