Omaveloxolone

Last updated

Omaveloxolone
Omaveloxolone structure.svg
Clinical data
Trade names Skyclarys
Other namesRTA 408
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
  • N-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-1 1-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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C33H44F2N2O3
Molar mass 554.723 g·mol−1
3D model (JSmol)
  • O=C4C(\C#N)=C/[C@@]5(/C3=C/C(=O)[C@H]2[C@](CC[C@@]1(NC(=O)C(F)(F)C)CCC(C)(C)C[C@H]12)(C)[C@]3(C)CC[C@H]5C4(C)C)C
  • InChI=1S/C32H43NO4/c1-27(2)11-13-32(26(36)37-8)14-12-31(7)24(20(32)17-27)21(34)15-23-29(5)16-19(18-33)25(35)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3/t20-,22-,24-,29-,30+,31+,32-/m0/s1 Yes check.svgY
  • Key:WPTTVJLTNAWYAO-KPOXMGGZSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich's ataxia. [1] [3] It is taken by mouth. [1]

Contents

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. [3]

Omaveloxolone was approved for medical use in the United States in February 2023. [1] [3] [4] [5] [6] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication. [7]

Medical uses

Omaveloxolone is indicated for the treatment of Friedreich's ataxia. [1] [3]

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. [3] The condition can also cause heart disease. [3] This disease tends to develop in children and teenagers and gradually worsens over time. [3]

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. [3]

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. [8]

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. [9]

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 [8] [10] and the ability to improve mitochondrial bioenergetics. [9] 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. [3] Study 1 enrolled 103 individuals with Friedreich's ataxia who received placebo (52 individuals) or omaveloxolone 150 mg (51 individuals) for 48 weeks. [3] Of the research participants, 53% were male, 97% were white, and the mean age was 24 years at study entry. [3] Nine (18%) patients were younger than age 18. [3] The primary objective was to evaluate the change in the modified Friedreich's Ataxia Rating Scale (mFARS) score compared to placebo at week 48. [3] The mFARS is a clinical assessment that measures disease progression, namely swallowing and speech (bulbar), upper limb coordination, lower limb coordination, and upright stability. [3] Individuals receiving omaveloxolone performed better on the mFARS than people receiving placebo. [3]

The US Food and Drug Administration (FDA) granted the application for omaveloxolone orphan drug, fast track, priority review, and rare pediatric disease designations. [3] [7]

Society and culture

Omaveloxolone was approved for medical use in the United States in February 2023. [1] [3]

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. [11] The applicant for this medicinal product is Reata Ireland Limited. [11]

Related Research Articles

<span class="mw-page-title-main">Friedreich's ataxia</span> Rare autosomal-recessive human disease

Friedreich's ataxia is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.

<span class="mw-page-title-main">Idebenone</span> Chemical compound

Idebenone is a drug that was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of neuromuscular diseases. In 2010, early clinical trials for the treatment of Friedreich's ataxia and Duchenne muscular dystrophy have been completed. As of December 2013 the drug is not approved for these indications in North America or Europe. It is approved by the European Medicines Agency (EMA) for use in Leber's hereditary optic neuropathy (LHON) and was designated an orphan drug in 2007.

Ustekinumab, sold under the brand name Stelara among others, is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23.

<span class="mw-page-title-main">Maribavir</span> Antiviral drug

Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV). Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.

<span class="mw-page-title-main">Bardoxolone methyl</span> Chemical compound

Bardoxolone methyl is an experimental and orally-bioavailable semi-synthetic triterpenoid, based on the scaffold of the natural product oleanolic acid. Pre-clinical studies indicate that the compound acts as an activator of the Nrf2 pathway and an inhibitor of the NF-κB pathway. A phase 3 clinical trial evaluating bardoxolone methyl for the treatment of chronic kidney disease (CKD) was terminated in October 2012 after patients treated with the drug were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations, and deaths.

Reata Pharmaceuticals, Inc. is a pharmaceutical company based in Plano, Texas. Founded in 2002, it is primarily focused on investigating experimental oral antioxidative and anti-inflammatory drugs, which dually activate the antioxidative transcription factor Nrf2 and inhibit the pro-inflammatory transcription factor NF-κB.

Abaloparatide, sold under the brand name Tymlos among others, is a parathyroid hormone-related protein (PTHrP) analog medication used to treat osteoporosis. It is an anabolic agent.

Anifrolumab, sold under the brand name Saphnelo, is a monoclonal antibody used for the treatment of systemic lupus erythematosus. It binds to the type I interferon receptor, blocking the activity of type I interferons such as interferon-α and interferon-β.

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).

Inebilizumab, sold under the brand name Uplizna, is a medication for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults. Inebilizumab is a humanized mAb that binds to and depletes CD19+ B cells including plasmablasts and plasma cells.

Mirikizumab, sold under the brand name Omvoh, is a monoclonal antibody used for the treatment of ulcerative colitis. It is designed to attach to interleukin-23 (IL-23) and block its activity.

Di-deuterated ethyl linoleate is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD). It is given by intravenous infusion. Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

<span class="mw-page-title-main">Ripretinib</span> Chemical compound

Ripretinib, sold under the brand name Qinlock, is a medication for the treatment of adults with advanced gastrointestinal stromal tumor (GIST), a type of tumor that originates in the gastrointestinal tract. It is taken by mouth. Ripretinib inhibits the activity of the kinases KIT and PDGFRA, which helps keep cancer cells from growing.

<span class="mw-page-title-main">Vericiguat</span> Medication

Vericiguat, sold under the brand name Verquvo, is a medication used to reduce the risk of cardiovascular death and hospitalization in certain patients with heart failure after a recent acute decompensation event. It is taken by mouth. Vericiguat is a soluble guanylate cyclase (sGC) stimulator.

<span class="mw-page-title-main">Lenacapavir</span> Antiretroviral medication

Lenacapavir, sold under the brand name Sunlenca, is an antiretroviral medication used to treat HIV/AIDS. It is taken by mouth or by subcutaneous injection.

<span class="mw-page-title-main">Ibrexafungerp</span> Medication

Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC). It is taken orally. It is also currently undergoing clinical trials for other indications via an intravenous (IV) formulation. An estimated 75% of women will have at least one episode of VVC and 40 to 45% will have two or more episodes in their lifetime.

<span class="mw-page-title-main">Mitapivat</span> Chemical compound

Mitapivat, sold under the brand name Pyrukynd, is a medication used to treat hemolytic anemia. It is taken as the sulfate hydrate salt by mouth. Mitapivat is a pyruvate kinase activator.

Spesolimab, sold under the brand name Spevigo, is a monoclonal antibody used for the treatment of generalized pustular psoriasis (GPP). It is an interleukin-36 receptor (IL-36R) antagonist. It is given via injection into a vein.

References

  1. 1 2 3 4 5 6 "Skyclarys- omaveloxolone capsule". DailyMed. 12 May 2023. Archived from the original on 1 July 2023. Retrieved 16 December 2023.
  2. ↑ "Skyclarys product information". Union Register of medicinal products. 12 February 2024. Retrieved 19 February 2024.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 "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.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. ↑ "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.
  5. ↑ 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.
  6. ↑ Subramony SH, Lynch DL (May 2023). "A Milestone in the Treatment of Ataxias: Approval of Omaveloxolone for Friedreich Ataxia". Cerebellum. doi:10.1007/s12311-023-01568-8. PMID   37219716. S2CID   258843532.
  7. 1 2 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.
  8. 1 2 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.
  9. 1 2 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.
  10. ↑ 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.
  11. 1 2 "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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.