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==Mechanism of action==
==Mechanism of action==
Bardoxolone methyl is an inducer of the [[KEAP1]]-Nrf2 pathway.
Bardoxolone methyl is an inducer of the [[KEAP1]]-[[Nrf2]] pathway.


==References==
==References==

Revision as of 11:46, 6 September 2012

Bardoxolone methyl
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.132.153 Edit this at Wikidata
Chemical and physical data
FormulaC32H43NO4
Molar mass505.69 g/mol g·mol−1
3D model (JSmol)
  • O=C4C(\C#N)=C/[C@@]5(/C3=C/C(=O)[C@H]2[C@](CC[C@@]1(C(=O)OC)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 checkY
  • Key:WPTTVJLTNAWYAO-KPOXMGGZSA-N checkY
  (verify)

Bardoxolone methyl (also known as “RTA 402” and “CDDO-methyl ester”) is an orally-available first-in-class synthetic triterpenoid. It is an inducer of the Nrf2 pathway, which can suppress oxidative stress and inflammation, and is undergoing clinical development for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients.

Clinical development

Bardoxolone methyl is currently being investigated by Reata Pharmaceuticals, Inc. in partnership with Abbott Laboratories and Kyowa Hakko Kirin, as an experimental therapy for advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients.[1][2][3]

Phase 1

Bardoxolone methyl was first advanced into the clinic to assess its anticancer properties. In two Phase 1 trials that included 81 oncology patients, bardoxolone methyl reduced serum creatinine levels, with a corresponding improvement in estimated glomerular filtration rate (eGFR). Improvements were more pronounced in a subset of patients with established CKD and were maintained over time in patients who continued on bardoxolone methyl therapy for 5 months. Based on these observed effects and the well-described role of oxidative stress and inflammation in CKD, especially in type 2 diabetes, it was hypothesized that bardoxolone methyl could improve renal function in CKD patients with type 2 diabetes.[4]

Phase 2

A multi-center, double-blind, placebo-controlled Phase 2b clinical trial (BEAM) conducted in the US studied 227 patients with moderate to severe CKD (eGFR 20 – 45 ml/min/1.73m²) and type 2 diabetes. The primary endpoint was change in estimated GFR following 24 weeks of treatment. Following 24 weeks, patients treated with bardoxolone methyl experienced a mean increase in estimated GFR of over 10 ml/min/1.73m², compared with no change in the placebo group. Approximately three-quarters of bardoxolone methyl treated patients experienced an improvement in eGFR of 10 percent or more, including one-quarter who saw a significant improvement of 50% or more compared to less than 2% of patients on placebo. Adverse events were generally manageable and mild to moderate in severity. The most frequently reported adverse event in the bardoxolone methyl group was muscle spasm. Final data was published in The New England Journal of Medicine.

Concerns have been raised whether there is a true improvement in kidney function because of the significant weight loss of the patients in the active-treatment-group that ranged from 7.7-10.1 kg (7-10% of the initial body weight) and whether this weight loss in patients receiving bardoxolone included muscle wasting with a commensurate decrease in the serum creatinine level. In that case the decrease in creatinine would not necessarily be a true improvement in kidney function.[5][6][7][8][9]

Phase 3

A multinational, double-blind, placebo-controlled Phase 3 outcomes study (BEACON) is currently ongoing, testing bardoxolone methyl’s impact on progression to ESRD or cardiovascular death in 1600 patients with Stage 4 CKD (eGFR 15 – 30 ml/min/1.73m²) and type 2 diabetes. Results are expected in 2013.[10]

Mechanism of action

Bardoxolone methyl is an inducer of the KEAP1-Nrf2 pathway.

References

  1. ^ "Bardoxolone methyl – Oral, Once Daily AIM for Renal/Cardiovascular/Metabolic Diseases". Reata Pharmaceuticals. Retrieved June 2, 2011.
  2. ^ "Abbott and Reata Pharmaceuticals Announce Agreement to Develop and Commercialize Bardoxolone Methyl for Chronic Kidney Disease Outside the U.S." (Press release). Reata Pharmaceuticals. September 23, 2010. Retrieved June 2, 2011.
  3. ^ "Reata Pharmaceuticals Licenses Chronic Kidney Disease Drug Bardoxolone Methyl to Kyowa Hakko Kirin" (Press release). Reata Pharmaceuticals. January 7, 2010. Retrieved June 2, 2011.
  4. ^ Pergola, P. E.; Krauth, M.; Huff, J. W.; Ferguson, D. A.; Ruiz, S.; Meyer, C. J.; Warnock, D. G. (2011). "Effect of Bardoxolone Methyl on Kidney Function in Patients with T2D and Stage 3b–4 CKD". American Journal of Nephrology. 33 (5): 469–476. doi:10.1159/000327599. PMID 21508635.
  5. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 21699484 , please use {{cite journal}} with |pmid= 21699484 instead.
  6. ^ van Laecke, S.; Vanholder, R. (2011). "Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes". New England Journal of Medicine. 365 (18): 1745, author reply 1746–1747. doi:10.1056/NEJMc1110239. PMID 22047578.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Rogacev, K. S.; Bittenbring, J. T.; Fliser, D. (2011). "Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes". New England Journal of Medicine. 365 (18): 1745–1746, author reply 1746–1747. doi:10.1056/NEJMc1110239. PMID 22047579.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Upadhyay, A.; Sarnak, M. J.; Levey, A. S. (2011). "Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes". New England Journal of Medicine. 365 (18): 1746, author reply 1746–1747. doi:10.1056/NEJMc1110239. PMID 22047580.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ McMahon, G. M.; Forman, J. P. (2011). "Communication: Bardoxolone methyl, chronic kidney disease, and type 2 diabetes". New England Journal of Medicine. 365 (18): 1746, author reply 1746–1747. doi:10.1056/NEJMc1110239. PMID 22047581.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Clinical trial number NCT01351675 for "Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON)" at ClinicalTrials.gov
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