Bardoxolone methyl

Bardoxolone methyl
Systematic (IUPAC) name
Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate
Clinical data
  • Investigational
Oral
Identifiers
218600-53-4 Yes
None
PubChem CID 400769
ChemSpider 355161 Yes
ChEMBL CHEMBL1762621 
Chemical data
Formula C32H43NO4
505.69 g/mol
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Bardoxolone methyl (also known as “RTA 402”, “CDDO-methyl ester”, and CDDO-Me) is an experimental and orally-available 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.[1][2]

Clinical development

Bardoxolone methyl is being investigated by Reata Pharmaceuticals in a partnership with Abbvie and Kyowa Hakko Kirin.

Phase 1

Bardoxolone methyl was assessed in a Phase 1 clinical trial to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and appropriate dosing for subsequent phase II studies, as well as to evaluate antitumor activity in patients with advanced solid tumor or lymphoid malignancy.[3] DLTs included grade 3 reversible liver transaminase elevations and the maximum tolerated dose was reported to be 900 mg/day. NQO1 mRNA levels, indicative of Nrf2 pathway activation, were increased in peripheral blood mononuclear cells (PBMCs), and tumor biopsies showed decreased levels of NF-κB and cyclin D1. An improvement in estimated glomerular filtration rate (eGFR) in patients treated with bardoxolone methyl was noted, and based on this finding it was suggested by the authors that the drug might be beneficial for patients with CKD.

Phase 2

A multi-center, double-blind, placebo-controlled Phase 2 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 eGFR following 24 weeks of treatment. Following 24 weeks, patients treated with bardoxolone methyl experienced a mean increase in eGFR 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.[4]

Phase 3

A multinational, double-blind, placebo-controlled Phase 3 outcomes study (BEACON) was started in June 2011, testing bardoxolone methyl’s impact on progression to end stage renal disease or cardiovascular death in 1600 patients with Stage 4 CKD (eGFR 15 – 30 ml/min/1.73m²) and type 2 diabetes. This phase 3 trial was halted in October 2012 after CKD patients in the drug arm were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations and deaths.[1][2]

A retrospective post-hoc analyses of the Phase 3 data conducted by the manufacturer identified prior hospitalization for heart failure and baseline brain natriuretic peptide (BNP), a marker of fluid retention, as predictors of heart failure hospitalizations in the BEACON trial. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo- treated patients was similar.[5]

Pulmonary Hypertension or Pulmonary Arterial Hypertension (PAH)

In vitro and animal studies on bardoxolone methyl have reported that the compound has antioxidative and anti-inflammatory properties, including beneficial effects on endothelial dysfunction, as well as anti-proliferative and anti-fibrotic effects.[6][7][8] Other studies have reported that bardoxolone methyl and analogs inhibit endothelin-1 signaling,[5] partly by reducing its expression, inhibit NF-κB and STAT3 signaling, as well as improve mitochondrial bioenergetics.[9][10][11] Reata initiated the LARIAT study,[12] a placebo-controlled, multicenter Phase 2 study, to assess the effects of bardoxolone methyl in PAH.[2][13][14]

Mechanism of action

Bardoxolone methyl is an activator of the KEAP1-Nrf2 pathway in mice.[15] Bardoxolone methyl also inhibits the pro-inflammatory transcription factor NF-κB in a tissue cultured human cell line.[16]

References

  1. ↑ 1.0 1.1 de Zeeuw D, Akizawa T, Audhya P et al. (2013). "Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.". N Engl J Med 369 (26): 2492–503. doi:10.1056/NEJMoa1306033. PMID 24206459.
  2. ↑ 2.0 2.1 2.2 Carroll, John. "After a taste of disaster, Reata plans a comeback for bardoxolone".
  3. ↑ Hong DS, Kurzrock R, Supko JG et al. (2012). "A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.". Clin Cancer Res 18 (12): 3396–406. doi:10.1158/1078-0432.CCR-11-2703. PMID 22634319.
  4. ↑ Pergola PE, Raskin P, Toto RD et al. (2011). "Bardoxolone methyl and kidney function in CKD with type 2 diabetes.". N Engl J Med 356 (4): 327–36. doi:10.1056/NEJMoa1105351. PMID 21699484.
  5. ↑ 5.0 5.1 Chin MP, Reisman SA, Bakris GL et al. (2014). "Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.". Am J Nephrol 39 (6): 499–508. doi:10.1159/000362906. PMID 24903467.
  6. ↑ Liby KT and Sporn MB (2012). "Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease.". Pharmacol Rev 64 (4): 972–1003. doi:10.1124/pr.111.004846. PMID 22966038.
  7. ↑ Kulkarni AA, Thatcher TH, Hsiao HM et al. (2013). "The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis.". PLOS ONE 8 (5): e63798. doi:10.1371/journal.pone.0063798. PMID 23741300.
  8. ↑ Wang YY, Zhe H, and Zhao R (2014). "Preclinical evidences toward the use of triterpenoid CDDO-Me for solid cancer prevention and treatment.". Mol Cancer 13: 30. doi:10.1186/1476-4598-13-30. PMID 24552536.
  9. ↑ Yore MM, Liby KT, Honda T et al. (2006). "The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta.". Mol Cancer Ther 5 (12): 3232–9. doi:10.1158/1535-7163.MCT-06-0444. PMID 17148759.
  10. ↑ Liby K, Voong Nga, Williams CR et al. (2006). "The Synthetic Triterpenoid CDDO-Imidazolide Suppresses STAT Phosphorylation and Induces Apoptosis in Myeloma and Lung Cancer Cells". Clin Cancer Res 12: 4288–93. doi:10.1158/1078-0432.CCR-06-0215. PMID 16857804.
  11. ↑ Neymotin A, Calingasan NY, Willie E et al. (2011). "Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis.". Free Radic Biol Med 51 (1): 88–96. doi:10.1016/j.freeradbiomed.2011.03.027. PMC 3109235. PMID 21457778.
  12. ↑ "Reata Begins Enrollment For PAH – LARIAT Phase 2 Study Examining Bardoxolone Methyl for Treating Pulmonary Arterial Hypertension".
  13. ↑ "Bardoxolone Methyl Evaluation in Patients With Pulmonary Arterial Hypertension (PAH) (LARIAT)".
  14. ↑ Cornish, Chris. "Reata Enrolls First Patient In Promising, New Pulmonary Arterial Hypertension Trial".
  15. ↑ Yates MS, Tauchi M, Katsuoka F et al. (2007). "Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.". Mol Cancer Ther 6 (1): 154–62. doi:10.1158/1535-7163.MCT-06-0516. PMID 17237276.
  16. ↑ Ahamd R, Raina D, Meyer C et al. (2006). "Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179.". J Biol Chem 281 (47): 35764–9. doi:10.1074/jbc.M607160200. PMID 16998237.

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