|This article relies too much on references to primary sources. (September 2014)|
|Systematic (IUPAC) name|
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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.
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. 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.
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.
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.
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.
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. Other studies have reported that bardoxolone methyl and analogs inhibit endothelin-1 signaling, partly by reducing its expression, inhibit NF-κB and STAT3 signaling, as well as improve mitochondrial bioenergetics. Reata initiated the LARIAT study, a placebo-controlled, multicenter Phase 2 study, to assess the effects of bardoxolone methyl in PAH.
Mechanism of action
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