Bardoxolone methyl

Bardoxolone methyl (also known as “RTA 402” and “CDDO-methyl ester”) is an orally-available first-in-class synthetic triterpenoid belonging to the antioxidant inflammation modulator (AIM) class. It is the most potent known inducer of the Nrf2 pathway to enter clinical development and works to suppress both oxidative stress and inflammation.

Clinical development
Bardoxolone methyl is currently being developed by Reata Pharmaceuticals, Inc. in partnership with Abbott Laboratories and Kyowa Hakko Kirin, for the treatment of advanced chronic kidney disease (CKD) in type 2 diabetes mellitus patients.

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.

Phase 2
In an exploratory multi-center, open-label Phase 2a study conducted in the US, the clinical activity and safety of bardoxolone methyl was assessed in 20 patients with moderate to severe CKD (eGFR 15 – 45 ml/min/1.73m²) and type 2 diabetes. Patients received 25 mg of bardoxolone methyl daily for 28 days, followed by 75 mg daily for another 28 days. Treatment with bardoxolone methyl resulted in a significant increase from baseline in eGFR of 7.2 ml/min/1.73m² (p < 0.001). Improvements were seen in approximately 90% of patients and showed a dose- and time-dependent increase in eGFR. The eGFR change paralleled a significant reduction in serum creatinine (-0.3 mg/dl) and blood urea nitrogen (-4.9 mg/dl), along with an increase in creatinine clearance (+14.6 ml/min/1.73m²), without a change in the 24-hour creatinine excretion rate. No changes were seen in markers of renal injury, NGAL and NAG, and eGFR remained significantly above baseline 30 days following drug withdrawal. These results were presented at the World Congress of Nephrology 2011 meeting.

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, and late-breaking clinical data were presented at the 2010 American Society of Nephrology Renal Week Conference. 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 an improvement of 50 percent or more compared to less than two percent of patients on placebo (p<0.001). 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, as well as presented at the 2011 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress in Prague, Czech Republic on June 24, 2011.

A multi-center, open-label, Phase 2 clinical trial of a new formulation of bardoxolone methyl that will be used going forward enrolled 130 patients with moderate to severe CKD (eGFR 15 – 45 ml/min/1.73m²) and type 2 diabetes. The formulation of bardoxolone methyl has improved oral bioavailability over the formulation used in previous studies, and was found to have a consistent safety and pharmacodynamic profile. Clinically and statistically significant improvements in eGFR were observed, and all dose levels were generally well tolerated. Interim results were presented at the 2011 World Congress of Nephrology meeting.

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.

Mechanism of action
CKD is the result of a progressive loss of kidney function over time. A growing body of evidence indicates that in CKD, oxidative stress and excessive inflammation have multiple deleterious effects on glomerular structure and function, which drive disease progression both before and in parallel with fibrosis. Short-term effects of oxidative stress and inflammation include mesangial cell contraction and glomerular endothelial dysfunction. Over time, hypertrophy of the mesangium and thickening of the glomerular basement membrane occur. Together, these effects reduce the glomerular surface area available for filtration, increase intraglomerular pressure, and cause a decline in glomerular filtration rate (GFR) that results in impaired kidney function often before fibrosis is evident.

Bardoxolone methyl is the most potent known inducer of Nrf2, a key regulator of the body’s natural anti-inflammatory and antioxidant response to enter clinical development. Activation of the Nrf2 pathway at the intracellular level by endogenous anti-inflammatory prostaglandins has dual effects that reduce oxidative stress and inflammation. However, in animal models of kidney disease, Nrf2 function is known to be suppressed, leading to renal structural abnormalities, glomerulonephritis, reduced creatinine clearance, and increased mortality. Because oxidative stress and inflammation occur throughout the course of CKD and are known to contribute to loss of GFR, agents that activate the Nrf2 pathway in patients with CKD may provide a novel method for preserving or improving kidney function.