Bardoxolone methyl (RTA 402) is an investigational oral therapy to treat the symptoms of chronic kidney disease (CKD) that occurs as a result of Alport syndrome. It is being developed by Reata Pharmaceuticals and also is being investigated for a range of other conditions.
How does bardoxolone methyl work?
Alport syndrome is caused by a mutation, or defect, in one of the collagen genes. Collagen is a major structural component of different organs and tissues in the body, including the kidneys.
The kidneys filter blood, removing excess water and waste substances from the body as urine. Collagen is essential to the integrity of the so-called glomerular basement membrane (GBM), part of the initial filtration unit of the kidneys.
In Alport syndrome, faulty collagen disrupts the GBM, altering what can pass through it. For example, it can lead to the abnormal filtering of proteins that are then reabsorbed into the body through a different part of the kidney. This reabsorption can lead to inflammation and permanent scarring (fibrosis) in the kidneys. As a result, Alport syndrome patients usually have a much lower estimated glomerular filtration rate (eGFR), which is a key measure of kidney function.
Another mechanism that leads to kidney damage in Alport syndrome is oxidative stress, which is caused by the production of damaging molecules called “reactive oxygen species” (ROS) by the mitochondria as a normal part of a cell’s energy production. Mitochondria are the “powerhouses” of the cell. Normally this process is tightly controlled to minimize damage, but in the case of chronic kidney disease, the excess production of ROS can lead to damage and death of kidney cells. Oxidative stress also may increase the production of pro-inflammatory proteins, which can contribute to chronic inflammation that leads to scarring.
Bardoxolone methyl is a small molecule that reduces oxidative stress and inflammation, which may improve kidney function in Alport syndrome patients. A “Nrf2 activator,” it acts by stimulating the Nrf2 pathway, thereby promoting normal mitochondrial function in the cell.
Bardoxolone methyl binds to a protein called KEAP1, preventing it from degrading the Nrf2 protein. The subsequent increased activation of Nrf2 stimulates the production of anti-oxidant proteins that remove the damaging ROS, reducing oxidative stress and damage to proteins that improve mitochondrial energy production.
By binding to KEAP1, bardoxolone methyl can also inhibit NF-κB, a pro-inflammatory protein complex, reducing inflammation in the kidneys.
Bardoxolone methyl in clinical trials
Bardoxolone methyl has been studied in several clinical trials to date, in a variety of conditions including cancer and different types of kidney disease.
Reata is currently investigating the safety and efficacy of bardoxolone methyl specifically as a CKD therapy in Alport syndrome patients in a Phase 2/3 clinical trial (NCT03019185). The trial is taking place at 35 locations in the U.S. and Australia.
The trial’s open-label Phase 2 portion has already enrolled 30 patients for a dose escalation study of bardoxolone methyl. Patients receive bardoxolone methyl once daily as an oral tablet, starting at a dose of 5 mg and increasing to a potential 30 mg over six weeks. Reata announced that bardoxolone methyl has significantly improved kidney function in patients, and that more than 80% of patients saw a clinically meaningful improvement in their kidney function by week 8. Furthermore, no serious adverse events (side effects) have so far been reported. These results were presented at the American Society of Nephrology Kidney Week 2017 Annual Meeting.
In the Phase 3 portion, some 150 patients took part in the randomized, double-blind, placebo-controlled trial. Its main measure of efficacy was the change in eGFR from the start of the trial after 48 weeks of either bardoxolone methyl or placebo once a day.
Reata announced in November 2019 that the study had met its primary and secondary endpoints. After 48 weeks of treatment, patients treated with bardoxolone methyl had a significant improvement in eGFR compared to the placebo group. Similar safety and tolerability measures were observed in this study as in the Phase 2 portion – 75 patients (97% of the treatment group) receiving bardoxolone methyl experienced an adverse event, as compared to 73 patients (91% of the placebo group). Nine patients from the treatment group and four from the placebo group discontinued the study following an adverse event.
Patients who participated in this Phase 2/3 clinical trial are eligible to enroll in an open-label Phase 3 extension trial (NCT03749447), which will assess the long-term safety and efficacy of bardoxolone methyl. The primary outcome measure of this trial will be the number of adverse and serious adverse events over the course of up to five years of treatment.
Other information
The U.S. Food and Drug Administration (FDA) granted bardoxolone methyl orphan drug designation in July 2017.
A previous Phase 3 clinical trial (NCT01351675) called BEACON investigated bardoxolone methyl as a CKD therapy in patients with type 2 diabetes. However, this trial was prematurely terminated due to safety concerns over increased heart failure events. Following an investigation, Reata determined that this mainly occurred in patients with high baseline levels of BNP, a protein associated with heart failure. Patients are now screened for levels of BNP and have been excluded from future bardoxolone methyl trials for safety reasons, and increased monitoring for all patients will take place within the first month of the trial.
Last updated: Nov. 14, 2019
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