Bardoxolone methyl (RTA 402) is an investigational 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 is also being investigated for a range of other indications.

How bardoxolone methyl works

Alport patients have a mutation, or defect, in one of the collagen genes. Collagen is a major structural component of various organs 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 glomerular basement membrane (GBM), part of the initial filtration unit.

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 patients generally have a much lower estimated glomerular filtration rate (eGFR) — a key measure of kidney function.

Another mechanism that leads to kidney damage 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 CKD, excess production of ROS can lead to kidney cell damage and death. Oxidative stress can also increase production of pro-inflammatory proteins, which can contribute to chronic inflammation that leads to scarring.

Bardoxolone methyl is a small molecule drug aimed at reducing oxidative stress and inflammation, which may improve kidney function in Alport patients. A “Nrf2 activator,” it acts by stimulating the Nrf2 pathway, thereby promoting normal mitochondria function in the body.

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 and proteins that improve mitochondrial energy production.

By binding to KEAP1, bardoxolone methyl can also inhibit NF-κB, a pro-inflammatory protein complex, reduce inflammation in kidneys.

Bardoxolone methyl in clinical trials

Bardoxolone methyl has been studied in several human 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 patients in a Phase 2/3 clinical trial (NCT03019185). The trial is taking place at 35 locations in the United States 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, 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 over 80 percent saw a clinically meaningful improvement in kidney function by week 8. Furthermore, no serious adverse events have so far been reported. These results were presented at the American Society of Nephrology Kidney Week 2017 Annual Meeting.

Following a recommendation from the U.S. Food and Drug Administration (FDA)’s Independent Data Monitoring Committee, Reata has started recruiting participants for the trial’s Phase 3 portion. Some 150 patients will take part in the randomized, double-blind, placebo-controlled trial. Its main measure of efficacy will be the change in eGFR from baseline after 48 weeks of either bardoxolone methyl or placebo taken once daily.

Other information

The FDA granted bardoxolone methyl orphan drug designation in July 2017.

A previous Phase 3 clinical trial called BEACON (NCT01351675) 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 high 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.

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