Bardoxolone methyl is a capsule taken by mouth that has been tested in many clinical studies with different diseases. In prior trials, bardoxolone methyl has consistently improved parameters of kidney function in some patients with CKD, cancer, and pulmonary hypertension. Research completed to date suggests that bardoxolone methyl may:
- • Decrease inflammation in the kidney, protect the kidney from injury, and prevent fibrosis (changes in the structures) within the kidney, based on data from animal models
- • Significantly increase glomerular filtration rate (GFR) in patients with diabetic kidney disease, Alport syndrome, IgA nephropathy, and autosomal dominant polycystic kidney disease
- • Produce GFR increases that are sustained for at least one year, with a portion of the increase retained 4 weeks after stopping treatment, in patients with diabetic kidney disease and Alport syndrome
Overall, baroxolone methyl has been well tolerated in clinical trials. The most common side effects have included muscle cramps and nausea.
A previous large study in over 2000 diabetic patients with severe, stage 3 and 4 chronic kidney disease was stopped early because bardoxolone methyl increased the risk for fluid retention in a subset of patients who had previously been hospitalized for heart failure and who had fluid retention prior to the start of the study.
The increased risk for fluid retention was only observed in the first month after starting treatment. The identified risk factors are now used to exclude patients who are more likely to retain fluid from participating in studies with bardoxolone methyl. To date, bardoxolone methyl has not been shown to increase the risk for fluid retention in subsequent studies, including those in diabetic chronic kidney disease, pulmonary arterial hypertension, Alport syndrome, IgA nephropathy, and autosomal dominant polycystic kidney disease patients.
FALCON will exclude patients with stage 4 chronic kidney disease and these risk factors. Additionally, patients will be monitored closely during the first two months of the trial to ensure they do not develop fluid retention.
How Might Bardoxolone Methyl Treat ADPKD?
Your glomerular filtration rate (GFR) is an estimate of how well your kidneys are working. In patients with ADPKD, genetic mutations in PKD1 and PKD2 genes leads to the formation of fluid-filled cysts in the kidneys and other organs. The cysts continue to grow and can cause the kidneys to expand up to five to seven times their normal volume, leading to pain and progressive loss of kidney function (and causes decrease in GFR). As in other forms of CKD, decreased mitochondrial function and chronic inflammation are key drivers of disease progression in ADPKD. Decreasing GFR ultimately results in the need for dialysis or kidney transplant.
In July 2018, Reata released 12-week data from PHOENIX, a Phase 2 study for patients with rare kidney diseases, for the ADPKD portion of the study. PHOENIX enrolled 31 ADPKD patients. Key observations from this patient population included:
- • Historical eGFR data from 29 of these patients showed their kidney function was declining at an average annual rate of 4.8 mL/min/1.73 m2 for three years prior to participating in the study
- • Significant eGFR increase of 9.3 mL/min/1.73m2 was seen after 12 weeks of treatment
- • Bardoxolone methyl was well-tolerated without any evidence of fluid overload. The most common side effect was muscle cramps.
- • Data suggest that long-term eGFR improvements and retained eGFR benefit observed in other forms of CKD may translate to patients with ADPKD
In previous studies in patients with diabetes and chronic kidney disease, bardoxolone methyl produced an increase in estimated GFR (eGFR) that was sustained for 1 year in some patients. It is not known whether an increase in eGFR, if achieved, will provide long-term benefit in patients with ADPKD. Consequently, FALCON is designed to test the effects of bardoxolone methyl on eGFR in patients with ADPKD through 2 years of treatment.