IRVING, Texas—Some people consider cardinals to be a sign of good luck, and that certainly seems to be the case for Reata Pharmaceuticals Inc., which has reported highly promising data from the Phase 2 portion of CARDINAL, its Phase 2/3 trial of bardoxolone methyl in patients with chronic kidney disease (CKD) caused by Alport syndrome.
Bardoxolone is an experimental, oral, once-daily activator of Nrf2, a transcription factor that triggers molecular pathways that help resolve inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling. Reata has received Orphan Drug designation from the FDA for the compound for the treatment of Alport syndrome.
“Alport syndrome is caused by mutations in type IV collagen, an important component of the filtration barrier within the kidney. These mutations cause the barrier to be leaky, resulting in excess filtration of proteins, which initiates inflammatory and fibrotic processes. This cascade promotes loss of kidney function, which ultimately leads to end-stage renal disease (ESRD) and a need for dialysis or kidney transplant in those patients,” Dr. Colin Meyer, chief medical officer of Reata, said in a conference call regarding the data. “These pathogenic processes and the rate of loss of kidney function are similar to type 2 diabetic CKD, where Reata has generated a substantial amount of data for bardoxolone, making Alport syndrome a compelling indication for us to study. In addition, there are no therapies approved for Alport syndrome, with most patients taking off-label ACE inhibitors, or ARBs, which have a modest effect on delaying time to ESRD.”
Thirty patients were enrolled in the Phase 2 study, with no discontinuations. The primary endpoint of the Phase 2 trial was improvement in kidney function, measured by the estimated glomerular filtration rate (eGFR) change from baseline at 12 weeks. From a mean baseline eGFR of 54.7 mL/min/1.73 m2, the data so far showed a mean improvement of 6.9 mL/min/1.73 m2 at week four, which increased to 12.7 mL/min/1.73 m2 at week 12. More than 80 percent of patients demonstrated a clinically meaningful improvement in eGFR of at least 3.0 mL/min/1.73 m2 by week eight. This treatment effect exceeds the threshold of 3.0 mL/min/1.73 m2, the minimum effect size necessary to advance the program to the Phase 3 portion of the trial. No serious adverse events have been reported, with the most common adverse event consisting of mild to moderate muscle spasms. In addition, the independent data monitoring committee reviewed bardoxolone’s safety data and voted to recommend moving into the Phase 3 trial.
“The ongoing Phase 2 portion of CARDINAL demonstrated clear improvements in renal function that are large in magnitude, occur in a high percentage of patients and are highly statistically significant,” said Meyer. “These results exceeded our expectations and bring us one step closer to the prospect of bardoxolone becoming the first effective treatment for this severe and life-threatening disease. We are eager to study bardoxolone in additional rare renal diseases driven by inflammatory processes that bardoxolone addresses.”
“Bardoloxone has consistently and dramatically improved kidney function as measured by estimated glomerular filtration rate, or EGFR, in every human clinical trial and setting it’s been tested in, including our prior clinical trials in CKD caused by type 2 diabetes,” President and CEO Warren Huff remarked in the company’s conference call.
Based on the data, Reata initiated screening for the Phase 3 trial, and announced the enrollment of its first patient on August 7. The trial is designed to support regulatory approval of bardoxolone in Alport syndrome. It will be a double-blind, placebo-controlled trial enrolling approximately 150 patients on a 1:1 basis to receive once-daily oral bardoxolone or placebo. eGFR change will be measured after 48 weeks while participants are on treatment and after 52 weeks when patients have stopped taking the study drug for a four-week withdrawal period. Per guidance from the FDA, the year two retained eGFR benefit data from this study may support full approval. The primary efficacy endpoint will be the on-treatment eGFR change from baseline in patients receiving bardoxolone relative to placebo at week 48. Data from the week 48 and week 52 analyses is expected in the second half of 2019.
Roughly 12,000 people in the United States and 40,000 people globally suffer from Alport syndrome, with approximately 50 percent of male patients needing dialysis or kidney transplant by age 25.
“The Alport Syndrome Foundation has worked for 10 years to encourage the development of therapies that will delay or prevent the need for dialysis and transplantation in patients with Alport syndrome, and we are encouraged to see this trial move forward and hope this will bring us closer to achieving our vision, to conquer Alport syndrome,” said Gina Parziale, executive director of the Alport Syndrome Foundation. “As there are no FDA-approved therapies to treat Alport syndrome, we are grateful to Reata for addressing this need and for engaging us in the process to ensure the patient perspective is incorporated.”