A Reata Pharmaceuticals drug for a rare kidney disorder has been rejected by the FDA, and if the company wants another shot at regulatory review, it must conduct another clinical trial to address the agency’s concerns.

The Reata drug, bardoxolone, is an experimental treatment for Alport syndrome. The disorder is a rare, inherited condition that leads to chronic kidney disease. According to the company, the FDA’s letter questioned the efficacy data for the drug, largely echoing concerns raised by an FDA advisory committee. Last December, that committee voted against recommending approval of bardoxolone. Specifically, the committee unanimously voted “no” on the question of whether evidence demonstrate the drug’s efficacy in slowing the progression of chronic kidney disease in Alport syndrome patients, and that the drug’s benefits outweigh its risks.

Warren Huff, CEO of Plano, Texas-based Reata, said in a prepared statement that the company will continue to work with the FDA to confirm the next steps for the Alport syndrome program.

Alport syndrome can affect children and adults. It’s caused by mutations in the genes that encode a protein family that is important to structural components of the kidney. The disorder leads to a progressive loss of the organ’s ability to filter waste from the blood. Patients may worsen to the point of end-stage kidney disease, which requires chronic dialysis treatment or a kidney transplant. The chronic kidney disease caused by Alport syndrome does not have any FDA-approved therapies.

Bardoxolone is an oral drug taken once daily. The small molecule is designed to target and activate Nrf2, a transcription factor that restores the function of mitochondria, which are components of the cell that produce energy. This approach is intended to stop the inflammation that damages the kidneys.

Reata had tested bardoxolone in a double-blind, placebo-controlled Phase 3 study enrolling 157 patients. Those participants were dosed for 100 weeks, followed by a four-week washout period in which they did not receive any of the drug. The main goal was to show a change in estimated glomerular filtration rate (eGFR), a measure of kidney function, after 100 weeks. The secondary goal was to assess patients after the four-week washout period. In late 2020, the company reported preliminary results showing that the drug met primary and secondary goals of the study.

In the FDA briefing documents prepared for the Dec. 8, 2021 advisory committee meeting, the agency said the design of the Phase 3 study does not allow for the evaluation of bardoxolone’s potential to slow disease progression. The eGFR values collected at weeks 52 and 104 still represent the reversible effects of the drug as assessed by the FDA’s model and the company’s, “and neither model suggests that bardoxolone slows the progression of decline in kidney function,” the FDA said.

FDA complete response letters are not public documents. According to Reata, the FDA said that evidence of effectiveness could come from a well-controlled study showing a clinically relevant effect on the rate of loss of kidney function in Alport syndrome patients. Alternatively, the study could show an effect on clinical outcomes, such as capturing how these patients feel, function, or survive.

According to the FDA briefing documents, the independent data monitoring committee had three main concerns about the pivotal bardoxolone study: the higher rate of death from all causes in the treatment group compared to the placebo arm; too much fluid in the body, leading to fluid overload serious adverse events including heart failure (these problems appeared to be limited to the first four weeks of treatment); and a risk-benefit profile that does not appear to weigh in favor of safety. While there were no reports of heart failure in the pivotal clinical trial, that study was designed to exclude patients with a history of heart failure or cardiac disease. The FDA still wants the company to address whether bardoxolone has a clinically relevant effect on the heart.

Bardoxolone is key to Reata, comprising much of its drug pipeline. In addition to Alport syndrome, the company has advanced the compound to separate clinical trials testing it as a treatment for chronic kidney disease associated with five other medical conditions. What happens with bardoxolone could affect another Reata drug. Omaveloxolone works similarly to bardoxolone and has reached pivotal testing in the neurological disorder Friedreich’s ataxia.

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