Article Questioning Safety of Phase 3 Bardoxolone Trial ‘Inaccurate,’ Reata CMO Says

Article Questioning Safety of Phase 3 Bardoxolone Trial ‘Inaccurate,’ Reata CMO Says

An article that reported concerns about the effectiveness and safety of bardoxolone methyl, now in a pivotal study of Alport syndrome patients, are “inaccurate” and “out of date,” according to Colin Meyer, MD, chief medical officer for Reata Pharmaceuticals.

Meyer was responding to the article, “Should We Increase GFR with Bardoxolone in Alport Syndrome?,” which appeared in the Journal of the American Society of Nephrology (JASN)story reporting on it was published recently in Alport Syndrome News. 

The JASN article addressed in a questioning tone the ongoing clinical development of bardoxolone, an oral, once-daily potential therapy that activates Nrf2, a transcription factor. Such proteins control the conversion of DNA into RNA. Nrf2 contributes to the proper functioning of mitochondria (a cell’s power source), inhibits inflammatory processes, and decreases oxidative stress.

Meyer took issue with points raised by its authors, Colin Baigent and Rachel Lennon, both U.K. researchers and trustees with Alport UK. “The article,” Meyer said, “was uninformed; it selectively ignored a large body of data from numerous peer-reviewed manuscripts that are in the scientific literature.”

It also was “inaccurate,” in that “many statements about the drug’s profile … contradict published data.” He also noted that neither author has had any involvement in bardoxolone’s clinical testing program.

Adding to the failings that Meyer alleges is the article’s timing, which could hurt an ongoing clinical trial in what might be a first treatment for kidney disease in Alport patients. The publication is “going out to patients and their families,” he said. “It’s unfortunate.”

Here is what is known about Reata’s bardoxolone program:

  • In Phase 1 trials, bardoxolone was found to raise levels of estimated glomerular filtration rate (eGFR), a key measure of proper kidney function.
  • This finding was supported by data from the Phase 2 BEAM trial (NCT00811889) in patients with moderate-to-severe chronic kidney disease (CKD) and type 2 diabetes (T2D).
  • But a Phase 3 study, called BEACON (NCT01351675) in 2,185 patients with CKD and T2D was stopped in 2014 due to safety concerns. An independent analysis based on early trial data found the treatment candidate led to a significant risks of heart failure. Treatment also was linked to higher levels of liver enzymes, lower levels of magnesium, more frequent muscle cramps, and elevated levels of urinary albumin — a marker of renal damage associated with a greater risk of end-stage renal disease (ESRD).
  • Reata worked on the compound, and shifted its focus to Alport syndrome. In 2017, bardoxolone was designated an orphan drug by the U.S. Food and Drug Administration as a potential Alport treatment. The company also launched the global Phase 2/3 CARDINAL study (NCT03019185) to assess the safety, tolerability, and effectiveness of bardoxolone in Alport patients.

Results of CARDINAL’s Phase 2 part in 30 patients, Meyer said in a May 7 interview, show that bardoxolone improves kidney function with “changes … durable for nine months” — much longer than the 12 weeks referenced by Baigent and Lennon.

The study’s Phase 3 part, currently recruiting, will randomize a planned 150 patients to a 48-week treatment with either bardoxolone (titrated up to 30 mg daily) or placebo. This will be followed by a four-week discontinuation, then 48 more weeks of the same treatment, with a final four-week discontinuation.

Scientists will evaluate changes in eGFR from the study’s start, extending to one and two years post-treatment, and against placebo.

Baigent and Lennon argued that with this design, the “CARDINAL Trial will not be able to detect any long-term increase in the rate of CKD progression, because the longest period that patients will be exposed to bardoxolone without interruption will be 48 weeks.” Bardoxolone’s safety and effectiveness, they wrote, should be studied in “long-term trials that include a wider range of patients.”

Meyer said that CARDINAL’s design was “specifically requested by FDA” and “includes two total years of treatment,” adding that enrolling a wide range of patients is difficult in rare diseases.

Data from a later analysis — recently published in the American Journal of Nephrology — also found benefits to the kidneys in treated patients in the halted BEACON trial.

“Using endpoints that have now been validated and are being used in other trials,” Meyer said, that analysis found “mean increases in eGFR [in bardoxolone-treated patients] that were sustained through study week 48.” Its authors — who include Meyer, another Reata researcher, along with scientists at universities in Alabama, Boston, California, Chicago, Colorado, Texas, Germany and the Netherlands — concluded that “[b]ardoxolone methyl preserves kidney function and may delay the onset of ESRD [end-stage renal disease] in patients with T2D and stage 4 CKD.”

This data, Meyer said, “show that the drug is affecting the structure of the kidney; it’s disease-modifying. It also rules out injury or harm.”

Meyer also called “not true” comments that bardoxolone’s precise mechanism of action is unknown and that the increase in eGFR could be due to raised pressure in the kidney. How the therapy works has been characterized in “multiple, peer-reviewedstudies and does not involve increased kidney pressure, he said. He provided a list of those studies.

Many people think the only way to change filtration in the kidney is to increase pressure, but that “is not correct,” he said. Studies have shown that bardoxolone elevates eGFR by increasing the kidneys’ surface area for filtration. In response to inflammation like that in Alport syndrome, he said, this glomerular filtration area contracts, which reduces eGFR. Bardoxolone works to block this effect.

As for safety signals that may be missed due to CARDINAL’s design, Meyer noted that BEACON trial data was used to evaluate bardoxolone’s safety extensively, and the fluid retention that risked heart failure was found in a subset of patients now excluded from ongoing trials. There was no evidence of cardiac or liver toxicity, he said, and lowered magnesium levels seen in treated BEACON patients were not due to kidney damage, “so it’s not been clinically concerning.”

Increases in urinary albumin indeed did relate to changes in the kidney due to bardoxolone, but not every increase in proteinuria is “necessarily a bad increase,” Meyer said. Rather, again citing the recent AJN study, “we’ve shown the increase in proteinuria is proportional to the increase in eGFR.”

“I think all of those [found in BEACON] are key adverse events,” Meyer said. But “a lot of these concerns were raised years ago, and we have been able to address them both with clinical data and preclinical data.” 

Meyer, also a vice president for product development at Reata, said he eventually will submit his own perspective to JASN. For now, though, he pointed to a commentary questioning Baigent and Lennon — published in the same journal issue — by Robert Toto, MD, a kidney disease specialist at UT Southwestern, and an investigator on the BEAM and BEACON trials. Toto is a member of the Data Monitoring Committee for the CARDINAL study.

“I think if someone were to read both of them,” Meyer said, “they would note that Bob Toto … does directly address some of these comments and the concerns they [Baigent and Lennon] generated.”

In his perspective piece, “Bardoxolone—the Phoenix?,” Toto wrote that CARDINAL was the result of “a community of scientists” arguing in favor of advancing bardoxolone testing to see if it might indeed prevent end-stage kidney disease in patients at high-risk, like those with Alport, a “progressive [disease] with no known treatment, which uniformly leads to ESRD.”

He also argued that “[l]essons learned from the BEACON Trial have proven useful” and the “rationale is strong: chronic inflammation is a constant histologic feature of common and rare causes of CKD.”

Toto continued: “[R]ecent post hoc analyses of the BEACON Trial showed that increases in eGFR in patients randomized to bardoxolone were durable for a year and that bardoxolone significantly reduced the risk of reaching a composite renal end point,” while BEAM and the BEACON patients treated for at least one year — who then stopped therapy for a four-week washout period — “showed a significant placebo-corrected increase in eGFR, suggesting that some of the effect persists and that the mechanism and clinical profile of bardoxolone are not likely to be deleterious.”

And, he concluded: “The CARDINAL Program is exemplary of the Orphan Drug Act’s intent to allow the pursuit of promising compounds that have the potential to improve human health.”

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