Unforced Error: Reata’s Decision To Ignore US FDA Endpoint Advice May Haunt Bardoxolone
Executive Summary
Advisory committee will vet FDA argument that even though the chronic kidney disease drug met its endpoints, the trial design didn’t allow Reata to demonstrate that bardoxolone slows decline in kidney function. Safety concerns and COVID-19 trial disruptions also likely to prove worrisome.
Reata Pharmaceuticals, Inc.’s failure to listen to the US FDA’s trial design advice looks likely to sink its rare disease chronic kidney disease treatment bardoxolone at the company’s 10 December advisory committee meeting. The agency believes the company’s sole Phase III study was not designed to adequately evaluate the potential of bardoxolone to slow the progression of decline in kidney function.
Reata is seeking approval of bardoxolone to slow the loss of progression of kidney disease caused by Alport syndrome in patients 12 and older.
But the company’s inability to convince FDA the drug has a clear clinical benefit, along with an array of safety concerns, doesn’t bode well for a positive vote from the Cardiovascular and Renal Drugs Advisory Committee or the agency’s final stamp of approval, despite the rare disease’s high unmet medical need.
The committee will vote on whether the provided evidence demonstrates that bardoxolone is effective in slowing the progression of chronic kidney disease in Alport syndrome and that its benefits outweigh its risks. (See table at the end of the story for a full list of the draft questions.)
Timing Of Secondary Endpoint Measurement Problematic
FDA’s advisory committee preview documents indicate it warned the sponsor as early as 2016 that its trial design could be problematic for demonstrating efficacy.
Reata’s Phase III clinical trial, the CARDINAL study, enrolled 157 patients in a randomized, placebo-controlled trial that measured the change from baseline in estimated glomerular filtration rate (eGFR) at week 48 and week 100. The key secondary endpoint looked at the change from baseline in eGFR following a 4-week drug treatment withdrawal period at week 52 and week 104.
While both endpoints were met, it is the timing of the measurement in the key secondary endpoint that raised FDA’s concerns about whether the drug slows the loss of kidney function and will reduce the risk of progression to kidney failure.
Reata should not be surprised by this concern as FDA says it raised issues about the design of the Phase III trial and its ability to differentiate bardoxolone’s pharmacodynamic effect on kidney function from its effect on disease progression throughout the course of development.
The agency recommended that the sponsor conduct a separate study to characterize the time course for resolution of bardoxolone’s pharmacodynamic effect or modify the CARDINAL Phase III to obtain the information by including additional off-treatment eGFR measurements.
FDA said it provided “extensive written feedback on,” on the planned Phase II/III trial in December 2016 following an October 2016 pre-Investigational New Drug meeting where it noted that due to the drug’s pharmacodynamic effect on kidney function, post-treatment assessment of creatine should be used to assess bardoxolone’s efficacy.
In particular, the agency says it “repeatedly voiced concerns” about needing to ensure it measured the off-treatment values at the appropriate timepoint so that they weren’t capturing the drug’s continued pharmacodynamic effect following discontinuation of treatment.
The agency recommended that the sponsor conduct a separate study to characterize the time course for resolution of bardoxolone’s pharmacodynamic effect or modify the CARDINAL Phase III to obtain the information by including additional off-treatment eGFR measurements.
In September 2018, FDA encouraged the sponsor to request an end-of-phase 2 meeting to discuss the program and ensure alignment but the company declined.
Ultimately, FDA believes the study’s 4-week washout was not long enough for the reversible pharmacodynamic effects on eGFR to resolve thus making it impossible to conclude that changes in eGFR compared with placebo at the end of the year-2 washout period indicate bardoxolone’s effect on slowing disease progression.
Even if the drug does provide a benefit on loss of kidney function, FDA says the pattern of the treatment effects on eGFR suggest “it is a one-time benefit that manifests shortly after initiating treatment and does not grow over time, calling into question the benefit of starting treatment at an early stage of disease.”
Could Drug Actually Accelerate Progression To Kidney Failure?
Three primary safety concerns, including two that may suggest the drug has the potential to worsen some kidney disease outcomes, are likely to further decrease bardoxolone’s chance of approval.
First, in the CARDINAL study, initiation of the drug was associated with an increase in albuminuria, which can be a marker of kidney damage.
Second, in another Phase III study of the drug in chronic kidney disease with type 2 diabetes patients which the FDA relied heavily on for safety due to the small Phase III study in Alport syndrome, bardoxolone was shown to increase both systolic blood pressure and diastolic blood pressure over 24 hours. Even small increases in blood pressure may be a concern in drugs intended for chronic use particularly if the population is at increased cardiovascular risk as chronic kidney disease patients can be, FDA said.
The third safety concern for FDA relates to weight loss seen in the CARDINAL trial in both pediatric and adult patients on the drug. The FDA is concerned about the weight loss and its impact on pediatric patients if the weight loss impacts their growth and development – though it notes it can’t conclude whether this will be an issue given uncertainty about the cause of the weight loss and the small pediatric sub population studied.
Further safety concerns arise from the BEACON type 2 diabetes study. That study aimed to look at 2,185 patients and assess the efficacy of the drug relative to placebo in delaying progression to end-stage renal disease and cardiovascular death. However, it was stopped early due to safety concerns including excess serious adverse events and mortality in the drug group. There was a higher rate of all-cause mortality in the drug group, higher rates of fluid overload-related SAEs including heart failure in the drug group and an overall unfavorable benefit-risk profile.
There were no deaths or concerning imbalances in the patterns of SAES in the CARDINAL study, though more patients discontinued treatment or had dose modifications in the drug. While there were no cases of heart failure in the CARDINAL study as in BEACON, the Alport syndrome study excluded patients with a history of heart failure or cardiac disease.
COVID-19 Complicated Study
The bardoxolone study had to be adjusted due to the COVID-19 pandemic. After week 75, between about 15% and 24% of the visits were impacted by the pandemic, including procedures not performed, and visited conducted out of window.
Reata made some trial adjustments to deal with the virus, including pushing back some patients' week 100 and week 104 visits and dispensing study medication by mail.
FDA’s review notes that there are “significant discrepancies” between the study’s finding for both year-2 on-treatment and off-treatment analyses in the subgroups that completed the study pre-COVID versus during COVID. The COVID subgroup was about two to three times larger than the pre-COVID subgroup who completed all their visits prior to 1 March 2020. The study’s findings were driven by the COVID subgroup but the reason for the differences in the subgroups remain unclear.