The FDA’s recent Complete Response Letter (CRL) to vadadustat — an oral therapy evaluating anemia in patients with chronic kidney disease (CKD) — was a huge surprise and disappointment for our community. These trials very convincingly demonstrated efficacy as measured by increased hemoglobin levels and safety as measured by major adverse cardiovascular events (MACE) in dialysis-dependent populations—findings that should have been approved but did not.
Confusingly, the FDA decided not to seek insights from the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) on vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Whether the FDA’s experience at the roxadustat advisory committee meeting, which voted overwhelmingly against approval of the drug for the treatment of CKD-related anemia in both dialysis-dependent and non-dialysis-dependent patient populations, sounded the death knell for vadadustat and HIF-PHI in general class of drugs?
Roxadustat is approved in Japan, South Korea, Chile and the European Union. Vadadustat was approved in Japan and is currently awaiting EU approval. As a regulatory agency, the FDA appears to be an outlier in that it does not see a positive benefit/risk assessment for this drug class. Any potential safety concerns the FDA may have with HIF-PHI can be easily addressed through a long-term pharmacovigilance program.
The FDA is primarily concerned with venous thromboembolism and vascular access thrombotic events with roxadustat; however, there is no indication that vadadustat is a safety concern. Data presented at the 2021 American Society of Nephrology Annual Meeting specifically focused on thromboembolic complications and vascular access thrombosis in dialysis and non-dialysis patients, and clearly demonstrated that vadadustat was non-inferior to the study comparator, darbepoetin. This should allay the CRDAC’s concerns about roxadustat, while indicating that vardarestat has a better safety record for MACE and venous thromboembolism and vascular access thrombosis.
The fact that the FDA didn’t even apply for a CRDAC for vadadustat suggests that regulators may have already made a decision on this class of drugs. This is disappointing and unfortunate for America’s vulnerable kidney patients.
One of the greatest unmet needs for treating anemia is the non-dialysis patient population, who lack convenient treatment options. Erythropoietin-stimulating agents (ESAs) are difficult to administer. These parenteral drugs may require patient visits to a healthcare facility for administration, which can be a burden for patients and their caregivers, especially given the frequency of administration. In contrast, HIF-PHI is an oral drug that improves iron absorption and mobilization, thereby reducing the need for iron in anemic CKD patients. Taking all these factors into consideration, HIF-PHI may be more effective and convenient for currently undertreated non-dialysis CKD patients.
health insurance data disturbing discovery: People 65 and older were more likely than iron or ESA to receive blood transfusions to treat anemia in the two years before dialysis started. Blood transfusions are not advisable because they cause allogeneic sensitization, potentially reducing the patient’s donor pool for future transplants.This runs counter to the mission of the federal government Advancing American Kidney Health (AAKH) initiative to increase kidney transplant rates. Going forward, stakeholders must assess how to align these incentives and the ability to use oral medications at home to treat anemia, avoid blood transfusions, and help meet the goals of increasing transplant rates. However, if the FDA has made a decision on the safety of this class of drugs, unfortunately, we will not see any significant improvement in the treatment of anemia in non-dialysis patients.
Dialysis-dependent patients differed from the non-dialysis patient population: 80% of patients in the former group achieved their target hemoglobin levels with moderate doses of ESA. However, the remaining 10-20% are low responders who are usually associated with inflammation for a variety of reasons. With a novel mechanism of action, HIF-PHI may be more effective at lowering hepcidin levels, thereby mobilizing iron, helping patients avoid blood transfusions, and improving quality of life associated with higher hemoglobin levels. Another focus is that one of the goals of the AAKH initiative is to increase home dialysis rates to 40-50% of patients. Given the burdens associated with managing parenteral ESAs, HIF-PHI will add value to treatment planning for patients who do not require regular visits to dialysis facilities.
Impact of FDA Decision on HIF-PHI Drug Class
Given how the FDA’s decision will affect other drugs currently in development in this class, one has to wonder about daprodustat, another HIF-PHI currently under review by the FDA.The results are published in New England Journal of Medicine (New England Journal of Medicine), presented at the American Society of Nephrology Annual Meeting in November 2021, showed non-inferiority of MACE in dialysis and nondialysis populations based on an intention-to-treat analysis (the gold standard for analyzing drug safety). MACE noninferiority of daplustat was demonstrated in the dialysis population in both intention-to-treat and treat-to-treat analyses.
With the CRL for vadadustat, the FDA made the puzzling decision to extrapolate the safety results of vadadustat in the non-dialysis population to the dialysis-dependent population, despite the latter’s noninferiority data. According to Akebia, TonHe is the developer of vadadustat, The FDA has cited hepatocyte injury and thromboembolic events, particularly vascular access thrombosis, as the basis for its rejection.However, published in New England Journal of Medicine It was clearly shown that these adverse events were no different from the active comparator – hepatocyte injury was not a problem in either population.Table S7 of additional materialsEmergent adverse events in the safety population were listed and did show increases in transaminases in ESA-naïve non-dialysis patients treated with vadadustat (1.8% of patients) compared with darbepoetin (1.0% of patients). However, the difference was negligible in the ESA-treated nondialysis subgroup receiving vadadustat (1.2%) or darbepoetin (1.3%).
In my opinion, this is not a valid reason to refuse the drug in the non-dialysis population studied, and certainly not in the dialysis population.
There was an increased incidence of esophageal and gastric erosions and an increased risk of cancer in the non-dialysis population treated with daprodustat compared with the population treated with darbepoetin. While this was not observed in dialysis patients treated with daprodustat, it could jeopardize the approval of daprodustat in both populations if the FDA took a similar stance on vadadustat and extrapolated safety results to both groups .
I strongly urge the FDA to do a CRDAC on daprodustat so we don’t see a duplication of the opaque decision on vadadustat that, in the eyes of many, the FDA made unilaterally based on the findings of the HIF-PHI drug roxadustat. The FDA is apparently conflating concerns about one drug with concerns about an entire class. We want to hear directly from CRDAC experts as they ask sponsors about specific drugs before making approval decisions. The FDA should consider each drug on its own merits, rather than treating the drugs as a whole in terms of efficacy and safety.
Another potentially valuable drug in nephrology, Tenapano, was rejected by the FDA last year, citing poor efficacy but no safety concerns. However, the benefit of the drug remains as it reduces the number of pills a patient needs to take to lower serum phosphorus levels. Such treatment options are important in the patient-centered culture we strive to achieve. Although nearly 40 million Americans suffer from some form of kidney disease, nephrology is one of the fields with the lowest NDA rates.
Ironically, AAKH and the Kidney Innovation Accelerator (KidneyX) – Both federal programs were conceptualized to improve nephrology care, slow the rate of CKD progression, and reduce costs associated with treating end-stage renal disease care – Unable to achieve their goals due to barriers to therapeutic innovation Then there are compelling reasons to deny a new drug application on record due to kidney disease.
In my opinion, I have no doubts about the efficacy of HIF-PHI, nor does the FDA. While FDA reviewers focus on drug safety, they have left the door open for drug developers to conduct some additional safety studies, perhaps in smaller groups of patients who may be theoretically at higher risk for adverse outcomes. It is my hope that the companies developing these drugs – usually small startups – will be able to find the resources or suitable partners to conduct these additional studies, albeit challenging due to the cost and time involved in such trials.
People with kidney disease need access to innovative therapies to expand treatment options and improve quality of life. FDA should carefully examine whether an appropriate benefit/risk assessment is being conducted for new drugs targeting this population. The FDA’s opaque rejection of vadadustat in the dialysis population in which efficacy is well established but no clear safety signal suggests the FDA has failed to act in the best interests of the patients it serves.
Editor’s Note: The author is a member of the Akebia Advisory Committee, which accepted the FDA’s rejection of vadadustat, an oral therapy used to treat anemia in patients with chronic kidney disease.
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