The FDA’s recent complete response letter (CRL) for vadadustat — an oral therapy evaluated for the treatment of anemia in patients with chronic kidney disease (CKD) — was a big surprise and disappointment for our community. The trials had quite convincingly demonstrated efficacy as measured by raising hemoglobin levels and safety as measured by major adverse cardiovascular events (MACE) for the dialysis-dependent population—findings that should have sealed the approval, but did not.

It was perplexing that the FDA decided against seeking insight from the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) for vadadustat, which is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Did the FDA’s experience with the roxadustat advisory committee meeting, in which they overwhelmingly voted against approving the drug for the treatment of anemia associated with CKD in the dialysis-dependent and non-dialysis-dependent patient populations, sound the death knell for vadadustat and the entire HIF-PHI class of drugs?

Roxadustat has already been approved in Japan, South Korea, Chile, and the EU. Vadadustat is approved in Japan and is currently pending approval in the EU. The FDA seems to be an outlier as a regulatory agency by failing to see the positive benefit/risk assessment of this drug class. Any potential safety concerns with HIF-PHIs that the FDA may have can easily be resolved with a long-term pharmacovigilance plan.

The FDA was primarily concerned with venous thromboembolism and vascular access thrombosis events with roxadustat; yet there was no indication that vadadustat had that safety issue. Data presented at the American Society of Nephrology’s annual meeting in 2021 specifically addressed thromboembolic complications and vascular access thrombosis in dialysis and non-dialysis patients and clearly showed that vadadustat was non-inferior to the study comparator, darbepoetin. This should have allayed the concerns that the CRDAC had with roxadustat, while distinguishing that vadadustat had a better safety record both in terms of MACE and of venous thromboembolism and vascular access thrombosis.

The fact that the FDA did not even request a CRDAC for vadadustat suggests that the regulators may have already made up their minds about this entire class of drugs. This is disappointing and unfortunate for America’s vulnerable kidney patients.

One of the greatest unmet needs in treating anemia is in the non-dialysis patient population, which lacks convenient treatment options. Erythropoietin stimulating agents (ESAs) are difficult to administer. These parenteral drugs may require patients to visit a healthcare facility for administration, which can be burdensome for patients and their caregivers, especially considering the frequency of administration. In contrast, HIF-PHIs are oral agents that improve both iron absorption and mobilization, thereby reducing the need for iron administration in anemic CKD patients. Considering all these factors, HIF-PHIs could be effective and more convenient for non-dialysis CKD patients who are receiving inadequate treatment today.

Medicare data indicate disconcerting findings: those 65 and older are more likely to have received a transfusion to treat their anemia than iron or ESAs during the two years prior to dialysis initiation. Transfusions are undesirable because they lead to allosensitization, potentially reducing the patient’s donor pool for a future transplant. This is counterproductive to the mission of the federal government’s Advancing American Kidney Health (AAKH) initiative, which aims to improve kidney transplantation rates. Moving forward, it will be critical for stakeholders to evaluate ways to align these incentives and the ability to administer an oral agent at home to treat anemia, avoid transfusions, and help fulfill the goals of improved transplantation rates. However, if the FDA has already made up its mind about the safety of this class of drugs, sadly, we will not see any significant improvements in the treatment of anemia for the non-dialysis patient population.

Dialysis-dependent patients are different from the non-dialysis patient population: 80% of individuals in the former group achieve their target hemoglobin levels with moderate doses of ESAs. However, the remaining 10-20% are hyporesponders for a variety of reasons usually related to inflammation.  With a novel mechanism of action, HIF-PHIs would likely be more effective in reducing hepcidin levels, thereby mobilizing iron, helping patients avoid transfusions, and improving quality of life related to higher hemoglobin levels. Another important point is that one of the AAKH initiative’s goals is to increase home dialysis rates to 40-50% of patients. Considering the burden associated with administering parenteral ESAs, HIF-PHIs would add value to the treatment plan of patients who do not require regular visits to a dialysis facility.

Impact of the FDA’s decision on the HIF-PHI drug class

Reflecting on how the FDA’s decision would impact other agents in the class that are currently under development, one has to wonder about daprodustat, another HIF-PHI currently under review by the FDA. Results published in the New England Journal of Medicine (NEJM), which were presented in November 2021 at the American Society of Nephrology annual meeting, showed non-inferiority for MACE in both dialysis and non-dialysis populations based on an intention to treat analysis—the gold standard for analyzing drug safety. MACE non-inferiority of daprodustat was demonstrated among the dialysis population in both intention-to-treat and the on-treatment analysis.

With the CRL for vadadustat, the FDA has made the puzzling decision to extrapolate the safety findings of vadadustat in the non-dialysis population to the dialysis-dependent population, despite non-inferiority data for the latter. According to Akebia, the developer of vadadustat, the FDA has cited hepatocellular injury and thromboembolic events, specifically vascular access thrombosis, as the basis for its rejection. However, the results published in NEJM clearly show these adverse events were no different than the active comparator—hepatocellular injury wasn’t an issue in either population. Table S7 of the supplemental information, which lists the emergent adverse events in the safety population, does show an increase in transaminases in the ESA-untreated non-dialysis patients treated with vadadustat (1.8% of patients) compared to darbepoetin (1.0% of patients). The difference, however, is negligible in the ESA-treated non-dialysis subgroups who received either vadadustat (1.2%) or darbepoetin (1.3%).

In my opinion, this is not a valid reason for rejecting the drug in the non-dialysis population that was studied, and most certainly not in the dialysis population.

The non-dialysis population treated with daprodustat demonstrated an increased incidence of esophageal and gastric erosions, as well as increased cancer risk compared to those treated with darbepoetin. While this was not observed in the dialysis patients treated with daprodustat, if the FDA takes a similar stand to vadadustat and extrapolates the safety results to both groups, it could jeopardize the approval of daprodustat in both populations.

I strongly urge the FDA to conduct a CRDAC for daprodustat so that we do not see a repeat of the non-transparent decision on vadadustat, where it appears to many that the FDA had unilaterally decided on the HIF-PHI class of drugs based on the findings with roxadustat. The FDA has apparently conflated concerns with one drug to concerns about the entire class. We would like to hear directly from experts on a CRDAC as they query the sponsor about a specific drug prior to an approval decision being made.  The FDA should consider each drug on its own merit instead of looking at these drugs as an entire class—both from an efficacy and safety perspective.

Another potentially valuable drug in the nephrology space, tenapanor, was rejected last year by the FDA citing less than robust efficacy, but there were no safety concerns.  However, the benefits of this drug still exist given that it could reduce the number of pills a patient needs to take to decrease serum phosphorus levels. Such treatment options are important in the patient-centered culture we are trying to achieve.  Nephrology has one of the lowest rates of new drug applications, despite the fact that nearly 40 million Americans are living with some form of kidney disease.

It is ironic that the AAKH and the Kidney Innovation Accelerator (KidneyX) -— both federal programs that were conceptualized to improve nephrology care, slow the rate of progression of CKD, and decrease the costs associated with treating end-stage renal disease care — are not able to realize their goals due to barriers to innovation in treatments for kidney disease resulting from the FDA’s track record of rejecting new drug applications for less-than-compelling reasons.

I have no doubt about the efficacy of the HIF-PHIs, and neither does the FDA, in my opinion. While the FDA reviewers are concerned with 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 at higher risk for theoretical adverse outcomes. I am hopeful that the companies developing these drugs — often small startups — will find the resources or right partners to conduct these additional studies, although the challenges are great due to cost and the time involved in such trials.

Kidney disease patients need access to innovative therapies to expand treatment choices and improve quality of life. The FDA should closely examine whether it is applying the appropriate benefit/risk assessment for new drugs intended for this population. The FDA’s non-transparent rejection of vadadustat in the dialysis population, where efficacy is well established and there is no clear safety signal, represents a failure by the FDA to act in the best interests of the patients it was created to serve.

Editor’s Note: The author is on the advisory board of Akebia, which received the FDA rejection of vadadustat — an oral therapy evaluated for the treatment of anemia in patients with chronic kidney disease.

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