The FDA’s latest full response letter (CRL) for vadadustat — an oral remedy evaluated for the therapy of anemia in sufferers with power kidney illness (CKD) — was an enormous shock and disappointment for our neighborhood. The trials had fairly convincingly demonstrated efficacy as measured by elevating hemoglobin ranges and security as measured by main adversarial cardiovascular occasions (MACE) for the dialysis-dependent inhabitants—findings that ought to have sealed the approval, however didn’t.
It was perplexing that the FDA determined in opposition to searching for perception from the Cardiovascular and Renal Medicine Advisory Committee (CRDAC) for vadadustat, which is an orally administered hypoxia-inducible issue prolyl hydroxylase inhibitor (HIF-PHI). Did the FDA’s expertise with the roxadustat advisory committee assembly, wherein they overwhelmingly voted in opposition to approving the drug for the therapy of anemia related to CKD within the dialysis-dependent and non-dialysis-dependent affected person populations, sound the dying knell for vadadustat and all the HIF-PHI class of medicine?
Roxadustat has already been authorised in Japan, South Korea, Chile, and the EU. Vadadustat is authorised in Japan and is presently pending approval within the EU. The FDA appears to be an outlier as a regulatory company by failing to see the constructive profit/threat evaluation of this drug class. Any potential security issues with HIF-PHIs that the FDA could have can simply be resolved with a long-term pharmacovigilance plan.
The FDA was primarily involved with venous thromboembolism and vascular entry thrombosis occasions with roxadustat; but there was no indication that vadadustat had that security concern. Knowledge offered on the American Society of Nephrology’s annual assembly in 2021 particularly addressed thromboembolic problems and vascular entry thrombosis in dialysis and non-dialysis sufferers and clearly confirmed that vadadustat was non-inferior to the research comparator, darbepoetin. This could have allayed the issues that the CRDAC had with roxadustat, whereas distinguishing that vadadustat had a greater security document each when it comes to MACE and of venous thromboembolism and vascular entry thrombosis.
The truth that the FDA didn’t even request a CRDAC for vadadustat means that the regulators could have already made up their minds about this whole class of medicine. That is disappointing and unlucky for America’s susceptible kidney sufferers.
One of many biggest unmet wants in treating anemia is within the non-dialysis affected person inhabitants, which lacks handy therapy choices. Erythropoietin stimulating brokers (ESAs) are tough to manage. These parenteral medication could require sufferers to go to a healthcare facility for administration, which could be burdensome for sufferers and their caregivers, particularly contemplating the frequency of administration. In distinction, HIF-PHIs are oral brokers that enhance each iron absorption and mobilization, thereby decreasing the necessity for iron administration in anemic CKD sufferers. Contemplating all these elements, HIF-PHIs could possibly be efficient and extra handy for non-dialysis CKD sufferers who’re receiving insufficient therapy in the present day.
Medicare knowledge point out disconcerting findings: these 65 and older usually tend to have acquired a transfusion to deal with their anemia than iron or ESAs in the course of the two years previous to dialysis initiation. Transfusions are undesirable as a result of they result in allosensitization, doubtlessly decreasing the affected person’s donor pool for a future transplant. That is counterproductive to the mission of the federal authorities’s Advancing American Kidney Well being (AAKH) initiative, which goals to enhance kidney transplantation charges. Transferring ahead, will probably be essential for stakeholders to guage methods to align these incentives and the flexibility to manage an oral agent at house to deal with anemia, keep away from transfusions, and assist fulfill the targets of improved transplantation charges. Nevertheless, if the FDA has already made up its thoughts in regards to the security of this class of medicine, sadly, we won’t see any important enhancements within the therapy of anemia for the non-dialysis affected person inhabitants.
Dialysis-dependent sufferers are totally different from the non-dialysis affected person inhabitants: 80% of people within the former group obtain their goal hemoglobin ranges with average doses of ESAs. Nevertheless, the remaining 10-20% are hyporesponders for quite a lot of causes often associated to irritation. With a novel mechanism of motion, HIF-PHIs would possible be more practical in decreasing hepcidin ranges, thereby mobilizing iron, serving to sufferers keep away from transfusions, and bettering high quality of life associated to increased hemoglobin ranges. One other vital level is that one of many AAKH initiative’s targets is to extend house dialysis charges to 40-50% of sufferers. Contemplating the burden related to administering parenteral ESAs, HIF-PHIs would add worth to the therapy plan of sufferers who don’t require common visits to a dialysis facility.
Affect of the FDA’s choice on the HIF-PHI drug class
Reflecting on how the FDA’s choice would impression different brokers within the class which might be presently below improvement, one has to surprise about daprodustat, one other HIF-PHI presently below evaluate by the FDA. Outcomes revealed within the New England Journal of Drugs (NEJM), which have been offered in November 2021 on the American Society of Nephrology annual assembly, confirmed non-inferiority for MACE in each dialysis and non-dialysis populations based mostly on an intention to deal with evaluation—the gold customary for analyzing drug security. MACE non-inferiority of daprodustat was demonstrated among the many dialysis inhabitants in each intention-to-treat and the on-treatment evaluation.
With the CRL for vadadustat, the FDA has made the puzzling choice to extrapolate the security findings of vadadustat within the non-dialysis inhabitants to the dialysis-dependent inhabitants, regardless of non-inferiority knowledge for the latter. In response to Akebia, the developer of vadadustat, the FDA has cited hepatocellular harm and thromboembolic occasions, particularly vascular entry thrombosis, as the idea for its rejection. Nevertheless, the outcomes revealed in NEJM clearly present these adversarial occasions have been no totally different than the lively comparator—hepatocellular harm wasn’t a difficulty in both inhabitants. Desk S7 of the supplemental info, which lists the emergent adversarial occasions within the security inhabitants, does present a rise in transaminases within the ESA-untreated non-dialysis sufferers handled with vadadustat (1.8% of sufferers) in comparison with darbepoetin (1.0% of sufferers). The distinction, nonetheless, is negligible within the ESA-treated non-dialysis subgroups who acquired both vadadustat (1.2%) or darbepoetin (1.3%).
In my view, this isn’t a sound motive for rejecting the drug within the non-dialysis inhabitants that was studied, and most definitely not within the dialysis inhabitants.
The non-dialysis inhabitants handled with daprodustat demonstrated an elevated incidence of esophageal and gastric erosions, in addition to elevated most cancers threat in comparison with these handled with darbepoetin. Whereas this was not noticed within the dialysis sufferers handled with daprodustat, if the FDA takes an analogous stand to vadadustat and extrapolates the security outcomes to each teams, it may jeopardize the approval of daprodustat in each populations.
I strongly urge the FDA to conduct a CRDAC for daprodustat in order that we don’t see a repeat of the non-transparent choice on vadadustat, the place it seems to many who the FDA had unilaterally selected the HIF-PHI class of medicine based mostly on the findings with roxadustat. The FDA has apparently conflated issues with one drug to issues about all the class. We want to hear instantly from consultants on a CRDAC as they question the sponsor a few particular drug previous to an approval choice being made. The FDA ought to contemplate every drug by itself benefit as an alternative of taking a look at these medication as a complete class—each from an efficacy and security perspective.
One other doubtlessly useful drug within the nephrology area, tenapanor, was rejected final yr by the FDA citing lower than sturdy efficacy, however there have been no security issues. Nevertheless, the advantages of this drug nonetheless exist provided that it may scale back the variety of drugs a affected person must take to lower serum phosphorus ranges. Such therapy choices are vital within the patient-centered tradition we are attempting to realize. Nephrology has one of many lowest charges of latest drug functions, even if practically 40 million People live with some type of kidney illness.
It’s ironic that the AAKH and the Kidney Innovation Accelerator (KidneyX) -— each federal applications that have been conceptualized to enhance nephrology care, sluggish the speed of development of CKD, and reduce the prices related to treating end-stage renal illness care — should not in a position to understand their targets because of limitations to innovation in therapies for kidney illness ensuing from the FDA’s monitor document of rejecting new drug functions for less-than-compelling causes.
I’ve little doubt in regards to the efficacy of the HIF-PHIs, and neither does the FDA, for my part. Whereas the FDA reviewers are involved with drug security, they’ve left the door open for drug builders to conduct some further security research, maybe in smaller teams of sufferers who could also be at increased threat for theoretical adversarial outcomes. I’m hopeful that the businesses creating these medication — usually small startups — will discover the sources or proper companions to conduct these further research, though the challenges are nice because of price and the time concerned in such trials.
Kidney illness sufferers want entry to revolutionary therapies to develop therapy selections and enhance high quality of life. The FDA ought to intently look at whether or not it’s making use of the suitable profit/threat evaluation for brand new medication supposed for this inhabitants. The FDA’s non-transparent rejection of vadadustat within the dialysis inhabitants, the place efficacy is effectively established and there’s no clear security sign, represents a failure by the FDA to behave in the very best pursuits of the sufferers it was created to serve.
Editor’s Word: The writer is on the advisory board of Akebia, which acquired the FDA rejection of vadadustat — an oral remedy evaluated for the therapy of anemia in sufferers with power kidney illness.
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