Vadadustat for anemia in chronic kidney disease: questions remain

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Oral vadadustat, one of the new inhibitors of prolyl hydroxylase (HIF-PHIs), a hypoxia-inducible factor, is effective in the treatment of anemia in people with chronic kidney disease (ERC), but cardiovascular safety outcomes do not surpass conventional injectable therapy in patients who are not dependent on dialysis, according to new data.

“We found that, among patients with CKD not dependent on dialysis, vadadustat was not less than darbepoetin alfa in terms of haematological efficacy, but did not meet the pre-specified non-inferiority criterion for cardiovascular safety, which was a death compound for any cause, not fatal myocardial infarctionor non-fatal stroke“say Glenn M. Chertow, MD, MPH, Stanford University School of Medicine, Palo Alto, California, and colleagues at work published this week at the New England Journal of Medicine.

Commenting on the investigation, Jay B. Wish, MD, medical director of the Outpatient Dialysis Unit at Indiana University Hospital, Indianapolis, said the findings raise some concerns.

“There are few questions about the effectiveness of vadadustat and HIF-PHIs in general, based on other studies, but there are still many questions to be answered about the safety of this new class of anemia agents.” he said. Medscape Medical News.

“The lack of non-inferiority of vadadustat versus darbepoetin is worrying in terms of time for a major adverse cardiovascular event (MACE) in the ERC population that is not dependent on dialysis and may be a barrier to the approval of U.S. Food and Drug Administration (FDA), ”he added.

In a accompanying editorial, Adeera Levin, MD, head of the Division of Nephrology at the University of British Columbia in Vancouver, Canada, agreed that the data offer notable advantages and disadvantages.

“The data are compelling that vadadustat is effective in increasing hemoglobin concentrations in both dialysis-dependent and non-dialysis-dependent populations, but they are less convincing in terms of safety,” he said.

Injectable Erythropoiesis stimulating agents have their own safety problems

Anemia is a common concern among patients with CKD, affecting up to 30% to 40% of patients who are not dependent on dialysis, and although injectable erythropoiesis-stimulating agents (AES) are recommended, along with correction of iron deficiency, a risk of cardiovascular events when treatment is directed at near-normal levels of hemoglobin concentrations, leading to a black box warning requirement for FDA agents.

Meanwhile, the development of oral HIF-PHIs has been received with excitement, as it may offer more comfort and adherence to treatment, and some agents of this class, including roxadustat, have already been approved in some countries.

To thoroughly compare the HAD-PHI vadadustat with the most widely used ESA, darbepoetin alfa (Aranesp), for safety and efficacy, the researchers conducted two pooled analyzes, each with two open non-inferiority assays, with an analysis in patients with CKD who did not require dialysis and another of the patients who were on dialysis.

At first, Chertow and co-authors examined the pooled data from two randomized, phase 3 non-inferiority trials of patients with CKD who were not on dialysis and who had previously been treated with an ESA (n = 1725) or not previously treated with a ESA (n = 1751).

With a mean follow-up of 1.63 and 1.80 years in both studies, vadadustat achieved non-inferiority compared to darbepoetin alfa for haematological efficacy, with mean changes of least squares in hemoglobin concentration from baseline to weeks 24 to 36 of 1.43 ± 0.05 g per deciliter in the vadadustat group and 1.38 ± 0.05 g per deciliter in the darbepoetin alfa group, falling with the non-inferiority margin pre-specified.

However, at the primary safety endpoint of time to the first MACE (a compound of death from any cause, nonfatal myocardial infarction, or nonfatal stroke) grouped in the two trials, a first MACE occurred in 22%. in the vadadustat group and 19.9% ​​in the darbepoetin alfa group, for a hazard ratio of 1.17, which did not reach the pre-specified non-inferiority margin of 1.25.

The authors note that an analysis of trial events suggested that the increased risk in the vadadustat group was largely the result of an excess of non-fatal myocardial infarctions and a higher incidence of death from non-fatal causes. cardiovascular; however, the causes of the highest non-cardiovascular deaths could not be determined.

No increased risk has been seen in dialysis-dependent patients

A la second study, by Kai-Uwe Eckardt, MD, of the Department of Nephrology and Intensive Care, Charité – Universitätsmedizin, Berlin, Germany, and colleagues, also published in NEJM this week, researchers examined two trials with 3,923 dialysis-dependent patients. This also showed that vadadustat was not inferior to darbepoetin alfa in the correction and maintenance of hemoglobin concentration, with the target hemoglobin concentrations achieved in both trials.

However, unlike the analysis of non-dialysis-dependent patients, the incidence of a first MACE event was similar between the two agents, thus achieving non-inferiority.

“The two international phase 3 clinical trials … met the pre-specified margins of non-inferiority for cardiovascular safety, grouped between the two trials and the haematological efficacy, assessed separately for each trial,” write Eckardt and co-authors .

However, the possibility that there are safety issues that may exceed those already seen with ESAs is problematic, said more, Wish, the Indiana nephrologist.

“The FDA already considers AES to be dangerous enough to deserve a black box warning and the restrictions on its use in non-dialysis patients (target Hb 10-10 g / dL) are even greater than which depend on dialysis patients (target Hb 10-11 g / dL), ”he said.

“Therefore, an agent that may be even less safe than ESAs in the population that is not dependent on dialysis may be considered by the FDA too toxic for approval.”

Increased risk in patients who did not depend on dialysis seen before

While the highest risk observed among patients who are not dependent on dialysis is puzzling, Wish noted that this is not the first time this pattern has been observed.

Peginesatide (Property) [an erythropoiesis-stimulating agent that was recalled by the FDA in 2013 due to some cases of fatal anaphylaxis] had this same problem with the demonstration of non-inferiority in dialysis-dependent patients, but lack of non-inferiority in non-dialysis-dependent patients, ”he noted.

“The possible explanations are that there is an adverse effect cardiovascular risk vadadustat property that is somehow blunt in the dialysis-dependent population or that the adverse risk property of darbepoetin is greater in the dialysis-dependent population, ”he explained.

Other considerations, in addition to MACE, include “long-term effects that may be due to transcription of genes outside the target induced by HIF-PHIs,” Wish added.

“There may be beneficial effects outside of targets, which along with long-term adverse effects, can only be responded to with long-term follow-up studies and records after drug approval.”

In his editorial, Levin further stressed the need for more research on these unanswered questions.

“The questions raised in these trials should motivate us to answer critical questions about the goals, risks, and benefits of therapy with trials specifically designed to do so,” he writes.

“To allow us to have informed discussions with our patients, we need to ask and answer many more questions,” he concludes.

The studies were supported by Akebia Therapeutics and Otsuka Pharmaceutical. Wish revealed that he had been invited to a meeting of the virtual vadadustat advisory committee in May 2021 by Otsuka and Akebia. Levin revealed that he has given educational seminars on the topic of anemia and HIF-PHIs, some of which were funded by AstraZeneca.

N Eng J Med. Published April 29, 2021.

Study by Chertow et al. Summary
Study Eckardt et al. Summary
Editorial

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