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

“We found that, among patients with non–dialysis-dependent CKD, vadadustat was noninferior to darbepoetin alfa with regard to hematologic efficacy but did not meet the prespecified noninferiority criterion for cardiovascular safety, which was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke,” say Glenn M. Chertow, MD, MPH, Stanford University School of Medicine, Palo Alto, California, and colleagues in their paper published this week in the New England Journal of Medicine.

In commenting on the research, Jay B. Wish, MD, medical director of the Out-Patient Dialysis Unit at Indiana University Hospital, Indianapolis, said the findings raise some concerns.

“There is little question regarding the efficacy of vadadustat — and HIF-PHIs in general, based on other studies, but there are still many questions to be answered regarding the safety of this new class of anemia agents,” he told Medscape Medical News.

“The lack of non-inferiority of vadadustat vs darbepoetin with regard to the time to a major adverse cardiovascular event (MACE) in the non-dialysis-dependent CKD population is of concern and may be a barrier to approval by the US Food and Drug Administration (FDA),” he added.

In an accompanying editorial, Adeera Levin, MD, head of the Division of Nephrology, University of British Columbia in Vancouver, Canada, agreed that the data offer pros — and notable cons.  

“The data are convincing that vadadustat is effective in increasing hemoglobin concentrations in both dialysis-dependent and non–dialysis-dependent populations but are less convincing with respect to safety,” she said.

Injectable Erythropoiesis-Stimulating Agents Have Safety Issues of Their Own

Anemia is a common concern among patients with CKD, affecting as many as 30% to 40% of patients who are not dependent on dialysis, and while injectable erythropoiesis-stimulating agents (ESAs) — along with iron deficiency correction — are recommended, ESAs carry a risk of cardiovascular events when treatment is targeted to near-normal levels of hemoglobin concentrations, resulting in a black-box warning requirement for the agents from the FDA.

The development of oral HIF-PHIs has meanwhile been greeted with excitement as potentially offering more convenience and adherence to treatment, and some agents in this class, including roxadustat, have already been approved in some countries.

To comprehensively compare the HIF-PHI vadadustat with the commonly used ESA, darbepoetin alfa (Aranesp), for safety and efficacy, researchers conducted two pooled analyses, each involving two open-label, noninferiority trials, with one analysis involving patients with CKD who did not require dialysis and another of patients who were undergoing dialysis.

In the first, Chertow and co-authors looked at the pooled data from two randomized, phase 3 noninferiority trials of patients with CKD who were not on dialysis, and who either were previously treated with an ESA (n = 1725) or were not previously treated with an ESA (n = 1751).

With a median follow-up of 1.63 and 1.80 years in the two studies, vadadustat did achieve noninferiority compared with darbepoetin alfa for hematologic efficacy, with least-squares mean changes in hemoglobin concentration from baseline to weeks 24 through 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 withing the prespecified noninferiority margin.

However, in the primary safety endpoint of the time to first MACE — a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke — pooled across 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 failed to meet the prespecified noninferiority margin of 1.25.

The authors note that an analysis of events in the trials suggested that the higher risk in the vadadustat group was largely the result of an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes; however, the causes of the higher noncardiovascular deaths could not be determined.

No Increased Risk Seen in Dialysis-Dependent Patients

In the second study, by Kai-Uwe Eckardt, MD, of the Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin, Berlin, Germany, and colleagues, also published in NEJM this week, the researchers looked at two trials with a combined 3923 patients who were dependent on dialysis. This also showed that vadadustat was noninferior to darbepoetin alfa in the correction and maintenance of hemoglobin concentration, with 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, therefore achieving noninferiority.

“The two international phase 3 clinical trials…met the prespecified noninferiority margins for cardiovascular safety, pooled across the two trials, and hematologic efficacy, assessed separately for each trial,” Eckardt and coauthors write.

Nevertheless, the possibility of safety issues that may exceed those already seen with ESAs is troublesome, Wish, the Indiana U. nephrologist, further commented.

“The FDA already considers ESAs to be dangerous enough to merit a black-box warning, and the restrictions regarding its use in non–dialysis-dependent patients (target Hb 10-10 g/dL) are even greater than those for dialysis-dependent patients (target Hb 10-11 g/dL),” he said. 

“So, an agent that may be even less safe than ESAs in the non–dialysis-dependent population may be considered by the FDA too toxic for approval.”

Higher Risk in Patients Not Dependent on Dialysis Seen Before

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

“Peginesatide (Omontys) [an erythropoiesis-stimulating agent that was recalled by the FDA in 2013 due to some cases of fatal anaphylaxis] had this exact same issue with 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 cardiovascular risk property of vadadustat that is somehow blunted 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 off-target gene transcription induced by HIF-PHIs,” Wish added. 

“There may be off-target beneficial effects as well, which along with long-term adverse effects, may only be answered with long-term follow-up studies and registries following drug approval.”

In her editorial, Levin further underscored the need for more research into these unanswered questions.

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

“To enable us to have informed discussions with our patients, many more questions need to be asked and answered,” she concludes.

The studies were supported by Akebia Therapeutics and Otsuka Pharmaceutical. Wish disclosed that he has been invited to a vadadustat virtual advisory board meeting in May 2021 by Otsuka and Akebia. Levin disclosed that she has provided 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.

Chertow et al study. Abstract
Eckardt et al study. Abstract
Editorial

For more news, follow Medscape on Facebook, Twitter, Instagram, YouTube, and LinkedIn