Vadadustat given three times weekly (TIW) to patients on dialysis allowed for more stable hemoglobin control and fewer serious adverse events as compared to treatment with an erythropoiesis-stimulating agent (ESA), according to new data.
The hospitalization rate was 10% lower in patients treated with vadadustat versus ESA, and those in the vadadustat group experienced 121.5 events/100 patient-years versus 134.2 events/100 patient-years with ESA. Hemoglobin rising out of normal range, or excursions, were less common in patients treated with vadadustat compared to ESA.
Geoffrey A. Block, MD, associate chief medical officer at US Renal Care, who presented findings from the VOICE trial at the American Society of Nephrology Kidney Week 2026, pointed out that these results are consistent with earlier data from a prior phase 3 trial of daily oral vadadustat administration in 4000 patients. “Our trial has 2,000 patients, and so now we have two randomized trials in 6,000 dialysis patients, both of which show identical results that vadadustat is associated with better outcomes for our patient, and it moves us beyond just managing anemia,” he said. “It moves us towards, I hope, managing the cardiovascular risk that is really unique to our dialysis population.”
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. It received regulatory approval in March 2024 and is indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least three months.
Block explained that in this trial, they wanted to find out if the mechanism of action of a HIF prolyl hydroxylase inhibitor resulted in better clinical outcomes. Organ stunning during hemodialysis leads to ischemic injury over time, he noted, and that this population is subject to repetitive organ stunning, particularly with hemodialysis, every time they receive treatment.
“So this is ischemic injury that accumulates over time, and this is exactly what a HIF prolyl hydroxylase inhibitor should be able to address,” he said. “It stabilizes HIF and helps cells respond to, adapt to, and survive ischemic injury. So there's a very biologically plausible reason that vadadustat would be beneficial in our patients.”
Block and colleagues conducted an active-control, pragmatic trial that evaluated whether TIW vadadustat was non-inferior to standard of care epoetin alfa (EPO). The primary composite endpoint was the unmatched hierarchical win-odds of all-cause mortality and all-cause hospitalization on treatment, while secondary outcomes included the individual components of the hierarchical composite endpoint. Events were identified using electronic health records and management of anemia was directed by the treating nephrologist.
Patients were randomized to TIW-vadadustat (n=943) or EPO (n=1030) and a total of 1,973 were included in the final analysis. Baseline characteristics were similar between treatment groups. The study was terminated in June 2026 when a pre-specified interim analysis met the superiority criterion.
Block explained that they were using the “win statistic,” which is an outcome that nephrology is not all that familiar with. “You're probably familiar with sort of traditional time to event, but the win statistic is quite different,” he said. “The win statistic creates pairs. For example, if you had 100 patients in one arm and 100 patients in another, it would compare every individual with every other individual. So you would get 10,000 comparisons.”
The win-difference was 7.56% overall, with –0.5% for mortality and 8.1% for hospitalization. The incidence rate ratio (IRR) for mortality was 1.00 and for hospitalization IRR was 0.90. Results also showed that mean hemoglobin over time was similar between groups, although patients receiving vadadustat were less likely to experience hemoglobin >12 g/dL (OR 0.36).
“Vadadustat was associated with 16% more wins when you use the win statistic of mortality and hospitalization, and it was driven by a significant reduction in hospitalization,” said Block. “Our win statistic has a p-value of 0.002. Our hospitalization shows a 10% reduction in hospitalization and no difference whatsoever in mortality.”
Serious adverse events occurred in 42% of patients treated with vadadustat compared to 55% with EPO/
“We had an important question that we knew needed to be answered,” Block concluded. “We designed that study and we got it done in honestly a very short amount of time, in a pragmatic way. And I think we've demonstrated that's a reasonable path that can be taken to move things forward.”
Abstract: FR-OR106 High Impact Clinical Trials; Vadadustat Three Times Weekly for the Treatment of Anemia in Patients Receiving Hemodialysis
The VOICE trial is a collaborative trial between U.S. Renal Care and Akebia Therapeutics
