Oral vadadustat noninferior to erythropoiesis-stimulating therapy for CKD-related anemia
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Key takeaways:
- Patients switched to oral vadadustat had hemoglobin levels similar to those on a long-acting erythropoiesis-stimulating agent.
- Vadadustat was noninferior to standard therapy.
Oral vadadustat three times per week was noninferior to a long-acting erythropoiesis-stimulating agent for treating anemia in patients with chronic kidney disease on dialysis, according to study data.
“Anemia in CKD is treated with regular iron supplementation erythropoiesis-stimulating agents (ESAs) and with red blood cell transfusions in patients who have not responded to ESA therapy,” Hakan R. Toka, MD, a nephrologist at Nova Clinical Research in Bradenton, Florida, wrote with colleagues. “However, targeting normal or near-normal hemoglobin concentrations with ESAs has been linked to increased risk of cardiovascular events” as well as additional potential considerations, they wrote, “highlighting an unmet clinical need for alternative therapies for the treatment of anemia in CKD.”
In a phase 3b, open-label, noninferiority trial, researchers assessed a switch to the hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat (Vafseo, Akebia Therapeutics) from the long-acting ESA methoxy polyethylene glycol-epoetin beta (MPG-EPO) by adults with CKD-related anemia from dialysis.
Researchers randomly assigned 456 patients, 1:1:1, to switch to vadadustat at 600 mg three times per week, to switch to vadadustat at 900 mg three times per week or to continue MPG-EPO. Treatment was administered for up to 52 weeks, and 4 safety follow-up weeks, with results evaluated between weeks 20 to 26 and again from weeks 46 to 52.
Researchers also evaluated the proportions of patients with hemoglobin levels in the target range and those who required ESA or red blood cell transfusion rescue for anemia. The study defined noninferiority on the lower end of the 95% confidence interval, above –0.75 g/dL, for the difference in mean change in hemoglobin from baseline.
Main safety endpoints were treatment-emergent serious adverse events.
Toka and colleagues found transfusion rates were similarly low at 2.7% in the combined vadadustat groups and 4% for MPG-EPO group.
Hemoglobin levels were similar for the vadadustat and MPG-EPO groups, with a mean treatment difference of –0.33 g/dL (95% CI, –0.53 to –0.13). Secondary tests showed similar efficacy with a difference of –0.33 g/dL (95% CI, –0.56 to –0.09).
All groups had stable mean hemoglobin concentrations aside from a minor initial decline in the 600-mg group that evened out by week 12, according to the researchers.
Patients in the vadadustat groups were less likely to need ESA rescue therapy during the primary evaluation period, with 14.2% of patients requiring intervention vs. 27.7% in the MPG-EPO group.
Incidences of treatment-emergent adverse events were similar across all groups, according to the researchers.
“Patients in the vadadustat 600-mg group often required dose adjustment after an initial decline in hemoglobin concentrations and were more likely to experience hemoglobin excursions to [less than] 9 g/dL than the vadadustat 900-mg group,” the researchers wrote. “Therefore, a 900 mg [three]-times-weekly starting dose may be preferred for in-center hemodialysis patients switching from MPG-EPO.”
Perspective
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The study by Toka and colleagues demonstrates non-inferiority of vadadustat to erythropoiesis-stimulating agents (ESAs) when vadadustat is administered three times weekly, which would make logistical sense for patients undergoing in-center hemodialysis. The vadadustat label specifies daily dosing, so administering the drug three times weekly would be off label unless Akebia receives a label change based on this newly published study.
Because vadadustat will be in the dialysis payment bundle, a dialysis provider could administer the drug in the facility three times weekly (off label). This is what some providers already do with cinacalcet, which also has a label for daily use. This new study may accelerate the transition from daily home use to three-times weekly dialysis administration among in-center hemodialysis patients who are prescribed the drug. This would give the dialysis provider better assurance that the patient is actually receiving the drug the provider is paying for.
Whether this increases the use of vadadustat vs. ESAs will also depend on the relative cost to the provider of the drugs and the fact that the 2025 Kidney Disease: Improving Global Outcomes anemia draft guidelines suggest that hypoxia-inducible factor prolyl hydroxylase inhibitors be used as second-line agents after ESAs.
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