Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease

Abstract

Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.

Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease

“…The reticulocyte profile mimicked the predicted response to altitude-associated hypoxia [22]. Similar results were observed in a 20-week, phase 2b trial of vadadustat administered to patients with anemia secondary to NDD-CKD [23]. …”

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

“…Participants were randomized from an ESA to 300 mg once daily, 450 mg once daily, or 450 mg thrice weekly. Mean change in Hb level within each cohort remained stable throughout the study (e.g., baseline to week 16 ranged from −0.02 to −0.04 g/dl) [57].…”

“…In a subsequent phase IIb, double-blind, placebo-controlled trial, 210 NDD-CKD stage tjhree to five participants were randomized 2:1 into three cohorts to receive a titratable dose of vadadustat (initial dose 450 mg) or placebo once daily for 20 weeks [57]. The three cohorts were based on Hb level and ESA treatment status at screening: cohort 1 were ESA naïve (Hb ≤10.5 g/dl); cohort 2 were previously treated with an ESA (Hb ≤10.5 g/dl), and cohort 3 were actively treated with ESA (Hb ≥9.5 to ≤12.0 g/dl).…”

“…In contrast to roxadustat phase II studies, vadadustat administration has not been associated with a change in total cholesterol [56,57]. In phase II studies, it was well tolerated, Open label, randomized, 3-way, cross-over study to evaluate the relative bioavailability, PK, food effect, and palatability of the pediatric formulation versus adult tablet.…”

Anaemia of Chronic Kidney Disease: What We Know Now

“…More recently, Pergola et al studied the effect of vadadustat as compared to placebo in 210 non-dialysis-dependent CKD patients (stages 3-5) in a 20-week multi-centre phase 2b study (81). They showed that 55% of the candidates who received vadadustat achieved the primary end point (percentage of participants who during the last 2 weeks of the treatment achieved or maintained a mean haemoglobin level of >11 g/dl or an increase in haemoglobin level of ≥1.2 g/dl over the pre-dose average) as compared to 10% of the placebotreated candidates, and the drug raised and maintained haemoglobin in a predictable manner with no significant side effects as compared to placebo.…”