Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease
Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease
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DOI：
10.1016/j.kint.2016.07.019
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发表时间：
2016-11-01
影响因子：
19.6
通讯作者：
Haase, Volker H.
中科院分区：
文献类型：
--
作者：
Pergola, Pablo E.;Spinowitz, Bruce S.;Haase, Volker H.
目前用红细胞生成刺激剂治疗慢性肾病（CKD）贫血可导致血红蛋白大幅波动超过目标范围和高水平的循环促红细胞生成素。Vadadustat（AKB-6548）是一种新型的、可滴定的、口服的缺氧诱导因子脯氨酰羟化酶抑制剂，可诱导内源性促红细胞生成素合成并增强铁动员。在这项为期20周、双盲、随机、安慰剂对照、2b期研究中，我们评估了vadadustat每日一次在3a至5期非透析依赖性CKD患者中的疗效和安全性。主要终点是在治疗的最后2周内达到或维持平均血红蛋白水平≥ 11.0 g/dl或血红蛋白较给药前平均值平均增加≥ 1.2 g/dl的患者百分比。值得注意的是，vadadustat组54.9%的患者和安慰剂组10.3%的患者达到了主要终点。与安慰剂组相比，vadadustat组患者的网织红细胞和总铁结合力显著增加，血清铁调素和铁蛋白水平显著降低。两组间不良事件的总体发生率相当。vadadustat组和安慰剂组分别有23.9%和15.3%的患者发生严重不良事件。vadadustat组发生3例死亡。因此，这项2b期研究表明，vadadustat以可预测和可控的方式升高并维持血红蛋白水平，同时增强非透析依赖性CKD患者的铁动员。
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.