vadadustat 治疗贫血及非透析依赖性慢性肾脏病患者的疗效。
Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.
机构信息
From Stanford University School of Medicine, Palo Alto, CA (G.M.C., E.F.L.); Renal Associates, San Antonio (P.E.P.), U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Akebia Therapeutics, Cambridge (Y.M.K.F., S.B., Z.K., W.L., B.J.M., A.S., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Excellentis Clinical Trial Consultants, George, South Africa (S.A.); Bihor County Hospital Oradea, Oradea, Romania (G.B.); Qway Research, Hialeah, FL (F.P.C.); the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.G.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); Firma Clinical Research, Hunt Valley (T.L.), and the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.) - both in Maryland; the Department of Medicine, Memorial University of Newfoundland, St. John's, Canada (P.S.P.); the Division of Nephrology and Hypertension, University of North Carolina Kidney Center, Chapel Hill, and the W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury - both in North Carolina (P.R.-C.); the Division of Nephrology, New York-Presbyterian Queens, Flushing (B.S.); Firma Clinical Research, Chicago (C.T.); Emory University School of Medicine, Atlanta (J.T.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.).
出版信息
N Engl J Med. 2021 Apr 29;384(17):1589-1600. doi: 10.1056/NEJMoa2035938.
BACKGROUND
Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.
METHODS
In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.
RESULTS
A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.
CONCLUSIONS
Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PROTECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
背景
vadadustat 是一种口服低氧诱导因子（HIF）脯氨酰羟化酶抑制剂，属于一类能稳定 HIF 并刺激促红细胞生成素和红细胞生成的药物。
方法
在两项 3 期、随机、开放标签、活性对照、非劣效性试验中，我们比较了 vadadustat 与促红细胞生成素刺激剂（ESA）darbepoetin alfa 在未经 ESA 治疗的非透析依赖性慢性肾病（NDD-CKD）患者中的疗效，这些患者的血红蛋白浓度低于每分升 10 克，以及 ESA 治疗的 NDD-CKD 患者，血红蛋白浓度为每分升 8 至 11 克（在美国）或每分升 9 至 12 克（在其他国家）。主要安全性终点是首次主要心血管不良事件（MACE；任何原因导致的死亡、非致死性心肌梗死或非致死性卒中的复合终点），在两项试验中进行时间事件分析评估。次要安全性终点包括扩展 MACE（MACE 加上因心力衰竭或血栓栓塞事件住院的患者）。每个试验的主要和关键次要疗效终点是从基线到两个评估期（第 24 周到 36 周和第 40 周到 52 周）血红蛋白浓度的平均变化。
结果
共有 1751 名未经 ESA 治疗的 NDD-CKD 患者和 1725 名接受 ESA 治疗的 NDD-CKD 患者在两项试验中进行了随机分组。在合并分析中，1739 名患者接受了 vadadustat 治疗，1732 名患者接受了 darbepoetin alfa 治疗，MACE 的风险比为 1.17（95%置信区间[CI]，1.01 至 1.36），未达到预设的非劣效性边界 1.25。在涉及未经 ESA 治疗的患者的试验中，第 24 周到 36 周血红蛋白浓度变化的组间平均差异为 0.05 克/分升（95%CI，-0.04 至 0.15），在涉及 ESA 治疗的患者的试验中，为-0.01 克/分升（95%CI，-0.09 至 0.07），达到了预设的非劣效性边界-0.75 克/分升。
结论
vadadustat 与 darbepoetin alfa 相比，在 NDD-CKD 患者中达到了血液学疗效的预设非劣效性标准，但未达到心血管安全性的预设非劣效性标准。（由 Akebia Therapeutics 和 Otsuka Pharmaceutical 资助；PROTECT 临床试验.gov 编号，NCT02648347 和 NCT02680574。）
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