Meadowcroft Amy M, Cizman Borut, Holdstock Louis, Biswas Nandita, Johnson Brendan M, Jones Delyth, Nossuli A Kaldun, Lepore John J, Aarup Michael, Cobitz Alexander R
Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Research Triangle Park, NC, USA.
Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA.
Clin Kidney J. 2019 Feb;12(1):139-148. doi: 10.1093/ckj/sfy014. Epub 2018 Mar 19.
This study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease.
Participants ( = 216) with baseline hemoglobin levels of 9-11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10-11.5 g/dL. The primary outcome was characterization of the dose-response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks.
Over the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from -0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and -0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population.
Daprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.
本研究评估了达泊西汀（一种口服的缺氧诱导因子脯氨酰羟化酶抑制剂，正处于慢性肾脏病贫血治疗的研发阶段）的血红蛋白剂量反应、其他疗效指标及安全性。
216名接受血液透析（HD）且基线血红蛋白水平为9 - 11.5g/dL、此前接受稳定剂量重组人促红细胞生成素（rhEPO）的参与者，被随机分配至一项为期24周的剂量范围、疗效及安全性研究中。参与者停用rhEPO，然后随机接受每日达泊西汀（4、6、8、10或12mg）或对照（安慰剂治疗4周，然后根据需要使用开放标签的rhEPO）。4周后，调整剂量以达到血红蛋白目标值10 - 11.5g/dL。主要结局是4周时达泊西汀与血红蛋白之间剂量反应关系的特征描述；此外，在24周内评估达泊西汀的疗效和安全性。
在最初4周内，血红蛋白较基线的平均变化量从 -0.29g/dL（达泊西汀4mg）剂量依赖性地增加至0.69g/dL（达泊西汀10mg和12mg）。24周时，达泊西汀联合组和对照组血红蛋白较基线（10.4g/dL）的平均变化量分别为0.03g/dL和 -0.11g/dL。对照组中观察到的血浆促红细胞生成素（EPO）水平中位数比达泊西汀联合组高约14倍。达泊西汀的不良事件谱与血液透析人群一致。
从稳定剂量的rhEPO转换后，达泊西汀在最初4周内使血红蛋白产生剂量依赖性变化，并在24周内维持血红蛋白目标水平。
