Supplementary Material for: A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

<b><i>Background:</i></b> Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis. <b><i>Methods:</i></b> Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0–12.0 g/dL in reference to a dose adjustment algorithm (Period 2). <b><i>Results:</i></b> In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated. <b><i>Conclusions:</i></b> Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.

<b><i>背景：</i></b> 依诺司他（enarodustat, JTZ-951）是一种口服缺氧诱导因子脯氨酰羟化酶抑制剂，可模拟低氧条件下的适应性反应，可为慢性肾脏病（chronic kidney disease, CKD）贫血患者提供全新的治疗策略。本研究评估了未接受透析的慢性肾脏病贫血患者使用依诺司他的疗效、安全性及维持给药剂量。
<b><i>方法：</i></b> 将促红细胞生成素刺激剂（erythropoiesis-stimulating agent, ESA）初治患者（校正组）与接受稳定剂量促红细胞生成素刺激剂治疗的患者（转换组）随机分组，分别接受每日一次2mg、4mg或6mg的依诺司他或安慰剂，以双盲方式治疗6周（阶段1）；随后进行24周开放标签的依诺司他治疗，依据剂量调整算法将受试者的血红蛋白（hemoglobin, Hb）水平维持在10.0–12.0 g/dL的目标范围内（阶段2）。
<b><i>结果：</i></b> 在校正组中，每周血红蛋白升高幅度呈剂量依赖性增加。阶段1期间，转换组中维持血红蛋白水平较基线波动在±1.0 g/dL范围内的受试者比例，在各依诺司他给药组与安慰剂组间无显著差异。阶段2治疗结束时，两组中超过70%的受试者均维持血红蛋白水平处于目标范围内。校正组与转换组的平均处方剂量分别为3.58mg/日与3.74mg/日。依诺司他可降低铁调素与铁蛋白水平，并升高总铁结合力，整体耐受性良好。
<b><i>结论：</i></b> 依诺司他可纠正并维持未接受透析的慢性肾脏病贫血患者的血红蛋白水平。