Supplementary Material for: Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study

Background: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. Methods: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. Results: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. Conclusion: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).背景：地西杜司他（Desidustat，ZYAN1）是一种口服缺氧诱导因子脯氨酰羟化酶抑制剂（hypoxia-inducible factor prolyl hydroxylase inhibitor, HIF-PHI），可刺激红细胞生成。通过脯氨酰羟化酶抑制剂稳定缺氧诱导因子，已发展为治疗慢性肾脏病（chronic kidney disease, CKD）继发性贫血的新型治疗策略。本试验评估了地西杜司他在未接受透析的成人CKD合并贫血患者中的安全性、耐受性与有效性。 方法：本研究为一项2期、随机、双盲、6周、安慰剂对照的剂量探索安全性与有效性研究。共计117名符合入组标准的患者被随机分配至4个组别：100mg、150mg、200mg地西杜司他组及安慰剂组。研究药物于空腹状态下隔日给药，持续6周。主要终点为血红蛋白（hemoglobin, Hb）从基线至第6周的变化值。 结果：所有治疗组的基线人口学特征均衡可比。在改良意向性治疗（modified intent-to-treat, mITT）人群中，经6周治疗后，100mg、150mg、200mg地西杜司他组的平均Hb水平分别升高1.57、2.22及2.92 g/dL。在mITT人群中，100mg组的应答率（Hb升高≥1 g/dL）为66%，150mg组为75%，200mg组为83%。共计18名患者出现至少1次治疗突发不良事件（treatment emergent adverse event, TEAE），5名患者报告至少1次与药物相关的轻度TEAE。试验期间未报告死亡或严重不良事件。 结论：相较于安慰剂组，mITT人群及符合方案（per-protocol, PP）人群中各剂量组的Hb水平均呈现剂量依赖性升高。地西杜司他还可使药代动力学参数峰浓度（Cmax）及曲线下面积（AUC）呈剂量依赖性增加。生命体征、心电图参数及安全性实验室指标均无显著变化。临床试验注册号为CTRI/2017/05/008534（2017年5月11日注册）。