Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Research and Development Japan, Bayer Yakuhin, Ltd., Osaka, Japan.
Am J Nephrol. 2021;52(10-11):884-893. doi: 10.1159/000518072. Epub 2021 Sep 16.
Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs.
This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events.
In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively.
DISCUSSION/CONCLUSION: Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.
促红细胞生成素刺激剂（ESAs）是目前透析患者慢性肾脏病（CKD）贫血的标准治疗方法。莫利司他是一种口服低氧诱导因子脯氨酰羟化酶抑制剂，正在被研究作为肾性贫血的替代治疗方法。莫利司他在五项 3 期研究中进行了评估，莫利司他每日一次改善肾性贫血的诱导促红细胞生成素（MIYABI）计划。本研究调查了莫利司他在日本未接受透析且之前接受过 ESA 治疗的肾性贫血患者中的安全性和疗效。
这是一项 52 周、活性对照、随机（1:1）、开放标签、平行组、多中心、3 期研究，纳入了日本因 CKD（3-5 期）导致贫血的患者。莫利司他根据之前的 ESA 剂量起始剂量为 25mg 或 50mg 每日一次。ESA 达贝泊汀（darbepoetin）根据之前的 ESA 剂量起始剂量给药，每 2 或 4 周皮下注射一次。剂量定期调整以维持血红蛋白（Hb）水平在 11.0-13.0g/dL 的目标范围内。主要疗效结局是评估期（30-36 周）内平均 Hb 水平及其变化。安全性结局包括所有不良事件的评估。
共 164 例患者随机接受莫利司他（n=82）或达贝泊汀（n=82）治疗。基线特征均衡。莫利司他的基线平均（标准偏差）Hb 水平为 11.31（0.68）g/dL，达贝泊汀为 11.27（0.64）g/dL。莫利司他（11.67[11.48-11.85]g/dL）和达贝泊汀（11.53[11.31-11.74]g/dL）的评估期平均 Hb 水平的平均值（95%置信区间[CI]）在目标范围内。基于 1.0g/dL 的非劣效性边界，莫利司他在评估期内的平均 Hb 水平变化与达贝泊汀相比不劣效，最小二乘均值（95%CI）差值（莫利司他-达贝泊汀）为 0.13（-0.15，0.40）g/dL。报告至少 1 例治疗后出现的不良事件（TEAE）的患者比例，莫利司他组为 92.7%，达贝泊汀组为 96.3%。莫利司他组有 2 例（2.4%）患者报告的 TEAEs 导致死亡，达贝泊汀组无此事件；分别有 32.9%和 26.8%的患者报告严重 TEAEs。
讨论/结论：莫利司他与达贝泊汀相比不劣效，可维持未接受透析且之前接受过 ESA 治疗的肾性贫血患者的 Hb 水平在预设的目标范围内。莫利司他耐受性良好，未观察到新的安全性信号。
