Phase 2b study of evocalcet (KHK7580), a novel calcimimetic, in Japanese patients with secondary hyperparathyroidism undergoing hemodialysis: A randomized, double-blind, placebo-controlled, dose-finding study

Background
Evocalcet has been developed as a new calcimimetic agent for hemodialysis (HD) patients with secondary hyperparathyroidism (HDSHPT), eliciting fewer gastrointestinal symptoms and drug interactions. We evaluated the efficacy, safety, and optimal starting dose of evocalcet in HDSHPT.
Methods
In this 3-week, Phase 2b, randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-finding study, Japanese HDSHPT with intact parathyroid hormone (iPTH) ≥240 pg/mL and serum calcium level corrected for albumin ≥8.4 mg/dL were randomized to evocalcet 0.5, 1, 2 mg/day administered orally or placebo under double-blind conditions, and cinacalcet 25 mg/day (open-label conditions).
Results
In total, 152 HDSHPT were randomized. The mean ± standard deviation (median, interquartile range) of percent changes in iPTH from baseline to end of treatment were −8.40±25.43% (−12.16, 39.60), −10.56±22.86% (−14.24, 27.85), and −20.16±34.23% (−23.83, 39.05) in the evocalcet 0.5, 1, and 2 mg/day groups and 5.44±25.85% (3.52, 35.39) and −25.86±27.76% (−29.79, 34.15) in the placebo and cinacalcet groups, respectively. The dose-response profile for each evocalcet group vs placebo showed statistically significant differences for all contrast patterns. Whole PTH, corrected calcium, ionized calcium, phosphorus, and intact fibroblast growth factor 23 decreased after treatment initiation in the evocalcet and cinacalcet groups. Adverse events were observed in 30%–50% of patients (all groups). Incidence of adverse events was similar among all groups except for decreased calcium, which occurred more frequently in the evocalcet 2 mg and cinacalcet groups.
Conclusions
The dose response and safety of all administered doses of evocalcet were confirmed, as well as the efficacy of evocalcet ≥1 mg in a strictly Japanese sample of HDSHPT. Therefore, evocalcet 1 mg was considered appropriate as an initial dose for HDSHPT.

背景
依伐卡托（Evocalcet）作为新型拟钙剂，被开发用于治疗血液透析（hemodialysis, HD）合并继发性甲状旁腺功能亢进症（secondary hyperparathyroidism, HDSHPT）的患者，其引发的胃肠道不良反应与药物相互作用更少。本研究旨在评估依伐卡托治疗继发性甲状旁腺功能亢进症的疗效、安全性及最优起始剂量。

方法
本研究为一项为期3周的2b期随机双盲安慰剂对照多中心平行组剂量探索研究。纳入血清全段甲状旁腺激素（intact parathyroid hormone, iPTH）≥240 pg/mL、校正白蛋白后的血清钙≥8.4 mg/dL的日本继发性甲状旁腺功能亢进症患者，按双盲方案随机分配至依伐卡托0.5、1、2 mg/日口服组、安慰剂组，以及西那卡塞（cinacalcet）25 mg/日开放标签组。

结果
总计152例继发性甲状旁腺功能亢进症患者完成随机分组。依伐卡托0.5、1、2 mg/日组患者从基线至治疗结束时的全段甲状旁腺激素百分比变化均值±标准差（中位数，四分位距）分别为-8.40±25.43%（-12.16，39.60）、-10.56±22.86%（-14.24，27.85）及-20.16±34.23%（-23.83，39.05）；安慰剂组与西那卡塞组则分别为5.44±25.85%（3.52，35.39）与-25.86±27.76%（-29.79，34.15）。各依伐卡托组与安慰剂组的剂量反应曲线对比均显示出统计学显著差异。依伐卡托与西那卡塞组患者在治疗启动后，全段甲状旁腺激素、校正血清钙、离子钙、磷及全段成纤维细胞生长因子23水平均出现下降。所有组别中30%~50%的患者报告了不良反应；除低钙血症外，各组不良反应发生率相近，而低钙血症在依伐卡托2 mg组与西那卡塞组中发生率更高。

结论
本研究证实了所有给药剂量下依伐卡托的剂量反应性与安全性，同时确认了在严格纳入的日本继发性甲状旁腺功能亢进症患者群体中，依伐卡托剂量≥1 mg时的疗效。因此，依伐卡托1 mg被认为是继发性甲状旁腺功能亢进症患者的适宜起始剂量。