口服低氧诱导因子脯氨酰羟化酶抑制剂FG-4592治疗中国贫血患者的2期研究。
Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
作者信息
Chen Nan, Qian Jiaqi, Chen Jianghua, Yu Xueqing, Mei Changlin, Hao Chuanming, Jiang Gengru, Lin Hongli, Zhang Xinzhou, Zuo Li, He Qiang, Fu Ping, Li Xuemei, Ni Dalvin, Hemmerich Stefan, Liu Cameron, Szczech Lynda, Besarab Anatole, Neff Thomas B, Peony Yu Kin-Hung, Valone Frank H
机构信息
Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Renji Hospital, Shanghai, China.
出版信息
Nephrol Dial Transplant. 2017 Aug 1;32(8):1373-1386. doi: 10.1093/ndt/gfx011.
BACKGROUND
FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD).
METHODS
In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed.
RESULTS
In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects.
CONCLUSIONS
FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.
背景
FG-4592（罗沙司他）是一种口服的缺氧诱导因子（HIF）脯氨酰羟化酶抑制剂（HIF-PHI），通过转录因子HIF促进协调性红细胞生成。在中国进行了两项2期研究，以探讨HIF-PHI FG-4592（通用名：罗沙司他，化学名称： ）在慢性肾脏病（CKD）贫血患者（包括依赖透析（DD）患者和非依赖透析（NDD）患者）中的安全性和有效性。
方法
在NDD研究中，91名参与者被随机分配至低剂量（1.1 - 1.75mg/kg）或高剂量（1.50 - 2.25mg/kg）FG-4592起始剂量组或安慰剂组。在DD研究中，87名患者被纳入低剂量（1.1 - 1.8mg/kg）、中剂量（1.5 - 2.3mg/kg）和高剂量（1.7 - 2.3mg/kg）FG-4592起始剂量组或继续接受促红细胞生成素α治疗。在两项研究中，仅允许口服补铁。
结果
在NDD研究中，低剂量组80.0%的受试者和高剂量组87.1%的受试者血红蛋白（Hb）较基线水平升高≥1g/dL，而安慰剂组为23.3%（两组P均<0.0001）。在DD研究中，低、中、高剂量组分别有59.1%、88.9%（P = 0.008）和100%（P = 0.0003）的受试者在5至6周后维持其Hb水平，而促红细胞生成素α治疗组为50%。在两项研究中，FG-4592治疗的受试者胆固醇显著降低，血清铁、总铁结合力（TIBC）和转铁蛋白稳定或升高（未静脉补铁）。在NDD研究中，与安慰剂组无变化相比，所有FG-4592治疗组的铁调素水平均显著降低。在DD研究中，与促红细胞生成素α治疗组相比，最高剂量组的铁调素水平也以剂量依赖的方式显著降低。FG-4592治疗组和对照组的不良事件相似。
结论
FG-4592可能是治疗CKD贫血的一种有效替代药物。目前正在一项关键的全球3期试验中进行研究。
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