Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
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DOI：
10.1681/asn.2020050595
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发表时间：
2021-01-01
影响因子：
13.6
通讯作者：
Davidson, Michael H.
中科院分区：
文献类型：
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作者：
Pergola, Pablo E.;Devalaraja, Matt;Davidson, Michael H.
背景 接受血液透析的 CKD 患者由于炎症性贫血而对红细胞生成刺激剂 (ESA) 反应低下。白细胞介素 6 (IL-6) 诱导的铁调素表达是此类炎症的关键介质。 方法 这项 1/2 期安慰剂对照试验评估了 ziltivekimab（一种新型抗 IL-6 配体抗体）对使用 rs855791 进行血液透析的患者的影响，rs855791 是 TMPRSS6 基因的单核苷酸多态性，假设它会增加对 IL-6 介导的炎症效应的易感性。在记录稳定 ESA 和铁剂量的筛选期后，我们将 61 名 IL-6 升高（>= 4 pg/ml）的患者随机分组接受安慰剂或 ziltivekimab（剂量为 2、6 或 20 mg），在血液透析期间每 2 周静脉注射一次，持续 12 周。 4 周后允许调整 ESA 剂量。我们分析了安全性以及对炎症、铁代谢、血清白蛋白和抗药物抗体的影响。结果没有患者出现剂量限制性毒性。四名患者（6 毫克和 20 毫克组各两名）死于治疗引起的不良事件。与接受安慰剂的患者相比，从基线到治疗结束，接受 ziltivekimab 治疗的患者的高敏 C 反应蛋白、血清淀粉样蛋白 A 和纤维蛋白原显着降低。与安慰剂组没有变化相比，2、6 和 20 mg ziltivekimab 队列中每名患者的中位 ESA 使用量分别减少了 15,000、15,000 或 33,000 IU/周。我们还注意到，ESA 抵抗指数降低、血清铁、总铁结合能力、转铁蛋白饱和度和血清白蛋白升高具有显着的剂量反应。 结论 对于患有炎症和对 ESA 治疗反应低的血液透析患者，Ziltivekimab 显着改善炎症标志物、降低 ESA 需求并增加血清白蛋白。
Background Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation.Methods This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (>= 4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies.Results No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin.Conclusions Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy.