Background

IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction.

Methods

RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117.

Findings

Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were –66·2% for the 7·5 mg group, –77·7% for the 15 mg group, and –87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia.

Interpretation

Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease.

Funding

Novo Nordisk.

中文翻译：

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ziltivekimab 在高动脉粥样硬化风险 (RESCUE) 患者中的 IL-6 抑制作用：一项双盲、随机、安慰剂对照、2 期试验

背景

IL-6 已成为动脉粥样硬化血栓形成的关键因素。然而，在动脉粥样硬化高风险但没有全身炎症性疾病的个体中，IL-6 抑制的安全性和有效性尚不清楚。因此，我们探讨了 ziltivekimab（一种针对 IL-6 配体的全人源单克隆抗体）是否能安全有效地降低心血管高危患者的炎症和血栓形成生物标志物。我们专注于高敏 CRP 升高和慢性肾病的个体，这是一个临床需求未得到满足的群体，之前的炎症抑制研究已显示其对减少心血管事件有效。

方法

RESCUE 是一项在美国 40 个临床中心进行的随机、双盲、2 期试验。纳入标准为 18 岁或以上、中度至重度慢性肾病和至少 2 mg/L 的高敏 CRP。参与者被随机分配（1:1:1:1）皮下给药安慰剂或 ziltivekimab 7·5 mg、15 mg 或 30 mg，每 4 周至 24 周。主要结果是与安慰剂相比，ziltivekimab 治疗 12 周后高敏 CRP 相对于基线的百分比变化，并在 24 周的治疗中收集了额外的生物标志物和安全性数据。在意向治疗人群中进行了初步分析。在接受至少一剂指定治疗的所有患者中评估安全性。该试验已在 ClinicalTrials.gov 注册，NCT03926117。

发现

2019 年 6 月 17 日至 2020 年 1 月 14 日期间，264 名参与者参加了试验，其中 66 名被随机分配到四个治疗组中的每一个。随机分组后 12 周，7·5 mg 组的高敏 CRP 水平中位数降低了 77%，15 mg 组降低了 88%，30 mg 组降低了 92%，而安慰剂组降低了 4%。因此，ziltivekimab 组和安慰剂组之间高敏 CRP 百分比变化的中位数成对差异，在分层对齐后，7·5 mg 组为 –66·2%，15 mg 组为 –77·7%组，而 30 mg 组为 –87·8%（所有 p<0·0001）。在 24 周的治疗期内效果稳定。还观察到纤维蛋白原、血清淀粉样蛋白 A、触珠蛋白、分泌型磷脂酶 A2 和脂蛋白 (a) 的剂量依赖性降低。Ziltivekimab 耐受性良好，

解释

Ziltivekimab 显着降低了与动脉粥样硬化相关的炎症和血栓形成的生物标志物。在这些数据的基础上，一项大规模的心血管结局试验将调查 ziltivekimab 对慢性肾病、高敏 CRP 升高和已确诊心血管疾病患者的影响。

资金

诺和诺德。