美国布列根和妇女医院和哈佛医学院Paul M Ridker团队研究了泽韦奇单抗抑制IL-6治疗高动脉粥样硬化风险患者的效果。2021年5月17日，《柳叶刀》杂志发表了该研究。
IL-6已成为动脉粥样硬化血栓形成的关键因素。然而，IL-6抑制在高动脉粥样硬化风险但无全身炎症障碍的个体中的安全性和有效性尚不清楚。为此，研究组探讨了泽韦奇单抗（一种针对IL-6配体的全人源单克隆抗体）是否可安全有效地降低心血管高危患者炎症和血栓形成的生物标志物。研究组聚焦高敏C反应蛋白升高和慢性肾脏疾病的个体，其临床需求没有得到充分满足，在这些个体中，先前的炎症抑制研究显示对减少心血管事件有效。
研究组在美国40个临床机构进行了一项随机、双盲、临床2期试验，招募年龄为18岁及以上、中重度慢性肾病、高敏C反应蛋白至少2 mg/L的患者。将受试者按1：1：1：1随机分配，分别接受皮下注射安慰剂或泽韦奇单抗7.5mg、15mg或30mg，每4周一次，直至24周。主要结局是与安慰剂相比，接受泽韦奇单抗治疗12周后，高敏C反应蛋白与基线水平的百分比变化，并在治疗24周内收集额外的生物标志物和安全性数据。对意向治疗人群进行初步分析。对至少接受一剂指定治疗的所有患者进行安全性评估。
2019年6月17日至2020年1月14日，共有264名参与者被纳入试验，每组66人。随机分组后12周，泽韦奇单抗7.5mg组、15mg组和30mg组的中位高敏C反应蛋白水平分别降低了77%、88%和92%，而安慰剂组仅降低4%。因此，在分层校正后，泽韦奇单抗7.5mg组、15mg组和30mg组和安慰剂组之间的高敏C反应蛋白百分比变化分别为-66.2%、-77.7%和-87.8%。
泽韦奇单抗各剂量组在24周的治疗期间疗效稳定。纤维蛋白原、血清淀粉样蛋白A、结合珠蛋白、分泌型磷脂酶A2和脂蛋白（A）也呈剂量依赖性降低。泽韦奇单抗耐受性良好，不影响总胆固醇与高密度脂蛋白胆固醇的比值，没有严重的注射部位反应、持续3级或4级中性粒细胞减少或血小板减少。
研究结果表明，泽韦奇单抗可显著降低与动脉粥样硬化相关的炎症和血栓形成的生物标志物。
附：英文原文
Title: IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial
Author: Paul M Ridker, Matt Devalaraja, Florian M M Baeres, Mads D M Engelmann, G Kees Hovingh, Milana Ivkovic, Larry Lo, Douglas Kling, Pablo Pergola, Dominic Raj, Peter Libby, Michael Davidson
Issue&Volume: 2021-05-17
Abstract:
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.
DOI: 10.1016/S0140-6736(21)00520-1
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00520-1/fulltext
LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
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投稿链接：http://ees.elsevier.com/thelancet
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