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期刊来源：JAMA

原文链接：https://doi.org/10.1001/jama.2024.0728

摘要内容如下：

重要性

血管紧张素原是肾素-血管紧张素-醛固酮系统的最上游前体，是血压（BP）调节的关键途径。Zilebesiran，一种正在研究的RNA干扰治疗药物，靶向肝脏血管紧张素原合成。

目的

评价不同给药方案的齐来贝西兰的降压疗效和安全性。

设计、设置和参与者

Zilebesiran与安慰剂的2期、随机、双盲、剂量范围研究在4个国家的78个地点进行。筛选开始于2021年7月，6个月研究的最后一次患者访视于2023年6月。轻度至中度高血压（定义为抗高血压药物洗脱后日间平均动态收缩压（SBP）为135至160 mm Hg）的成人被随机分组。

干预措施

随机分配至4个皮下注射齐来贝西兰方案（每6个月一次150、300或600 mg或每3个月一次300 mg）或安慰剂（每3个月一次）中的1个，为期6个月。

主要成果和措施

主要终点是从基线到第3个月的24小时平均动态收缩压的最小二乘平均值（LSM）变化的组间差异。

结果

在394名随机分组的患者中，377名（302名接受齐来贝西兰治疗，75名接受安慰剂治疗）构成了完整的分析集（93名黑人患者[24.7%]；167名[44.3%]妇女；平均[SD]年龄，57[11]岁）。在3个月时，每6个月服用一次150 mg的Zilebesiran，24小时平均动态收缩压相对于基线的变化为-7.3 mm Hg（95%CI，-10.3至-4.4）；-10.0 mm Hg（95%CI，-12.0至-7.9），使用Zilebesiran，300 mg，每3个月或每6个月一次；-8.9 mm Hg（95%CI，-11.9至-6.0），每6个月一次，每次600 mg；安慰剂组为6.8 mm Hg（95%CI，3.6-9.9）。LSM与安慰剂相比，从基线到第3个月的变化差异为-14.1 mm Hg（95%CI，-19.2至-9.0；P<.001），每6个月一次，每次150 mg；-16.7毫米汞柱（95%置信区间，-21.2至-12.3；P<.001），每3个月或每6个月一次，每次300 mg；和-15.7毫米汞柱（95%可信区间为-20.8~-10.6；P<.001），每6个月服用一次600 mg的齐来贝西兰。在6个月内，接受Zilebesiran治疗的患者中有60.9%发生了不良事件，而接受安慰剂治疗的患者中有50.7%发生了不良事件，3.6%发生了严重不良事件，而接受安慰剂治疗的患者中有6.7%发生了严重不良事件。16.9%接受Zilebesiran治疗的患者和8.0%接受安慰剂治疗的患者发生了非严重药物相关不良事件（主要是注射部位反应和轻度高钾血症）。

结论和相关性

在患有轻度至中度高血压的成人中，在间隔3个月或6个月的剂量范围内，齐来贝西兰治疗显著降低了第3个月的24小时平均动态收缩压。

试用注册

ClinicalTrials.gov标识符：NCT04936035。

英文原文如下：

Abstracts

Importance  Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis.

Objective  To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.

Design, Setting, and Participants  This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized.

Interventions  Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.

Main Outcomes and Measures  The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP.

Results  Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients.

Conclusions and Relevance  In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.

Trial Registration  ClinicalTrials.gov Identifier: NCT04936035.

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