美国芝加哥大学医学院George L. Bakris团队研究了RNA干扰剂Zilebesiran治疗轻度至中度高血压患者的疗效与安全性。2024年2月16日出版的《美国医学会杂志》发表了这项成果。

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，是调节血压（BP）的关键途径。Zilebesiran是一种研究性RNA干扰治疗药物，靶向肝脏血管紧张素原合成。

为了评价Zilebesiran不同给药方案的降压疗效和安全性，研究人员在4个国家的78个地点进行了一项Zilebesiran与安慰剂的2期随机、双盲、剂量范围研究。筛查开始于2021年7月，6个月研究的最后一次患者就诊于2023年6月。将患有轻度至中度高血压的成年人随机分组，定义为降压药物洗脱后日间平均动态收缩压（SBP）为135至160毫米汞柱。

将患者随机分为四种皮下注射Zilebesiran方案中的一种（每6个月150、300或600 mg或每3个月300 mg）或安慰剂（每3个月1次），持续6个月。主要终点是24小时平均动态收缩压从基线到第3个月的最小二乘平均值（LSM）变化的组间差异。

在394名随机患者中，377名（302名接受Zilebesiran和 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名女性[44.3%]；平均[SD]年龄，57[11]岁）。治疗3个月后，Zilebesiran 150 mg、每6个月一次组的24小时平均动态收缩压变化为-7.3 mm Hg；Zilebesiran 300 mg、每3个月或每6个月一次组为−10.0 mm Hg；Zilebesiran 600 mg、每6个月一次组为−8.9 mm Hg；安慰剂组为6.8 mm Hg。

从基线到第3个月，Zilebesiran 150 mg、每6个月一次组与安慰剂组的LSM变化差异为−14.1 mm Hg；Zilebesiran 300 mg、每3个月或每6个月一次组与安慰剂组的差异为−16.7 mm Hg；Zilebesiran 600 mg、每6个月一次组与安慰剂组的差异为−15.7 mm Hg。

在6个月的时间里，接受Zilebesiran治疗的患者中有60.9%发生不良事件，而接受安慰剂治疗的患者有50.7%发生；接受Zilebesiran治疗的患者中有3.6%发生严重不良事件，安慰剂治疗组有6.7%发生。16.9%的Zilebesiran治疗患者（主要是注射部位反应和轻度高钾血症）和8.0%的安慰剂治疗患者发生了非严重的药物相关不良事件。

研究结果表明，在患有轻度至中度高血压的成年人中，以3个月或6个月为间隔的一系列剂量的Zilebesiran治疗，显著降低了第3个月的24小时平均动态收缩压。

附：英文原文

Title: RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial

Author: George L. Bakris, Manish Saxena, Anil Gupta, Fadi Chalhoub, Jongtae Lee, Daniel Stiglitz, Nune Makarova, Nitender Goyal, Weinong Guo, Dion Zappe, Akshay S. Desai, KARDIA- Study Group, George Carr, Christopher Case, Lauren Jaeger, Lisa Bruns, Ginger Stratman, Christy Kidwell, Suzin Cunningham, Nicholas Piccone, Mordecai Klein, Maria Acuna, Srishti Arora, Amanda Clark, Ezekiel Fink, Cesia Garcia, Astrid George, Elizabeth Gray, Caroline Mahaffey, Maria McElheney, Elizabeth Ortiz, Sunny Saumya, Adele Wallace, Jenelle Watts, Daisy Zambrana, Douglas Denham, Erica Rivera, Ayoade Avworo, Parke Hedges, Corri Fancher, Rafik Abadier, Lisa Braud, Laura Cenatiempo, Amanda Elwood, Linda Gray, Peter Gray, Kimberly Griffin, Hasibul Khan, Nadeen Kongquee, Susan LaTorraca, Tiffany Liles, Jill Livingston, Marc Lozano, Amy Lupton, Tiffany Lyles, Deana Mardini, Susan Moss, Karen Packer, Aakash Patel, Tina Russ, Brianna Scinicariello, Shannon Trull, Blair Warren, Fadi Chalhoub, Susan Angel, Sujeeta Dhakhwa, Ivy Gabon, Leticia Goodwin, Nandita Joshi Jones, Mark Joyce, Niketa Kamble, Brooke McFall, Rose Githiiyu, Leticia Robinson, Lauren Tomlinson

Issue&Volume: 2024-02-16

Abstract:

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 and75 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.

DOI: 10.1001/jama.2024.0728

Source: https://jamanetwork.com/journals/jama/fullarticle/2815379