Desai Akshay S, Karns Adam D, Badariene Jolita, Aswad Ahmad, Neutel Joel M, Kazi Farhana, Park Wansu, Stiglitz Daniel, Makarova Nune, Havasi Andrea, Zappe Dion H, Saxena Manish
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Entertainment Medical Group, Beverly Hills, California.
JAMA. 2025 May 28. doi: 10.1001/jama.2025.6681.
In prior monotherapy studies of patients with hypertension, single subcutaneous doses of zilebesiran, an investigational RNA interference therapeutic, reduced serum angiotensinogen levels and systolic blood pressure (SBP) at 3 and 6 months.
To evaluate the efficacy and safety of zilebesiran vs placebo when added to a standard antihypertensive medication.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2, randomized, prospective, double-blinded trial enrolled adults with uncontrolled hypertension from 150 sites across 8 countries between January 2022 and June 2023. The final follow-up date was December 11, 2023, and analyses were conducted on March 1, 2024.
Eligible patients were initially randomized in cohorts to receive open-label run-in treatment for at least 4 weeks with indapamide 2.5 mg, amlodipine 5 mg, or olmesartan 40 mg (4:7:10 randomization), each administered once daily. Within cohorts, adherent patients with 24-hour mean ambulatory SBP of 130 mm Hg to 160 mm Hg were subsequently randomized (1:1) to additional blinded treatment to receive single subcutaneous doses of zilebesiran 600 mg or matching placebo.
The primary end point in each cohort was the difference between zilebesiran and placebo in change from baseline in 24-hour mean ambulatory SBP at 3 months.
Of 1491 patients entering the run-in phase, 663 (130 receiving indapamide, 240 receiving amlodipine, and 293 receiving olmesartan) were randomized to receive zilebesiran (n = 332) or placebo (n = 331). The least-squares mean difference between zilebesiran and placebo in change from baseline to 3 months in 24-hour mean ambulatory SBP was -12.1 mm Hg (95% CI, -16.5 to -7.6; P < .001) for indapamide, -9.7 mm Hg (95% CI, -12.9 to -6.6; P < .001) for amlodipine, and -4.5 mm Hg (95% CI, -8.2 to -0.8; P = .02) for olmesartan. Across cohorts, more patients who received zilebesiran than placebo experienced hyperkalemia (18 [5.5%] vs 6 [1.8%]), hypotension (14 [4.3%] vs 7 [2.1%]), and acute kidney failure (16 [4.9%] vs 5 [1.5%]) events, but most episodes were mild and resolved without medical intervention.
In patients with uncontrolled hypertension despite treatment with indapamide, amlodipine, or olmesartan, the addition of single-dose zilebesiran resulted in significant SBP reductions compared with placebo at 3 months, with low rates of serious adverse events.
ClinicalTrials.gov Identifier: NCT05103332.
在先前针对高血压患者的单药治疗研究中，研究性RNA干扰疗法齐列贝司兰单次皮下给药可在3个月和6个月时降低血清血管紧张素原水平和收缩压（SBP）。
评估在标准抗高血压药物基础上加用齐列贝司兰与安慰剂相比的疗效和安全性。
设计、地点和参与者：这项2期随机、前瞻性、双盲试验于2022年1月至2023年6月期间在8个国家的150个地点招募了未控制高血压的成年人。最终随访日期为2023年12月11日，分析于2024年3月1日进行。
符合条件的患者最初按队列随机分组，接受至少4周的开放标签导入治疗，使用吲达帕胺2.5毫克、氨氯地平5毫克或奥美沙坦40毫克（4:7:10随机分组），均每日给药一次。在各队列中，24小时平均动态SBP为130毫米汞柱至160毫米汞柱的依从性患者随后被随机分组（1:1）接受额外的盲法治疗，以接受单次皮下注射600毫克齐列贝司兰或匹配的安慰剂。
每个队列的主要终点是3个月时齐列贝司兰与安慰剂在24小时平均动态SBP自基线变化方面的差异。
在进入导入期的1491名患者中，663名（130名接受吲达帕胺，240名接受氨氯地平，293名接受奥美沙坦）被随机分组接受齐列贝司兰（n = 332）或安慰剂（n = 331）。吲达帕胺组中，齐列贝司兰与安慰剂在24小时平均动态SBP自基线至3个月变化方面的最小二乘均值差异为-12.1毫米汞柱（95%置信区间，-16.5至-7.6；P <.001）；氨氯地平组为-9.7毫米汞柱（95%置信区间，-12.9至-6.6；P <.001）；奥美沙坦组为-4.5毫米汞柱（95%置信区间，-8.2至-0.8；P = 0.02）。在所有队列中，接受齐列贝司兰的患者比接受安慰剂的患者发生高钾血症（18例[5.5%]对6例[1.8%]）、低血压（14例[4.3%]对7例[2.1%]）和急性肾衰竭（16例[4.9%]对5例[1.5%]）事件的更多，但大多数发作较轻，无需医疗干预即可缓解。
在尽管接受了吲达帕胺、氨氯地平或奥美沙坦治疗但仍未控制高血压的患者中，加用单剂量齐列贝司兰在3个月时与安慰剂相比可显著降低SBP，严重不良事件发生率较低。
ClinicalTrials.gov标识符：NCT05103332。
