■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,血压(BP)调节的关键途径。齐勒贝西兰,一种研究性RNA干扰治疗剂,目标肝血管紧张素原合成。
■评估不同给药方案的抗高血压疗效和安全性。
■第二阶段,随机,双盲,在4个国家/地区的78个地点进行了齐列贝西兰与安慰剂的剂量范围研究.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。患有轻度至中度高血压的成年人,定义为抗高血压冲洗后的白天平均动态收缩压(SBP)为135至160mmHg,是随机的。
■随机分为4种皮下齐列贝西兰方案(每6个月一次150、300或600mg或每3个月一次300mg)或安慰剂(每3个月一次)中的1种,持续6个月。
■主要终点是从基线到第3个月的24小时平均动态SBP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(302名接受齐列贝西兰,75名接受安慰剂)包括完整的分析集(93名Black患者[24.7%];167名[44.3%]女性;平均[SD]年龄,57[11]年)。3个月时,齐列贝西兰患者的24小时动态SBP相对于基线的平均变化为-7.3mmHg(95%CI,-10.3至-4.4),150毫克,每6个月一次;-10.0mmHg(95%CI,-12.0至-7.9)300毫克,每3个月或每6个月一次;-8.9mmHg(95%CI,-11.9至-6.0)600毫克,每6个月一次;安慰剂和6.8mmHg(95%CI,3.6-9.9)。从基线到第3个月,LSM与安慰剂的差异为-14.1mmHg(95%CI,-19.2至-9.0;P<.001),150毫克,每6个月一次;-16.7mmHg(95%CI,-21.2至-12.3;P<.001),300毫克,每3个月或每6个月一次;和-15.7mmHg(95%CI,-20.8至-10.6;P<.001)600毫克,每6个月一次。超过6个月,60.9%的患者接受zilebesiran的患者有不良事件,50.7%的患者接受安慰剂,3.6%的患者有严重不良事件,6.7%的患者接受安慰剂。非严重药物相关的不良事件发生在16.9%的齐列贝西兰治疗的患者(主要是注射部位反应和轻度高钾血症)和8.0%的安慰剂治疗的患者中。
■在患有轻度至中度高血压的成年人中,在3个月或6个月的不同剂量范围内,齐列贝西兰治疗显著降低了第3个月时的24小时平均动态SBP.
■ClinicalTrials.gov标识符:NCT04936035。
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.
To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.
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.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT04936035.