Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial.

Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown.

Tonlamarsen是一种针对肝脏血管紧张素原合成的实验性反义寡核苷酸；其在高血压患者中的有效性和安全性尚不明确。

The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo.

本研究旨在评估每月一次皮下注射90毫克tonlamarsen，连续5个月，与单剂量tonlamarsen及其后续安慰剂相比的安全性和有效性。

Methods

This randomized, placebo-controlledtrial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications.

这项随机、安慰剂对照试验招募了办公室收缩压（BP）>135毫米汞柱且正在接受2至5种降压药物治疗的成年人。

Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks.

参与者进入了一个包含每月给药的3阶段治疗期，首先是为期4周的安慰剂导入期，随后是为期4周的活性药物导入期，期间给予单剂量的tonlamarsen，然后随机分配接受额外4剂的tonlamarsen或匹配的安慰剂，持续16周。

The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP.

主要终点是两组之间从基线到第20周血浆血管紧张素原变化和办公室收缩压变化的差异。

Results

A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized.

共有279名参与者接受了安慰剂导入期治疗，206名在活性导入期接受了90毫克的tonlamarsen治疗，随后有198名被随机分配。

The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively.

随机分配的参与者在安慰剂导入期前后平均血压分别为147/90毫米汞柱和147/89毫米汞柱。

Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg.

经过活性启动期使用托那马森后，平均血压为140/87毫米汞柱。

Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001).

在首次使用托那马森后的二十周，血浆血管紧张素原水平的最小二乘（LS）平均百分比变化为单剂量托那马森和随后的安慰剂后为-23.0%（95%置信区间：-27.8%至-18.2%），以及每月使用托那马森后为-67.2%（95%置信区间：-71.9%至-62.4%），LS平均差异为-44.1%（97.5%置信区间：-51.9%至-36.4%；P < 0.0001）。

The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97).

对于接受单剂量tonlamarsen和随后安慰剂治疗的参与者，办公室收缩压的LS平均变化为-6.7毫米汞柱（95%置信区间：-9.8至-3.5毫米汞柱），而接受每月tonlamarsen治疗的参与者的LS平均变化为-6.7毫米汞柱（95%置信区间：-9.8至-3.6毫米汞柱），LS平均差异为-0.1毫米汞柱（95%置信区间：-4.5至-4.4毫米汞柱；P = 0.97）。

Serious adverse events were infrequent and similar between treatment groups.

严重不良事件在治疗组之间发生频率较低且相似。

Conclusions

Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction.

在未控制高血压的患者中，每月一次的tonlamarsen给药比单次剂量的tonlamarsen更能有效降低血浆血管紧张素原水平，但并未带来额外的血压降低。

(A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).

（一项研究探讨tonlamarsen治疗未控制高血压成人患者的效果 [KARDINAL]; NCT06864104）。