[医学论文翻译] Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

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ORIGINAL ARTICLE

原创文章

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

Zilebesiran，一种用于高血压的RNA干扰治疗剂

Akshay S. Desai, M.D., M.P.H., David J. Webb, M.D., D.Sc., Jorg Taubel, M.D., Sarah Casey, M.B., Ch.B., Yansong Cheng, Ph.D., Gabriel J. Robbie, Ph.D., Don Foster, M.S., Stephen A. Huang, M.D., Sean Rhyee, M.D., M.P.H., Marianne T. Sweetser, M.D., Ph.D., and George L. Bakris, M.D.

ABSTRACT

BACKGROUND

背景

From the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston (A.S.D.), and Alnylam Pharmaceuticals, Cambridge (Y.C., G.J.R., D.F., S.A.H., S.R., M.T.S.) — both in Massachusetts; the Centre for Cardiovascular Science, University of Edinburgh, Edinburgh (D.J.W.), Richmond Pharmacology and St. George's University of London, London (J.T.), and the Medicines Evaluation Unit, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester (S.C.) — all in the United Kingdom; and University Chicago Medicine, Chicago (G.L.B.). Dr. Desai can be contacted at adesai@bwh.harvard.edu or at the Division of Cardiovascular Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.

来自马萨诸塞州波士顿的布莱根妇女医院心血管医学部（A.S.D.），以及剑桥的Alnylam制药公司（Y.C., G.J.R., D.F., S.A.H., S.R., M.T.S.）；来自英国爱丁堡大学心血管科学中心（D.J.W.）、伦敦的里士满药理学和圣乔治大学（J.T.），以及曼彻斯特大学NHS基金信托的药物评估单位，位于曼彻斯特的威瑟斯豪医院（S.C.）；以及芝加哥大学医学中心（G.L.B.）。Desai博士的联系方式为adesai@bwh.harvard.edu，或通过布莱根妇女医院心血管医学部，地址：75 Francis St., Boston, MA 02115。

Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angio-tensinogen synthesis.

血管紧张素原是血管紧张素肽的唯一前体，在高血压的发病机制中发挥着关键作用。Zilebesiran是一种研究中的RNA干扰治疗剂，具有延长的作用持续时间，能够抑制肝脏血管紧张素原的合成。

METHODS

方法

In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran $({10},{25}$ , 50,100,200,400,or ${800}\mathrm{{mg}}$ ) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.

在这项第一阶段研究中，高血压患者被随机分配为2:1的比例，接受单次递增的皮下剂量的zilebesiran $({10},{25}$ （50、100、200、400或 ${800}\mathrm{{mg}}$ ）或安慰剂，并随访24周（A部分）。B部分评估了800毫克zilebesiran在低盐或高盐饮食条件下对血压的影响，E部分评估了该剂量与厄贝沙坦共同给药时的效果。终点包括安全性、药代动力学和药效学特征，以及通过24小时动态血压监测测量的收缩压和舒张压的基线变化。

RESULTS

结果

Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r=-0.56 at week $8;{95}\%$ confidence interval,-0.69 to -0.39). Single doses of zilebesiran $\left( { \geq {200}\mathrm{{mg}}}\right)$ were associated with decreases in systolic blood pressure $\left( { > {10}\mathrm{\;{mm}}\mathrm{{Hg}}}\right)$ and diastolic blood pressure $\left( { > 5\mathrm{\;{mm}}\mathrm{{Hg}}}\right)$ by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.

在107名入组患者中，有5名出现了轻微的、短暂的注射部位反应。没有报告低血压、高钾血症或肾功能恶化导致的医疗干预。在A部分，接受zilebesiran治疗的患者血清血管紧张素原水平下降，与所给药物剂量相关（r=-0.56在第 $8;{95}\%$ 周，置信区间为-0.69至-0.39）。单剂量的zilebesiran $\left( { \geq {200}\mathrm{{mg}}}\right)$ 与第8周收缩压 $\left( { > {10}\mathrm{\;{mm}}\mathrm{{Hg}}}\right)$ 和舒张压 $\left( { > 5\mathrm{\;{mm}}\mathrm{{Hg}}}\right)$ 的下降相关；这些变化在昼夜周期中是一致的，并在24周时持续存在。B部分和E部分的结果与高盐饮食对血压影响的减弱以及与伊贝沙坦共同给药的增强效果一致。

CONCLUSIONS

结论

Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of ${200}\mathrm{{mg}}$ or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.)

血清血管紧张素原水平和24小时动态血压的剂量依赖性下降在接受单次皮下给药zilebesiran后持续了长达24周；观察到轻微的注射部位反应。（由Alnylam Pharmaceuticals资助；ClinicalTrials.gov编号，NCT03934307；EudraCT编号，2019-000129-39。）

leading preventable factor in death from cardiovascular causes worldwide. ${}^{1 - 4}$ Despite effective therapeutic options, nearly half the patients with hypertension do not reach guideline-recommended blood-pressure targets, ${}^{5}$ partly as a consequence of physician failure to initiate or intensify antihypertensive therapy and poor patient adherence to prescribed daily oral medications. ${}^{6 - 8}$ Even when blood pressure appears to be well managed on the basis of intermittent office measures, control may remain suboptimal owing to marked variability in blood pressure over the diurnal cycle and in the long term. ${}^{9 - {11}}$

全球心血管原因死亡的主要可预防因素。 ${}^{1 - 4}$ 尽管有有效的治疗选择，近一半的高血压患者未能达到指南推荐的血压目标， ${}^{5}$ 部分原因是医生未能启动或加强抗高血压治疗，以及患者对处方口服药物的依从性差。 ${}^{6 - 8}$ 即使在间歇性门诊测量的基础上，血压看似得到良好管理，控制仍可能由于血压在昼夜周期和长期内的显著波动而保持在次优水平。 ${}^{9 - {11}}$

The renin-angiotensin-aldosterone system (RAAS) plays a central role in blood-pressure regulation. Zilebesiran is an investigational RNA interference therapeutic agent (a small interfering RNA [siRNA] covalently linked to an N-acetyl-galactosamine [GalNAc] ligand) that binds with high affinity to the hepatic asialoglycoprotein receptor. It is designed to achieve specific reduction in hepatic angiotensinogen messenger RNA (mRNA) levels, thereby reducing the production of angiotensinogen, a therapeutic target for hypertension. ${}^{12}$ Angiotensinogen is the sole precursor of all angiotensin peptides, so RAAS inhibition with this approach may theoretically limit compensatory angiotensin activation associated with angiotensin-converting-enzyme inhibition or angiotensin-receptor blockade. ${}^{{12} - {14}}$ Moreover, with hepatocyte-targeted delivery, extrahepatic angiotensinogen expression may be preserved, limiting off-target effects in the kidney and other tissues. Liver-specific effects of this approach are supported both by data from preclinical studies of a GalNAc-conjugated angiotensinogen siRNA, which suggests near-complete knockdown of hepatic angiotensinogen mRNA expression without affecting renal angiotensinogen mRNA, ${}^{{13},{15}}$ and by early clinical experience with GalNAc-conjugated antisense oligonucleotides targeting angio-tensinogen. ${}^{{12},{13}}$ Consistent and prolonged pharmacodynamic effects of GalNAc-siRNAs offer the potential for sustained reduction of blood pressure over a 24-hour period and for months, with twice-yearly or quarterly subcutaneous administration.

肾素-血管紧张素-醛固酮系统（RAAS）在血压调节中发挥着核心作用。Zilebesiran是一种研究中的RNA干扰治疗剂（小干扰RNA [siRNA] 与N-乙酰-半乳糖胺 [GalNAc] 配体共价连接），它与肝脏非糖基化糖蛋白受体具有高亲和力结合。它旨在特异性降低肝脏血管紧张素原信使RNA（mRNA）水平，从而减少血管紧张素原的产生，血管紧张素原是高血压的治疗靶点。 ${}^{12}$ 血管紧张素原是所有血管紧张素肽的唯一前体，因此，采用这种方法抑制RAAS理论上可能限制与血管紧张素转化酶抑制或血管紧张素受体阻断相关的补偿性血管紧张素激活。 ${}^{{12} - {14}}$ 此外，通过肝细胞靶向递送，可能保留肝外血管紧张素原的表达，从而限制对肾脏和其他组织的脱靶效应。这种方法的肝脏特异性效应得到了来自GalNAc结合的血管紧张素原siRNA的临床前研究数据的支持，该数据表明几乎完全抑制了肝脏血管紧张素原mRNA的表达，而不影响肾脏血管紧张素原mRNA， ${}^{{13},{15}}$ 以及早期临床经验中使用GalNAc结合的反义寡核苷酸靶向血管紧张素原的结果。 ${}^{{12},{13}}$ GalNAc-siRNA的一致且持久的药效学效应提供了在24小时内持续降低血压的潜力，并且可以持续数月，通过每年两次或每季度的皮下给药实现。

A Quick Take is available at NEJM.org

在NEJM.org上可以找到快速概述。

In this phase 1 study, we assessed the safety, pharmacokinetic, and pharmacodynamic profiles of zilebesiran in patients with hypertension. We also explored the potential of the drug to modulate blood pressure, including under controlled conditions of dietary salt intake. We further assessed the effect of zilebesiran in combination with irbesartan on safety end points and blood pressure.

在这项阶段 1 研究中，我们评估了 zilebesiran 在高血压患者中的安全性、药代动力学和药效学特征。我们还探讨了该药物调节血压的潜力，包括在控制的饮食盐摄入条件下。我们进一步评估了 zilebesiran 与 irbesartan 联合使用对安全性终点和血压的影响。

METHODS

方法

STUDY DESIGN AND OVERSIGHT

研究设计与监督

This was a four-part, multicenter, phase 1 study of zilebesiran designed to assess safety, pharmacokinetic and pharmacodynamic characteristics, and exploratory antihypertensive efficacy with 24-hour ambulatory blood-pressure monitoring in patients with hypertension. This report presents data from Parts A and B, which were double-blind, randomized, placebo-controlled studies of a single ascending dose (Part A) and a single fixed dose during low- and high-salt diet conditions (Part B), and from Part E, an open-label study of a single fixed dose of zilebesiran with daily irbesartan coadministration. Part D is ongoing; Part $\mathrm{C}$ was planned as a multidose phase but was removed during a protocol amendment (see the protocol, available with the full text of this article at NEJM.org).

这是一项四部分的多中心阶段 1 研究，旨在评估 zilebesiran 的安全性、药代动力学和药效学特征，以及在高血压患者中进行 24 小时动态血压监测的探索性抗高血压疗效。本报告呈现了 A 部分和 B 部分的数据，这两部分是双盲、随机、安慰剂对照的单次递增剂量研究（A 部分）和在低盐和高盐饮食条件下的单次固定剂量研究（B 部分），以及 E 部分的开放标签研究，研究中每日联合使用固定剂量的 zilebesiran 和 irbesartan。D 部分正在进行中；部分 $\mathrm{C}$ 原计划为多剂量阶段，但在方案修订过程中被移除（请参见协议，完整文本可在 NEJM.org 上获取）。

The study was conducted at four sites in the United Kingdom (see the Supplementary Appendix, available at NEJM.org). The study was approved by the relevant research ethics committees within the Research Ethics Service of the U.K. Health Departments and was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation and the provisions of the Declaration of Helsinki. All the patients provided written informed consent. A safety review committee conducted periodic assessments.

该研究在英国的四个地点进行（请参见 NEJM.org 上的补充附录）。该研究获得了英国卫生部门研究伦理服务内相关研究伦理委员会的批准，并按照国际协调理事会的良好临床实践指南和赫尔辛基宣言的规定进行。所有患者均提供了书面知情同意。安全审查委员会进行了定期评估。

The study was sponsored by Alnylam Pharmaceuticals and was designed by the sponsor in collaboration with the principal investigators. Data were collected by the study investigators and analyzed by the sponsor; interpretation of the data was performed by the sponsor, the first four authors, and the last author. The first draft of the manuscript was prepared by the first author, who had access to all the study data, and all the authors participated in the decision to submit the manuscript for publication. OPEN Health provided editorial assistance, funded by Alnylam Pharmaceuticals. All the authors contributed to the interpretation of the data and critical revision of the manuscript and attest to the accuracy and completeness of the data and the fidelity of the study to the protocol. All the investigators, their institutions, and the sponsor were required to maintain data confidentiality during the study.

该研究由 Alnylam Pharmaceuticals 资助，并由赞助方与主要研究者合作设计。数据由研究调查员收集，并由赞助方分析；数据的解释由赞助方、前四位作者和最后一位作者进行。手稿的初稿由第一作者准备，第一作者获得了所有研究数据的访问权限，所有作者参与了提交手稿以供出版的决定。OPEN Health 提供了编辑协助，资金由 Alnylam Pharmaceuticals 提供。所有作者均参与了数据的解释和手稿的关键修订，并证明数据的准确性和完整性以及研究对协议的忠实性。所有调查员、他们的机构和赞助方在研究期间都必须保持数据的机密性。

STUDY PARTICIPANTS

研究参与者

Eligible patients included adults 18 to 65 years of age with treated or untreated hypertension who had a mean seated systolic blood pressure as assessed by automated cuff of more than 130 to ${165}\mathrm{\;{mm}}\mathrm{{Hg}}$ (Parts A and B) or more than 135 to ${165}\mathrm{\;{mm}}\mathrm{{Hg}}$ (Part E) and a mean systolic blood pressure of ${130}\mathrm{\;{mm}}\mathrm{{Hg}}$ or more as assessed by 24-hour ambulatory blood-pressure monitoring after washout of antihypertensive medications for at least 2 weeks. Among the key exclusion criteria were secondary hypertension, postural hypotension, diabetes, previous cardiovascular events, and current or anticipated treatment with $\beta$ -adrenergic receptor-blocking drugs. Full inclusion and exclusion criteria are provided in the protocol.

符合条件的患者包括年龄在 18 至 65 岁之间的成年人，他们有经过治疗或未治疗的高血压，经过自动袖带评估的坐位收缩压平均值超过 130 至 ${165}\mathrm{\;{mm}}\mathrm{{Hg}}$ （A 和 B 部分）或超过 135 至 ${165}\mathrm{\;{mm}}\mathrm{{Hg}}$ （E 部分），并且在停用抗高血压药物至少 2 周后，通过 24 小时动态血压监测评估的收缩压平均值为 ${130}\mathrm{\;{mm}}\mathrm{{Hg}}$ 或更高。主要排除标准包括继发性高血压、体位性低血压、糖尿病、既往心血管事件以及当前或预期使用 $\beta$ -肾上腺素受体阻滞药物。完整的纳入和排除标准在协议中提供。

STUDY DESIGN

研究设计

In Part A, eligible patients (12 per cohort) were randomly assigned in a $2 : 1$ ratio to receive a single subcutaneous dose of zilebesiran $({10},{25}$ , 50, 100, 200, 400, or 800 mg) or placebo (Fig. S1 in the Supplementary Appendix). Add-on antihypertensive therapy was permitted at the discretion of the investigator at 8 weeks for uncontrolled hypertension.

在 A 部分，符合条件的患者（每组 12 人）以 $2 : 1$ 的比例随机分配接受单次皮下注射 zilebesiran $({10},{25}$ （50、100、200、400 或 800 毫克）或安慰剂（见补充附录中的图 S1）。在 8 周时，对于未控制的高血压，研究者可酌情允许添加抗高血压治疗。

In Part B, after sequential administration of a low-salt diet $({0.23}\mathrm{\;g}$ per day) and a high-salt diet (5.75 g per day) from days -21 through -8, patients were randomly assigned in a $2 : 1$ ratio to a single dose of ${800} - \mathrm{{mg}}$ zilebesiran or placebo and rechallenged with the same dietary protocol from days 43 through 56 (corresponding to the timing of the expected peak effect of zilebesiran). The principal goal of Part B was to assess the potential for dietary salt intake to modulate the blood-pressure-lowering effects of zilebesiran. N ENGL J MED 389;3 NEJM.ORG JULY 20, 2023

在 B 部分，在第 -21 天至第 -8 天期间，患者依次接受低盐饮食 $({0.23}\mathrm{\;g}$ 和高盐饮食（每天 5.75 克），然后以 $2 : 1$ 的比例随机分配接受单次剂量的 ${800} - \mathrm{{mg}}$ zilebesiran 或安慰剂，并在第 43 天至第 56 天期间重新挑战相同的饮食方案（对应于预期的 zilebesiran 峰值效应的时间）。B 部分的主要目标是评估饮食盐摄入对 zilebesiran 降压效果的调节潜力。N ENGL J MED 389;3 NEJM.ORG 2023 年 7 月 20 日

In Part E, all the patients received a single 800-mg dose of zilebesiran. Patients with a systolic blood pressure of ${120}\mathrm{\;{mm}}\mathrm{{Hg}}$ or more at week 6 as assessed by 24-hour ambulatory blood-pressure monitoring received additional treatment with irbesartan at a dose of ${300}\mathrm{{mg}}$ once daily for 2 weeks.

在 E 部分，所有患者接受了一次 800 毫克的 zilebesiran 注射。在第 6 周通过 24 小时动态血压监测评估收缩压 ${120}\mathrm{\;{mm}}\mathrm{{Hg}}$ 或更高的患者，接受了每日一次的 irbesartan 额外治疗，剂量为 ${300}\mathrm{{mg}}$ ，持续 2 周。

After the conclusion of the treatment period at week 12 for Parts A, B, and E, patients entered an extended safety follow-up period (see the Supplementary Appendix). All the patients were given guidance regarding moderation of alcohol intake, avoidance of supplements that might affect blood pressure, and dietary salt restriction to ${2.0}\mathrm{\;g}$ per day for the study duration,except as otherwise instructed in Part B.

在 A、B 和 E 部分的治疗期结束后，患者进入扩展安全性随访期（见补充附录）。所有患者都获得了关于适度饮酒、避免可能影响血压的补充剂以及在研究期间将饮食盐限制在 ${2.0}\mathrm{\;g}$ 每天的指导，除非在 B 部分另有指示。

END POINTS AND ASSESSMENTS

终点和评估

The primary end point was the frequency of adverse events. Secondary end points were the change from baseline in the serum angioten-sinogen level and pharmacokinetic characteristics. Exploratory end points included changes from baseline in systolic and diastolic blood pressure as measured by 24-hour ambulatory blood-pressure monitoring at weeks 6, 8, 12, and 24 in Part A; during low- and high-salt intake before and after dose administration in Part B; and before and after daily irbesartan coadministration in Part E.

主要终点是不良事件的发生频率。次要终点是血清血管紧张素原水平的基线变化和药代动力学特征。探索性终点包括在A部分第6、8、12和24周通过24小时动态血压监测测量的收缩压和舒张压的基线变化；在B部分低盐和高盐摄入前后剂量给药的情况；以及在E部分每日与厄贝沙坦共同给药前后的情况。

Safety assessments included monitoring of adverse events, laboratory assessments, and vital signs. Pharmacodynamic assessments included measurement of serum angiotensinogen levels (enzyme-linked immunosorbent assay; IBL-America) as well as plasma levels of renin-angiotensin system metabolites. Noncompart-mental pharmacokinetic measurements were calculated from plasma and urine samples with the use of Phoenix WinNonLin, version 8.3 (Certara).

安全性评估包括对不良事件的监测、实验室评估和生命体征的监测。药效学评估包括测量血清血管紧张素原水平（酶联免疫吸附测定；IBL-America）以及肾素-血管紧张素系统代谢物的血浆水平。非分 compartment 药代动力学测量是通过使用Phoenix WinNonLin 8.3版（Certara）从血浆和尿液样本中计算得出的。

STATISTICAL ANALYSIS

统计分析

Power calculations were not used to determine sample size, and data were analyzed primarily by means of descriptive statistics. No formal statistical hypothesis testing was performed, and the widths of the confidence intervals were not adjusted for multiplicity and should not be used for hypothesis testing. Data from patients who received placebo were combined across dose cohorts in Part A. The relationship between individual serum angiotensinogen level and 24- hour mean systolic blood pressure was explored by combining data from all zilebesiran dose groups and placebo in Part A. A log-linear model was used to describe the relationship between the decrease in serum angiotensinogen level and the decrease in 24-hour mean systolic blood pressure. All statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute). Further details of the statistical analyses are provided in the Supplementary Appendix.

并未使用功效计算来确定样本量，数据主要通过描述性统计进行分析。未进行正式的统计假设检验，置信区间的宽度未针对多重性进行调整，因此不应用于假设检验。在A部分，接受安慰剂的患者数据在剂量组之间进行了合并。通过将A部分所有厄贝沙坦剂量组和安慰剂的数据结合，探讨了个体血清血管紧张素原水平与24小时平均收缩压之间的关系。使用对数线性模型描述血清血管紧张素原水平下降与24小时平均收缩压下降之间的关系。所有统计分析均使用SAS软件9.4版（SAS Institute）进行。统计分析的进一步细节在补充附录中提供。

Plus-minus values are means $\pm$ SD. Percentages may not total 100 because of rounding.
正负值是均值 $\pm$ 标准差。由于四舍五入，百分比可能总和不为100。

$\uparrow$ Part E was a single-group study, with all the patients receiving a single 800-mg dose of zilebesiran. Patients with a systolic blood pressure of 120 mm Hg or more at week 6 as assessed by 24-hour ambulatory blood-pressure monitoring received additional treatment with irbesartan at a dose of ${300}\mathrm{{mg}}$ once daily for 2 weeks and are shown in the zilebesiran + irbesartan column.

$\uparrow$ E部分是一个单组研究，所有患者接受了一次800毫克的zilebesiran剂量。在第6周，经过24小时动态血压监测评估，收缩压在120 mm Hg或以上的患者接受了额外的irbesartan治疗，剂量为 ${300}\mathrm{{mg}}$ ，每日一次，持续2周，并在zilebesiran + irbesartan列中显示。

I Five patients from Part A participated in Part E.

I A部分的五名患者参与了E部分。

Race was reported by the patients.

种族由患者报告。

¶Shown are mean 24-hour blood-pressure levels as assessed by ambulatory blood-pressure monitoring.

¶显示的是通过动态血压监测评估的平均24小时血压水平。

$\parallel$ The body-mass index is the weight in kilograms divided by the square of the height in meters.

$\parallel$ 体重指数是体重（千克）除以身高（米）的平方。

From May 30, 2019, through January 26, 2022, a total of 107 patients were enrolled, including 84 patients in Part A (56 assigned to zilebesiran and 28 to placebo), 12 in Part B (8 assigned to zilebe-siran and 4 to placebo), and 16 in Part E, 5 of whom had previously participated in Part A and received only placebo. The characteristics of the patients at baseline are summarized according to study part and study-group assignment in Table 1.

从2019年5月30日到2022年1月26日，共有107名患者入组，其中A部分有84名患者（56名分配到zilebesiran，28名分配到安慰剂），B部分有12名患者（8名分配到zilebesiran，4名分配到安慰剂），E部分有16名患者，其中5名患者之前参与了A部分并仅接受了安慰剂。患者在基线的特征根据研究部分和研究组分配在表1中总结。

In the pooled population (107 patients), the mean age was 53.5 years (range,35 to 65), 62% were men, 25% were Black, and the mean (±SD) 24-hour systolic blood pressure was ${140.3} \pm {9.0}$ $\mathrm{{mm}}\mathrm{{Hg}}$ . With regard to sex and race,the enrolled population was generally representative of the broader population of persons with hypertension in the United Kingdom. However, the study population was slightly younger because patients older than 65 years of age were excluded from participation (Table S1). Randomization,

在汇总人群中（107名患者），平均年龄为53.5岁（范围，35至65岁），62%为男性，25%为黑人，平均（±标准差）24小时收缩压为 ${140.3} \pm {9.0}$ $\mathrm{{mm}}\mathrm{{Hg}}$ 。关于性别和种族，入组人群通常代表了英国高血压患者的更广泛人群。然而，研究人群略显年轻，因为65岁以上的患者被排除在参与之外（表S1）。随机化，

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