Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension 翻译-CSDN博客

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原文链接: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2208391

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 $\left( { > {10}\mathrm{\;{mm}}\mathrm{ {Hg}}}\right)$