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Baxdrostat治疗难治性高血压患者可剂量依赖性降压
作者:小柯机器人 发布时间:2022/11/15 20:45:00

英国伦敦玛丽女王大学Morris J. Brown团队研究了Baxdrostat治疗难治性高血压的2期试验结果。2022年11月7日出版的《新英格兰医学杂志》发表了这项成果。

醛固酮合成酶控制醛固酮的合成,几十年来一直是治疗高血压的药理学靶点。选择性抑制醛固酮合成酶是必要的,但很难实现,因为皮质醇合成由另一种酶催化,该酶与醛固酮合成酶具有93%的序列相似性。在临床前和1期研究中,baxdrostat对酶抑制的选择性为100:1,并且在几种剂量水平下,baxdrostat降低血浆醛固酮水平,但不降低皮质醇水平。

在这项多中心、安慰剂对照试验中,研究组随机将患有顽固性高血压、血压为130/80 mm Hg或更高、接受至少三种稳定剂量的抗高血压药物(包括利尿剂)的患者分为两组,一组每天接受一次baxdrostat(0.5 mg、1 mg或2 mg),持续12周或安慰剂治疗。主要终点是与安慰剂组相比,每种剂量baxdrostat组从基线到第12周收缩压的变化。

共有248名患者完成了试验。在baxdrostat 2 mg组、1 mg组、0.5 mg组和安慰剂组分别观察到-20.3 mm Hg、-17.5 mm Hg、-12.1 mm Hg和-9.4 mm Hg的收缩压剂量依赖性变化。2 mg组和安慰剂组之间收缩压变化的差异为−11.0 mm Hg,1 mg组与安慰剂组之间的差异为−8.1 mm Hg,组间差异均显著。

试验期间未发生死亡,研究人员未将严重不良事件归因于baxdrostat,也未出现肾上腺皮质功能不全。2名患者与baxdrostat相关的钾水平升高至6.0 mmol/L或更高,但在停药和重新用药后,这些升高没有复发。

研究结果表明,接受baxdrostat治疗的难治性高血压患者的血压有剂量相关性降低。

附:英文原文

Title: Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension | NEJM

Author: Mason W. Freeman, M.D.,, Yuan-Di Halvorsen, Ph.D.,, William Marshall, M.D.,, Mackenzie Pater, Ph.D.,, Jon Isaacsohn, M.D.,, Catherine Pearce, D.H.Sc.,, Brian Murphy, M.D., M.P.H.,, Nicholas Alp, M.D.,, Ajay Srivastava, M.D.,, Deepak L. Bhatt, M.D., M.P.H.,, and Morris J. Brown, M.D.

Issue&Volume: 2022-11-07

Abstract:

Background

Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.

Methods

In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.

Results

A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of 20.3 mm Hg, 17.5 mm Hg, 12.1 mm Hg, and 9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was 11.0 mm Hg (95% confidence interval [CI], 16.4 to 5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was 8.1 mm Hg (95% CI, 13.5 to 2.8; P=0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level of 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.

Conclusions

Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure.

DOI: 10.1056/NEJMoa2213169

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2213169

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home