Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension
Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension
复制标题
DOI：
10.1056/nejmoa2213169
复制
发表时间：
2022-11-07
影响因子：
158.5
通讯作者：
Brown，Morris J. J.
中科院分区：
文献类型：
--
作者：
Freeman，Mason W. W.;Halvorsen，Yuan-Di;Brown，Morris J. J.
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，因为皮质醇的合成是由另一种酶催化的，该酶与醛固酮合成酶具有93%的序列相似性。在临床前和一期研究中，巴司他对酶抑制的选择性为100:1，几个剂量水平的巴司他降低了血浆醛固酮水平，但没有降低皮质醇水平。方法在这项多中心安慰剂对照试验中，我们随机分配患有治疗抵抗性高血压，血压为130/80 mm Hg或更高，并且接受至少三种稳定剂量的降压药（包括利尿剂）的患者，每天一次接受巴司他（0.5 mg， 1 mg或2 mg），持续12周或安慰剂。主要终点是与安慰剂组相比，每个巴司他组从基线到第12周的收缩压变化。结果共有248例患者完成了试验。在2 mg、1 mg、0.5 mg和安慰剂组中，分别观察到收缩压的剂量依赖性变化，分别为- 20.3 mm Hg、- 17.5 mm Hg、- 12.1 mm Hg和- 9.4 mm Hg。2 mg组与安慰剂组的收缩压变化差异为- 11.0 mm Hg(95%可信区间[CI]， - 16.4至- 5.5；P<0.001)， 1 mg组与安慰剂组的收缩压变化差异为- 8.1 mm Hg （95% CI, - 13.5至- 2.8；P=0.003）。在试验期间没有发生死亡，研究者没有发现巴司他引起的严重不良事件，也没有出现肾上腺皮质功能不全的情况。2例患者发生了与巴司他相关的钾水平升高至6.0 mmol / l或更高，但这些升高在停药和重新开始用药后没有复发。结论顽固性高血压患者接受巴司他治疗后血压有剂量相关性降低。（由cinor Pharma资助；BrigHTN ClinicalTrials.gov编号：NCT04519658）
BackgroundAldosterone 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.MethodsIn 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.ResultsA 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 to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.ConclusionsPatients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.)