美国Mineralys医疗公司David Rodman团队研究了Lorundrostat在高血压失控和难治性高血压患者中的应用。2025年6月30日出版的《美国医学会杂志》发表了这项成果。

不受控制的高血压仍然是一个全球性的健康问题，醛固酮分泌失调是其核心机制。Lorundrostat是一种新型醛固酮合成酶抑制剂，可减少醛固酮的产生，对不受控制的高血压患者（包括治疗难治性高血压患者）有效。

为了评价lorundrostat在2 - 5种降压药的处方方案中对未控制的高血压和难治性高血压患者降压的疗效和安全性，研究组进行了一项3期随机临床试验，2023年11月至2024年9月期间，在13个国家的159个临床站点招募了未控制的高血压成年人，包括那些治疗抵抗性高血压患者。最后一次随访日期为2025年1月24日。他们随机分配比例为1:2:1至50mg /d的lorundrostat，持续6周，然后如果符合预先规定的标准，连续6周100mg /d的lorundrostat（n= 270）， 50mg /d的lorundrostat，持续12周（n= 541），或每日安慰剂12周（n= 272）。预先指定的标准包括收缩压130毫米汞柱或更高，钾水平4.8 mmol/L或更低，钠水平135 mmol/L或更高，估计肾小球滤过率（eGFR）大于45 mL/min/1.73 m²， eGFR降低小于25%。主要结局是随机分配到50mg lorundrostat和安慰剂组的参与者第6周自动办公室收缩压的变化。特别关注的不良事件包括由于高钾血症、低钠血症和肾功能下降等事件导致的剂量减少、中断或停药。

1083名参与者的平均年龄为61.6岁（SD， 10.3岁），508名（46.9%）为女性，311名（28.7%）为黑人或非裔美国人，733名（67.7%）为白人，685名（63.3%）体重指数为30或以上（肥胖）。在随机分组时，432名参与者（39.9%）服用2种处方抗高血压药物，651名参与者（60.1%）服用3种或以上药物。对于lorundrostat合并50 mg组（n = 808），第6周自动办公室收缩压的最小二乘平均变化为16.9 mm Hg (95% CI， 19.0至14.9 mm Hg)，而安慰剂组的最小二乘平均变化为7.9 mm Hg (95% CI， 11.5至4.2 mm Hg)(最小二乘平均差异，9.1 mm Hg)。低钠血症、高钾血症和肾功能下降在lorundrostat组比安慰剂组更常见。在50mg lorundrostat组（可能增加到100mg）中，1名参与者（0.37%）因高钾血症停药，1名参与者（0.37%）因低钠血症停药，0名参与者因肾功能下降停药。在50mg lorundrostat组中，2名参与者（0.37%）因高钾血症停药，2名参与者（0.37%）因低钠血症停药，3名参与者（0.56%）因肾功能下降停药。49.9%的参与者（538/1078）发生了治疗后出现的不良事件，严重程度大多为轻度或中度。

研究结果表明，lorundrostat（一种醛固酮合成酶抑制剂）的有效性和安全性被证明可以降低成人高血压患者的血压，包括治疗难治性高血压患者。

附：英文原文

Title: Lorundrostat in Participants With Uncontrolled Hypertension and Treatment-Resistant Hypertension: The Launch-HTN Randomized Clinical Trial

Author: Manish Saxena, Luke Laffin, Claudio Borghi, Beatriz Fernandez Fernandez, Jalal K. Ghali, Branko Kopjar, Krishna Polu, Simon D. Roger, B. T. Slingsby, Frank Strutz, Liffert Vogt, Matthew R. Weir, David Rodman, Launch-HTN Investigators, John Mark Joyce, Nandita Jones, Sujeeta Dhakhwa, Susan Angel, Fadi Chalhoub, Leticia Goodwin, Tatyana Miroshnikova, Patricia Ann W. Brown, Robert Molpus, Felipe Suplicy, Beckie Klipper, Keung Lee, Andrew Chow, Karla Alfonsin, Becky Hogan, Lon Lynn, Paul Lunseth, Alexandra Lynch, Andres Patron, George Kaleel Rafeedie, Marilyn Patron, Igor Lukianov, George Rafeedie, John David Lentz, Luis A. Diaz-Secades, Esmil Perez, Damarys Sacasa, Leticia Jimenez, Yadiel Sanchez, Atul Chugh, Jai Radhakrishnan, Vijay U. Rao, Kaitlin E. Ziedonis, Ayanna Guzman-Nguyen, Lora McGill, Lisa S. Usdan, Valerie K. Arnold, Carolyn J. Scatamacchia, Keerthi G. Heckle, Codi Anthony, Melissa Flowers, Henry Punzi, Kathy Cassidy, Waymon Drummond, John Flack, Farrell Mendelsohn, James Powell, Hunter Coore, Nakeydia Bryant, Farah Madhani-Lovely, Sujatha Pitani, Angela Dunlap, Amanda Merlino, Alexis Steele-Griffen, Charles Crump, Scott Harnsberger, Alexander White, Richard Marshall, Bhanu Visvalingam, Viviana Hargis, Richard Mohammed, Nora Borello

Issue&Volume: 2025-06-30

Abstract:

Importance  Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension.

Objective  To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension.

Design, Setting, and Participants  In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025.

Intervention  Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n=270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n=541), or daily placebo for 12 weeks (n=272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR.

Main Outcome and Measures  The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function.

Results  Of the 1083 participants, the mean age was 61.6 years (SD, 10.3 years), 508 (46.9%) were female, 311 (28.7%) were Black or African American, 733 (67.7%) were White, and 685 (63.3%) had a body mass index of 30 or greater (obesity). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more. For the pooled 50 mg of lorundrostat group (n=808), the least-squares mean change in automated office systolic BP at week 6 was 16.9 mm Hg (95% CI, 19.0 to 14.9 mm Hg) vs 7.9 mm Hg (95% CI, 11.5 to 4.2 mm Hg) for the placebo group (least-squares mean difference, 9.1 mm Hg [95% CI, 13.3 to 4.9 mm Hg]; P<.001). Hyponatremia, hyperkalemia, and reduction in kidney function were reported more often with lorundrostat vs placebo. In the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 participant (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function. In the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 participants (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function. Treatment-emergent adverse events occurred in 49.9% of participants (538/1078) and were mostly mild or moderate in severity.

Conclusions and Relevance  The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension.

DOI: 10.1001/jama.2025.9413

Source: https://jamanetwork.com/journals/jama/fullarticle/2835763