Natriuretic Peptide Receptor-1 Agonist for Resistant Hypertension: A Randomized Phase 2 Trial.

Activation of NPR-1 may lower blood pressure (BP) in patients with resistant hypertension through increases in the second messenger cyclic guanosine monophosphate.

激活 NPR-1 可能通过增加第二信使环磷酸鸟苷（cyclic guanosine monophosphate）的水平，降低难治性高血压患者的血压（BP）。

The aim of this study was to determine the effect of NPR-1 agonism on 24-hour BP.

本研究旨在确定NPR-1激动剂对24小时血压的影响。

Methods

This phase 2, multicenter, randomized, double-blind, placebo-controlledtrial evaluated 4 once-monthly subcutaneous doses of XXB750 (30 mg, 60 mg, 120 mg, and 240 mg) administered at baseline, week 4, and week 8 in patients with resistant hypertension.

这项2期、多中心、随机、双盲、安慰剂对照试验评估了在基线、第4周和第8周对难治性高血压患者进行的4种每月一次的XXB750皮下剂量（30 mg、60 mg、120 mg和240 mg）的效果。

Resistant hypertension was defined as 24-hour systolic BP (SBP) ≥135 mm Hg despite treatment with 3 or 4 guideline-directed antihypertensive agents.

难治性高血压被定义为尽管使用3种或4种指南推荐的降压药物治疗，24小时收缩压（SBP）≥135毫米汞柱。

The primary endpoint was the dose-response relationship of XXB750 vs placebo in reducing the mean 24-hour SBP from baseline to week 12.

主要终点是XXB750与安慰剂相比，在减少从基线到第12周的平均24小时收缩压（SBP）的剂量反应关系。

Results

The study population (N = 189) had a mean age of 61 years, was 69% male, 61% White, 20% Asian, and 14% Black/African American, and had a baseline mean 24-hour ambulatory BP of 148/81 ± 11/10 mm Hg.

研究人群（N = 189）的平均年龄为61岁，其中69%为男性，61%为白人，20%为亚洲人，14%为黑人/非裔美国人，并且基线平均24小时动态血压为148/81 ± 11/10毫米汞柱。

Plasma concentrations of XXB750 dose-dependently increased in the XXB750 groups, and XXB750 dose-dependently increased plasma and urine cyclic guanosine monophosphate concentrations by week 12.

XXB750组的血浆浓度呈剂量依赖性增加，到第12周时，XXB750剂量依赖性地增加了血浆和尿液中的环鸟苷酸浓度。

However, paradoxically, there was no significant dose-dependent change from baseline in mean 24-hour SBP at week 12.

然而，具有讽刺意味的是，在第12周时，与基线相比，平均24小时收缩压（SBP）没有显著的剂量依赖性变化。

In fact, none of the doses of XXB750 had a greater BP-lowering effect than placebo.

实际上，XXB750的任何剂量都没有比安慰剂更强的降压效果。

Changes in ambulatory BP were not affected by the development of anti-drug antibodies.

抗药物抗体的产生并未影响门诊血压的变化。

Although there were no changes from baseline in urinary sodium excretion, there were small increases in plasma renin levels in the XXB750 groups.

尽管尿钠排泄量从基线期没有变化，但在XXB750组中血浆肾素水平有小幅上升。

Adverse events with XXB750 were numerically higher than with placebo.

XXB750相关的不良事件数量高于安慰剂。

Adherence to background antihypertensive medications, assessed by drug assays in 88 patients with available plasma samples, was consistent across all treatment groups at both baseline and week 12.

通过药物检测评估的88名有可用血浆样本的患者对背景抗高血压药物的依从性，在基线和第12周时在所有治疗组中保持一致。

Conclusions

XXB750, an NPR-1 agonist, had a neutral effect on 24-hour ambulatory SBP in patients with resistant hypertension, despite showing a robust dose-response relationship for engagement of the target of pharmacologic action as indicated by increases in cyclic guanosine monophosphate levels.

XXB750，一种NPR-1激动剂，在耐药性高血压患者中对24小时动态收缩压（SBP）没有影响，尽管它显示出与药理作用目标的参与度有显著的剂量反应关系，这通过环磷酸鸟苷水平的增加得到指示。

(An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients; NCT05562934).

（XXB750在耐药性高血压患者中的疗效、安全性、耐受性和剂量探索研究；NCT05562934）。