The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Here we assess XXB750, a human monoclonal antibody activating natriuretic peptide receptor 1, in patients with heart failure.

在这里，我们评估了XXB750，一种激活利钠肽受体1的人源化单克隆抗体，在心力衰竭患者中的效果。

Patients with heart failure and a left ventricular ejection fraction <50% were enrolled.

招募了左心室射血分数小于50%的心力衰竭患者。

Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60 mg XXB750, 120 mg XXB750 or placebo in a blinded fashion or sacubitril/valsartan treatment in an open-label fashion.

那些正在接受血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂治疗的患者被随机分配接受60毫克XXB750、120毫克XXB750或安慰剂的双盲治疗，或者接受沙库巴曲/缬沙坦的开放标签治疗。

Those patients on background sacubitril/valsartan treatment were randomized to either 60 mg XXB750, 120 mg XXB750 or placebo treatment in a blinded fashion.

在背景治疗为沙库巴曲/缬沙坦的患者中，随机分为60毫克XXB750、120毫克XXB750或安慰剂治疗，采用双盲方式。

The primary endpoint was the change in NT-proBNP levels at 16 weeks after treatment initiation, and safety was also assessed.

主要终点是治疗开始后16周NT-proBNP水平的变化，同时评估安全性。

We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 (n = 26), 120 mg XXB750 (n = 55), matching placebo (n = 29) or sacubitril/valsartan (n = 25).

我们随机将136名参与者（70%为男性，30%为女性）分为60毫克XXB750组（n = 26），120毫克XXB750组（n = 55），匹配安慰剂组（n = 29）或沙库巴曲/缬沙坦组（n = 25）。

At 16 weeks, NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval(CI) 1.07-1.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65-0.91) in the pooled XXB750 arms, whereas NT-proBNP levels declined from baseline (ratio of change from baseline 0.70, 95% CI 0.45-1.10), and cGMP levels rose (ratio of change from baseline 1.38, 95% CI 1.13-1.69) in the sacubitril/valsartan arm.

在16周时，XXB750联合组的NT-proBNP水平上升（基线变化比率为1.34，95%置信区间（CI）为1.07-1.66），而环鸟苷酸（cGMP）水平下降（基线变化比率为0.77，95% CI为0.65-0.91），而在沙库巴曲/缬沙坦组中，NT-proBNP水平从基线下降（基线变化比率为0.70，95% CI为0.45-1.10），cGMP水平上升（基线变化比率为1.38，95% CI为1.13-1.69）。

Death or worsening heart failure events occurred more frequently in those receiving XXB750 (25%) compared with those receiving sacubitril/valsartan (8%), or placebo (0%).

在接受XXB750治疗的患者中，死亡或心力衰竭恶化事件的发生率（25%）高于接受沙库巴曲/缬沙坦治疗的患者（8%）或安慰剂组（0%）

Because of the excess heart failure events in participants receiving XXB750, the data monitoring committee recommended stopping the trial prematurely.

由于接受XXB750治疗的参与者心力衰竭事件过多，数据监测委员会建议提前终止试验。

In contrast to the expected mechanism of drug action, XXB750 treatment led to increased NT-proBNP levels, lowered cGMP levels and more worsening heart failure events, suggesting that XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure.

与预期的药物作用机制相反，XXB750治疗导致NT-proBNP水平升高，cGMP水平降低以及心力衰竭事件的恶化，这表明XXB750可能在心力衰竭患者中作为内源性利钠肽的功能性拮抗剂产生悖论性作用。

Clinicaltrials.gov registration: NCT06142383 .

Clinicaltrials.gov注册号：NCT06142383。