Consistent Safety and Efficacy of Sotatercept for Pulmonary Arterial Hypertension in BMPR2 Mutation Carriers and Noncarriers: A Planned Analysis of a Phase II, Double-Blind, Placebo-controlled Clinical Trial (PULSAR).

Objectives: To evaluate the effect of genetic variant status on the efficacy of sotatercept and the effect of sotatercept treatment on biomarkers in pulmonary arterial hypertension.

目的：评估遗传变异状态对sotatercept治疗肺动脉高压（PAH）疗效的影响，以及sotatercept治疗对PAH生物标志物的影响。

Methods: PULSAR (A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension; NCT03496207) was a phase II, randomized controlled study of sotatercept versus placebo added to background therapy for pulmonary arterial hypertension.

方法：PULSAR（一项关于Sotatercept治疗肺动脉高压的研究；NCT03496207）是一项II期、随机对照研究，比较了在肺动脉高压背景治疗基础上加用Sotatercept与安慰剂的效果。

Participants underwent DNA sequencing at baseline to detect genetic variants in disease-associated genes (ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA3, KCNK3, and SMAD9).

参与者在基线时进行了DNA测序，以检测与疾病相关的基因（ACVRL1、BMPR2、CAV1、EIF2AK4、ENG、KCNA3、KCNK3和SMAD9）中的遗传变异。

Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-min-walk distance) were assessed by variant status and treatment at 24 weeks.

安全性（不良事件）和有效性（肺血管阻力、6分钟步行距离）通过24周时的变异状态和治疗进行评估。

Serum concentrations of BMPR2 mRNA and N-terminal prohormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status.

在基线和24周时，通过治疗和变异状态评估BMPR2 mRNA和N末端前体B型利钠肽的血清浓度。

Analysis of covariance was used to compare the change from baseline by treatment and variant status.

使用协方差分析比较基线变化，按治疗和变异状态分组。

Measurements and Main Results: Among 76 participants included, pathogenic variants were detected in 25 (23 BMPR2, 2 other), and 51 had no variants or variants of uncertain significance.

测量和主要结果：在纳入的76名参与者中，检测到致病性变异的有25例（23例BMPR2，2例其他），另外51例没有变异或变异意义不明。

BMPR2 mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline.

BMPR2突变携带者年龄较小，更常使用三联疗法，但在基线时临床特征较不严重。

Changes at 24 weeks in pulmonary vascular resistance and 6-minute-walk distance did not differ by variant status.

24周时肺血管阻力和6分钟步行距离的变化与变异状态无关。

BMPR2 gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status.

BMPR2基因表达随时间变化小于基线的两倍，无论治疗或变异状态如何。

The adverse eventprofile was generally consistent with that seen in the parent PULSAR study.

不良事件特征总体上与母本PULSAR研究中观察到的一致。

Conclusions: These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of BMPR2 variant status.

结论：这些结果表明，无论BMPR2变异状态如何，sotatercept治疗肺动脉高压的安全性和临床疗效是一致的。