德国汉诺威医学院Marius M. Hoeper团队研究了Sotatercept治疗肺动脉高压的疗效与安全性。2023年3月6日，《新英格兰医学杂志》发表了这一成果。

肺动脉高压是一种进行性疾病，涉及肺血管的增生性重塑。尽管治疗取得了进展，但与疾病相关的发病率和死亡率仍然很高。Sotatercept是一种融合蛋白，可捕获与肺动脉高压相关的激活素和生长分化因子。

研究组进行了一项多中心、双盲、临床3期试验，接受稳定背景治疗的肺动脉高压成人（世界卫生组织功能II或III级）以1:1的比例随机分配，每3周接受皮下注射sotatercept（起始剂量，0.3毫克/千克体重；目标剂量，0.7毫克/千克）或安慰剂。主要终点是第24周6分钟步行距离与基线的变化。

按以下顺序分层测试的9个次要终点为多成分改善、肺血管阻力改变、N端B型利钠肽前体水平改变、世界卫生组织功能分级改善、死亡时间或临床恶化、法国风险评分，以及肺动脉高压-症状和影响（PAH-SYMPACT）物理影响、心肺症状和认知-情绪影响领域得分的变化；除死亡或临床恶化时间外，所有患者均在第24周进行评估，这是在最后一名患者完成第24周随访时评估的。

共有163名患者接受sotatercept治疗，160名患者接受安慰剂治疗。第24周，sotatercept组6分钟步行距离与基线相比的中值变化为34.4 m，安慰剂组为1.0 m。Hodges–Lehmann估计，sotatercept组与安慰剂组在第24周6分钟步行距离内与基线相比的变化差异为40.8 m。与安慰剂组相比，sotatercept组的前8个次要终点显著改善，而PAH-SYMPACT认知-情感影响领域得分则没有改善。Sotatercept比安慰剂更频繁发生的不良事件包括鼻出血、头晕、毛细血管扩张、血红蛋白水平升高、血小板减少和血压升高。

研究结果表明，在接受稳定背景治疗的肺动脉高压患者中，sotatercept治疗后的运动能力（通过6分钟步行试验评估）比安慰剂有更大的改善。

附：英文原文

Title: Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension | NEJM

Author: Marius M. Hoeper, M.D.,, David B. Badesch, M.D.,, H. Ardeschir Ghofrani, M.D.,, J. Simon R. Gibbs, M.D.,, Mardi Gomberg-Maitland, M.D.,, Vallerie V. McLaughlin, M.D.,, Ioana R. Preston, M.D.,, Rogerio Souza, M.D., Ph.D.,, Aaron B. Waxman, M.D., Ph.D.,, Ekkehard Grünig, M.D.,, Grzegorz Kope, M.D., Ph.D.,, Gisela Meyer, M.D.,, Karen M. Olsson, M.D.,, Stephan Rosenkranz, M.D.,, Yayun Xu, Ph.D.,, Barry Miller, M.S.,, Marcie Fowler, Ph.D.,, John Butler, M.D.,, Joerg Koglin, M.D., Ph.D.,, Janethe de Oliveira Pena, M.D., Ph.D.,, and Marc Humbert, M.D., Ph.D.

Issue&Volume: 2023-03-06

Abstract:

Background

Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.

Methods

We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro–B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive–Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.

Results

A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, 0.3 to 3.5) in the placebo group. The Hodges–Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive–Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.

Conclusions

In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo.

DOI: 10.1056/NEJMoa2213558

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2213558