Montani David, McLaughlin Vallerie V, Gibbs J Simon R, Gomberg-Maitland Mardi, Hoeper Marius M, Preston Ioana R, Souza Rogerio, Waxman Aaron B, Escribano Subias Pilar, Feldman Jeremy, Meyer Gisela M, Olsson Karen M, Coulet Florence, Manimaran Solaiappan, Zhao Yujie, Lau Anna, de Oliveira Pena Janethe, Badesch David B, Humbert Marc
Université Paris-Saclay, INSERM Unité Mixte de Recherche en Santé 999, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), European Reference Network for Rare Respiratory Diseases (ERN-LUNG), Le Kremlin-Bicêtre, France.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Am J Respir Crit Care Med. 2025 Jun;211(6):1028-1037. doi: 10.1164/rccm.202409-1698OC.
It is unclear whether carriers of pathogenic variants in PAH-associated genes have a distinct response to PAH treatment. 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. 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. Participants underwent DNA sequencing at baseline to detect genetic variants in disease-associated genes (, , , , , , , and ). Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-min-walk distance) were assessed by variant status and treatment at 24 weeks. Serum concentrations of mRNA and N-terminal prohormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status. Analysis of covariance was used to compare the change from baseline by treatment and variant status. Among 76 participants included, pathogenic variants were detected in 25 (23 , 2 other), and 51 had no variants or variants of uncertain significance. mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline. Changes at 24 weeks in pulmonary vascular resistance and 6-minute-walk distance did not differ by variant status. gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status. The adverse event profile was generally consistent with that seen in the parent PULSAR study. These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of variant status.
尚不清楚PAH相关基因的致病变体携带者对PAH治疗是否有不同反应。为评估基因变体状态对司他特截治疗肺动脉高压疗效的影响以及司他特截治疗对肺动脉高压生物标志物的影响。PULSAR（司他特截治疗肺动脉高压研究；NCT03496207）是一项II期随机对照研究，比较司他特截与安慰剂加用肺动脉高压背景治疗的效果。参与者在基线时进行DNA测序以检测疾病相关基因（、、、、、、和）中的基因变体。在24周时通过变体状态和治疗评估安全性（不良事件）和疗效（肺血管阻力、6分钟步行距离）。通过治疗和变体状态在基线和24周时评估mRNA和N末端前体激素B型利钠肽的血清浓度。采用协方差分析比较治疗和变体状态导致的相对于基线的变化。在纳入的76名参与者中，25名（23名，2名其他）检测到致病变体，51名没有变体或意义不确定的变体。突变携带者更年轻，更频繁地接受三联疗法，但基线时临床特征较轻。肺血管阻力和6分钟步行距离在24周时的变化不因变体状态而异。无论治疗或变体状态如何，基因表达随时间从基线变化小于两倍。不良事件谱总体上与原PULSAR研究中观察到的一致。这些结果表明，无论变体状态如何，司他特截治疗肺动脉高压的安全性和临床疗效均一致。
