Robert P Frantz, Vallerie V McLaughlin, Sandeep Sahay, Pilar Escribano Subías, Ronald L Zolty, Raymond L Benza, Richard N Channick, Kelly M Chin, Anna R Hemnes, Luke S Howard, Olivier Sitbon, Jean-Luc Vachiéry, Roham T Zamanian, Matt Cravets, Robert F Roscigno, David Mottola, Robin Osterhout, Jean-Marie Bruey, Erin Elman, Cindy-Ann Tompkins, Ed Parsley, Richard Aranda, Lawrence S Zisman, Hossein-Ardeschir Ghofrani
{"title":"Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.","authors":"Robert P Frantz, Vallerie V McLaughlin, Sandeep Sahay, Pilar Escribano Subías, Ronald L Zolty, Raymond L Benza, Richard N Channick, Kelly M Chin, Anna R Hemnes, Luke S Howard, Olivier Sitbon, Jean-Luc Vachiéry, Roham T Zamanian, Matt Cravets, Robert F Roscigno, David Mottola, Robin Osterhout, Jean-Marie Bruey, Erin Elman, Cindy-Ann Tompkins, Ed Parsley, Richard Aranda, Lawrence S Zisman, Hossein-Ardeschir Ghofrani","doi":"10.1016/S2213-2600(24)00072-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy.</p><p><strong>Methods: </strong>The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm<sup>5</sup> and ≥800 dyne·s/cm<sup>5</sup>). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm<sup>5</sup> or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed.</p><p><strong>Findings: </strong>From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm<sup>5</sup> (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm<sup>5</sup> (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm<sup>5</sup> (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group.</p><p><strong>Interpretation: </strong>Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH.</p><p><strong>Funding: </strong>Gossamer Bio.</p>","PeriodicalId":51307,"journal":{"name":"Lancet Respiratory Medicine","volume":null,"pages":null},"PeriodicalIF":38.7000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Respiratory Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/S2213-2600(24)00072-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy.
Methods: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed.
Findings: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group.
Interpretation: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH.
期刊介绍:
The Lancet Respiratory Medicine is a renowned journal specializing in respiratory medicine and critical care. Our publication features original research that aims to advocate for change or shed light on clinical practices in the field. Additionally, we provide informative reviews on various topics related to respiratory medicine and critical care, ensuring a comprehensive coverage of the subject.
The journal covers a wide range of topics including but not limited to asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), tobacco control, intensive care medicine, lung cancer, cystic fibrosis, pneumonia, sarcoidosis, sepsis, mesothelioma, sleep medicine, thoracic and reconstructive surgery, tuberculosis, palliative medicine, influenza, pulmonary hypertension, pulmonary vascular disease, and respiratory infections. By encompassing such a broad spectrum of subjects, we strive to address the diverse needs and interests of our readership.