Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

Autor:	Frantz RP; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address: frantz.robert@mayo.edu., McLaughlin VV; Department of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA; Frankel Cardiovascular Center, Ann Arbor, MI, USA., Sahay S; Division of Pulmonary, Critical Care & Sleep Medicine, Houston Methodist Hospital, Houston, TX, USA., Escribano Subías P; Department of Cardiology, CIBERCV, Complutense University, Madrid, Spain; University Hospital 12 de Octubre, Madrid, Spain., Zolty RL; Department of Cardiovascular Medicine, University of Nebraska College of Medicine, Omaha, NE, USA; University of Nebraska Medical Center, Omaha, NE, USA., Benza RL; Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Hospital, New York, NY, USA., Channick RN; Department of Clinical Medicine, University of California Los Angeles, Los Angeles, CA, USA; UCLA Medical Center, Los Angeles, CA, USA., Chin KM; Division of Pulmonary and Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA; UT Southwestern Medical Center, Dallas, TX, USA., Hemnes AR; Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA; Vanderbilt University Medical Center, Nashville, TN, USA., Howard LS; National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, London, UK; Hammersmith Hospital, London, UK., Sitbon O; Department of Respiratory Medicine, Hôpital Bicêtre (AP-HP), Le Kremlin-Bicêtre, France; Université Paris-Saclay, Le Kremlin-Bicêtre, France., Vachiéry JL; Department of Cardiology, Université Libre de Bruxelles, Brussels, Belgium; HUB-Hôpital Erasme, Brussels, Belgium., Zamanian RT; Department of Medicine-Pulmonary, Allergy & Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Medicine, Stanford, CA, USA., Cravets M; Gossamer Bio, San Diego, CA, USA., Roscigno RF; Gossamer Bio, San Diego, CA, USA., Mottola D; Gossamer Bio, San Diego, CA, USA., Osterhout R; Gossamer Bio, San Diego, CA, USA., Bruey JM; Gossamer Bio, San Diego, CA, USA., Elman E; Gossamer Bio, San Diego, CA, USA., Tompkins CA; Gossamer Bio, San Diego, CA, USA., Parsley E; Gossamer Bio, San Diego, CA, USA., Aranda R; Gossamer Bio, San Diego, CA, USA., Zisman LS; Gossamer Bio, San Diego, CA, USA., Ghofrani HA; Department of Internal Medicine, Justus-Liebig-University Giessen and Marburg Lung Center (UGMLC), Giessen, Germany; Institute for Lung Health, Cardio-Pulmonary Institute, Giessen, Germany; German Center for Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College, London, UK.
Jazyk:	angličtina
Zdroj:	The Lancet. Respiratory medicine [Lancet Respir Med] 2024 Jul; Vol. 12 (7), pp. 523-534. Date of Electronic Publication: 2024 May 02.
DOI:	10.1016/S2213-2600(24)00072-9
Abstrakt:	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/cm 5 and ≥800 dyne·s/cm 5 ). 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 5 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/cm 5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm 5 (-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 5 (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. Funding: Gossamer Bio. Competing Interests: Declaration of interests ARH reports having received consulting fees from United Therapeutics, Tenax Therapeutics, Merck, and Janssen; having served as an advisory committee member for Gossamer Bio; and having held stock from Tenax Therapeutics. CT, DM, EE, EP, J-MB, LSZ, MC, RA, RFR, and RO report stocks or stock options from Gossamer Bio; and employment at Gossamer Bio. LSZ also reported patents related to seralutinib (assigned to Gossamer Bio or Pulmokine); stocks or stock options from Pulmokine. RFR also reported previous consulting fees from Gossamer Bio. H-AG reports having received consulting fees from Gossamer Bio, Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Bayer AG, Janssen and Actelion, and MSD and Acceleron; participated as an advisory committee member for Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; and as a member of a data and safety monitoring board for Insmed. J-LV reports having received consulting fees from Gossamer Bio, ShouTi, Janssen, Enzyvant, Bayer HealthCare, Merck, Liquidia, Aerami, and Insmed; received payment or honoraria (payment to their institution) for lectures, presentations, or educational events from Janssen, Merck, Novartis, and Boehringer Ingelheim; received payment for expert testimony from Actelion Pharmaceuticals; received either support for attending meetings or travel (payment to their institution) from Merck; participated on a data safety monitoring board (payment to their institution) from Janssen, GSK, and Moderna; membership on steering committees for Gossamer Bio, Insmed, Merck, and United Therapeutics. KMC reports having received grants or contracts (payment made to their institution) for clinical studies overseen by her from Gossamer Bio, Janssen, United Therapeutics, Merck, Acceleron, and Altavant; received consulting fees from Acceleron; received fees for participating on an advisory board for Merck; received fees for work as an advisory committee member for Gossamer Bio; received fees for work as a steering committee member for Janssen; received fees for work on an adjudication committee for Arena and United Therapeutics; and received fees for an editorial role with the American Heart Association. LSH reported having received payment or honoraria for speaker bureau membership from Janssen; participated as an advisory board member for Janssen, MSD, Altavant, and United Therapeutics, and as an advisory committee member for Gossamer Bio; and having stock or stock options at ATXA Therapeutics, iOWNA, and Circular. OS reports having received grants or contracts for research (payment made to their institution) from Janssen, MSD, and AOP Orphan; payment or honoraria for lectures or an educational event from AOP Orphan, Ferrer, Janssen, and MSD; support for attending meetings or travel from MSD and Janssen; and participated on an advisory committee for Gossamer Bio, AOP Orphan, Enzyvant, Ferrer, Janssen, and MSD. PES reports having received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, and AOT; support for either attending meetings or travel from Janssen and MSD; participated in a data safety monitoring board or advisory board for Janssen, MSD, Ferrer, Gossamer Bio, and AOT; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gossamer Bio. RLB reports having received consulting fees from Merck, United Therapeutics, KEROS, Aerovate, Insmed, and Cereno; served as an advisory committee member for Gossamer Bio; served as an advisory board member for Altavant, Merck, Janssen, and Insmed; served on a data safety monitoring board for Janssen; and served on a scientific advisory board for Cereno. RLZ reports having received consulting fees from Johnson & Johnson, United Therapeutics, Bayer, and Alnylam. RNC reports having received consulting fees from Gossamer Bio, Janssen, Bayer, United Therapeutics, and Third Pole; payment or honoraria for lectures from Janssen and Bayer; and participated on an advisory committee for Gossamer Bio, Janssen, and Bayer. RPF reports having royalties or licenses from UpToDate; receiving consulting fees from Janssen and Liquidia; participated on a data safety monitoring board or advisory board from Gossamer Bio (as an advisory committee member); participated on an advisory board for Janssen, Liquidia, Tenax Therapeutics, ShouTi, Insmed, and Merck; and participated on a data safety monitoring board for Aerovate. RTZ reports having received grants or contracts for industry-supported research from United Therapeutics, Janssen, Tenax Therapeutics, and Gossamer Bio; consulting fees from Janssen, Vivus, Morphogen-IX, Merck, and Gossamer Bio; and stock or stock options from Selten. SS reports having received a research grant from United Therapeutics; speaker honoraria (received by his institute) from Janssen and United Therapeutics; served as an advisor to Janssen, Bayer, United Therapeutics, Gossamer Bio, Altavant Sciences, and Merck; served as a steering committee member for Bayer, Keros, and Liquidia Technologies; and served as a data safety monitoring board committee member for the National Institutes of Health K23 grant. VVM reports having received grant support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovie; consulting fees from Aerami, Aerovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex; and participated as an advisory committee member for Gossamer Bio. All authors report receiving medical writing and editorial support for the present manuscript funded by Gossamer Bio. (Copyright © 2024 Elsevier Ltd. 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