Background:The incidence and mortality of arterial pulmonary hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast cell or stem cell growth factor receptor kinase stimulates inflammatory, proliferative, and fibrotic pathways that drive pulmonary vascular remodeling in PAH. Seralutinib is an inhaled kinase inhibitor that targets these pathways. The aim of this study was to evaluate the efficacy and safety of seratinib in patients with PAH receiving standard background therapy. Methods: The TORREY trial was a phase 2, randomized, multicenter, transnational, double-blind, placebo-controlled study. Patients with PAH from 40 hospitals and community sites were randomly assigned to receive seraglutinib (60 mg twice/d for 2 weeks, then increased to 90 mg twice/d depending on tolerability) by interactive response technique in a 1:1 ratio, or placebo twice daily via a dry powder inhaler for 24 weeks. Based on baseline pulmonary vascular resistance (PVR<800 dyn s-1• cm-5and ≥800 dyn·s-1• cm-5) Stratification of randomized groups. If the patient is classified as WHO Group 1 PH (PAH), WHO Functional Class II or III and has a PVR of 400 dyn·s-1• cm-5Or above, with a 6-min walking distance between 150 and 550 m, patients were eligible for enrollment. The primary endpoint was the change in PVR from baseline to 24 weeks. Endpoint efficacy analyses were performed in randomly assigned patients (intent-to-treat population). The safety analysis included all patients receiving study drug. TORREY has completed registration with ClinicalTrials.gov (NCT04456998).Results:A total of 151 patients were screened between Nov. 12, 2020 and Apr. 20, 2022, and 86 adults receiving background therapy for PAH were randomly assigned to either seraglutinib (44, of which 4 males and 40 females) or placebo (42, of which 4 males and 38 females). The least squares mean change in PVR from baseline to week 24 was 21.2 dyn s in the placebo group-1• cm-5（95%CI: -37.4 to 79.8) and-74.9 dyn·s in the serutinib group-1• cm-5（95%CI：-139.7~-10.2）。 The least squares mean difference in PVR change between the seraglutinib and placebo groups was-96.1 dyn s-1• cm-5（95%CI：-183.5~-8.8；P=0.03）。 The most common treatment-emergent adverse event in both treatment groups was cough: cough occurred in 16 of 42 patients in the placebo group (38%); 19 of 44 patients (43%) in the celatinib group.Conclusion:Patients in the seralutinib-treated group had a significantly reduced change in PVR at 24 weeks compared with the placebo group, reaching the primary endpoint of the study. In addition, the Seralutinib treatment group also showed certain advantages in other efficacy endpoints, such as improved 6-min walking distance and WHO functional grading. In terms of safety, the incidence of adverse events was similar in the seralutinib-treated and placebo groups.
