TORREY Phase 2 Study of Seralutinib in Pulmonary Arterial Hypertension (PAH): Circulating Biomarkers of Proliferation, Inflammation and Fibrosis Improve with Treatment

Seralutinib is a novel, inhaled tyrosine kinase inhibitor targeting PDGFRα/ß, CSF1R, and c-KIT pathways that drive pulmonary arterial vascular remodeling in PAH. In the phase 2 TORREY study of seralutinib in patients with WHO Group 1 PH (Functional Class II/III on stable PAH-specific background therapy; NCT04456998), seralutinib met its primary endpoint by demonstrating a significant reduction in pulmonary vascular resistance at Week 24 (-14.3%; p=0.0310). In an exploratory analysis, circulating proteins were measured to characterize the impact of seralutinib on biomarkers and their correlation with hemodynamic response. Plasma samples were collected at baseline and Week 24. Proteomics data were generated using the Olink Explore 3072 assay. Robust regression models were applied to identify treatment-associated protein changes. Paired proteomics data were available for 70 patients (31 seralutinib, 39 placebo). 223 proteins were associated with seralutinib treatment (p<0.05), spanning functions relevant to PAH disease biology and the seralutinib mechanism of action, including proliferation, inflammation, fibrosis, extracellular matrix and vascular remodeling. For example, NT-proBNP, Endoglin, COL1A1, FLT1 and ANGPT2 were downregulated by seralutinib, whereas IL10 was upregulated. Enriched pathways were consistent with results seen in preclinical models. Many of the pharmacodynamic effects were correlated with cardiopulmonary hemodynamics and measures of right heart function and were directionally consistent with improvement in disease activity. The observed protein biomarker changes suggest that seralutinib has a significant impact on inflammatory, proliferative and fibrotic pathways, concordant with clinical improvement in patients with PAH. A phase 3 study of seralutinib in PAH is enrolling (PROSERA, NCT05934526). Publication History Article published online: 18 March 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany