Inhaled Seralutinib Exhibits Potent Efficacy in Models of Pulmonary Arterial Hypertension

Abstract

Background: Signaling through platelet-derived growth factor receptor (PDGFR), colony stimulating factor 1 receptor (CSF1R), and c-KIT plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. Methods: Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signaling were examined. PDGFR, CSF1R, and cKIT immunohistochemistry (IHC) in rat and human PAH lung samples and miRNA analysis in the SU5416/H model were performed. Results: Seralutinib potently inhibited PDGFRα/β, c-KIT and CSF1R. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signaling, and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary hemodynamics and reduced small pulmonary artery muscularization and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary hemodynamics, restored lung BMPR2 protein levels, and decreased n-terminal prohormone of brain natriuretic peptide (NT-proBNP) more than imatinib. Quantitative IHC in human lung PAH samples demonstrated increased PDGFR, CSF1R, and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. Conclusions: Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary hemodynamics, reduction in NT-proBNP, reverse remodeling of pulmonary vascular pathology, and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.