Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension.

BACKGROUND

Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (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 signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed.

RESULTS

Seralutinib potently inhibited PDGFRα/β, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry 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 haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.

Informations de copyright

Copyright ©The authors 2022.

Déclaration de conflit d'intérêts

Conflict of interest: A. Galkin, R. Sitapara, B. Clemons, E. Garcia, M. Kennedy, D. Guimond, L.L. Carter, A. Douthitt, R. Osterhout, D. Slee, L. Salter-Cid and L.S. Zisman are employees of and hold stock options in Gossamer Bio, Inc. A. Gandjeva reports support for the present work from Gossamer Bio, Inc. (rat tissue slides for analysis provided to institution) and consulting fees from Gossamer Bio, Inc., outside the submitted work. R.M. Tuder reports grants P01HL152961 and R24HL123767 from NIH and stock options from Pulmokine, outside the submitted work. L.S. Zisman reports employment at Pulmokine, Inc., grants from NIH (HL102946) and patents for non-selective kinase inhibitors and spray dry formulations, outside the submitted work.