Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension

Abstract

BackgroundSignalling 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.MethodsSeralutinib 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.ResultsSeralutinib 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.ConclusionsInhaled 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.

New trends in pulmonary hypertension

“…Seralutinib is a PDGFR, CSF1R and c-KIT kinase inhibitor that upregulates BMPRII protein expression. Pre-clinical studies have demonstrated efficacy of inhaled seralutinib in animal models of PAH [ 31 ]. The TORREY study is a phase 2 study of inhaled seralutinib in patients with PAH and FC II and III symptoms [ 32 ].…”

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

“…Two additional PDGFR-related kinases have also been involved in the pathobiology of PAH: the colony stimulating factor 1 receptor (CSF1R) and the tyrosine-protein kinase KIT (c-KIT). CSF1R is expressed on monocytes and macrophages, which secrete PDGF ligands and inflammatory cytokines, thereby promoting inflammation and remodeling of the pulmonary vasculature [ 55 , 56 ]. C-KIT is expressed on endothelial progenitor cells and mast cells, and it has been observed in plexiform lesions from patients with PAH.…”

“…Treatment strategies available to date are aimed at antagonizing the inappropriate vasoconstriction that occurs in PAH and target three different major signaling pathways: (1) the nitric oxide and soluble guanylate cyclase pathway (phosphodiesterase inhibitors [sildenafil, tadalafil] and soluble guanylate cyclase stimulators [riociguat]); (2) the endothelin pathway (endothelin receptor antagonists [ambrisentan, bosentan, macitentan]) [ 12 , 13 ]; and (3) the prostacyclin pathway (prostacyclin analogues [epoprostenol, iloprost, treprostinil] and prostacyclin receptor agonist [selexipag]) [ 3 , 11 , 14 , 86 , 87 ]. Current and upcoming preclinical and clinical research is focused on the development of compounds that directly act in the different molecular pathways associated with the development of PAH to counteract the obstructive vascular remodeling and small vessel loss [ 56 , 88 , 89 ]. Specifically, drugs targeting various pathogenic mechanisms are being developed: bone morphogenetic protein signaling, tyrosine kinase receptors, serotonin metabolism, angiogenesis, extracellular matrix, estrogens or epigenetics [ 51 , 90 , 91 ].…”

“…Furthermore, seralutinib, a highly potent (13- to 20-fold greater than imatinib) and specific inhaled tyrosine kinase inhibitor that targets PDGFR, CSF1R and c-KIT, has been specifically designed as a treatment for PAH ( Figure 3 C,D). Preclinical studies involving seralutinib have reported efficacy in preventing PAH progression and vascular remodeling, restored lung BMPR2 expression, reduced levels of pro-inflammatory biomarkers, improved hemodynamics, decreased NT-proBNP levels, and showed greater efficacy when compared with imatinib [ 56 ]. A phase-2, randomized, double-blind, placebo-controlled trial, the TORREY study, evaluating the safety and efficacy of inhaled seralutinib has recently announced its results: the primary endpoint (decrease in PVR), as well as several secondary endpoints (6MWD, NT-proBNP, echocardiographic structural and functional parameters) were met for seralutinib.…”

Novel and emerging therapies in pulmonary arterial hypertension

“…Seralutinib (formerly known as GB002) is an inhaled, nonselective inhibitor of platelet-derived growth factor receptor (PDGFR) -α and -β, as well as colony stimulating factor 1 receptor (CSF1R) and c-KIT. In Sugen-hypoxia and monocrotaline rat models of PAH, seralutinib increased BMPR2 levels and caused reductions in right ventricular systolic pressure, mean pulmonary artery pressure, and pulmonary arteriolar muscularization (Galkin et al, 2022). The TORREY trial (NCT04456998) is a current phase 2 controlled randomized trial evaluating seralutinib on WHO Functional Class II and III PAH patients, with change in pulmonary vascular resistance at 24 weeks as its primary outcome (Frantz et al, 2021).…”