Pharmacologic characterization of GB002, a novel inhaled PDGFR kinase inhibitor in development for pulmonary arterial hypertension (PAH)

Background: PAH is characterized by vascular remodeling, increased pulmonary arterial pressure (PAP) and right ventricular hypertrophy. Dysregulation of BMPR2 signaling is linked to hereditary and idiopathic forms of PAH. PDGF signaling plays an important role in BMPR2 regulation and is activated in human PAH. Here we studied effects of GB002, a novel inhaled PDGFRα/β inhibitor on PDGFR pathway inhibition and BMPR2 modulation. Methods: In vitro GB002 potency was evaluated in biochemical and cell-based assays. In vivo dose- and time-dependent modulation of PDGFR phosphorylation and BMPR2 expression was assessed in healthy Sprague Dawley rats. Impact of GB002 on disease progression was evaluated in the SU5416 Hypoxia rat PAH model. Statistical analysis was performed with one-way ANOVA (p Results: GB002 potently inhibited PDGFRα (IC50 8nM) and β (IC50 10nM) activity in enzyme assays and PDGF-induced PDGFR and ERK phosphorylation, as well as cell proliferation in human lung fibroblasts. GB002 inhibited PDGFR phosphorylation in presence of intratracheally delivered PDGF in vivo. PDGFR inhibition correlated with increased BMPR2 expression in a dose- and time- dependent manner. In the SU5416 Hypoxia PAH model, GB002 reduced PAP by 40% (p Conclusions: Lung localized delivery of GB002 inhibits PDGFR signaling and restores BMPR2 expression in vivo, translating to improved cardiopulmonary hemodynamics and disease reverse remodeling in the SU5416/H rat PAH model. GB002 is in clinical development for PAH (NCT03926793).