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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).

Introduction: Inhalation profiles to support use of DPIs for drug delivery in PAH subjects have not been reported. Objective: Evaluate the inspiratory flow pattern associated with low and medium flow resistance DPI devices (RS01L, RS01M, respectively) in subjects with PAH. Methods: This single center study enrolled subjects with PAH associated with connective tissue disease (aPAH, n=10) and idiopathic PAH (iPAH, n=10) to measure the following inhalation parameters: inspiratory effort (kPa), peak inspiratory flow rate (L/min), inhaled volume (L), and flow increase rate (L/s2) using the two devices. Results: On average, peak inspiratory flow rate was higher with RS01L vs. RS01M (84 ± 19.73 L/min vs. 70.47 ± 13.26 L/min; p=0.015). In the overall group, no differences between RS01L and RS01M were observed for inhaled volume, inspiratory effort, or flow increase rate. Inhaled volume with RS01L was higher in aPAH vs iPAH subjects: 1.67 ± 0.43L vs. 1.31 ± 0.26L; p=0.042. For the RS01L, inhaled volume correlated with forced expiratory volume in one second (r=0.460, p=0.030) and forced vital capacity (r=0.507, p=0.015). In subjects with aPAH using RSO1L, inspiratory effort was highly correlated with pulmonary vascular compliance (PVC) (r=0.903), and flow increase rate with PVC (r=0.906). For RSO1M, inspiratory effort was highly correlated with PVC (r=0.81). Conclusions: Use of RS01L and RS01M DPI devices allowed adequate inspiratory flow in PAH subjects. The correlation between flow increase rate and PVC in aPAH deserves further investigation.