Abstract 4365510: Platelet-derived growth factor antagonist antibody attenuates pulmonary arterial hypertension and prevents right heart dysfunction in the Sugen-Hypoxia rat model

Abstract

Background: Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and elevated pulmonary artery pressure that leads to right ventricular (RV) failure. Platelet-derived growth factor (PDGF) signaling contributes to PAH pathogenesis. Research question: To understand the contribution of PDGF signaling on PAH disease progression, using a fully human monoclonal antibody (REGN13335) that binds and neutralizes PDGF with high affinity. Methods: REGN13335 treatment was initiated in 3 independent PAH rodent models (Sugen-Hypoxia [SuHx] mouse, monocrotaline rat, SuHx rat) to study the impact of PDGF inhibition on RV systolic pressure (RVSP). Utilizing the SuHx rat PAH model, we conducted a longitudinal multimodal imaging study using micro-ultrasound (US) and cardiac MRI to evaluate the therapeutic potential of REGN13335 on RV remodeling and dysfunction. Arterial oxygen saturation was measured to evaluate pulmonary health. RV gene expression analysis was performed to evaluate cardiac stress biomarkers (Nppb, Myh7, Gdf15) and PDGF receptor (PDGFR-β) expression. Results: REGN13335 (10-25 mg/kg/wk) significantly lowered RVSP in 3 rodent models of PAH. Longitudinal US imaging was conducted in the SuHx rat PAH model and revealed significant RV hypertrophy, chamber dilation, and reduced pulmonary artery flow. Sildenafil, a standard of care (SOC) treatment in PAH, attenuated RV dysfunction in this model suggesting its translatability to study RV function in PAH. REGN13335 treatment significantly attenuated RV remodeling, limiting increases in wall thickness compared to isotype control at wk 4 and wk 8. Importantly, REGN13335 preserved cardiac output (61% improvement compared to controls [p<0.0001)] at wk 4; 40% improvement at wk 8 [p<0.01]; Figure). MRI measurements at wk 4 showed REGN13335 treatment preserved RV fractional area change by 28% (p<0.05) compared to SuHx isotype control treated rats (Figure). REGN13335 treatment preserved heart rate and arterial oxygen saturation in SuHx rats. Also, REGN13335 prevented transcriptional upregulation of Pdgfrb and reduced cardiac stress biomarkers (Nppb, Myh7, and Gdf15) in SuHx rat RV tissue. Conclusion: Longitudinal cardiac imaging revealed RV dysfunction in the SuHx rat model of PAH. Treatment with SOC or REGN13335 improved RV hypertrophy, systolic function and output. REGN13335 may represent a novel therapeutic approach to address RV remodeling and dysfunction in patients with PAH.