Abstract 12203: Sotatercept Analog RAP-011 is More Effective Than Sildenafil in Improving Pulmonary Hypertension and Reducing Right Ventricular Hypertrophy in a ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (PH-HFpEF) is the most prevalent form of WHO Group 2 PH but lacks effective treatment options. We previously found that sequestration of activins and growth differentiation factors with the sotatercept analog RAP-011, an activin receptor type IIA-Fc fusion protein, reverses pathological remodeling of pulmonary arteries and the right ventricle (RV) in experimental models of pulmonary arterial hypertension (PAH, Group 1 PH). This strategy of selective multi-ligand neutralization offers a promising new approach for treating patients with PAH and is under active clinical evaluation (PULSAR, SPECTRA, and STELLAR). Here, we compared the cardiopulmonary effects of therapeutic treatment with RAP-011 to those of sildenafil in a rat model of PH-HFpEF. Methods: PH was induced in adult male obese ZSF1 rats by a single subcutaneous injection of SU5416 (100 mg/kg). To model the timeline of diagnosis and treatment for Group 2 PH patients, we initiated treatment with RAP-011 and sildenafil 8 weeks post SU5416 administration—at which point RV dysfunction is prominent—and continued treatment for 8 weeks. RV systolic pressure (RVSP), pulmonary artery acceleration time (PAAT), RV hypertrophy, and tricuspid annular plane systolic excursion (TAPSE) were evaluated by right heart catheterization and echocardiography following the 8-week treatment regimen. Results: Obese ZSF1 rats treated with SU5416 displayed significantly increased RVSP (P < 0.0001) and decreased PAAT (P < 0.0001). RAP-011 treatment fully reversed changes in RVSP (P < 0.0001) and PAAT (P < 0.0001), whereas sildenafil treatment improved RVSP by 19% (P < 0.05) and PAAT by 36% (P < 0.001). Treatment with RAP-011, but not sildenafil, normalized RV hypertrophy (P < 0.0001) and increased TAPSE (P < 0.0001). Conclusions: Therapeutic treatment with the sotatercept analog RAP-011 exerted beneficial cardiopulmonary effects in a ZSF1 rat model of PH-HFpEF that were significantly greater than those produced by sildenafil, fully normalizing PH and RV hypertrophy and improving RV function. These findings support evaluation of sotatercept in patients with PH-HFpEF (Group 2 PH).