Abstract 16179: Rap-011, a Murine Ortholog of ActRIIA-Fc (Sotatercept), Improves Pulmonary Hemodynamics and Restores Right Ventricular Structure and Function in a Preclinical Model of Severe Angio-Obliterative Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) Vol. 138; no. Suppl_1 Suppl 1; p. A16179
• Main Authors: Joshi, Sachindra R, Liu, Jun, Pearsall, R S, Li, Gang, Kumar, Ravindra
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 06.11.2018
• ISSN: 0009-7322; 1524-4539

IntroductionNovel therapies that repair remodeled pulmonary arteries, improve pulmonary hemodynamics and restore right ventricular (RV) structure and function are warranted in pulmonary arterial hypertension (PAH). Aberrant BMP/TGFβ signaling plays a prominent role in pulmonary vascular remodeling. ActRIIA-Fc was recently shown to rebalance BMP/TGFβ signaling and attenuate early stage PAH in preclinical models. Sotatercept, a selective ligand trap for activin/GDFs, is currently being evaluated in the PULSAR Phase 2 trial in PAH.HypothesisWe hypothesized that ActRIIA-Fc is distinct from sildenafil in its ability to improve pulmonary hemodynamics as well as restore RV structure and function. As such, it may also have additional benefit when combined with sildenafil in the advanced stage of PAH in a preclinical model.MethodsAdult male Sprague-Dawley rats were induced severe angio-obliterative PAH via a single injection of SU5416 combined with hypoxia followed by normoxia (Fig 1). To better approximate the diagnosis and treatment of PAH patients in the advanced stages, ActRIIA-mFc (RAP-011), sildenafil, or a combination therapy was administered in the advanced stages of PAH for 4 weeks beginning at week 5 (Mid Stage) or week 9 (Late stage) (Fig 1). Pulmonary hemodynamics and RV structure and function were assessed.ResultsIn comparison to the sildenafil treated group, ActRIIA-mFc significantly decreased the elevated PA pressure, reduced RV dilatation, decreased RV wall thickness, and improved cardiac function in the advanced stage PAH. Additionally, in contrast to sildenafil treatment, ActRIIA-mFc treatment restored the proper septal curvature (Fig 1). Combination therapy with sildenafil is currently being evaluated and will be presented during the meeting.ConclusionsActRIIA-Fc treatment restores pulmonary hemodynamics, RV structure and cardiac function, and may provide a novel disease-modifying benefit to current therapies for PAH.