Novel therapies are needed for patients with PAH, in which aberrant signaling by bone morphogenetic proteins (BMP) and transforming growth factor-β (TGFβ) play a prominent role. A murine analog of the homodimeric fusion protein sotatercept, RAP-011 consists of the extracellular domain of human ActRIIA linked to a murine immunoglobulin G1 Fc domain. RAP-011 selectively traps certain TGFβ superfamily ligands and was recently shown to attenuate early-stage PAH in preclinical models by rebalancing BMP/TGFβ signaling. Sotatercept is currently being evaluated in the PULSAR phase 2 trial in patients with PAH. Hypothesis: RAP-011 (sotatercept) is distinct from sildenafil in its ability to reverse pulmonary vascular remodeling, improve pulmonary hemodynamics, and improve RV structure and function.
Severe angio-obliterative PAH was induced in adult male Sprague-Dawley rats by a single injection of Sugen 5416 combined with hypoxia (10% O2) for 3 weeks followed by normoxia for up to 13 weeks. To better
approximate treatment of PAH patients diagnosed at an advanced stage, RAP-011 (5 mg/kg twice weekly) or sildenafil (30 mg/kg twice daily) were administered starting at Week 5 or Week 9 for 4 weeks. Pulmonary vascular remodeling, pulmonary hemodynamics, and RV structure and function were assessed at study completion (Weeks 9 or 13; n=3-8 per group).
As determined by lung histology, RAP-011 reversed pulmonary vascular remodeling whereas sildenafil did not. RAP-011 vs. sildenafil significantly reduced pulmonary vascular resistance index (52% vs. 25%), RV
systolic pressure (35% vs. 11%), and RV hypertrophy (29% vs. 5%). Echocardiographic analysis showed reversal of septal wall flattening and improvement of RV fractional area by 40% with RAP-011.
RAP-011 reverses vascular remodeling, improves pulmonary hemodynamics, and improves RV structure and function in a preclinical model of PAH, thereby suggesting that sotatercept has the potential to be an important treatment for PAH patients