04 February 2019 by Sachindra Joshi

RAP-011, a Murine Analog of Sotatercept (ActRIIA-Fc), Reverses Pulmonary Vascular Remodeling, Improves Pulmonary Hemodynamics, and Restores Right Ventricular Structure and Function in a Preclinical Model of Severe Angio-Obliterative Pulmonary Arterial Hypertension

Introduction:

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.

Methods:

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).

Results:

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.

Conclusion:

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

 

Key Contributors

Sachindra R. Joshi, PhD 1, Jun Liu, MS 1, R. Scott Pearsall, PhD 1, Gang Li, PhD 1, Ravindra Kumar, PhD 1 : 1 Acceleron Pharma, Cambridge MA


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