Abstract 14345: Cardiopulmonary Best Abstract Award: Improves Right Ventricular - Pulmonary Arterial Coupling and Right Ventricular Function in the Pulsar Study: A Phase 2, Double-blind, Placebo-controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

Abstract

Background: The right ventricle (RV) and pulmonary arteries become uncoupled as RV function deteriorates in PAH, a consequence of pulmonary vascular remodeling which is ultimately fatal. Restoration of RV-PA coupling and RV function is a crucial aim of PAH treatment. Preclinically, sotatercept, a first-in-class fusion protein, has been shown to reverse right heart remodeling and improve right heart structure and function and acts by suppressing TGF-β signaling and rebalancing BMPR2 signaling. The PULSAR study (NCT03496207, EudraCT 2017-004738-27) released positive topline results earlier this year. Methods: The PULSAR study enrolled 106 patients with WHO Group 1 PAH and WHO functional classes (FC) II-III; age ≥18; pulmonary vascular resistance of ≥5 Wood units by right heart catheterization; stable PAH standard of care (SOC) therapy (all combinations allowed). Sotatercept was administered by SC injection every 21 days for a 24-week double-blind, placebo-controlled treatment period in 3 arms: placebo + SOC, 0.3 mg/kg sotatercept + SOC, 0.7 mg/kg sotatercept + SOC. 2D Doppler echocardiography was performed at baseline and 24 weeks and read in a central laboratory. RV-PA coupling was assessed by TAPSE/PASP. Results: Significant improvement was seen in LS mean (SE) change from baseline to week 24 in RV-PA coupling, RVFAC, RVEDA, RVESA, PASP, and RAP in both sotatercept dose level groups vs placebo. No changes were seen in TAPSE or, notably, in CO. For RV-PA coupling, all patients started below the 0.31 mm/mmHg prognostic threshold; both treatment arms improved above that threshold by 24 weeks while the placebo arm remained below. Conclusions: In the PULSAR study, treatment with sotatercept compared to placebo was associated with statistically significant improvements in RV-PA coupling and RV function. Sotatercept has the potential to be a new treatment option for PAH patients with consistent and encouraging effects on RV-PA coupling and RV function.