Pulmonary arterial hypertension (PAH) is a rare and chronic, rapidly progressing disorder characterized by the obstructive remodeling of small pulmonary arteries resulting in elevated pulmonary vascular resistance and blood pressure in the pulmonary circulation. PAH results in significant strain on the heart, often leading to limited physical activity, heart failure, and reduced life expectancy. The 5-year survival rate for patients with PAH is approximately 60%. Available therapies generally act by promoting the dilation of pulmonary vessels without addressing the underlying cause of the disease. As a result, PAH often progresses despite standard of care treatment. A growing body of research has implicated imbalances in BMP and TGF-beta signaling as a primary driver of PAH in familial, idiopathic, and acquired forms of the disease. Sotatercept is an investigational reverse-remodeling agent designed to be a selective ligand trap for members of the TGF-beta superfamily to rebalance BMPR-II and ActRIIA signaling, which are key molecular drivers of PAH. The PULSAR Phase 2 trial is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of sotatercept in patients with PAH. The primary endpoint of the trial was the change from baseline in pulmonary vascular resistance (PVR) over a 24-week treatment period. PVR, as measured by right heart catheterization, is the resistance that the heart must overcome to pump blood through the pulmonary circulatory system. The key secondary endpoint was six-minute walk distance (6MWD), a measure of functional capacity/endurance. Other exploratory analyses included change in N-terminal brain natriuretic propeptide (NT-proBNP), a hormone secreted by cardiac muscle cells in response to stretching caused by increased blood volume in the heart; mean pulmonary arterial pressure, a hemodynamic measure of average pressure in the main pulmonary arteries, which is elevated in PAH patients; and WHO functional class. A total of 106 patients were randomized in a 3:3:4 ratio to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg subcutaneously every three weeks on top of standard-of-care therapies. At 24 weeks, treatment with sotatercept resulted in a reduction in PVR, an increase in 6MWD and a decrease in NT-proBNP levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. This result suggests that sotatercept could bring a novel mechanistic approach to the treatment of patients with PAH. Additional Phase 3 studies in PAH are currently active or planned. This study was funded by Acceleron Pharma, a biopharmaceutical company dedicated to the discovery and development of TGF-beta superfamily therapeutics to treat serious and rare diseases such as PAH (PULSAR, NCT03496207).
Sotatercept for the Treatment of Pulmonary Arterial Hypertension
Marc Humbert, M.D., Ph.D., Vallerie McLaughlin, M.D., J. Simon R. Gibbs, M.D., Mardi Gomberg-Maitland, M.D., Marius M. Hoeper, M.D., Ioana R. Preston, M.D., Rogerio Souza, M.D., Ph.D., Aaron Waxman, M.D., Ph.D., Pilar Escribano Subias, M.D., Ph.D., Jeremy Feldman, M.D., Gisela Meyer, M.D., David Montani, M.D., Ph.D., et al., for the PULSAR Trial Investigators*
N Engl J Med 2021; 384:1204-15.
Targeting transforming growth factor beta receptors in pulmonary hypertension
Christophe Guignabert, Ph.D., Marc Humbert M.D., Ph.D.
Eur Respir J 2021 ; 57 : 2002341.