Sotatercept
Cardiovascular / PulmonaryAlso known as: Winrevair, ACE-011, Sotatercept-csrk
Mechanism
Sotatercept is a first-in-class treatment for pulmonary arterial hypertension (PAH) that works by a completely novel mechanism. It acts as a trap for activin and other TGF-beta superfamily ligands that drive abnormal blood vessel growth in the lungs. By rebalancing growth-promoting and growth-inhibiting signals, it reverses the vascular remodeling that causes PAH. It was a major breakthrough as the first new mechanism for PAH in over a decade.
Technical detail
Sotatercept is a fusion protein of the extracellular domain of activin receptor type IIA (ActRIIA) linked to the Fc domain of human IgG1. It functions as a ligand trap, sequestering activin A, activin B, GDF-8, GDF-11, and other TGF-beta superfamily members that signal through ActRIIA-Smad2/3 (growth-promoting) pathways. By reducing activin signaling, sotatercept restores the balance toward BMPR2-Smad1/5/8 (growth-inhibiting, anti-proliferative) signaling in pulmonary vascular cells. This reverses pathological smooth muscle and endothelial cell proliferation in pulmonary arterioles. In the STELLAR trial, it improved 6-minute walk distance, reduced NT-proBNP, and improved WHO functional class.