Sotatercept

Sotatercept is a recombinant fusion protein, rather than a short peptide, formed by joining the extracellular domain of the human activin receptor type IIA to the Fc region of human immunoglobulin G1. It was originally developed by Acceleron Pharma, which was acquired by Merck in 2021. Interestingly, sotatercept was first studied for bone loss and anaemia, and researchers noticed rises in haemoglobin during those early studies before its focus shifted to the pulmonary vasculature.

Sotatercept was approved by the FDA in 2024 and subsequently by the EMA, marketed as Winrevair, for pulmonary arterial hypertension. It is the first approved agent designed to target the signalling imbalance within the vessel wall, rather than primarily dilating pulmonary arteries. Genetic studies had long linked pulmonary arterial hypertension to loss-of-function mutations in BMPR2, the bone morphogenetic protein receptor type II gene, and sotatercept was developed to rebalance this growth-promoting versus growth-inhibiting signalling. Its phase 3 programme generated considerable research interest in reversing vascular remodelling. WADA lists it as prohibited.

Sotatercept acts as a ligand trap for activins and growth differentiation factors, particularly activin A, GDF8 and GDF11. In pulmonary arterial hypertension, reduced BMPR-II signalling through SMAD1/5/8 coexists with excess activin-driven SMAD2/3 signalling, favouring proliferation of vascular smooth muscle and endothelial cells and thickening of small pulmonary arteries. By sequestering activin-class ligands, sotatercept reduces SMAD2/3 activation and is proposed to restore balance toward anti-proliferative BMP signalling. In rodent models of pulmonary hypertension, this produced reduced vessel wall thickening and improved haemodynamics, supporting its characterisation as a reverse-remodelling agent.