Figure 2. Proposed Mechanism of Action for Sotatercept in Pulmonary Arterial Hypertension. The proposed mechanism of action for Sotatercept involves rebalancing growth-promoting and growth-inhibiting signaling in pulmonary arterial hypertension. This condition is characterized by dysregulation of the BMP receptor type II (BMPR-II)–Smad1/5/8 pathway in pulmonary vascular smooth muscle and endothelial cells, resulting in an imbalance between proproliferative and antiproliferative signaling pathways. Down-regulation of the BMPR-II–Smad1/5/8 pathway leads to increased production of activin ligands (e.g., activin A, GDF8, and GDF11), which in turn up-regulate the ActRIIA–Smad2/3 pathway. This pathway activation, indicated by increased phosphorylated Smad (pSmad)2/3 activity, promotes the expression of endogenous BMP antagonists, gremlin-1 and noggin. Gremlin-1 and noggin subsequently reduce BMP–Smad1/5/8 signaling, resulting in a decrease in antiproliferative signaling. This shift favors proproliferative activin–Smad2/3 signaling, leading to pulmonary vascular remodeling.
A significant clinical research program involving patients with PH, including the phase 2 PULSAR project, is evaluating the clinical effectiveness and safety of sotatercept when it’s added to PH medication [74, 75]. The sotatercept medication significantly decreased pulmonary vascular resistance (PVR) during the 24-week placebo-controlled treatment phase of the PULSAR study from baseline, when compared to placebo. In addition, in comparison with placebo, sotatercept increased the levels of the 6MWD and the N-terminal pro-B-type natriuretic peptide (NT-proBNP).
An ongoing innovative exploratory investigation called the SPECTRA project (NCT03738150) aims to assess the influence of sotatercept by invasive cardiopulmonary exercise testing (iCPET). Hemodynamics, exercise tolerance, and capacity showed encouraging outcomes in this preliminary examination of participants in the continuing SPECTRA trial. Safety was comparable with other reports in patient populations with PH and other conditions. These outcomes emphasize the sotatercept’s clinical effectiveness and potential as a brand-new therapy for PH patients [76].