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].