Sotatercept is a new medication used to treat pulmonary arterial hypertension (PAH), a severe condition characterized by elevated blood pressure in the arteries supplying the lungs. PAH leads to right heart strain, progressive heart failure, and eventually death if untreated.
The FDA recently approved this medication for the treatment of PAH. Sotatercept works through a unique mechanism, targeting a pathway not addressed by conventional PAH therapies.
The primary mode of action of sotatercept is its ability to influence the signaling pathways of the transforming growth factor-beta (TGF-β) superfamily, particularly the bone morphogenetic protein (BMP) pathway. This pathway is vital for maintaining vascular homeostasis (fine balance between the cell proliferation and anti proliferation in the pulmonary arteries) and plays a significant role in PAH development when disrupted. In PAH, there is an imbalance between two TGF-β superfamily pathways: the BMPR2 (BMP receptor type 2) pathway, which typically promotes vascular repair and health ( the antiproliferative arm), and the activin signaling pathway ( the proliferative arm), which promotes vascular remodeling and maladaptive changes. In PAH patients this balance is lost. The BMPR2 signaling is reduced, and activin signaling is upregulated, contributing to arterial stiffening, vascular wall thickening, and fibrosis in the lungs ( worsening PAH).
Sotatercept functions as a ligand trap (works like a sponge) for certain TGF-β superfamily ligands, specifically targeting and neutralizing activin A and other related proteins. By inhibiting these ligands, sotatercept restores balance, allowing BMPR2 signaling to be more effective. This restoration reduces abnormal cell proliferation and encourages proper vascular remodeling, leading to improved pulmonary vascular resistance (PVR) and decreased pressure within pulmonary arteries. Clinical studies show that sotatercept significantly reduces pulmonary vascular resistance and improves functional status in PAH patients.
By offering a novel approach distinct from current vasodilators, sotatercept holds promise as a disease-modifying therapy, potentially reversing or slowing the disease progression in PAH and providing new hope for patients with limited options.
This drug was recently tested in a phase 3 clinical trial (STELLAR) comparing Sotatercept to placebo, administered subcutaneously every 21 days alongside standard PAH therapies in 323 adult patients with PAH. The primary endpoint was based on the assessment of 6 minute walk test at week 24. Sotatercept significantly increased the median change in the 6MWT compared to placebo (about 40.8m). Sotatercept also improved secondary outcome measures including an 84% reduction in risks of death of any cause or worsening of PAH. The longer term efficacy of this medication will be continually evaluated by physicians.