At the 2025 American College of Cardiology (ACC) meeting in Chicago, new real-world safety data were presented on sotatercept, a novel fusion protein for pulmonary arterial hypertension (PAH). A retrospective analysis of the FDA Adverse Event Reporting System (FAERS) revealed key adverse events (AEs) associated with sotatercept, including cerebrovascular accidents (CVAs), flushing, diarrhoea, neutropenia, and asthenia. The study emphasised a higher incidence of AEs in elderly patients (65–85 years), highlighting the need for vigilant monitoring in this population.
PAH is a rare and progressive disease characterised by increased pulmonary vascular resistance, ultimately leading to right heart failure. Despite therapeutic advancements, PAH remains associated with high morbidity and mortality, necessitating the development of new disease-modifying agents. Sotatercept, a first-in-class activin signalling inhibitor, has demonstrated significant improvements in exercise capacity and haemodynamic parameters in clinical trials. However, its long-term safety profile in broader patient populations is still being evaluated.
Go deeper with GlobalData
The FAERS analysis, which included 11 reported AEs as of June 2024, found that CVAs, flushing, diarrhoea, and neutropenia each accounted for 18.18% of reported cases. The age-based analysis revealed that 54.55% of AEs occurred in patients aged 65–85 years, with fewer incidents reported in younger cohorts. While no statistically significant differences were observed in AEs across organ system groups, the findings underscore potential safety concerns, particularly for elderly PAH patients.
Key opinion leaders (KOLs) have previously emphasised sotatercept’s transformative impact on PAH management. A European KOL noted: “Sotatercept is probably the most important development in PAH over the past ten years. It will change the complete treatment landscape and positioning of other compounds in the treatment algorithm.” This statement highlights the significant clinical and commercial implications of sotatercept’s entry into the PAH treatment paradigm.
From a pharmaceutical strategy perspective, the FAERS findings introduce several critical considerations. First, the emergence of cerebrovascular events, although limited in frequency, may influence risk-benefit assessments during future regulatory reviews and labelling decisions. This could lead to targeted safety monitoring requirements or risk management plans (RMPs), particularly for older patients. Secondly, while sotatercept is positioned as an add-on therapy, the magnitude of its clinical benefits raises the possibility of earlier-line use. This could disrupt the current PAH treatment sequencing and challenge the market positioning of established endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is). Lastly, the real-world safety signals from FAERS may prompt payers to introduce stricter prior authorisation criteria or outcomes-based agreements, tying reimbursement to patient outcomes to mitigate potential safety risks.
Despite the identified AEs, sotatercept’s novel mechanism of action and clinically meaningful efficacy gains position it as a valuable addition to the PAH treatment landscape. As longer-term real-world data and larger post-marketing studies become available, the comprehensive safety profile of sotatercept will become clearer, helping to define its optimal role in PAH management.
