Sotatercept's 3-Pronged Effect on the Right Ventricle in PAH, With Anjali Vaidya, MD

Sotatercept, an activin signaling inhibitor approved for pulmonary arterial hypertension (PAH), continues to build an evidence base spanning exercise capacity, hemodynamics, and hard clinical outcomes. Anjali Vaidya, MD, of Temple University, discussed a 3-pronged framework for understanding the drug's effect on the right ventricle (RV), covering afterload, RV structure, and RV function, in an interview with HCPLive following her presentation at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.

Sotatercept's efficacy is grounded in a pair of pivotal phase 3 trials. The STELLAR trial demonstrated significant improvement in 6-minute walk distance and 8 of 9 secondary end points, supporting US Food and Drug Administration (FDA) approval in 2024, and the more recent ZENITH trial in high-risk patients with PAH found a 76% reduction in the risk of death, lung transplantation, or PAH-related hospitalization, halting enrollment early for efficacy.¹²

Sotatercept's Distinct Effect on RV Afterload in PAH

Vaidya described sotatercept as a fundamentally different mechanism than existing PAH therapies: "It works as an anti-proliferative and really getting to the basis of the pathophysiology of pulmonary arterial hypertension," she said. "We're seeing dramatic improvements and reversals in pulmonary vascular resistance, the load on the right heart... but we are seeing dramatic improvements in all of the clinical markers of pulmonary pressures, right ventricular structure, size, function, biomarkers, and and really so many of the metrics that we have known for many years now that correlate with prognosis and risk assessment."

Asked what changes in pulmonary vascular resistance and other hemodynamic parameters were most informative, Vaidya said the drug's effect is specific to afterload itself, including impedance to flow, vascular resistance, and pulmonary arterial compliance, rather than pressure reduction alone. She noted these parameters are not always measured directly in standard clinical care, despite being central to the hemodynamic abnormalities driving downstream structural and functional changes in the right heart.

Vaidya said the magnitude of this afterload effect distinguishes sotatercept from prior pulmonary vasodilator classes, describing the pattern as fundamentally different and greater in scale than what other PAH therapies have achieved. Despite multiple effective agents across several classes and pathways developed over recent years, she said the activin signaling inhibitor produces a markedly larger reduction in afterload and pulmonary vascular resistance in many patients.

RV Function, Structure, and the Case for Reverse Remodeling

On evidence for RV function improvement specifically, rather than simply reduced workload, Vaidya pointed to a broad set of metrics. "We're seeing improvements in RV work, the magnitude of energy generated by the right ventricle in... every heartbeat of... stroke volume into the pulmonary artery. We're seeing improvements in RV size. We're seeing improvements in RV to LV relationships in size. We're seeing improvements in RV fractional area change. We're seeing improvements in biomarkers of NT-proBNP and BNP. We're seeing dramatic improvements as well in tricuspid regurgitation, another marker of overall right heart performance," she explained.

On RV structure specifically, Vaidya said reverse remodeling encompasses right ventricular size, right ventricle-to-left ventricle relationships, and end-diastolic and end-systolic volumes. She acknowledged some of these changes are likely related to the drop in afterload, but noted the durability of the improvements raises the possibility of an intrinsic effect on the right ventricle beyond load reduction alone, an area she said warrants further study.²

Asked which of the 3 domains, afterload, structure, or function, is the primary driver of clinical benefit, Vaidya described them as inseparable. "The pathogenesis begins in the afterload, in the pulmonary arterial circulation, but the disease manifests in the structure and performance of the right side of the heart," she said. "You look at the right heart to see what's happening in the pulmonary circulation, and the coupling of the two together is really what... manifests in the greatest long-term benefit for our patients."

Editors’ note: Vaidya reports relevant disclosures with Johnson & Johnson, Merck, and United Therapeutics.

References

1. Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558

2. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987-2000.