Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling

TL;DR

Sotatercept is a new treatment for pulmonary arterial hypertension that improves patient outcomes by targeting key molecular pathways involved in vascular remodelling.

Contribution

This paper reviews sotatercept's novel mechanism and clinical evidence as a disease-modifying therapy for PAH.

Findings

Sotatercept improves exercise capacity and hemodynamics in PAH patients.

Clinical trials show sotatercept reduces risk status in patients with PAH.

Sotatercept promotes reverse remodelling by inhibiting activin signaling.

Abstract

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management.

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