ABSTRACT Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling and vascular obliteration that results in right heart failure and death. PAH pathogenesis is strongly associated with mutations of the Transforming Growth Factor Beta (TGF‐β) superfamily signaling pathway, which has previously been challenging to target therapeutically. Sotatercept, a fusion protein of the extracellular portion of the activin type 2 receptor A (ACVR2A) and the human IgG1 Fc domain, is the first activin signaling inhibitor (ASI) FDA‐approved for the treatment of PAH, demonstrating efficacy across the risk spectrum in PAH. This soluble protein binds to a range of circulating TGF‐β superfamily ligands, including activins A and B, growth and differentiation factors (GDFs) 8 and 11, as well as some bone morphogenetic proteins (BMPs). Other ASIs have been developed primarily for hematologic indications, such as anemias and cytopenias associated with β‐thalassemia, myelodysplastic syndromes, and myelodysplastic neoplasms. Fundamental questions remain regarding the basic biological mechanisms of ASIs, their short‐ and long‐term side effect profiles, and their potential utility across the spectrum of different etiologies of pulmonary hypertension (PH). In this state‐of‐the‐art review, we brought together basic and clinical researchers, and industry scientists under the umbrella of the Pulmonary Vascular Research Institute (PVRI) Innovative Drug Discovery Initiative (IDDI) to discuss the biology of ASIs, the importance of specific BMP ligands, efficacy and side effect profiles, and considerations in the development of next‐generation ASIs.
Rajagopal et al. (Tue,) studied this question.