Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.CHEST 2022; 161(4):1060-1072

Automated summary

Pulmonary arterial hypertension (PAH) is a rare disease characterized by abnormally elevated pulmonary pressures and right heart failure, resulting in high morbidity and mortality. Current therapies are insufficient in preventing small-vessel loss and obstruction, leading to active interest in identifying drugs that target angiogenesis and mechanisms involved in cell growth and fibrosis regulation. Preclinical studies have identified promising compounds that target seven major mechanisms associated with PAH pathogenesis, including bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. This review discusses the prioritization of these mechanisms through preclinical studies, as well as ongoing clinical trials testing novel interventions. The authors anticipate that the next generation of compounds will build upon the current standard of care and improve clinical outcomes and quality of life for PAH patients.