Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension

Abstract

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.

Keywords: clinical trials; pathogenesis; pulmonary hypertension; therapeutics.

Figure 1

Tyrosine kinase inhibitor signaling, inhibition, and relevant pathways to pulmonary arterial hypertension pathogenesis. CSF1R = colony-stimulating factor 1 receptor; MAP = mitogen-activated protein; PDGF-R = platelet-derived growth factor receptor.

Figure 2

Sotatercept mechanism of action in the context of BMP/SMAD signaling. ACTRII A/B = activin receptor type IIA/B; ALK = activin receptor-like kinase; BMP = bone morphogenetic protein; BMPR2 = bone morphogenetic protein receptor type 2; GDF = growth differentiation factor; PAH = pulmonary arterial hypertension.

Figure 3

Estrogen signaling pathway with therapeutic targets of repurposed drugs for pulmonary arterial hypertension therapy. COMT = catechol-O-methyltransferase; CYPs = cytochrome P450 enzymes; CYP1B1 = cytochrome P450 family 1, subfamily B, member 1; DHEA = dehydroepiandrosterone; 3β-HSD = 3β-hydroxysteroid dehydrogenase.

Figure 4

The role of serotonin in pathologic pulmonary arterial hypertension cell behavior and target site of rodatristat ethyl. MAPK = mitogen-activated protein kinase; ROCK = Rho-associated kinase; ROS = reactive oxygen species; SERT = serotonin transporter; TPH1 = tryptophan hydroxylase 1.