Drugs targeting novel pathways in pulmonary arterial hypertension

Over the past three decades, several drugs have been developed to target three major dysfunctional pathways in pulmonary arterial hypertension (PAH), including the prostacyclin, endothelin and nitric oxide pathways. Despite these advances, PAH remains incurable, necessitating further drug discovery efforts. New therapies focus on previously untargeted pathways, especially the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β signalling pathway. Dysregulation of this pathway, involving the Smad2/3 and Smad1/5/8 signalling branches, plays a key role in pulmonary vascular remodelling. Sotatercept, a fusion protein acting as an activin receptor ligand trap to rebalance growth-promoting and growth-inhibiting signalling has shown promise in clinical trials by reducing pulmonary vascular resistance, improving exercise capacity and lowering risk of a composite of morbi-mortality events. Other emerging treatments aim to restore balance within the BMP/TGF-β pathway. Therapies targeting receptor tyrosine kinases (RTKs), such as imatinib, inhibit the platelet-derived growth factor pathway. Though oral imatinib has shown efficacy, its side-effects have limited widespread use. Additional strategies exploring lower doses of imatinib and novel delivery methods, such as inhalation, to reduce systemic side-effects failed to demonstrate clinical benefit. Novel RTK inhibitors such as seralutinib administered by inhalation have shown promising results in a phase 2 clinical trial. Other emerging approaches include anti-inflammatory therapies, hormonal modulation and metabolism-targeting agents like ranolazine and sodium-glucose cotransporter 2 inhibitors, which could expand the therapeutic landscape for PAH. Overall, the continued development of novel drugs targeting these pathways offers hope for better disease management and improved outcomes for patients with PAH.