Seralutinib in pulmonary arterial hypertension: exploring mechanisms of reverse remodeling versus vasodilation

Background : Seralutinib is an inhaled tyrosine kinase inhibitor inhibiting PGDFRα/ß, CSF1R, and c-KIT with anti-inflammatory, anti-proliferative, and anti-fibrotic properties. Seralutinib is currently being investigated in the registrational phase 3 PROSERA study in patients with pulmonary arterial hypertension (PAH; NCT05934526). Concordant with the clinical benefits observed in the phase 2 TORREY (NCT04456998) and open-label extension (NCT04816604) studies, computed tomography imaging, biomarkers, and preclinical studies are supportive of a reverse remodeling effect. Given that PDGFR can regulate pulmonary vessel tone through calcium signaling, we sought to further inform the mechanism of action (MOA) of seralutinib by investigating its acute effects in preclinical models of vasoconstriction. Methods : Pulmonary artery smooth muscle cells (PASMCs) were stimulated with PDGF-BB and treated with seralutinib (0.1 and 1 µM) or vehicle, and calcium flux was measured. In an acute hypoxia-induced vasoconstriction rat model with continuous mean pulmonary artery pressure (mPAP) monitoring, seralutinib (0.2 and 2 mg/kg), treprostinil (6 μg/kg) or vehicle control was administered via intratracheal delivery. Seralutinib (up to 10 μM) effect on vascular tone was assessed using mouse pulmonary artery (PA) rings. Results : In PASMCs, seralutinib inhibited PDGF-BB–induced calcium influx at all evaluated concentrations. In the acute hypoxia-induced vasoconstriction model, seralutinib produced a weak and transient vasodilatory effect at a therapeutically relevant dose, whereas the vasodilator treprostinil fully restored mPAP to normoxic levels for the length of the study. Neither PDGF-BB (50 ng/mL) nor seralutinib (10 μM) altered the tension of isolated PA rings.