Preclinical models support the synergistic potential of seralutinib and sotatercept in treating pulmonary arterial hypertension (PAH)

Background. PAH is a progressive disease characterized by pathogenic remodeling of the pulmonary vasculature, driven by inflammation, proliferation, and fibrosis. Seralutinib, an investigational inhaled PDGFRα/ß, CSF1R, and c-KIT kinase inhibitor, targets these pathways. Sotatercept, a new PAH therapy, targets TGF-ß superfamily ligands to restore balance between pro- and anti-proliferative pathways. While both compounds have distinct mechanisms, evidence for intersecting pathways suggests that combined inhibition of PDGF and TGF-ß might offer complementary benefits. We examined the efficacy of seralutinib+ACTRIIA-Fc (sotatercept analog) in preclinical models. Methods. The combination of seralutinib+ACTRIIA-Fc was evaluated in the SuHx rat model of PAH. Proliferation was measured in normal and idiopathic (I) PAH patient-derived pulmonary artery smooth muscle cells (hPASMCs). The release of fibrotic markers was assessed in human lung fibroblasts (HLF) and human cardiac fibroblasts (HCF). Results. In the SuHx model, treatment with seralutinib and ACTRIIA-Fc alone decreased mean pulmonary artery pressure (mPAP) by 23% and 28%, respectively. The combination produced a 78% reduction in mPAP at clinically relevant doses. Combined treatment also significantly reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary vascular resistance index, and muscularization of small pulmonary arteries compared to vehicle control and individual seralutinib or ACTRIIA-Fc treatments. In normal and IPAH-derived hPASMCs, seralutinib completely inhibited PDGFBB and human serum-induced proliferation, while ACTRIIA-Fc alone showed modest inhibition of proliferation at clinically relevant concentrations; combination did not show an additive anti-proliferative effect. In HLFs and HCFs, combination treatment led to a greater-than-additive reduction in fibrotic markers fibronectin and pro-collagen Iα1. Summary. Our results highlight the complementary mechanisms of action of seralutinib and sotatercept, suggesting the clinical potential of combination therapy. Preliminary combination experience is expected from the phase 2 open-label extension (NCT04816604) and phase 3 PROSERA studies (NCT05934526), which allow for protocol-specified use of sotatercept with seralutinib. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany