Introduction: Therapies targeting underlying mechanisms of pulmonary arterial hypertension (PAH) could modify disease progression and improve outcomes. The genetics of PAH implicate deficient bone morphogenetic protein (BMP) signaling as a pathogenetic driver. Lung tissues from experimental pulmonary hypertension (PH) and human PAH exhibit deficient BMP and excessive TGFβ signaling. Consistent with a role of imbalanced BMP/TGF signaling, administration of BMP9 or a TGFβ ligand trap ameliorate experimental PH. ACTRIIA-Fc (sotatercept) is an Activin- and GDF8/11-specific ligand trap in Phase II studies for anemia. Hypotheses: ACTRIIA-Fc rebalances BMP vs. Activin/GDF signaling in vascular cells, and attenuates PH and pulmonary vascular (PV) remodeling in rodent models.
Methods: The impact of ACTRIIA-Fc on BMP and TGFβ signaling was examined in A204, C2C12, and human pulmonary arterial endothelial and smooth muscle cells. ActRIIa-Fc (15 mg/kg s.c. twice weekly), sildenafil (30 mg/kg p.o. twice daily) or vehicle were administered for 4 weeks to adult male Sprague-Dawley rats developing PH via a single injection of monocrotaline (MCT) or via single injection of SU5416 combined with hypoxia (FIO2=0.10), after which pulmonary artery pressure, right ventricular hypertrophy (RVH) and PV remodeling were assessed.
Results: In cellular assays, ACTRIIA-Fc enhanced BMP9-induced SMAD1/5/9 activation and transcriptional activity, and reversed inhibition of BMP9 signaling by exogenous Activin A or human plasma. In vivo, ACTRIIA-Fc attenuated PH, RVH and PV remodeling in MCT and SU-Hx rats, and with markedly more potency than sildenafil.
Conclusions: ACTRIIA-Fc rebalances the ratio of BMP9 to Activin signaling in vascular cells and potently inhibits manifestations of experimental PH. Given its tolerability in human studies, ACTRIIA-Fc may be a suitable candidate for clinical trials in PAH as a novel, mechanism-targeted therapy.