Abstract Body (Do not enter title and authors here): Background: Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary condition characterized by pulmonary vasoconstriction and vascular remodeling. This results in elevated pulmonary artery pressure and right ventricle (RV) dysfunction and failure. RKER-012 is a modified activin receptor type IIB (ActRIIB) ligand trap designed to specifically bind and inhibit select TGF-β ligands associated with PAH, including activins A and B and GDFs 8 and 11. RKER-012 has previously been shown to provide cardio-protection in several preventative preclinical models of PAH. To study RKER-012 in a more clinically relevant setting, we evaluated the cardiopulmonary effect of RKER-012 in an established monocrotaline (MCT)-induced rat experimental PAH model.

Methods: Male Wistar rats were divided into 3 groups: normal control vehicle-treated (Nor-Veh), MCT-exposed (40mg/kg;sc) vehicle-treated (MCT-Veh) and MCT-exposed RKER-012-treated (MCT-RKER-012) rats. Rats were treated with either vehicle or RKER-012 (10mg/kg twice weekly for 2 weeks; sc) two-week post-MCT administration, at which point RV systolic pressure (RVSP) has been shown to be elevated¹ (~50mmHg). At day 28, RVSP, RV hypertrophy, cardiac echography and pulmonary vascular remodeling using Microfil^® infusion were examined.

Results: Increases in RV systolic pressure (RVSP, +96.8%;p<0.005) and Fulton index (FI, +60.8%;p<0.005) were observed in MCT-Veh rats vs Nor-Veh rats, consistent with RV dysfunction and hypertrophy in PAH. Treatment with RKER-012 reduced MCT-induced increases in RVSP (-44.9%;p<0.004) and FI (-24.3%;p<0.021) supporting the reversal of RV dysfunction and hypertrophy. Cardiac echography showed near amelioration of flattening of the septal wall and RV dilation in MCT-RKER-012 rats compared to MCT-Veh. Microfil^®-infused angiograms of MCT-Veh rats showed decreased pulmonary arterial bed density indicating pulmonary vascular remodeling. In contrast, treatment with RKER-012 nearly restored the MCT-induced decrease in pulmonary arterial bed density, supporting potential reversal of the pathology underpinning PAH (Fig. 1).

Conclusion: Treatment with RKER-012 reversed increased RVSP, RV hypertrophy pulmonary vascular remodeling and restored RV geometry in MCT-induced experimental PAH, suggesting potentially translatable benefit for patients with PAH. These preclinical findings further support the rationale for the ongoing Phase 2 TROPOS trial in patients with PAH (NCT05975905).

¹ PMID:17496210