Abstract 4366887: HS235, a Novel Activin Signaling Inhibitor, is Highly Efficacious in Preclinical Models of Pulmonary Hypertension and Heart Failure

Background: HS235 is an activin receptor (ActR)-based ligand trap designed to potently neutralize Activins and growth differentiation factors (GDFs) while sparing homeostatic bone morphogenetic proteins (BMPs) including BMP-9 and BMP-10. Pulmonary Hypertension (PH), Heart Failure (HF), and metabolic syndrome are associated with dysregulated Activin and GDF signaling. In contrast, BMP-9 and -10 play important roles in vascular and lymphatic homeostasis and their neutralization should be avoided. HS235’s neutralization profile has the potential to achieve both improved safety and efficacy compared to first generation Activin signaling inhibitors. Methods: HS235’s efficacy in PH and HF was explored in a Group 2 PH mouse transverse aortic constriction (TAC) model. Briefly, mice underwent TAC surgery, recovered for 2 weeks, and were then treated with vehicle, HS235, or wild-type ActRIIA-Fc (a sotatercept surrogate) for 4 weeks. HS235’s efficacy in HF and obesity was confirmed in the High Fat Diet (HFD)/L-NAME model of obesogenic HFpEF. Briefly, mice were fed HFD and L-NAME for 10 weeks and then were treated with HS235 for 4 weeks. Results: In the TAC model, HS235 dose-dependently corrected left ventricular (LV) dysfunction, decreased TAC-induced pulmonary vessel muscularization and displayed greater efficacy than ActRIIA-Fc across readouts. Consistent with these results, HS235 more potently decreased levels of follicle-stimulating hormone (FSH, a circulating biomarker of Activin/GDF target engagement) relative to ActRIIA-Fc. In the HFD/L-NAME model, HS235 returned LV pressures to lean control levels and reduced fat while increasing lean mass. Importantly, these improvements resulted in a complete rescue of exercise tolerance. In both models, HS235 increased lean skeletal muscle mass, induced a more metabolically favourable muscle gene expression profile, and improved circulating NT-proBNP levels. Conclusion: HS235 improved PH, HF, body composition and exercise tolerance in in vivo models. These results demonstrate the differentiated therapeutic profile of HS235 and support its further development as a novel treatment of cardiopulmonary and cardiometabolic diseases.