Introduction: Activins and growth differentiation factors (GDFs) are known drivers of cardiopulmonary pathology. Sotatercept (ActRIIA-Fc), which targets activins and GDFs, has recently reported Phase 3 success in Group 1 PH. However, its potential is curtailed by incomplete target engagement at the clinical target dose. HS135 is a rationally designed activin receptor-based trap with best-in-class in vivo target engagement of pathological activins and GDFs, while sparing BMP-9. HS135?s differentiated efficacy profile was explored in preclinical models of Group 1 and 2 PH, and compared to ActRIIA-Fc.

Methods: Efficacy in Group 1 and 2 PH was assessed using the 4-week rat monocrotaline (MCT) and the mouse transaortic constriction (TAC) models, respectively. In each case, HS135 was compared to ActRIIA-Fc, and tissue remodelling in the heart and lungs was assessed by IHC and RNA-seq.

Results: Administration of MCT deregulated pathways related to inflammation and energy balance in the right ventricle, which were only modestly improved by ActRIIA-Fc. On the other hand, these pathways in HS135-treated animals were nearly indistinguishable from naïve mice. Similarly, in the lung, HS135 was more efficacious than ActRIIA-Fc at improving inflammation markers. In the TAC model, HS135, but not ActRIIA-Fc, completely reversed lung remodelling, and returned expression of genes related to fibrosis and heart failure back to baseline in the left ventricle.

Conclusion: The best-in-class target engagement profile of HS135 translates into superior and differentiated heart and lung efficacy in Group 1 and 2 PH models, which warrants further exploration in clinical trials.