HS135, A Best-in-class Activin And GDF Ligand Trap, Is Efficacious In Experimental Left Heart Failure

• Published in: Journal of cardiac failure 2024-01, Vol.30 (1), p.169-169
• Main Authors: Schang, Gauthier, de Molliens, Mathilde Poujol, Brûlé, Emilie, Sours, Ariane, Chauvet, Cristina, Denis, Jean-François, Ganesh, Vannakambadi, Tikhomirov, Ilia, Tremblay, Gilles, Schoelermann, Julia, O'Connor-McCourt, Maureen
• Format: Article
• Language: English
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2023.10.127

Six million patients in the US have left-sided heart failure (HF), a majority of which exhibit preserved Ejection Fraction (HFpEF). Obesity is an established risk factor for the development of HF, particularly HFpEF, with an estimated 80% of HFpEF patients living with obesity. Novel treatments that address both HF pathology and obesity are thus urgently needed. Activin and growth differentiation factor (GDF) cytokines are genetically and clinically validated drivers of HF and obesity. HS135 is a novel, rationally designed Activin and GDF ligand trap with a best-in-class ligand neutralization profile to treat HF with obesity. Here, we explored the cardiac and metabolic efficacy of HS135 in preclinical models of HF including obesity-associated HFpEF. The transverse aortic constriction (TAC) and High-Fat Diet (HFD)/L-NAME mouse models were used to explore the potential of HS135 in left-sided HF and obesity-associated HFpEF, respectively. Fourteen days post-TAC surgery, animals were treated with 3, 10 and 30 mg/kg HS135 twice weekly for 28 days. Obesity-associated HFpEF was established by feeding mice HFD in combination with L-NAME supplied in drinking water ad libitum for 5 weeks before initiating twice weekly treatment with HS135 (5 and 25 mg/kg), empagliflozin (10 mg/kg daily), or both (25 mg/kg twice weekly and 10 mg/kg daily, respectively) for three weeks. In both the TAC and HFD/L-NAME models, changes in heart function, body composition, as well as plasma biomarkers were evaluated at the end of the study. Tissue remodelling in the heart and lungs was assessed by IHC and gene expression analyses. In the TAC model, HS135 achieved rebalancing of pathological Activin/GDF signalling, reversed markers of LV failure and fibrosis, and was efficacious at reversing lung remodeling. RNA sequencing of the LV revealed that TAC surgery negatively affected genes associated with cellular respiration and mitochondrial function while up-regulating genes associated with fibrotic adaptation. HS135 dose-dependently normalized these expression profiles and was efficacious at improving gene expression associated with positive metabolic function while reducing inflammatory pathways. In the HFD/L-NAME model, HS135 and/or empagliflozin were efficacious in normalizing left atrium weight, left-ventricular posterior wall thickness, and cardiac output. Importantly, HS135, but not empagliflozin, led to profound increases in skeletal muscle mass while decreasing white adipose tissue ma