SUN-679 HS235, A Novel Lean Mass-Preserving Treatment for Obesogenic Heart Failure with Preserved Ejection Fraction with Pleiotropic Metabolic Effects

Abstract Disclosure: G. Schang: None. E. Brûlé: None. F. Dilasser: None. I. Nandi: None. J. Denis: None. A. Sours: None. V. Ganesh: None. R. Samadfam: None. G. Tremblay: None. J. Schoelermann: None. M. O'Connor: None. Introduction: HS235 is a clinical-stage activin receptor ectodomain-based Fc-fusion protein with extended half-life that has been rationally designed to selectively and potently trap Activins and growth differentiation factors (GDFs). Activins and GDFs are members of the TGF-beta superfamily and are extensively validated targets controlling body composition, metabolism, and bone health. Furthermore, overactive Activin signaling is associated with worsening heart failure (HF) in patients. HF, especially Heart Failure with Preserved Ejection Fraction (HFpEF), is associated with high rates of obesity as well as skeletal muscle dysfunction and atrophy. It is increasingly recognized that obesity is a pathogenic driver of HFpEF highlighting the need to address left ventricular (LV) and metabolic dysfunction concomitantly. HS235 has been designed to specifically block Activins and GDFs to selectively target excess adiposity while maintaining or increasing skeletal muscle, as well as improving LV function. HS235’s proposed dual mode of action on body composition and cardiac function was evaluated in several murine models. Methods: Efficacy in obesity-associated HFpEF was assessed using the murine High Fat Diet and L-NAME model. HS235 was evaluated at different dose levels, and its efficacy on heart function, exercise tolerance, as well as skeletal muscle and adipose tissue changes was investigated. HS235’s effect on excess adiposity, muscle, and bone was further assessed in diet-induced obese (DIO) mice, non-human primates, as well as orchidectomized male mice. Results: In the obesogenic HFpEF mouse model, HS235 decreased fat mass, increased lean mass, and improved cardiac function to levels comparable to lean control animals as assessed by echocardiography and hemodynamic measurements. Through this dual mode of action, HS235 completely rescued exercise tolerance in HFpEF animals to lean control levels. These phenotypic observations were supported by gene expression readouts in heart, skeletal muscle, and adipose tissue. Additionally, in lean mice and NHPs, HS235 led to a significant increase in muscle fiber size and diameter. In DIO mice, the combination of HS235 and glucagon-like peptide-1 receptor agonism (GLP-1RA) led to fat-selective weight loss that was characterised by increased fat loss compared to GLP-1RA alone without any loss of lean muscle mass. Finally, in orchidectomized mice, HS235 improved bone health as assessed by DXA. Conclusion: These data demonstrate that HS235 represents a novel approach to treating obesity and associated co-morbidities in a manner that is complementary and orthogonal to currently approved incretin-based medications. Specifically, these data support the development of HS235 in obesogenic HFpEF and as a fat-selective anti-obesity agent. Presentation: Sunday, July 13, 2025