FRI112 HS135, A Novel Activin And GDF Trap With Dual Cardiopulmonary And Metabolic Mode Of Action, Is Efficacious In An Obesogenic Model Of Heart Failure

Disclosure: G. Schang: Employee; Self; 35Pharma Inc. M. Poujol de Molliens: Employee; Self; 35Pharma Inc. E. Brûlé: Employee; Self; 35Pharma Inc. C. Chauvet: Employee; Self; 35Pharma Inc. J. Denis: Employee; Self; 35Pharma Inc. A. Sours: Employee; Self; 35Pharma Inc. V. Ganesh: Employee; Self; 35Pharma Inc. G. Tremblay: Employee; Self; 35Pharma Inc. J. Schoelermann: Employee; Self; 35Pharma Inc. M. O'Connor-McCourt: Employee; Self; 35Pharma Inc. Introduction: Heart failure with preserved ejection fraction (HFpEF) remains one of the largest unmet medical needs in cardiovascular medicine. Eighty percent of HFpEF patients are obese, and adiposity is associated with increased HF-related hospitalization. Lean mass, conversely, is a major driver of cardiorespiratory fitness (CRF) in HFpEF, with greater CRF being a predictor of more favourable survival. Therefore, improvement of body composition in addition to cardiac parameters is a desirable treatment goal for novel HFpEF agents. Activins and growth differentiation factors (GDFs) have been validated preclinical and clinically as targets driving the pathophysiology of cardiopulmonary diseases as well as controlling body composition and metabolism. While previous activin targeting agents have shown therapeutic promise in clinical trials, full pathway inhibition remains unachieved. HS135 is an activin receptor ectodomain-based (ActRII) Fc-fusion protein, rationally designed to achieve best-in-class potency against activins and GDFs, without dose-limiting effects that would impede achieving full activity. We have previously demonstrated that HS135 achieves best-in-class in vivo target engagement and induces positive effects on lean body mass and muscle metabolism. Here we sought to assess the combined effect of HS135 on cardiac efficacy and body composition in an obesogenic model of HFpEF. HS135 was also explored in combination with empagliflozin, a recently approved SGLT2 inhibitor in HFpEF which, though effective at reducing HF-related hospitalization, has minimal effect on body composition in patients. Methods: The ability of HS135 to improve heart function was assessed using a validated HFpEF rodent model. Mice were fed a high-fat diet in conjunction with water containing L-NAME for a period of 5 weeks. The mice were then treated with HS135 (5 or 25 mg/kg, twice weekly), empagliflozin (10 mg/kg daily), or a combination of both over 3 weeks. The efficacy of HS135 and empagliflozin was assessed at the end of study by echocardiography, hemodynamics, histological assessments, and biomarker readouts. Results: Animals treated with HS135, empagliflozin, or both, displayed improvements in HF-related readouts. Specifically, test agents significantly decreased heart hypertrophy and lung congestion, and improved cardiac diastolic function and exercise tolerance. Notably, HS135 alone and in combination with empagliflozin significantly increased lean body mass while decreasing fat mass. Conclusion: Potent and selective inhibition of activins and GDFs represents a novel treatment strategy in HFpEF targeting both cardiac effects as well as improvement in body composition in this largely obese patient population. Collectively, these data support the development of HS135 as a novel agent in cardiometabolic and cardiopulmonary diseases, including heart failure. Presentation: Friday, June 16, 2023