298-OR: Precision-Engineered Activin and GDF Ligand Trap HS235—A Novel Lean Mass–Preserving Treatment for Obesity

Introduction: Incretin mimetics have revolutionized the pharmacotherapy of obesity leading to unprecedented weight loss and improvement of cardiometabolic health. However, incretins reduce body mass in a non-selective manner. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. LBM preservation is a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to incretins. HS235 is an activin receptor ectodomain-based Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study. Results: In DIO mice, HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. This data supports the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss. Disclosure G. Schang: Employee; 35Pharma. M. De Molliens: Employee; 35Pharma. E. Brûlé: Employee; 35Pharma. A. Sours: Employee; 35Pharma. J. Denis: Employee; 35Pharma. C. Chauvet: Employee; 35Pharma. V. Ganesh: Employee; 35Pharma. G. Tremblay: Employee; 35Pharma. J. Schoelermann: Employee; 35Pharma. M. O'Connor: Employee; 35Pharma.