Abstract
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: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, this loss of fat mass is accompanied by undesirable loss of lean body mass (LBM) which can account for 15 - 40% of overall weight loss. Loss of LBM by incretin-based therapies negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and improvement of overall health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. Aims and objectives: HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. In vivo target engagement and pharmacodynamic response to HS235 were assessed in mice by quantifying metabolic biomarkers including muscle hypertrophy, muscle and fat gene expression, as well as plasma metabolites. To further 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, glucose metabolism, exercise tolerance, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both 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 prevented this loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy. Collectively, these data support the development of HS235 as a novel anti-obesity agent that may also complement currently approved incretin-based medications. Presentation: Friday, June 16, 2023