2180-LB: Bimagrumab Augments Metabolic Rate to Improve Incretin-Induced Weight Loss in Obese Mice

Introduction and Objective: TGFβ-like ligands, such as myostatin, GDF3 and Activin E, signal via the activin type II receptors (ACVR2A/B) in skeletal muscle and adipose tissue to negatively impact muscle growth and promote excess adiposity. Hence, targeting the myostatin/activin pathway may provide a greater magnitude and quality weight loss in the management of excess adiposity. Methods: The primary objective of the current investigation was to determine whether the ACVR2A/B antagonist mAb bimagrumab provides a greater quality of weight loss when dosed in combination with incretin based multi-receptor agonists in obese mice. Results: A major finding of our studies is that treatment with bimagrumab enhanced GLP-1R agonist and tirzepatide induced weight loss in animals housed at thermoneutrality, while there was no effect of a neutralizing mAb targeting myostatin. Notably, bimagrumab not only promoted a greater negative energy balance, but also provided quality of body weight loss by enhancing the loss of fat mass and blunting the loss of lean mass when dosed in combination with incretin therapeutics. Intriguingly, although bimagrumab was unable to prevent weight regain following withdrawal of the multi-receptor agonists, blockade of ACVR2A/B signaling negated preferential fat mass accrual and promoted lean mass regain. Importantly, bimagrumab stimulated a greater negative energy balance in combination with incretin-based therapeutics by boosting caloric expenditure. Mechanistically, omics analyses suggested that inhibition of ACVR2A/B augmented the combustion of excess calories via the recruitment of thermogenic pathways in adipose tissue. Conclusion: Collectively, our findings provide further support to the notion that inhibition of the myostatin/activin pathway in adipose tissue may promote a greater quality of weight loss in the management of excess adiposity. Disclosure J.M. Poret: None. B. Droz: None. E. Hawkins: Employee; Eli Lilly and Company. V. Pirro: Employee; Eli Lilly and Company. M.J. Pearson: Employee; Eli Lilly and Company. R.J. Samms: None.