OR10-03 Murine Bimagrumab Co-administration With Incretin Agonists Results In Additive Efficacy And Superior Quality Weight Loss In The Mouse Diet-induced Obesity Model

Abstract Disclosure: K. Nguyen: Employee; Self; Versanis Bio. X. Wang: None. D. Xu: None. L.B. Klickstein: Employee; Self; Versanis Bio. Stock Owner; Self; Novartis Pharmaceuticals. Bimagrumab is an activin type II receptor (ActRII) antagonist currently in phase 2b clinical development for the treatment of obesity and other cardiometabolic diseases. In overweight and obese patients with T2DM, bimagrumab caused >20% body fat loss over 48 weeks of therapy while concomitantly producing a 4% increase in muscle mass; the net effect is higher quality weight loss than that achieved by dieting or incretin agonists, with weight loss quality defined as the percentage of weight loss represented by fat mass loss. Because the mechanisms of action and target organs for bimagrumab and incretin agonists are largely non-overlapping, we designed mouse experiments to investigate whether adding bimagrumab to incretin therapy might be additive with respect to fat mass loss and improve the quality of weight loss by attenuating the lean mass loss that accompanies incretin treatment. C57Bl/6J mice at 5-6 weeks of age were fed a 60% fat diet for 25 weeks and reached an average body weight of 54 grams at the start of drug therapy. Each group of mice (n=8) received a murinized version of bimagrumab, CDD866, 20 mg/kg i.p. weekly and/or semaglutide 40 µg/kg s.c. daily, tirzepatide at 45 µg/kg s.c. daily, or liraglutide at 20 µg/kg s.c. twice daily. The high fat diet was continued through the 3-week treatment period. Food intake and body weight were monitored twice weekly, while clinical observations, body composition by MRI and physical activity were assessed once weekly. At the doses and schedules above, the rank order of efficacy with the three incretin agonists tested, as assessed by change in body weight over 3 weeks, was tirzepatide (-13.7g) > semaglutide (-8.6g) > liraglutide (-4.0g), the same order of efficacy as is observed in humans. Adding CDD866 20 mg/kg i.p. weekly to each of tirzepatide, semaglutide or liraglutide therapy increased weight loss to -14.5g, -9.8g and -4.5 g, respectively. The weight loss quality (100 x calculated fat mass loss in grams divided by total body weight loss in grams), was 74.7%, 58.8% and 42.5% for tirzepatide, semaglutide and liraglutide, respectively, and in combination with CDD866 weight loss quality improved to 96.4%, 104.6% and 122.8%, respectively. Fat mass loss > 100% of total weight loss reflects both the additive fat mass loss and the muscle mass gain due to CDD866. A phase 2b clinical study of bimagrumab +/- semaglutide is ongoing to learn if these favorable results will translate to humans (NCT05616013). Presentation: Friday, June 16, 2023