Bimagrumab co-administration with incretins drives additive fat loss while preserving - PowerPoint Presentation

1. Bimagrumab co-administration with incretins drives additive fat loss while preserving muscle mass in obese miceKevin Nguyen PhD, Vicki Sung, PhD, Xingjuan Wang, PhD, Deming Xu, PhD and Lloyd Klickstein MD, PhDObesity WeekNovember 2, 2022

2. Activin type II receptors directly regulate metabolism in muscle and adipose tissues2 |Copyright 2022 VersanisMuscle AtrophyProteolysisPre-Adipocyte Differentiation Lipid StorageDifferential binding of specific ligands (activins, myostatin) and type 1 receptors (ALK4, ALK7) to ActRIIA and ActRIIB in muscle and adipose tissues directly inhibits muscle growth while promoting lipid storage and visceral fat accumulation    

3. Muscle AtrophyProteolysisTargeting activin type II receptors increases muscle mass and decreases fat mass3 |Copyright 2022 VersanisBimagrumab TreatmentBimagrumab is a potent first-in-class, fully human monoclonal antibody that blocks ligand binding to ActRIIA and ActRIIB, with direct effects in muscle and adipose tissue to increase muscle mass while promoting fat lossPre-Adipocyte Differentiation Lipid StorageIncreased Muscle MassDecreased Adipose Tissue Mass

4. Bimagrumab Studied in 21 Clinical Trials to date IN OVER 1000 PATIENTSConsistent muscle mass increase and substantial fat loss demonstrated during clinical developmentGenerally safe and well tolerated with <5% of patients discontinuing across the entire program Bimagrumab was originally developed to address muscle wasting syndromes, but was also found to induce substantial fat loss4 |Copyright 2022 VersanisMuscle hypertrophyLipid mobilization from adipose storesAppetite control and feeling of satietySlower gastric emptyingBimagrumabIncretinsReduction in fat mass, increase in muscle massReduction in both fat and lean massMechanism of ActionEffects on Body CompositionCombination of bimagrumab and incretin therapy could provide additive loss of fat mass while preserving muscle mass, resulting in improved outcomesHypothesis

5. Bimagrumab is immunogenic in mice: Murine bimagrumab (CD866‡) was constructed to decrease immunogenicity and facilitate repeat dose mouse experiments3 weeks drug treatment & assessments**Study design for murine bimagrumab‡ + incretin combination pharmacology studies in a diet induced obesity (DIO) mouse modelStart drug treatment22 g20-25 weeks49-54 g60% fat dietTerminationTissue analysis4-6 week old C57Bl/6J mice*‡CD866, a chimeric murine bimagrumab analog is referred to as murine bimagrumab or “bima” throughout this presentation*n=8 mice per group; **Assessments included food consumption, body weight, clinical exam, quantitative activity measurement, body composition by MRI, terminal assessments including muscle and fat weightsStudy 1Murine bimagrumab ± semaglutideStudy 2Murine bimagrumab ± semaglutideMurine bimagrumab ± tirzepatide5 |Copyright 2022 Versanis

6. Effect of murine bimagrumab + incretin treatment on fat mass6 |Copyright 2022 VersanisFat (g)Combination of murine bimagrumab with semaglutide or tirzepatide drove additive reduction in fat mass Abbreviations: bima – murine bimagrumab; sema – semaglutide; tirze – tirzepatide. Effect on Fat Mass by MRI (Study 2)Fat (g)Effect on Fat Mass by MRI (Study 1)Bima 20 mg/kg + Sema 5 ug/kgBima 20 mg/kg + Sema 40 ug/kgVehicleBima 20 mg/kgSema 5 ug/kgSema 40 ug/kgFat (g)Sema 40 ug/kgVehicleBima 20 mg/kgBima 20 mg/kg + Sema 40 ug/kgTirze 45 ug/kgBima 20 mg/kg + Tirze 45 ug/kg

7. Effect of murine bimagrumab + incretin treatment on leptin7 |Copyright 2022 Versanis*Similar results seen in study 1 with murine bimagrumab and semaglutide Leptin (ng/ml)VehicleBima 20 mg/kgSema 40 ug/kgBima 20 mg/kg + Sema 40 ug/kgTirze 45 ug/kgBima 20 mg/kg + Tirze 45 ug/kgCombination of murine bimagrumab + semaglutide or tirzepatide reduced circulating leptin levels by ~80%Effect on Circulating Leptin (Study 2)*

8. Effect of murine bimagrumab + incretin treatment on peri-renal fat8 |Copyright 2022 Versanis*Similar results seen in study 1 with murine bimagrumab and semaglutide on inguinal fatVehicleBima 20 mg/kgSema 40 ug/kgBima 20 mg/kg + Sema 40 ug/kgTirze 45 ug/kgBima 20 mg/kg + Tirze 45 ug/kgCombination of murine bimagrumab + semaglutide or tirzepatide reduced peri-renal fat by ~60%Peri-renal Fat (mg)Effect on Peri-renal Fat (Study 2)*

9. Effect of murine bimagrumab + incretin treatment on lean mass9 |Copyright 2022 Versanis*Similar results seen in both studies with murine bimagrumab and semaglutide on terminal measurement of gastrocnemius muscle weight VehicleBima 20 mg/kgEffect on Lean Mass by MRI (Study 2)*Lean Mass (g)Sema 40 ug/kgTirze 45 ug/kgBima 20 mg/kg + Sema 40 ug/kgBima 20 mg/kg + Tirze 45 ug/kgMurine bimagrumab rescued lean mass loss induced by both semaglutide and tirzepatide

10. Conclusions: bimagrumab + incretins in the mouse DIO model10 |Copyright 2022 VersanisThe two MoAs are additive with respect to fat mass lossMurine bimagrumab triggered muscle hypertrophy and was able to reverse the muscle mass loss caused by incretin agonists No adverse effects of the drug combinations were evidentDIO mouse model studies support investigation of bimagrumab + incretindrug combination in humansBELIEVEPhase 2b clinical study to start in the near future!

11. Acknowledgements11 |Copyright 2022 VersanisThe authors thank the Versanis Bio team for overall support and our friends and colleagues at Novartis who expedited production of a new lot of CDD866 for these experiments.Thank you for your attention!