Slide 1: SRK-439 Promotes Healthy Body Composition in Combination with GLP-1RAs in a Mouse Model of Obesity
The Anti-Myostatin Antibody SRK-439 Promotes Healthy Body Composition in Combination with GLP-1RAs in a Mouse Model of Obesity M e l i s s a A . F u l h a m , C h r i s t o p h e r D . C h a p r o n , F r a n c i s T. D a n e h y, J r. , F r e d e r i c k C . S t r e i c h , J r. , B r i a n L i a n
Slide 2: Presenter disclosure
2 Melissa Fulham Employee and Stock/Shareholder of Scholar Rock, Inc. Presenter disclosure
Slide 3: Photography prohibited
3 PHOTOGRAPHY PROHIBITED PLEASE DO NOT take photos of this presentation
Slide 4: Maintaining weight loss is challenging
4 Maintaining weight loss is challenging Christoffersen, B.Ø., et al. Obesity (Silver Spring). 2022. PMID: 35333444
Slide 5: Lean mass is reduced during weight loss regardless of intervention
5 Lean mass is reduced during weight loss regardless of intervention Chaston, T. B., et al. Int J Obes. 2007. PMID: 17075583 Sargeant, J. A., et al. Endocrinol Metab. 2019. PMID: 31565876 Wilding J.P.H., et al. Diabetes Obes Metab. 2022. PMID: 35441470
Slide 6: Muscle is critical for overall health
6 Muscle is critical for overall health 1. Aristizabal,J.C., et al. Eur J Clin Nutr. 2015. 2. Lindegaard, B., et al. J Clin Endocrinol Metab. 2008. 3. Srikanthan, P. and Karlamangla, A.S. J Clin Endocrinol Metab. 2011. 4. Severinsen, M.C.K. and Pedersen, B.K. Endocr Rev. 2020. 5. Wewege, M.A., et al
Slide 7: GLP-1RA withdrawal leads to weight regain and loss of cardiometabolic benefits
7 GLP-1RA withdrawal leads to weight regain and loss of cardiometabolic benefits Wilding J.P.H., et al. Diabetes Obes Metab. 2022. PMID: 35441470 STEP 1 trial extension: Participants regained weight after semaglutide withdrawal
Slide 8: How can we maintain or increase lean mass during weight loss?
8 ▪ This is not unique to GLP-1RAs; weight is regained with all weight loss methods ▪ How can we maintain or increase lean mass during weight loss? Can we mitigate weight regain and loss of metabolic benefit? Skeletal Muscle Muscle growth↓ Muscle atrophy↑ ActRIIB Myostatin Lee, S.J. PLoS One. 2007.
Slide 9: Selectively targeting myostatin is challenging but critical
9 Selectively targeting myostatin is challenging but critical Promyostatin Pro-GDF-11 Proactivin GDF-11 Activin A ActRIIA/B Myostatin Oh, S.P. and Li, E. Genes Dev. 1997.; Matzuk, M. M., et al. Nature. 1995.; McPherron, A.C., et al. Nat Genet. 1999.; Garito, T., et al. Clin Endocrinol (Oxf). 2018.;
Slide 10: SRK-439 binds to pro- and latent myostatin and enables muscle growth
10 Promyostatin Latent Myostatin Mature Myostatin Skeletal Muscle Muscle growth↓ Muscle atrophy↑ Prodomain Mature Prodomain Mature Prodomain Mature Prodomain Mature Mature Mature ActRIIB SRK-439 SRK-439 binds to pro- and latent myostatin and enables muscle growth ▪ SRK-439 binds to pro- and latent m
Slide 11: SRK-439 is exquisitely selective for pro- and latent-myostatin
11 SRK-439 is exquisitely selective for pro-and latent-myostatin 0.001 0.01 0.1 1 10 100 1000 0.0 0.5 1.0 1.5 2.0 2.5 SRK-439 Specificity SRK-439 Hu IgG4 (nM) Binding (AU) Hu Latent Myostatin Hu Latent GDF11 Hu Latent Activin A KD = 0.579 nM Promyostatin Pro-GDF-11 Proactivin GDF-11 Activin A ActRII
Slide 12: Therapeutic hypothesis
12 Inhibiting myostatin, a negative regulator of muscle mass, during GLP-1RA-induced weight loss will maintain lean mass and result in a favorable body composition after GLP-1RA withdrawal Therapeutic hypothesis
Slide 13: Administering SRK-439-mIgG1 to DIO mice during and after semaglutide treatment
13 Day -7 Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 Day 63-64 45% HFD 20-week-old Male DIO mice 60% HFD qNMR qNMR qNMR qNMR qNMR Serum Tissue weight semaglutide or vehicle 0.04 mg/kg QD SRK-439-mIgG1 or mIgG1 control 10 mg/kg QW Diet Ab GLP-1RA Chow IgG vehicle HFD IgG vehicle HFD
Slide 14: Semaglutide discontinuation caused weight regain
14 -7 0 7 14 21 28 35 42 49 56 63 25 30 35 40 45 50 Body Weight Days in study Body Weight (g) Chow + IgG HFD + IgG HFD + IgG +Sema HFD + 439 + Sema Semaglutide discontinuation caused weight regain 45% HFD Sema SRK-439
Slide 15: SRK-439 maintained lean mass in combination with semaglutide administration
15 45% HFD Sema SRK-439 SRK-439 maintained lean mass in combination with semaglutide administration 0 7 1 4 2 1 2 8 3 5 4 2 4 9 5 6 6 3 2 0 2 5 3 0 Absolute Lean Mass Days in study Lean Mass (g) Chow + IgG HFD + IgG HFD + IgG +Sema HFD + 439 + Sema -6
Slide 16: SRK-439 increased relative lean mass and skeletal muscle weight
16 Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0.0 0.1 0.2 0.3 Gastrocnemius weight Weight (g) ns ✱✱✱✱ ns ✱✱✱ ✱✱✱✱ Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0 20 40 60 80 Relative Lean Mass Day 63 Lean Mass/BW (%) ✱✱✱✱ ns ns ✱✱✱✱ ✱✱✱ SRK-439 increased relative lean mass and skeletal muscle weight SR
Slide 17: SRK-439 attenuated fat mass regain after discontinuation of semaglutide
17 0 7 14 21 28 35 42 49 56 63 0 5 10 15 20 Absolute Fat Mass Days in study Fat Mass (g) Chow + IgG HFD + IgG HFD + IgG +Sema HFD + 439 + Sema -6 SRK-439 attenuated fat mass regain after discontinuation of semaglutide 45% HFD Sema SRK-439
Slide 18: SRK-439 treatment improved body composition
18 Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0 10 20 30 40 50 Relative Fat Mass Day 63 Fat Mass/BW (%) ✱✱✱✱ ✱✱ ns ✱✱✱ ✱✱ Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0.0 0.5 1.0 1.5 2.0 Inguinal Adipose Weight Weight (g) ✱✱✱✱ ns ns ns ns Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0.0 0.5 1.0 1.5 Epid
Slide 19: SRK-439 improved circulating metabolic biomarkers
19 Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0 20 40 60 Fasted Leptin Leptin (ng/mL) ✱✱✱✱ ✱✱ ns ✱✱ ✱✱ Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0 500 1000 1500 2000 Fasted Insulin Insulin (IU/mL) ✱✱ ✱ ns ns ns Chow IgG HFD IgG HFD IgG Sema HFD 439 Sema 0 50 100 150 200 250 Fasted Glucose Glucose (
Slide 20: Summary
20 ▪ Lean mass decreases during weight loss, regardless of the intervention ▪ Selectively inhibiting myostatin increases lean mass without the potential liabilities of non-selective targeting of the broader family ▪ SRK-439-mIgG1 administration prevented lean mass loss during semaglutide-induced wei
Slide 21: Acknowledgements
21 Acknowledgements Scholar Rock, Inc. ▪Co-authors ▪SRK-439 Program Team ▪Adam Fogel ▪Ryan Frieler ▪Jonathan Hamm ▪Molly MacLeod ▪Atsuko Polzin
Slide 22: Scholar Rock
- s ScholarRock