EX-99.2 3 srrk-20240624xex99d2.htm EX-99.2
Exhibit 99.2

GRAPHIC

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 g , C h r i s t o p h e r J . B o s t o n , J u s t i n W. J a c k s o n , Ya n H u a n g , S a m a n t h a B . N i c h o l l s , L e s l i e K . C o r t e s , M o Q a t a n a n i

GRAPHIC

2 Melissa Fulham Employee and Stock/Shareholder of Scholar Rock, Inc. Presenter disclosure

GRAPHIC

3 PHOTOGRAPHY PROHIBITED PLEASE DO NOT take photos of this presentation

GRAPHIC

4 Maintaining weight loss is challenging Christoffersen, B.Ø., et al. Obesity (Silver Spring). 2022. PMID: 35333444

GRAPHIC

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

GRAPHIC

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. Sport Med. 2022. 6. Zurlo, F., et al. J Clin InvestI. 1990. 7. Fukushima, Y., et al. Diabetes Metab J. 2016. 8. Roh, E. and Choi, K.M. Front. Endocrinol (Lausanne). 2020. 9. Volpi, E., et al. Curr Opin Clin Nutr Metab Care. 2004. Increase basal metabolic rate (BMR)1 Enhance glucose homeostasis2 and better insulin sensitivity and lower risk of prediabetes3 Signal to other systems as an endocrine organ impacting overall health4 Reduce visceral fat5 Increase caloric expenditure post-exercise6 Increase bone density, strength, function, and longevity and decreased risk of injury and disability7-9 KEY M ETABOLIC ORGAN

GRAPHIC

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

GRAPHIC

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. PMID: 17726519 Belgian blue cattle; MSTN-null Mstn-/- mice

GRAPHIC

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.; Bloise, E. et al. Physiol Rev. 2019.; Ravenscroft, T.A., et al. Genet Med. 2021. ▪ Developing an anti-myostatin agent is difficult due to a high degree of similarity with Activin A and GDF-11 ▪ Selectively targeting myostatin is important: ▪ ActRIIB/Activin A/GDF11 KO mice all have perinatal lethality due to developmental defects in multiple organ systems ▪ GDF11 LOF variants are associated with severe craniofacial, neurological, and skeletal phenotypes in humans ▪ Inhibition of ActRII or Activin A in adult humans is associated with several health risks, including significant reduction in follicle-stimulating hormone levels

GRAPHIC

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 myostatin and blocks the conversion of the latent form to mature myostatin ▪ By inhibiting the release of mature myostatin, SRK-439 prevents myostatin from interacting with receptors which results in the inhibition of signaling and promotes muscle growth

GRAPHIC

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 ActRIIA/B Myostatin

GRAPHIC

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

GRAPHIC

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 IgG sema HFD SRK-439 sema Administering SRK-439-mIgG1 to DIO mice during semaglutide treatment and after discontinuation *IgG = mIgG1 *SRK-439 or 439 = SRK-439-mIgG1

GRAPHIC

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

GRAPHIC

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

GRAPHIC

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 SRK-439 administration in combination with and after withdrawal of semaglutide results in lean mass composition similar to chow-fed animals

GRAPHIC

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

GRAPHIC

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 Epididymal Adipose Weight Weight (g) ✱✱✱ ns ns ✱ ns SRK-439 treatment improved body composition SRK-439 administration in combination with and after withdrawal of semaglutide lowers percent fat mass and reduces adipose depot size

GRAPHIC

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 (mg/dL) ✱ ✱ ✱ ns ns ns SRK-439 improved circulating metabolic biomarkers SRK-439 administration in combination with and after withdrawal of semaglutide reduces circulating leptin which confirms reduced adiposity

GRAPHIC

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 weight loss and increased lean mass after semaglutide discontinuation ▪ SRK-439-mIgG1 administration resulted in lower body fat composition and lower circulating leptin during weight regain SRK-439-mIgG1 maintains a healthy body composition during GLP-1RA-induced weight loss and subsequent regain following discontinuation Summary

GRAPHIC

21 Acknowledgements Scholar Rock, Inc. ▪Co-authors ▪SRK-439 Program Team ▪Adam Fogel ▪Ryan Frieler ▪Jonathan Hamm ▪Molly MacLeod ▪Atsuko Polzin

GRAPHIC

22 Thank you!