Scholar Rock Holding Corporation · NASDAQ:SRRK
Scholar Rock — American Diabetes Association (ADA) Scientific Sessions 2024
23 slides from Scholar Rock's conference presentation, June 2024
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
Presenter disclosure Melissa Fulham Employee and Stock/Shareholder of Scholar Rock, Inc. 2
Slide 3: Photography prohibited
PHOTOGRAPHY PROHIBITED PLEASE DO NOT take photos of this presentation 3
Slide 4: 4
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Slide 5: Maintaining weight loss is challenging
Maintaining weight loss is challenging 5 Christoffersen, B.Ø., et al. Obesity (Silver Spring). 2022. PMID: 35333444
Slide 6: Lean mass is reduced during weight loss regardless of intervention
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 6 Wilding J.P.H., et al. Diabetes Obes Metab. 2022. PMID: 35441470
Slide 7: Muscle is critical for overall health
KEY M ET A BO LI C O RGA N Muscle is critical for overall health 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 calor
Slide 8: GLP-1RA withdrawal leads to weight regain and loss of cardiometabolic benefits
GLP-1RA withdrawal leads to weight regain and loss of cardiometabolic benefits STEP 1 trial extension: Participants regained weight after semaglutide withdrawal Wilding J.P.H., et al. Diabetes Obes Metab. 2022. PMID: 35441470 8
Slide 9: Can we mitigate weight regain and loss of metabolic benefit?
Can we mitigate weight regain and loss of metabolic benefit? ▪ 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? Myostatin ActRIIB Skeletal Muscle Belgian blue cattle; Muscle growth↓ Mstn-/- mice MSTN-null
Slide 10: Selectively targeting myostatin is challenging but critical
Selectively targeting myostatin is challenging but critical ▪ 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: Promyostatin Pro-GDF-11 Proactivin ▪ ActRIIB/Activin A/GDF11 KO mice all have per
Slide 11: SRK-439 binds to pro- and latent myostatin and enables muscle growth
SRK-439 binds to pro- and latent myostatin and enables muscle growth SRK-439 Prodomain Mature Prodomain Mature Mature Prodomain Mature Prodomain Mature Mature Promyostatin Latent Myostatin Mature Myostatin ▪ SRK-439 binds to pro- and latent myostatin and blocks the conversion of the latent form to m
Slide 12: SRK-439 is exquisitely selective for pro- and latent-myostatin
SRK-439 is exquisitely selective for pro-and latent-myostatin SRK-439 Specificity 2.5 Hu Latent Myostatin Hu Latent GDF11 2.0 Binding (AU) Hu Latent Activin A Promyostatin Pro-GDF-11 Proactivin 1.5 1.0 0.5 Myostatin GDF-11 Activin A 0.0 0.001 0.01 0.1 1 10 100 1000 ActRIIA/B SRK-439 Hu IgG4 (nM) KD
Slide 13: Therapeutic hypothesis
Therapeutic hypothesis 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 13
Slide 14: Administering SRK-439-mIgG1 to DIO mice during semaglutide treatment and after discontinuation
Administering SRK-439-mIgG1 to DIO mice during semaglutide treatment and after discontinuation 20-week-old 45% HFD SRK-439-mIgG1 or mIgG1 control 10 mg/kg QW Male DIO mice 60% HFD semaglutide or vehicle 0.04 mg/kg QD Day -7 Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 Day 63-64 qNMR
Slide 15: Semaglutide discontinuation caused weight regain
Semaglutide discontinuation caused weight regain Body Weight 50 Chow + IgG 45 HFD + IgG Body Weight (g) HFD + IgG +Sema 40 HFD + 439 + Sema 35 30 25 -7 0 7 14 21 28 35 42 49 56 63 Days in study Sema SRK-439 45% HFD 15
Slide 16: SRK-439 maintained lean mass in combination with semaglutide administration
SRK-439 maintained lean mass in combination with semaglutide administration Absolute Lean Mass 30 Chow + IgG HFD + IgG Lean Mass (g) HFD + IgG +Sema 25 HFD + 439 + Sema 20 -6 0 7 14 21 28 35 42 49 56 63 Days in study Sema SRK-439 45% HFD 16
Slide 17: SRK-439 increased relative lean mass and skeletal muscle weight
SRK-439 increased relative lean mass and skeletal muscle weight Relative Lean Mass Day 63 Gastrocnemius weight ✱✱✱✱ ns ✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ns ✱✱✱ ns ns 80 0.3 Lean Mass/BW (%) 60 Weight (g) 0.2 40 0.1 20 0 0.0 Chow HFD HFD HFD Chow HFD HFD HFD IgG IgG IgG 439 IgG IgG IgG 439 Sema Sema Sema Sema SRK-4
Slide 18: SRK-439 attenuated fat mass regain after discontinuation of semaglutide
SRK-439 attenuated fat mass regain after discontinuation of semaglutide Absolute Fat Mass 20 Chow + IgG HFD + IgG 15 Fat Mass (g) HFD + IgG +Sema 10 HFD + 439 + Sema 5 0 -6 0 7 14 21 28 35 42 49 56 63 Days in study Sema SRK-439 45% HFD 18
Slide 19: SRK-439 treatment improved body composition
SRK-439 treatment improved body composition Relative Fat Mass Day 63 Inguinal Adipose Weight Epididymal Adipose Weight ✱✱ ns ns ✱✱✱ ns ✱ 50 ✱✱✱✱ ns ✱✱ 2.0 1.5 ✱✱✱✱ ns ns ✱✱✱ ns ns Fat Mass/BW (%) 40 1.5 Weight (g) Weight (g) 1.0 30 1.0 20 0.5 10 0.5 0 0.0 0.0 Chow HFD HFD HFD Chow HFD HFD HFD Chow H
Slide 20: SRK-439 improved circulating metabolic biomarkers
SRK-439 improved circulating metabolic biomarkers Fasted Glucose Fasted Insulin Fasted Leptin ✱ ✱ ✱✱ ns ns ✱✱ ✱✱ ns ns ✱✱ ns ns ✱✱✱✱ ns ✱✱ 250 2000 60 Glucose (mg/dL) 200 Insulin (IU/mL) Leptin (ng/mL) 1500 40 150 1000 100 20 500 50 0 0 0 Chow HFD HFD HFD Chow HFD HFD HFD Chow HFD HFD HFD IgG IgG Ig
Slide 21: Summary
Summary ▪ 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-induc
Slide 22: Acknowledgements
Acknowledgements Scholar Rock, Inc. ▪ Co-authors ▪ SRK-439 Program Team ▪ Adam Fogel ▪ Ryan Frieler ▪ Jonathan Hamm ▪ Molly MacLeod ▪ Atsuko Polzin 22
Slide 23: Thank you!
Thank you! 23 S$ ScholarRock
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