Scholar Rock Holding Corporation · NASDAQ:SRRK

Scholar Rock — Investor Presentation (January 2025)

105 slides from Scholar Rock's investor presentation, Jan 13, 2025

1. Slide 1: Deep Insights Advancing Impactful Medicines: Company Overview

   © 2025 Scholar Rock, Inc. All rights reserved. Deep Insights Advancing Impactful Medicines Company Overview | January 2025 Exhibit 99.1

2. Slide 2: Forward-Looking Statements

   © 2024 Scholar Rock, Inc. All rights reserved. Forward-Looking Statements Various statements in this presentation concerning the future expectations, plans and prospects of Scholar Rock Holding Corporation and Scholar Rock, Inc. (collectively, “Scholar Rock”), including without limitation, Scholar R

3. Slide 3: Our Mission

   © 2024 Scholar Rock, Inc. All rights reserved. 3 OUR MISSION To discover, develop, and deliver life-changing therapies by harnessing cutting-edge science to create new possibilities for people living with serious diseases Industry-leading technology, life-changing potential

4. Slide 4: Today's Focus: Moving with a Sense of Urgency

   © 2025 Scholar Rock, Inc. All rights reserved. TODAY’S FOCUS Scholar Rock is Moving with a Sense of Urgency To Bring Transformative Medicines to Patients 4 *Pending regulatory approval. EXPAND Apitegromab Development Program: Building a Pipeline in a Product COMMERCIALIZE Execute a Successful Commer

5. Slide 5: Scholar Rock's Target: Latent Growth Factor

   © 2025 Scholar Rock, Inc. All rights reserved. Scholar Rock’s Target Latent Growth Factor Traditional Target “Mature” Active Growth Factor 5 Scholar Rock Has Succeeded Where Others Have Failed Selectivity Drives Success Targeting the ‘cage’ before growth factor is released allows for exquisite selec

6. Slide 6: Growing Pipeline Across High Value Therapeutic Areas

   © 2025 Scholar Rock, Inc. All rights reserved. 6 Growing Pipeline Across High Value Therapeutic Areas Industry-leading Anti-myostatin Programs *undisclosed indication **UC=urothelial cell carcinoma; RCC=renal cell carcinoma. THERAPEUTIC AREA PRODUCT (target) Discovery/ Preclinical PHASE 1 PHASE 2 PH

7. Slide 7: 2025 Milestones: A Transformative Year for Scholar Rock

   © 2025 Scholar Rock, Inc. All rights reserved. 2025 Milestones: A Transformative Year for Scholar Rock 7 * Pending regulatory approval. Apitegromab is an investigational drug candidate under evaluation and has not been approved by any regulatory agency. • Submit FDA and EMA applications in 1Q 2025 •

8. Slide 8: Delivering on the Mission of Bringing Transformative Medicines to Patients

   © 2025 Scholar Rock, Inc. All rights reserved. 8 Delivering on the Mission of Bringing Transformative Medicines to Patients * Pending approval from regulatory agencies. Apitegromab is an investigational drug candidate under evaluation and has not been approved by any regulatory agency. Leveraging R&

9. Slide 9: Transforming the Treatment of Spinal Muscular Atrophy with Apitegromab

   © 2024 Scholar Rock, Inc. All rights reserved. Transforming the Treatment of Spinal Muscular Atrophy with Muscle-Targeted Therapy Apitegromab

10. Slide 10: Innovating a New Era in the Treatment of Spinal Muscular Atrophy

    © 2024 Scholar Rock, Inc. All rights reserved. Scholar Rock has an industry-leading, highly selective antibody engineering platform that has succeeded where others have failed. Apitegromab is the first and only muscle targeted therapy to show clinically meaningful and statistically significant funct

11. Slide 11: Hallmarks of SMA

    © 2024 Scholar Rock, Inc. All rights reserved. 11 Hallmarks of SMA Motor Neuron Loss and Muscle Atrophy Leads to Progressive Muscle Weakness SMA=Spinal muscular atrophy; SMN=Survival motor neuron. 1. Hua Y, et al. Nature. 2011;478(7367):123-6. 2. Figure adapted from: SMA Foundation Overview. http://

12. Slide 12: SMA Leads to Deterioration in Essential Muscle Function

    © 2024 Scholar Rock, Inc. All rights reserved. SMA Leads to Deterioration in Essential Muscle Function Quotes are from patient advocates who participated in 2022 Cure SMA FDA Patient-Led Listening Session and not from the pictured individuals. Summary of the listening session can be found on the FDA

13. Slide 13: SMA Today: More Patients Screened and Treated

    © 2024 Scholar Rock, Inc. All rights reserved. 13 SMA Today: More Patients Screened and Treated CHF=Swiss franc; LTM=last twelve months; SMA=Spinal muscular atrophy; SMN=Survival motor neuron; WW=worldwide. 1. Cure SMA 2022 Report: 9042022_State-of-SMA_vweb.pdf (curesma.org) 2. Lally et al. Indirect

14. Slide 14: Muscle-Targeted Therapy: A New Treatment Frontier

    © 2024 Scholar Rock, Inc. All rights reserved. 14 Muscle-Targeted Therapy: A New Treatment Frontier *Percentages represent percent of patients who named these unmet needs when asked, “What are your most significant current unmet needs that you hope new therapies would address?” HFMSE=Hammersmith Fun

15. Slide 15: HFMSE Appears to Plateau After Initial Gains

    © 2024 Scholar Rock, Inc. All rights reserved. -2 -1 0 1 2 3 4 Motor Function With SMN Therapies as Assessed by HFMSE HFMSE appears to Plateau After Initial Gains 15 1. Mercuri E, et al. Presented at: World Muscle Society Congress 2020, P. 257 2. Oskoui M, et al. Presented at: 2021 Muscular Dystroph

16. Slide 16: Apitegromab: Potential to Transform the Standard of Care in SMA

    © 2025 Scholar Rock, Inc. All rights reserved. Apitegromab: Potential to Transform the Standard of Care in SMA Finkel RS et al. “Final Safety and Efficacy Data From the SHINE Study in Participants With Infantile-Onset and Later-Onset SMA.” Presented at Cure SMA Annual Conference, July 2024 *Patient

17. Slide 17: Apitegromab Offers Significant Potential to Address Unmet Needs

    © 2024 Scholar Rock, Inc. All rights reserved. 17 Apitegromab Offers Significant Potential to Address Unmet Needs * Based on Animal Model Data; 1. Long KK, et al. Hum Mol Genet. 2019;28(7):1077-1088; 2. Pirruccello-Straub M, et al. Sci Reports. 2018;8(1):2292. doi:10.1038/s41598-018-20524-9 3. Figur

18. Slide 18: $2B+ Global Opportunity for Apitegromab in SMA

    © 2025 Scholar Rock, Inc. All rights reserved. $2B+ Global Opportunity for Apitegromab in SMA ~$4.5B1 Global revenue for three SMN-targeted therapies Apitegromab global revenue potential >$2.0B2 Apitegromab global revenue potential $2B+2 1st And only muscle-targeted treatment to show clinical benefi

19. Slide 19: SMA is a Defined Market and Optimal For Apitegromab Launch

    © 2025 Scholar Rock, Inc. All rights reserved. SMA is a Defined Market and Optimal For Apitegromab Launch Patients are diagnosed and treated, but still need more Patients Identified and Treated ~25K patients in US and EU 100% US newborn screening 2/3 of US patients on treatment Patient, HCP, and pay

20. Slide 20: Preparing for a Successful Launch

    © 2025 Scholar Rock, Inc. All rights reserved. Preparing for a Successful Launch Delivering Apitegromab Customer Engagement Commercial launch supply secured Rare disease distribution partners selected Home infusion at launch Account team with average 30 years experience engaging with US commercial a

21. Slide 21: SMA is Only the Beginning: Additional Neuromuscular Diseases

    © 2025 Scholar Rock, Inc. All rights reserved. SMA is Only the Beginning: Creating Possibilities with Apitegromab in Additional Neuromuscular Diseases *Numbers represent prevalence in the US and Europe based on internal market research. SM=Spinal Muscular Atrophy; ALS=Amyotrophic Lateral Sclerosis;

22. Slide 22: Apitegromab is the Foundation of a Future Neuromuscular Franchise

    © 2025 Scholar Rock, Inc. All rights reserved. Apitegromab is the Foundation of a Future Multi-Billion Dollar Neuromuscular Franchise* *Subject to regulatory approval. Commercial Launch* Global expansion, starting with Europe SMA expansion with Ph 2 OPAL trial for patients under 2 and subcutaneous f

23. Slide 23: Positive Topline Results from Pivotal Phase 3 SAPPHIRE Trial

    © 2025 Scholar Rock, Inc. All rights reserved. Positive Topline Results from Pivotal Phase 3 SAPPHIRE Trial of Apitegromab SMA

24. Slide 24: The Only Muscle-Targeted Therapy with Clinical Success in SMA

    © 2025 Scholar Rock, Inc. All rights reserved. SELECTIVITY DRIVES SUCCESS The Only Muscle-Targeted Therapy with Clinical Success in SMA 24 * Based on apitegromab combined dose (10 mg/kg and 20 mg/kg) + SOC versus placebo + SOC (Hochberg multiplicity adjustment). † 12.5% of patients on placebo + SOC

25. Slide 25: SAPPHIRE Trial Designed for Clinical Success

    © 2024 Scholar Rock, Inc. All rights reserved. SAPPHIRE Trial Designed for Clinical Success 25 Randomized, double-blind, placebo-controlled, parallel arm design (n=204) Enrolling patients who are on SMN-directed therapy (nusinersen or risdiplam) Completed enrollment in Q3 2023 TREATMENT (52 weeks) A

26. Slide 26: SAPPHIRE Patient Disposition

    © 2024 Scholar Rock, Inc. All rights reserved. 26 *1 patient from 2-12 age group opted not to enroll in the ONYX study. † 1 subject (1%) in the 20 mg/kg apitegromab arm in the 2-12 age group withdrew consent. 1 subject (3%) in the 20 mg/kg apitegromab arm in the 13-21 age group withdrew consent. Nei

27. Slide 27: Baseline Demographics and Disease Characteristics Well Balanced

    © 2024 Scholar Rock, Inc. All rights reserved. 27 Baseline Demographics and Disease Characteristics Well Balanced Max=Maximum; Min=Minimum; SD=standard deviation; SMN=Survival Motor Neuron; SMA=Spinal Muscular Atrophy, SOC=standard of care. SAPPHIRE – APITEGROMAB IN SMA Ages 2-12 Ages 13-21 Placebo

28. Slide 28: Prespecified Statistical Analysis Plan

    © 2024 Scholar Rock, Inc. All rights reserved. 28 Prespecified Statistical Analysis Plan SAPPHIRE – APITEGROMAB IN SMA Apitegromab (20 mg/kg) + SOC Apitegromab (10 mg/kg) + SOC Placebo + SOC R 1:1:1 • Prespecified analyses to assess dose: combined apitegromab doses (10 mg/kg + 20 mg/kg), 20 mg/kg, a

29. Slide 29: Clinically Meaningful and Statistically Significant Improvement in HFMSE

    © 2024 Scholar Rock, Inc. All rights reserved. 29 *Hochberg method prespecified for multiplicity adjustment; **nominal p value HFMSE=Hammersmith Functional Motor Scale Expanded. Analysis n Results (vs Placebo, n=50) Unadjusted P-value Apitegromab 10+20 mg/kg combined 106 1.8 0.0192* Apitegromab 20 m

30. Slide 30: Improvement in HFMSE Consistent Across Doses and Age Groups

    © 2024 Scholar Rock, Inc. All rights reserved. -5 -4 -3 -2 -1 0 1 2 3 4 5 30 Improvement in HFMSE Consistent Across Doses and Age Groups SAPPHIRE – APITEGROMAB IN SMA LS Mean Difference (95% CI) [Active-Placebo] 2-12 years apitegromab combined dose (10 & 20 mg/kg; n=106) vs. placebo (n=50) 1.8 (0.30

31. Slide 31: Early and Increasing HFMSE Improvement vs. Placebo

    © 2024 Scholar Rock, Inc. All rights reserved. 31 CI=Confidence Interval; EXP=Exploration Subpopulation; HFMSE=Hammersmith Functional Motor Scale Expanded; LS=Least Squares; MEP=Main Efficacy Population; SOC=standard of care. SAPPHIRE – APITEGROMAB IN SMA Early and Increasing HFMSE Improvement vs. P

32. Slide 32: 30% of Apitegromab Patients Achieved ≥3 Points on HFMSE

    © 2024 Scholar Rock, Inc. All rights reserved. 32 30% of Apitegromab Patients Achieved ≥3 Points on HFMSE HFMSE=Hammersmith Functional Motor Scale Expanded; SOC=standard of care. SAPPHIRE – APITEGROMAB IN SMA ≥3 Point Improvement in HFMSE 30.4% 12.5% 0% 5% 10% 15% 20% 25% 30% 35% Apitegromab Combine

33. Slide 33: Well-Tolerated Safety Consistent With Established Profile

    © 2024 Scholar Rock, Inc. All rights reserved. 33 Well-Tolerated Safety Consistent With Established Profile AE=Adverse Event; SAE= serious adverse event; SOC=standard of care; SMN=survival motor neuron; ADA=anti-drug antibodies; all AEs are coded using the MedDRA version 26.1. Summary of Adverse Eve

34. Slide 34: Total Latent Myostatin Levels Over Time

    © 2024 Scholar Rock, Inc. All rights reserved. 34 Total Latent Myostatin Levels Over Time MEP=main efficacy population; SD=standard deviation. • Robust and sustained target engagement were observed following apitegromab dosing • Similar levels of target engagement were observed for 10 mg/kg and 20 m

35. Slide 35: Potential to Transform Standard of Care in SMA

    © 2024 Scholar Rock, Inc. All rights reserved. 35 Potential to Transform Standard of Care in SMA 1.8-point improvement in HFMSE (p=0.0192) compared to placebo Patients improving on apitegromab vs. declining on placebo Favorable safety profile supports durability of treatment >48 months treatment exp

36. Slide 36: Expanding our Impact: Initiating Phase 2 OPAL Trial in mid-2025

    © 2025 Scholar Rock, Inc. All rights reserved. 36 Expanding our Impact: Initiating Phase 2 OPAL Trial in mid-2025 Studying apitegromab in patients under 2 years old Potential to alter the course of SMA in a broad population CHANGING More Lives Reaching patients earlier in their treatment journey TIM

37. Slide 37: Next Horizon in Antimyostatin Therapies: Cardiometabolic Disorders

    © 2025 Scholar Rock, Inc. All rights reserved. Next Horizon in Antimyostatin Therapies: Cardiometabolic Disorders

38. Slide 38: Differentiated Expertise Developing Muscle-Targeted Therapies

    © 2024 Scholar Rock, Inc. All rights reserved. Differentiated Expertise Developing Muscle-Targeted Therapies 38 Next Frontier in Antimyostatin Leveraging Our R&D Platform to Expand into Cardiometabolic Disorders Pioneered unique approach to develop antibodies that bind to pro-and latent forms of myo

39. Slide 39: GLP-1 RAs are Transforming Weight Loss for Millions of People

    © 2025 Scholar Rock, Inc. All rights reserved. GLP-1 RAs are Transforming Weight Loss for Millions of People Source: UBS Bank, GLP-1: A medication worth $126 billion in sales by 2029? https://www.ubs.com/global/en/investment-bank/insights-and-data/2024/glp-1-a-medication.html. GLP-1 RA=GLP-1 recepto

40. Slide 40: However, Patients Want Healthier Weight Loss

    © 2025 Scholar Rock, Inc. All rights reserved. However, Patients Want Healthier Weight Loss* *Source: Scholar Rock market research, completed December 2024. GLP-1 RA=GLP-1 receptor agonist. WEAKNESS is a Concern Patients complain of reduced strength after GLP-1 RA treatment Patients hope for a combi

41. Slide 41: Maintaining Muscle is Important for Healthy Weight Loss

    © 2024 Scholar Rock, Inc. All rights reserved. 41 Maintaining Muscle is Important for Healthy Weight Loss GLP-1 RA=Glucagon-like peptide-1 receptor agonist. 1. Aristizabal JC, Freidenreich DJ, Volk BM, et al. Effect of resistance training on resting metabolic rate and its estimation by a dual-energy

42. Slide 42: Potential to Optimize Benefit-Risk with Myostatin Selectivity

    © 2025 Scholar Rock, Inc. All rights reserved. Signaling receptor shared by Myostatin, GDF-11 & Activin A 42 Potential to Optimize Benefit-Risk with Myostatin Selectivity Promyostatin Pro-GDF-11 Proactivin GDF-11 Activin A ActRIIA/B Apitegromab SRK-439 Other Approaches • GI problems, e.g., diarrhea,

43. Slide 43: Why We Are Confident in SRK-439

    © 2024 Scholar Rock, Inc. All rights reserved. Why We Are Confident in SRK-439 43 • A new anti-myostatin specifically suited for obesity • Targets pro and latent forms of myostatin designed to minimize undesirable off-target effects • Preclinical data demonstrated favorable muscle mass preservation

44. Slide 44: SRK-439 Selectively Binds Latent Myostatin

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-439 Selectively Binds Latent Myostatin Scholar Rock’s Target: Latent Myostatin SRK-439: Exquisite Selectivity for Myostatin 44 • Increasing SRK-439 concentrations lead to increased signal of binding to myostatin with no signal observed for GDF-11 or

45. Slide 45: Strong Scientific Validation and Promising Preclinical Evidence

    © 2025 Scholar Rock, Inc. All rights reserved. 45 GLP-1 RA: GLP-1 receptor agonist. Preclinical data to date show strong potential to support healthier weight loss in combination with GLP-1 RAs: Preservation of lean mass Improvement in metabolic parameters Increase in lean mass and attenuation of fa

46. Slide 46: SRK-439: Potential for Healthier Weight Loss Management with GLP-1 RA

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-439: Potential for Healthier Weight Loss Management in Combination with GLP-1 RA 46 • Considerable lean mass loss with semaglutide treatment • Combination with SRK-439 led to dose-dependent lean mass preservation ‒ Effects seen with doses as low as

47. Slide 47: SRK-439 Increased Lean Mass and Attenuated Regain of Fat Mass

    © 2024 Scholar Rock, Inc. All rights reserved. 47 SRK-439 Increased Lean Mass and Attenuated Regain of Fat Mass After GLP-1 RA Withdrawal in Obesity Mouse Model Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 GLP-1 RA: GLP1 receptor agonist. Day 7 is s

48. Slide 48: SRK-439 Improved Body Composition After GLP-1 RA Withdrawal

    © 2024 Scholar Rock, Inc. All rights reserved. 48 SRK-439 Improved Body Composition After GLP 1-RA Withdrawal Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 GLP-1 RA: GLP1 receptor agonist. HFD: High Fat Diet • SRK-439 attenuates regain of fat mass af

49. Slide 49: SRK-439: Further Improvement of Metabolic Health

    © 2024 Scholar Rock, Inc. All rights reserved. ! "! #!! #"! A!! A"! %C'(FG+ -KL012L 34RLST24280 98 -:;098< =>K?S;2 98 %24:<>K09@2AL2:02@ B894:>; - : ; 098 < =>K ? S ; 2 C4 <a@ Ec !d# !dG # G eS80LS> I %24: eS80LS> %C'(FG+ AL2:04280 ! ! ! SRK-439: Further Improvement of Metabolic Health 49 Key Observ

50. Slide 50: SRK-439 Is More Potent than Anti-ActRII Antibody

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-439 Is More Potent than Anti-ActRII Antibody at Maintaining Lean Mass During GLP-1 RA-Induced Weight Loss 50 LOW EFFICACIOUS DOSE AND COMPETITIVE PROFILE Head-to-Head Comparison to Non-Selective Myostatin Inhibitor in DIO Mouse Model !"# !$% !$# !%

51. Slide 51: SRK-439 with Metformin Increased Lean Mass (Young Mice)

    © 2024 Scholar Rock, Inc. All rights reserved. LOW EFFICACIOUS DOSE AND COMPETITIVE PROFILE SRK-439: Selective Inhibition of Myostatin in Combination with Metformin Increased Lean Mass 51 Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 OBESITY Lean and

52. Slide 52: SRK-439 with Metformin Increased Lean Mass (Older Mice)

    © 2024 Scholar Rock, Inc. All rights reserved. LOW EFFICACIOUS DOSE AND COMPETITIVE PROFILE SRK-439: Selective Inhibition of Myostatin in Combination with Metformin Increased Lean Mass Study conducted in Diet Induced Obesity (DIO) mouse model utilizing a murine chimera of SRK-439 OBESITY 52 • Older

53. Slide 53: SRK-439 Protects from Tirzepatide-Induced Muscle Loss in DIO Mice

    © 2025 Scholar Rock, Inc. All rights reserved. SRK-439 Protects from Tirzepatide-Induced Muscle Loss in DIO Mice qNMR % Lean Mass Change from Baseline Key Observations • Considerable lean mass loss with tirzepatide treatment • Combination with SRK-439 led to dose-dependent lean mass preservation • L

54. Slide 54: SRK-439: Best in Class Potential

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-439: Best in Class Potential 54 SRK-439 ActRII Ab Ligand Trap Adnectin Selectivity for myostatin Action limited to muscle Combination GLP-1 RA data in obesity preclinical models1-3 Low efficacious dose in preclinical obesity models1-3 Lower risk of

55. Slide 55: Industry-Leading Anti-Myostatin Platform: Advancing the Obesity Program

    © 2025 Scholar Rock, Inc. All rights reserved. 55 Industry-Leading Anti-Myostatin Platform: Leveraging Apitegromab’s Success to Advance the Obesity Program *Expected timelines POC=Proof of Concept; GLP-1 RA=GLP-1 receptor agonist. POC data readout Q2* Ph 2 proof-of-concept trial APITEGROMAB + tirzep

56. Slide 56: Phase 2 Proof-of-Concept Study of Apitegromab in Obesity

    © 2025 Scholar Rock, Inc. All rights reserved. 56 Data from Phase 2 Proof-of-Concept Study of Apitegromab in Obesity Expected Q2 2025 *Due to expedited enrollment and timing of semaglutide clinical supply, all enrolled patients received tirzepatide. Apitegromab dose regimen will be 10 mg/kg Q4W, bas

57. Slide 57: Goals of the EMBRAZE Proof-of-Concept Study

    © 2025 Scholar Rock, Inc. All rights reserved. Goals of the EMBRAZE Proof-of-Concept Study Initiated trial in May 2024, ahead of target timeline Enrollment completed in September 2024 Topline data expected in Q2 2025 57 INSIGHTS GAINED FROM EMBRAZE STUDY to inform SRK-439 development Study Aims to D

58. Slide 58: Tirzepatide-Induced Weight Loss Accompanies Significant Muscle Loss

    © 2025 Scholar Rock, Inc. All rights reserved. Tirzepatide-Induced Weight Loss Accompanies Significant Muscle Loss Figure from Jastreboff, A.M. et al. N Engl J Med. 2022;387(3):205-216. * Data from Phase 3 clinical trial of tirzepatide in adults with obesity. Tirzepatide DECREASE in lean mass of 10.

59. Slide 59: FDA Guidelines Added Clinical Benefit Regulatory Pathway

    © 2024 Scholar Rock, Inc. All rights reserved. FDA Guidelines Added Clinical Benefit 59 Regulatory Pathway CARDIOMETABOLIC DEVELOPMENT PROGRAM *Clinical Outcome Assessment: Frequently Asked Questions: https://www.fda.gov/about-fda/clinical-outcome-assessment-coa-frequently-asked-questions#Considerat

60. Slide 60: SRK-439: The Right Molecule for Healthy Weight Loss

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-439: The Right Molecule for Healthy Weight Loss 60 IN SUMMARY g Highly selective approach g Targets muscle g Efficacy without potential liabilities of non-selective approaches g Designed for subcutaneous low frequency dosing with robust subcutaneous

61. Slide 61: Fibrosis

    © 2025 Scholar Rock, Inc. All rights reserved. Fibrosis

62. Slide 62: TGFβ is Established as Key Driver of Fibrosis

    © 2024 Scholar Rock, Inc. All rights reserved. TGFβ is Established as Key Driver of Fibrosis Across Multiple Diseases 62 Nature Reviews , April 25, 2016 NATURE REVIEWS | NEPHROLOGY TGF-β: the master regulator of fibrosis Xiao-ming Meng1, David J. Nikolic-Paterson2 and Hui Yao Lan3 Nature Reviews. Au

63. Slide 63: Targeting Latent TGFβ-1 Complexes Creates Multiple Handles for Selectivity

    © 2024 Scholar Rock, Inc. All rights reserved. GARP Presents TGFβ on Tregs LRRC33 Presents TGFβ on Macrophages LTBP1 & 3 Present TGFβ in Connective Tissue Targeting Presenting Molecule/TGFβ-1 Complexes Provides Context Specificity Targeting Latent TGFβ-1 Complexes Creates Multiple “Handles” For Sele

64. Slide 64: LTBP-49247 Reduced TGFβ Signaling and Fibrosis in Kidney Models

    © 2024 Scholar Rock, Inc. All rights reserved. LTBP-49247 Reduced TGFβ Signaling and Fibrosis in Preclinical Models of Kidney Fibrosis 64 !" !" !" " # $ ! % & ' ! # $ % & ' ( ) * +,-./ !"# $%&G() +H 5678 -.I01G23G4 ()*+) !! LTBP-49247 reduced a TGFβ PD biomarker in kidneys of Col4a3 KO mice (Alport

65. Slide 65: Opportunities Across Multiple Fibrotic Indications

    © 2024 Scholar Rock, Inc. All rights reserved. Significant Opportunities to Address High Unmet Need Across Multiple Fibrotic Indications 65 Alport Syndrome (AS) Focal Segmental Glomerulosclerosis (FSGS) IgA Nephropathy (IgAN) Primary Sclerosing Cholangitis (PSC) Diffuse Cutaneous Systemic Sclerosis

66. Slide 66: Upcoming Planned Key Milestones

    © 2024 Scholar Rock, Inc. All rights reserved. 66 Upcoming Planned Key Milestones * If approved by relevant health authorities • Submit FDA and EMA applications in Q1 2025 • Request priority review (FDA) and accelerated assessment (EMA) Apitegromab Regulatory Submissions • US launch in Q4 2025 and E

67. Slide 67: Appendix

    Appendix 8... SSS ea

68. Slide 68: Summary of TOPAZ Data

    © 2024 Scholar Rock, Inc. All rights reserved. Substantial and Sustained Improvement over 48 MONTHS1 1- A total of 11 patients in the population had scoliosis surgery during the study and their data was excluded from any HFMSE and RULM assessments at 48 months. PRO=Patient Reported Outcome *Pooled n

69. Slide 69: TOPAZ: Motor Function Outcomes by HFMSE Over 48 Months

    © 2024 Scholar Rock, Inc. All rights reserved. 3.4 4.6 5.2 4.8 6.4 0 1 2 3 4 5 6 7 8 9 Baseline 6 months 12 months 24 months 36 months 48 months Apitegromab TOPAZ Clinical Trial: Motor Function Outcomes by HFMSE Over 48 Months Improvements Were Substantial and Sustained 1. For the 48-month evaluatio

70. Slide 70: TOPAZ: Motor Function Outcomes by RULM Over 48 Months

    © 2024 Scholar Rock, Inc. All rights reserved. 0.2 1.2 2.2 2.8 4.5 0 1 2 3 4 5 6 Baseline 6 Months 12 Months 24 Months 36 Months 48 Months 0.6 1.3 2.3 2.4 3.6 0 1 2 3 4 5 6 Baseline 6 Months 12 Months 24 Months 36 Months 48 Months Apitegromab TOPAZ Clinical Trial: Motor Function Outcomes by RULM Ove

71. Slide 71: SAPPHIRE Design is Optimized by Insights from TOPAZ

    © 2024 Scholar Rock, Inc. All rights reserved. 71 SAPPHIRE Phase 3 Design is Optimized by Insights from TOPAZ HFMSE=Hammersmith Functional Motor Scale Expanded. Substantial HFMSE gains observed in the nonambulatory Type 2/3 SMA cohorts Exploratory age 2-12 analysis in nonambulatory Type 2/3 showed t

72. Slide 72: SRK-181: Backbone for a New Era of Cancer Immunotherapy

    © 2025 Scholar Rock, Inc. All rights reserved. SRK-181: Potential Transformative Backbone for a New Era of Cancer Immunotherapy

73. Slide 73: Resistance to Checkpoint Inhibitor Therapies Remains a Clinical Challenge

    © 2024 Scholar Rock, Inc. All rights reserved. Resistance to Checkpoint Inhibitor (CPI) Therapies Remains a Significant Clinical Challenge 73 1. Source: Gores, M. (2022). In the eye of the storm: PD-(L)1 inhibitors weathering turbulence [White paper]. IQVIA. https://www.iqvia.com/library/white-paper

74. Slide 74: Scientific Rationale for TGFβ Inhibition in Immuno-Oncology

    © 2024 Scholar Rock, Inc. All rights reserved. Strong Scientific Rationale for the Role of TGFβ Inhibition in Immuno-Oncology 74 “Bristol Myers Squibb Enters Agreement to Acquire Forbius TGF-beta Program” August 2022. “Merck to Acquire Tilos Therapeutics: Merck Gains Portfolio of Investigational Ant

75. Slide 75: SRK-181: Latent TGFβ-1 Selective Approach

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181: Unique Latent TGFβ-1 Selective Approach Designed to Overcome Checkpoint Inhibitor Resistance 75 Traditional Target “Mature” growth factor 1. Wakefield LM, Winokur TS, Hollands RS, Christopherson K, Levinson AD, Sporn MB. Recombinant latent tran

76. Slide 76: SRK-181-mIgG1 + Anti-PD1 Overcomes Immune Exclusion

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181-mIgG1 + Anti-PD1 Overcomes Immune Exclusion 76 Anti-PD1 Anti-PD1/ SRK-181-mIgG1 Overcoming immune exclusion Tumor micro-environment Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med. 2020 Mar 25;12(53

77. Slide 77: Phase 1 Clinical Trial Overview

    © 2024 Scholar Rock, Inc. All rights reserved. Phase 1 Clinical Trial Overview *Cohort Any Other was terminated early and HNSCC was added. ADA, anti drug antibody; BOR, best overall response; ccRCC, clear cell renal cell carcinoma; DCR, disease control rate; DoR, duration of response; ECOG, eastern

78. Slide 78: SRK-181 with Anti-PD1 Increases CD8+ T Cell Infiltration in Melanoma

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181 in Combination with Anti-PD1 Increases Infiltration of CD8+ T Cells in Melanoma 78 • Paired biopsies from 2 melanoma patients were analyzed for CD8 content. • An increase in CD8+ T cell infiltration was observed in both biopsy pairs, overcoming

79. Slide 79: Preliminary Safety and Efficacy: Dose Escalation

    © 2024 Scholar Rock, Inc. All rights reserved. Preliminary Safety and Efficacy Phase 1 Dose Escalation Phase 79 Part A1 (n=19) Part A2 (n=15) • SRK-181 was well tolerated: No DLTs observed; no Grade 4 or 5 treatment-related AEs Safety Efficacy • Part A1, Single-Agent Dose Escalation Ø All 3 ovarian

80. Slide 80: Patient Demographics and Disposition: Dose Expansion

    © 2024 Scholar Rock, Inc. All rights reserved. Patient Demographics and Disposition Phase 1 Dose Expansion Phase 80 Category All# N 78 Age, median (range) 65y (32-81y) Gender, M, n (%) 56 (71.8) Prior Lines of Therapy, median (range) 3 (1-9) Number of Lines of Prior Anti-PD-(L)1, n (%) 1 2 3 4 48 (6

81. Slide 81: Manageable Safety Profile: Dose Expansion

    © 2024 Scholar Rock, Inc. All rights reserved. Manageable Safety Profile Phase 1 Dose Expansion Phase 81 Treatment-Emergent AEs Related to SRK-181 or Anti-PD(L)1 Adverse Event All Grades (>5%) N=78 ≥Grade 3 N= 78 Rash# 25 (32.1%)* 10 (12.8%)* Pruritus 20 (25.6%)* 1 (1.3%)* Fatigue 16 (20.5%) 1 (1.3%

82. Slide 82: Efficacy in Cohort ccRCC

    © 2024 Scholar Rock, Inc. All rights reserved. Efficacy in Cohort ccRCC Clinical Responses in Heavily Pre-treated and Anti-PD-1 Resistant Patients Efficacy Intent To Treat N=30 ORR 7 (23.3%) Confirmed PR 6 (20%) mDoR (Months) 7.7+ (2.5+, 20.9+) DCR 17 (56.7%) • IMDC score: intermediate 67%; poor 30%

83. Slide 83: Proof of Mechanism: Proinflammatory Microenvironment

    © 2024 Scholar Rock, Inc. All rights reserved. Proof of Mechanism SRK-181 and Pembrolizumab Treatment Creates a Proinflammatory Microenvironment 83 • SRK-181 and pembrolizumab increase CD8+ T-cells infiltration into tumors across multiple tumor types • CD8+ T-cell were activated (CD8+GrmB+) in respo

84. Slide 84: Biomarker Data May Inform Patient Selection Strategy

    © 2024 Scholar Rock, Inc. All rights reserved. Biomarker Data May Inform Patient Selection Strategy Baseline CD8+ T-cell Infiltration Status and Baseline Treg Levels Suggest a Higher Chance of Clinical Response 84 • Baseline data was available from 14 patients and 10 were infiltrated • If enrollment

85. Slide 85: SRK-181 Summary

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181 Summary PD-1=Programmed cell death ligand 1; TGFβ=Transforming growth factor-beta; ccRCC=Clear cell renal cell carcinoma. 1.Sumanta Kumar Pal et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carc

86. Slide 86: DRAGON Phase 1 POC Trial Design

    © 2024 Scholar Rock, Inc. All rights reserved. DRAGON Phase 1 POC Trial to Evaluate SRK-181’s Ability to Overcome Primary Resistance to Checkpoint Inhibitors 86 * A cohort of 2000 mg Q2W (n=3) was also evaluated. **The clear cell RCC and HNSCC cohorts will also explore the effects of SRK-181 in pati

87. Slide 87: DRAGON Part A: Safety

    © 2024 Scholar Rock, Inc. All rights reserved. DRAGON Part A: Safety PART A1 Monotherapy Treatment-Emergent AEs Related to SRK-181, All Grades >10% PART A2 Combination Treatment Treatment-Emergent AEs Related to SRK-181 or Anti-PD(L)1, All Grades >10% Dose (MG) 80 N=1 240 N=1 800 N=3 1600 N=4 2400 N

88. Slide 88: DRAGON Part A: Preliminary Efficacy Data

    © 2024 Scholar Rock, Inc. All rights reserved. Duration of Treatment DRAGON Part A: Preliminary Efficacy Data* 88 Part A1 (n=19) Part A2 (n=15) 8 patients had a best response of stable disease (SD) All 3 patients with ovarian cancer were stable for 6-10 months Yap T et al. Safety and Efficacy Result

89. Slide 89: Mechanism of Action: SRK-181 Overcomes CPI Resistance

    © 2024 Scholar Rock, Inc. All rights reserved. Mechanism of Action SRK-181, a Selective Anti-TGFβ1 Antibody, Overcomes CPIs Resistance 1.Batlle E, et al. Immunity. 2019; 50(4):924-940. CPI, checkpoint inhibitor; GLP, good laboratory practice; MDSC, myeloid derived suppressor cells; TGFβ1, transformi

90. Slide 90: Efficacy in Cohort MEL

    © 2024 Scholar Rock, Inc. All rights reserved. Efficacy in Cohort MEL Clinical Responses in Anti-PD-1 Non-responders 90 Efficacy Intent To Treat N=11 ORR 3 (27.3%) Confirmed CR 1 (9.1%) Confirmed PR 1 (9.1%) mDoR (Months) 4.9 (1.8, 7.1) DCR 8 (72.7%) • Median lines of prior cancer therapy: 3 (range

91. Slide 91: Efficacy in Cohort UC

    © 2024 Scholar Rock, Inc. All rights reserved. Efficacy in Cohort UC Clinical Responses in Anti-PD-1 Non-responders 91 91 Efficacy Intent To Treat N=11 ORR 1 (9.1%) Confirmed PR 1 (9.1%) mDoR (Months) 12.9 (12.9, 12.9) DCR 5 (45.5%) • Median lines of prior cancer therapy: 4 (range 2 – 5) Ø All have

92. Slide 92: Efficacy in Cohort HNSCC

    © 2024 Scholar Rock, Inc. All rights reserved. Efficacy in Cohort HNSCC Clinical Responses in Heavily Pre-treated and Anti-PD-1 Resistant Patients 92 Efficacy Intent To Treat N=11 ORR 2 (18.2%) Confirmed PR 1 (9.1%) mDoR (Months) 2.2+ (0.1, 4.3+) DCR 4 (36.4%) Pt#1: Screening Lung nodule 16 mm Pt#1:

93. Slide 93: SRK-181: Transformative Potential as the Backbone for Cancer Therapy

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181: Transformative Potential as the Backbone For Next Era of Cancer Therapy 93 CPI Combination (solid tumors) Other Combinations (solid tumors) & Hematologic Other immunotherapies Chemotherapy XRT Other applications Myelofibrosis Liquid tumors 1st

94. Slide 94: SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ-1 Inhibitor

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ-1 Inhibitor 94 SRK-181* Bifunctional TGFβ/CPI ALK5 Inhibitor Nonselective TGFβ antibody Selectivity for TGFβ-1: potential for wider therapeutic window and improved safety Ability to com

95. Slide 95: TGFβ-1 Blockade Rendered Preclinical Tumor Models Susceptible to Anti-PD1

    © 2024 Scholar Rock, Inc. All rights reserved. TGFβ-1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1 Therapy 95 Days after treatment initiation Tumor volume (mm3) Anti-PD1/ SRK-181-mIgG1 (3 mg/kg QW) 4/14 Anti-PD1/ SRK-181-mIgG1 (10 mg/kg QW) 8/14 Preclinical d

96. Slide 96: Combination Treatment Led to Melanoma Tumor Regression and Survival Benefit

    © 2024 Scholar Rock, Inc. All rights reserved. SRK-181-mIgG1 Combination Treatment Led to Melanoma Tumor Regression and Survival Benefit 96 *P<0.01. † P<0.05 Log-rank (Mantel-Cox test) vs anti-PD1. * * † Days after treatment initiation Tumor Regression Survival Benefit Anti-PD1 + SRK-181-mlgG1 (30 m

97. Slide 97: Selectivity of SRK-181 Offers Potential to Overcome Toxicity

    © 2024 Scholar Rock, Inc. All rights reserved. Selectivity of SRK-181 Offers Potential to Overcome Toxicity and Dose-limiting Challenges of Non-selective TGFβ Pathway Approaches 97 Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med 2020 Mar 25;12(536): eaa

98. Slide 98: TGFβ-1 as Driver of Primary Resistance to Checkpoint Inhibitors

    © 2024 Scholar Rock, Inc. All rights reserved. Bladder urothelial carcinoma Had & neck squamous carcinoma Kidney clear cell carcinoma Kidney papillary cell carcinoma Liver hepatocellular carcinoma Lung adenocarcinoma Skin cutaneous melanoma Stomach adenocarcinoma Acute myeloid leukemia Adrenocortica

99. Slide 99: Biomarker Strategies Employed in DRAGON Trial

    © 2024 Scholar Rock, Inc. All rights reserved. Biomarker Strategies Employed in DRAGON Trial 99 Multiple tissue-based and circulating biomarker analyses to be evaluated in DRAGON study • Higher resolution histochemical characterization of tumor immune contexture (e.g. CD8+) ⎼ Classification of infla

100. Slide 100: Clear Evidence of Target Engagement

     © 2024 Scholar Rock, Inc. All rights reserved. Clear Evidence of Target Engagement Pharmacodynamic Biomarker Results for Part A: Circulatory TGFβ-1 100 Yap T et al. SRK-181, a latent TGFβ1 inhibitor: safety, efficacy, and biomarker results from the dose escalation portion of a phase I trial (DRAGON

101. Slide 101: Preclinical Rationale to Evaluate Peripheral Samples for SRK-181 Activity

     © 2024 Scholar Rock, Inc. All rights reserved. Preclinical Data Provide Scientific Rationale to Evaluate Peripheral Samples for Evidence of SRK-181 Activity 101 MBT-2 bladder tumor model IgG, anti-PD-1 and SRK-181-mIgG1 dosed d1, d7 Analysis on day 10 ! "!! #!!! ! $! %! C! D! ()*+, .+/)*M 1**23 45,S

102. Slide 102: Iron-Restricted Anemia

     © 2024 Scholar Rock, Inc. All rights reserved. Iron-Restricted Anemia

103. Slide 103: BMP6/RGMc Pathway is a Validated Regulator of Systemic Iron Homeostasis

     © 2024 Scholar Rock, Inc. All rights reserved. BMP6/RGMc Pathway is a Well Validated Regulator of Systemic Iron Homeostasis 103 Fig: Muckenthaler, M.U., Rivella, S., Hentze, M.W. and Galy, B. (2017) A Red Carpet for Iron Metaboism. Cell, 168(3): 344-361 1: Kuns-Hashimoto R, et al. (2008) Selective b

104. Slide 104: HJV-35202: Selective Inhibition of HJV/RGMc

     © 2024 Scholar Rock, Inc. All rights reserved. HJV-35202: An Investigational High-Affinity Antibody Demonstrating Selective Inhibition of HJV/RGMc and Robust PK/PD in Cynos 104 !"# !"A !# A #A "AA #%A% '() *+, -.L Potent in vitro binding affinity (KD=3.9E-11) Highly specific to RGMc/HJV with well un

105. Slide 105: Opportunities to Target Iron-Restricted Anemias

     © 2024 Scholar Rock, Inc. All rights reserved. Significant Opportunities to Target Iron-Restricted Anemias Across Multiple Indications 105 Chronic Kidney Disease (CKD) Anemia of Chronic Inflammation (AI) Myelofibrosis (MF) Targeting RGMc/HJV for anemia is well validated and relatively de-risked • Hi

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