Scholar Rock Holding Corporation · NASDAQ:SRRK
Scholar Rock — 40th Annual J.P. Morgan Healthcare Conference 2022
50 slides from Scholar Rock's conference presentation, Jan 10, 2022
Slide 1: Deep Insights Advancing Impactful Medicines
Deep Insights Advancing Impactful Medicines 40th Annual J.P. Morgan Healthcare ConferenceJanuary 10-13, 2022
Slide 2: Disclaimers
Disclaimers Various statements in this presentation concerning the future expectations, plans and prospects of Scholar Rock, Inc. (“Scholar Rock”), including without limitation, Scholar Rock’s expectations regarding its strategy, its product candidate selection and development timing, including timi
Slide 3: Bringing a Revolutionary Approach to Highly Sought-After Growth Factors
3 Bringing a Revolutionary Approach to Highly Sought-AfterGrowth Factors Implicated in Devastating Diseases Scholar Rock’s TargetGrowth Factor Precursor (Latent Form) Scholar Rock’s R&D PlatformTransform Medical Practice Pursue important targets with well-validated biology but are difficult to drugA
Slide 4: Portfolio Spanning All Stages of Discovery and Development
DRAGON Part A: dose escalation and continued follow-up Apitegromab Spinal Muscular Atrophy (SMA) SRK-181Immuno-Oncology and Oncology Preclinical/ Platform SAPPHIRE Phase 3 Trial Portfolio Spanning All Stages of Discovery and Development TOPAZ extension (55 of the 57 patients who completed TOPAZ 12-m
Slide 5: Apitegromab Positioned to be Next Potential Transformative Therapy for Patients with SMA
Apitegromab Positioned to be Next Potential Transformative Therapy for Patients with SMA
Slide 6: Potential to Pioneer a New Treatment Era
6 Potential to Pioneer a New Treatment Era: Opportunity for Muscle-Directed Therapy to Complement SMN Upregulators Phase 3 Trial Design Indication Market Penetration Non-ambulatory Type 2/32-12 years of agePrimary endpoint: Mean change from baseline in HFMSE at 15 months >11,000* patients treated WW
Slide 7: Spinal Muscular Atrophy Overview
7 Spinal Muscular Atrophy Overview Significant, progressive motor function impairment; many lose ambulation Infantile onset; unable to sit upindependently Severe, progressive disabilities and unable to walk independently Type 114% Type 251% Type 335% Global disease with 30,000-35,000 affected in U.S
Slide 8: TOPAZ Top-Line Data Showed Apitegromab's Transformative Potential
8 TOPAZ Top-Line Data Showed Apitegromab’sTransformative Potential in Patients with Type 2/3 SMA ✔ Apitegromab led to HFMSE improvements in both non-ambulatory cohorts (including patients started on nusinersen at age > 5) * Pooled cohorts of non-ambulatory patients treated with apitegromab 20 mg/kg
Slide 9: SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ
SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ 9 TOPAZ Learnings SAPPHIRE Design Elements Largest HFMSE gains observed in the non- ambulatory Type 2/3 SMA cohorts Study population: Non-ambulatory Type 2/3 SMAPrimary efficacy endpoint: HFMSE Exploratory age 2-12 analysis in non-ambulatory T
Slide 10: SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ
SAPPHIRE Phase 3 Design Optimized by Insights from TOPAZ 10 TOPAZ Learnings SAPPHIRE Design Elements Largest HFMSE gains observed in the non- ambulatory Type 2/3 SMA cohorts Study population: Non-ambulatory Type 2/3 SMAPrimary efficacy endpoint: HFMSE Exploratory age 2-12 analysis in non-ambulatory
Slide 11: SAPPHIRE (Phase 3) Trial Overview
SAPPHIRE (Phase 3) Trial Overview Apitegromab (20 mg/kg IV q4w) + SMN upregulator N = 5252 weeks treatmentRandomized, double-blind, placebo-controlled, parallel arm designAdd-on to background SMN therapy (enrolling patients on nusinersen as well as patients on risdiplam)Primary efficacy endpoint: me
Slide 12: Additional Therapeutic Opportunities May Be Pursued With Separate Development Strategies
Additional Therapeutic Opportunities May Be Pursued With Separate Development Strategies Global disease with 30,000-35,000 affected inU.S. and Europe alone A Ambulatory patients Smaller population but high unmet need as benefits of SMN regulators not well-establishedTOPAZ suggests potential clinical
Slide 13: SRK-181: Potential Transformative Backbone for a New Era of Cancer Immunotherapy
SRK-181: Potential Transformative Backbone for a New Era ofCancer Immunotherapy
Slide 14: SRK-181: Unique TGFβ1-Selective Approach to Overcoming Checkpoint Inhibitor Resistance
SRK-181: Unique TGFβ1-Selective Approach to OvercomingCheckpoint Inhibitor Resistance 14 Scholar Rock’s TargetSRK-181: Latent TGFβ1 InhibitorInhibits TGFβ1 pathway - implicated in CPI resistanceHighly selective targeting - avoids inhibiting latent TGFβ2 and TGFβ3 isoformsAimed at increasing therapeu
Slide 15: SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ1 Inhibitor
SRK-181 Therapeutic Hypothesis: Potential Advantages of Latent TGFβ1 Inhibitor 15 SRK-181* BifunctionalTGFβ/CPI ALK5Inhibitor NonselectiveTGFβ antibody Selectivity for TGFβ1: potential for widertherapeutic window and improved safety ✔ X X X Ability to combine with any anti-PD-(L)1 ✔ X ✔ ✔ Ability to
Slide 16: TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1
16 TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1 Therapy Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med. 2020 Mar 25;12(536):eaay8456. https://scholarrock.com/platform/publications. Anti-PD1/SRK-181-mIgG1(1
Slide 17: TGFβ1 Isoform Specificity of SRK-181 Improved Preclinical Toxicity Profile
TGFβ1 Isoform Specificity of SRK-181 Improved Preclinical Toxicity Profile Preclinical data published in Science Translational Medicine. Martin CJ, et al. Sci Transl Med 2020 Mar 25;12(536): eaay8456.*Source: Anderton MJ, et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Tox
Slide 18: DRAGON Phase 1 POC Trial Design
DRAGON Phase 1 POC Trial to Evaluate SRK-181’s Abilityto Overcome Primary Resistance to Checkpoint Inhibitors Note: In Part A, SRK-181 is administered q3w, with the exception of a 2000 mg q2w cohort in Part A1. In Part B, SRK-181 is administered at 1500 mg q3w for combination with anti-PD-(L)1 thera
Slide 19: DRAGON Part A: Preliminary Anti-Tumor Effects
DRAGON Part A: Preliminary Anti-Tumor Effects* 19 Part A1 (n=19)8 patients had best response of stable disease (SD)3 ovarian cancer patients had best response of SD, with tumor regressions in 2 of these individualsPart A2 (n=10)At 800 mg q3w, 1 partial response (PR) was observed in patient with anti
Slide 20: DRAGON Has Advanced to Part B to Test Proof of Concept
Part B dose selected based upon Part A data & PK modeling: 1500 mg q3w*Estimated to offer drug exposure at levels exceeding those hypothesized as needed for anti-tumor effect based on preclinical data and PK modelingPart B encompasses multiple POC cohorts (enrolling up to 40 patients each)Enrolling
Slide 21: Biomarker Strategies Employed in DRAGON Trial
Biomarker Strategies Employed in DRAGON Trial 21 ImmunophenotypingAssessment of immune landscapeExamples:Histochemical characterization tumor immune contexture (e.g. CD8+)Classification of inflamed, excluded or immune desert tumors and tumor nestsAbility of SRK-181 to overcome tumor immune exclusion
Slide 22: Preclinical data provide rationale to evaluate peripheral samples for SRK-181 activity
Preclinical data provide scientific rationale to evaluateperipheral samples for evidence of SRK-181 activity ImmunophenotypingAssessment of immune landscapeMeasurement of MDSCs in circulation may provide indirect evidence of drug action on the tumorMyeloid-derived suppressor cells (MDSCs) have immun
Slide 23: New Horizons in TGFβ Selectivity
New Horizons in TGFβ Selectivity
Slide 24: Selectively Targeting Large Latent Complexes To Achieve Context-Dependent TGFβ1 Inhibition
Selectively Targeting Large Latent Complexes To AchieveContext-Dependent TGFβ1 Inhibition Immune CellsGARP presents TGFβ1on Tregs LRRC33 presents TGFβ1on macrophages Fibrotic TissueLTBP1 and LTBP3present TGFβ1 in connective tissue GARPorLRRC33 Large latent complexes present TGFβ1 thoughcovalent inte
Slide 25: Specificity for LTBP-Selective Context Maintains Anti-Fibrotic Activity
Specificity for LTBP-Selective Context Maintains Anti-Fibrotic Activity Antifibrotic efficacy and safety demonstrated in multiple rodent models of kidney fibrosis with context selective LTBP-TGF�1 antibodyLTBP-selective inhibition is as effective as context-dependent inhibition suggesting that LTBP-
Slide 26: Portfolio Spanning All Stages of Discovery and Development
DRAGON Part A: dose escalation and continued follow-up Apitegromab Spinal Muscular Atrophy (SMA) SRK-181Immuno-Oncology and Oncology Preclinical/ Platform SAPPHIRE Phase 3 Trial Portfolio Spanning All Stages of Discovery and Development TOPAZ extension (55 of the 57 patients who completed TOPAZ 12-m
Slide 27: Appendix
Appendix S88 ScholarRock
Slide 28: Key Characteristics of Spinal Muscular Atrophy (SMA)
Key Characteristics ofSpinal Muscular Atrophy (SMA) Scholar Rock’s Guiding Principles forNeuromuscular Indication SelectionYounger populationAt least partially intact innervation andno structural muscle abnormalitiesNeed for increase in fast-twitchmuscle fibersClinical trial endpoint driven by fast-
Slide 29: Apitegromab: Muscle-Directed Therapy Aimed at Complementing SMN Upregulators
Apitegromab: Muscle-Directed Therapy Aimed at Complementing SMN Upregulators 29 Adapted from images courtesy of the SMA Foundation Myostatin is a negative regulator of skeletal muscle growthApitegromab is a fully human, mAb that specifically binds to proforms of myostatin and inhibits myostatin acti
Slide 30: Apitegromab Phase 2 Trial Design
Apitegromab Phase 2 Trial Design 30 Patients with Type 2 and 3 SMA Ambulatory Type 3 patients (ages 5-21)Apitegromab 20 mg/kg IV Q4W monotherapy or with chronic nusinersen maintenance Key objectives: RHS and safety at 12 months Non-ambulatory Type 2 patients (ages ≥2) on chronicmaintenance nusinerse
Slide 31: Baseline Characteristics
Baseline CharacteristicsNusinersen-treated patients well into chronic maintenance phase 31 Non-Ambulatory,Ages ≥2 and initiated nusinersen <5 years Non-Ambulatory, Ages 5-21 Ambulatory, Ages 5-21 20 mg/kg+nusinersen 2 mg/kg+nusinersen Pooled 20 mg/kg+nusinersen 20 mg/kgmonotherapy 20 mg/kg+nusinerse
Slide 32: Non-Ambulatory Type 2 Cohort: Initiated nusinersen age <5
Non-Ambulatory Type 2 Cohort:Initiated nusinersen age <5 32 Apitegromab (20 mg/kg) + nusinersen n=8 Mean change from baseline in HFMSE (95% CI) +7.1(1.8, 12.5) # (%) patients achieving: ≥1-pt increase in HFMSE 7/8 (88%) ≥3-pt increase in HFMSE 5/8 (63%) ≥5-pt increase in HFMSE 5/8 (63%) Baseline cha
Slide 33: Non-Ambulatory Type 2/3 Cohort: Initiated nusinersen age ≥5
Non-Ambulatory Type 2/3 Cohort:Initiated nusinersen age ≥5 Apitegromab (20 mg/kg) + nusinersen Per Protocol Population* (n=13) Intent-to-Treat Population (n=14) Mean change from baseline in HFMSE (95% CI) +1.2(-0.5, 2.9) +0.6(-1.4, 2.7) # (%) patients achieving: ≥1-pt increase in HFMSE 9/13 (69%) 9/
Slide 34: Majority of Ambulatory Patients Maintained or Improved in RHS Score
Majority of Ambulatory Patients Maintained or Improved in RHS Score from Baseline 34 Apitegromab 20 mg/kg monotherapy Apitegromab 20 mg/kg + nusinersen Mean change from baseline in RHS (95% CI) -0.4 (-3.9, 3.1) -0.3 (-2.0, 1.4) # (%) patients achieving: ≥0-pt increase in RHS 6/11 (55%) 7/12 (58%) ≥1
Slide 35: Pharmacokinetic and Pharmacodynamic Data Supportive of Clinically Observed Effects
Dose-proportional and sustained drug exposure following chronic administration of apitegromab Pharmacokinetic and Pharmacodynamic Data areSupportive of Clinically Observed Effects Both 2 mg/kg and 20 mg/kg doses yielded high levels of target engagement (>100-fold increase from baseline)20 mg/kg dose
Slide 36: HFMSE Improvements Observed Across Age Range of Non-Ambulatory Patients
HFMSE Improvements Observed Across Age Range of Non-Ambulatory Patients with Relatively Larger Gains from Earlier Treatment *Pooled cohorts of non-ambulatory patients treated with apitegromab 20 mg/kg and 2 mg/kg; excludes 4 patients who each missed 3 doses of apitegromabdue to COVID-19-related site
Slide 37: TOPAZ Age 2-12 Exploratory Analysis
Analysis overview*:Pooled patients (n =16) of age 2-12 years from the intent-to-treat population of the two non-ambulatory cohortsNusinersen initiated at age < 5 years: n = 8Nusinersen initiated at age > 5 years: n = 812 months of apitegromab 20 mg/kg as add-on to background nusinersenPatients were
Slide 38: TOPAZ Age 2-12 Analysis in Pooled Non-Ambulatory Cohorts
Mean HFMSE increase of 4.4 points, with majority experiencing > 3-point increases on top of background SMN therapyHFMSE gains also notable in subset of individuals in this analysis who had started background nusinersen at age > 5: 75% (6/8) with > 1-point increase and 50% (4/8) with > 3-point increa
Slide 39: SAPPHIRE Details
39 SAPPHIRE Details Main population Endpoints Analysis Additional Data Opportunities Primary efficacy: HFMSEAdd’l efficacy measures: RULM, WHO, other outcome measuresSafety, PK/PD, ADA Topline readout based upon main efficacy population (age 2-12) and focused upon apitegromab 20 mg/kg* vs. placeboIn
Slide 40: Increases in HFMSE Not Correlated with Duration of Prior Nusinersen Treatment
Increases in HFMSE Not Correlated with Duration of PriorNusinersen Treatment Change in HFMSE Not Correlated With Number of Nusinersen Maintenance Doses(post-hoc analysis of TOPAZ non-ambulatory patients) Further data suggesting increases in HFMSE may be attributable to apitegromab No correlation bet
Slide 41: WHO Motor Development Milestone Achievement Further Support Apitegromab's Potential
WHO Motor DevelopmeSupport Apitegromab nt Milesto’s Potential ne Achievementto Improve Mot s Furtheror Function Non-ambulatory Type 2/3 Patients Pooled Initiated nusinersen age <5 Initiated nusinersen age ≥5 # of patients gaining ≥1 WHO motor milestone(s) 7/35 4/20 3/15 41 WHO motor milestone analys
Slide 42: Inhibition of TGFβ1: Multipronged Approach for Immuno-Oncology
Inhibition of TGFβ1: Multipronged Approach forImmuno-Oncology 42 TGFβ1 Tumor Associated Macrophage Cancer Associated Fibroblasts (Stromal cells) Tumor cells TGFβ1 is a key driver of immune system evasion by cancer cellsRegulatory T cell Pathway analysis in patienttumors points to TGFβ1 as major dete
Slide 43: TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1
TGFβ1 Blockade with SRK-181-mIgG1 Rendered Preclinical Tumor Models Susceptible to Anti-PD1 Therapy Days after treatment initiation Tumor volume (mm3) Anti-PD1/SRK-181-mIgG1(10 mg/kg QW) Anti-PD1/SRK-181-mIgG1(3 mg/kg QW) 4/14 8/14 Preclinical data published in Science Translational Medicine. Martin
Slide 44: Longer-term treatment with nusinersen: SHINE study
44 “Longer-term treatment with nusinersen: results in later-onset spinal muscular atrophy from the SHINE study” P.257, World Muscle Society Congress 2020 This third-party information is provided for background only and is not intended to convey or imply a comparison to the TOPAZ clinical trial resul
Slide 45: Nusinersen and risdiplam benefit in later-onset SMA
†Source: Mercuri E, et.al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378:625-635. † †Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA) Roche/PTC Therapeutics *This third-party informa
Slide 46: Safety Results from TOPAZ 12-Month Top-Line Analysis
Safety Results fromSupport Evaluation TOPAZ 12-Montof Apitegromab h Top-Line Anin Phase 3 Tria alysisl Treatment-emergent adverse events (TEAEs) Apitegromab 2 mg/kg (n=10) Apitegromab 20 mg/kg (n=48) Total (n=58) Any TEAE 9 (90.0%) 44 (91.7%) 53 (91.4%) Any Serious TEAE 1 (10.0%) 4 (8.3%) 5 (8.6%) A
Slide 47: Significant Interest in Potential Role of TGFβ Inhibition in Immuno-Oncology
Significant Interest in Potential Role of TGFβ Inhibition inImmuno-Oncology Nature (online), Feb. 14, 2018. AuthorsWilly Hugo, Jesse M. Zaretsky, Lu Sun, Douglas B. Johnson, Antoni Ribas, Roger S. LoVolume 165, Issue 1, 24 March 2016, Pages 35-44 July 24, 2020: https://doi.org/10.1038/ s41571-020-04
Slide 48: Emerging Evidence Implicates TGFβ1 as Driving Primary Resistance to Checkpoint Inhibitors
Cancer Genome Atlas RNAseq analysis of>10,000 samples spanning 33 tumor types* Substantial % of solid tumors exhibit immune exclusion Emerging Evidence Implicates TGFβ1 as Driving Primary Resistance to Checkpoint Inhibitors Human Tumor Analyses Reveal TGFβ1 as Most Likely Driver of TGFβ Signaling Pa
Slide 49: DRAGON Part A: Dose Escalation Update and Safety Data
DRAGON Part A: Dose Escalation Update and Safety Data 49 Median number of prior lines of therapy was 4 (range 1, 9) for Part A1 and 4 (range 2, 6) for Part A2No dose-limiting toxicities have been observed with SRK-181 in Part A (as of Oct. 12, 2021), evaluating doses as high as the following thus fa
Slide 50: DRAGON Part A: Preliminary Pharmacokinetics (PK) Summary of SRK-181
DRAGON Part A: Preliminary Pharmacokinetics (PK)Summary of SRK-181 50 SRK-181 displayed typical monoclonal antibody PK characteristicsBased on a power model, dose- proportional PK was observed for SRK-181The T1/2 of SRK-181 was 5.4 to 10.7days
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