Scholar Rock Holding Corporation · NASDAQ:SRRK
Scholar Rock — Investor Presentation (November 2019)
36 slides from Scholar Rock's investor presentation, Nov 19, 2019
Slide 1: From New Insights to New Medicines
November 2019 From New Insights to New Medicines
Slide 2: Disclaimers
2 Disclaimers Various statements in this presentation concerning Scholar Rock’s future expectations, plans and prospects, including without limitation, Scholar Rock’s expectations regarding its strategy, its product candidate selection and development timing, inclu din g timing for the initiation of
Slide 3: Novel Approach to Selective Modulation of Growth Factor Signaling
3 Novel Approach to S elective M odulation of Growth F actor S ignaling Traditional Target “Mature” Growth Factor Scholar Rock’s Target Growth Factor Precursor (Latent Form) …but have been limited by: • Structural similarities • Overlapping sets of related receptors • Diverse and overlapping physiol
Slide 4: Pipeline programs and anticipated milestones
4 Target / Program Indication Discovery / Early Preclinical Preclinical Phase 1 Phase 2 Rights / Partner Next Anticipated Milestone INTERNAL PROPRIETARY PROGRAMS Pro/Latent Myostatin SRK - 015 Spinal Muscular Atrophy (3 distinct Type 2 and Type 3 patient populations) Interim Efficacy and Safety Resu
Slide 5: Upcoming Key R&D Milestones
5 Upcoming Key R&D Milestones Spinal Muscular Atrophy (SMA) x Initiate SRK - 015 Phase 2 proof - of - concept SMA trial by the end of 1Q19 x Commence patient dosing in SRK - 015 Phase 2 SMA proof - of - concept trial in 2Q19 x Present final Phase 1 results at Cure SMA Annual Conference being held Ju
Slide 6: Inhibitor of Myostatin Activation: Potential First Muscle-Directed Therapy for SMA
SRK - 015: Inhibitor of Myostatin Activation Potential First Muscle - Directed Therapy for SMA
Slide 7: Highly Specific Inhibitor of Latent Myostatin
7 SRK - 015: Highly Specific Inhibitor of Latent Myostatin • Myostatin is a genetically - validated, negative regulator of muscle mass expressed in skeletal muscle tissue • Vertebrates lacking the myostatin gene are healthy and display increased muscle mass and strength • Preclinical and clinical da
Slide 8: Significant Unmet Need Remains Despite Current Therapies
8 Significant Unmet Need Remains Despite Current Therapies Mean improvement in HFMSE score experienced by patients with later - onset SMA in the Phase 3 CHERISH clinical trial of nusinersen 0 20 40 60 80 HFMSE Score at Month 15 Mean Baseline Score Mean Improvement with nusinersen Unmet Medical Need
Slide 9: Opportunity in Spinal Muscular Atrophy
9 SRK - 015 Opportunity in Spinal Muscular Atrophy Overall Prevalence of 30,000 - 35,000 in U.S. and Europe Potential to use SRK - 015 in conjunction with SMN upregulators Potential to use SRK - 015 as monotherapy or in conjunction with SMN upregulators Lally et al, Orphanet Journal of Rare Diseases
Slide 10: Phase 2 TOPAZ Trial Design
10 SRK - 015 Phase 2 Trial Design Cohort 1 Cohort 3 Design Subjects • N= 20; ages 5 - 21 • Open - label, single - arm • 20 mg/kg SRK - 015 IV Q4W • 12 - month treatment period • Ambulatory Type 3 SMA Cohort 2 • N= 15; ages 5 - 21 • Open - label, single - arm • 20 mg/kg SRK - 015 IV Q4W • 12 - month
Slide 11: Preliminary PK Data Shows Exposure in Patients with SMA
11 Preliminary PK Data Shows SRK - 015 Exposure in Patients with SMA Consistent with that in Healthy Volunteers SRK - 015 Displayed Well - Behaved, Linear PK Profile • Minimal variability across TOPAZ cohorts • Preliminary PK observations consistent with Phase 1 trial results in healthy volunteers •
Slide 12: Preliminary Biomarker Data Show Target Engagement in Patients with SMA
12 Preliminary Biomarker Data Provide First Demonstration of Target Engagement in Patients with SMA Robust Target Engagement Observed in TOPAZ • ~100 - fold increases in serum latent myostatin levels following a single 20 mg/kg dose in all cohorts • Increases in latent myostatin were dose - dependen
Slide 13: Path to Top-Line Results in TOPAZ SMA Trial
13 SRK - 015: Path to Top - Line Results in TOPAZ SMA Trial End of 2019 1H 2020 4Q20 - 1Q21 2Q19 1Q19 Initiated trial - Start - up activities, including contracts and IRB submissions with trial sites Commenced patient dosing - Provided additional details of Phase 2 trial design Preliminary PK/PD dat
Slide 14: TGFβ1: Significant Opportunities in Oncology/Immuno-oncology
TGFβ1: Significant Opportunities in Oncology/Immuno - oncology
Slide 15: Anti-PD(L)1 Becoming Backbone Therapy; Significant Unmet Need Remains
15 Anti - PD(L)1 Becoming Backbone Therapy Across Oncology; Significant Unmet Need Remains Source: Company information, Wall Street research, Evaluate Pharma $16.2 $22.0 $26.7 $31.1 $35.1 $39.0 $42.4 2018 2019 2020 2021 2022 2023 2024 Merck BMS Roche AZ Regeneron Pfizer GSK All Others Checkpoint Mar
Slide 16: Inhibition of TGFβ1: Multipronged Approach for Immuno-Oncology
16 Inhibition of TGF β 1: Multipronged Approach for Immuno - Oncology TGF β 1 is a key driver of immune system evasion by cancer cells TGF β 1 Regulatory T cell Tumor Associated Macrophage Cancer Associated Fibroblasts (Stromal cells) Tumor cells • Pathway analysis in patient tumors points to TGFβ1
Slide 17: TGFβ is the Predominant Isoform in Most Human Tumors
17 TGF β 1 is the Predominant Isoform in Most Human Tumors TGFB1 TGFB2 TGFB3 bladder urothelial carcinoma head & neck squamous cell carcinoma kidney clear cell carcinoma kidney papillary cell carcinoma liver hepatocellular carcinoma lung adenocarcinoma skin cutaneous melanoma stomach adenocarcinoma
Slide 18: SRK-181 Potential to Expand Patients Who Could Benefit from Checkpoint Inhibitors
18 SRK - 181 has Potential to Meaningfully Expand Number of Patients Who Could Benefit from Checkpoint Inhibitors Differentiated approach with SRK - 181 ▪ Highly selective inhibitor of the activation of latent TGFβ1 ▪ Minimal or no binding to latent TGFβ2 and TGFβ3 isoforms ▪ Fully human mAb *SRK -
Slide 19: TGFβ Blockade Rendered Preclinical Tumor Models Susceptible to Anti-PD1
19 TGF β 1 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) SRK - 181 - mIgG1* (10 mg/kg QW) 0/13 4/14 8/14 Ant
Slide 20: Inhibiting TGFβ Alone Sensitized Preclinical Breast Cancer Model
20 Inhibiting TGF β 1 Alone Was Sufficient to Sensitize Preclinical TGF β 1/3 - Expressing Breast Cancer Model • EMT6 model expresses both TGF β1 and TGF β 3 • Model is poorly responsive to PD1 blockade as a monotherapy • Combination of SRK - 181 - mIgG1 and anti - PD1 resulted in tumor regression o
Slide 21: Combination Led to Significant Survival Benefit in Preclinical Models
21 EMT6 Breast Cancer Model Days after treatment initiation Survival (%) SRK - 181 - mIgG1 † Combined with Anti - PD1 Therapy Led to Significant Survival Benefit in Preclinical Tumor Models MBT - 2 Bladder Cancer Model Days after treatment initiation Survival (%) Cloudman S91 Melanoma Model Survival
Slide 22: Combination Enabled Infiltration and Expansion of CD8+ T cells
22 Anti - PD1/SRK - 181 - mIgG1 (10 mg/kg) led to increase in CD8+ cells Anti - PD1 SRK - 181 - mIgG1 Combination Therapy Enabled Infiltration and Expansion of CD8 + T cells in Preclinical Bladder Cancer Model Preclinical data shown above as presented at American Association of Cancer Research (AACR
Slide 23: TGFβ1 Isoform Specificity of SRK-181: Improved Preclinical Toxicity Profile
23 TGFβ1 Isoform Specificity of SRK - 181 Improved Preclinical Toxicity Profile • Animals dosed with pan - TGF β inhibitors, LY2109761 (inhibitor of ALK5, common TGF β receptor kinase) or pan - TGF β antibody, exhibited expected cardiac findings based on published data • Exposure as assessed by SRK
Slide 24: RGMc Program: Targeting the BMP6 Signaling Pathway
RGMc Program: Targeting the BMP6 Signaling Pathway
Slide 25: Anti-RGMc Therapy for Iron-Restricted Anemias
25 Anti - RGMc Therapy: Rational Solution that Directly Addresses the Underlying Pathobiology of Iron - Restricted Anemias BMP6 RGMc BMP Receptor SMAD 1/5/8 SMAD 4 P Hepcidin BMP6 Genetically validated pathway of iron regulation in humans Adapted from Crielaard et al , Nature Reviews , 2017 RGMc (HJ
Slide 26: RGMc-Selective Antibodies Show Potent Increase in Serum Iron In Vivo
26 Scholar Rock’s RGMc - Selective Antibodies Show Potent Increase in Serum Iron In Vivo Antibodies showed up to 3 weeks prolonged increase in serum iron in SD rats (single 20 mpk dose) Antibodies resulted in increases in serum iron and decreases in UIBC 200 300 400 500 600 S e r u m i r o n ( g /
Slide 27: Upcoming Key R&D Milestones
27 Upcoming Key R&D Milestones Spinal Muscular Atrophy (SMA) x Initiate SRK - 015 Phase 2 proof - of - concept SMA trial by the end of 1Q19 x Commence patient dosing in SRK - 015 Phase 2 SMA proof - of - concept trial in 2Q19 x Present final Phase 1 results at Cure SMA Annual Conference being held J
Slide 28: Appendix
Appendix SCHOLAR ROCK
Slide 29: Traditional Approaches Can Raise Significant Safety Concerns
29 Traditional Approaches Can Raise Significant Safety Concerns Activin A GDF11 Myostatin BMP9 • Most inhibitors of active myostatin also inhibit GDF11 and may inhibit other growth factors as well • Antibodies to ActRIIb and ligand trap approaches inhibit signaling of multiple ligands GDF11 Deletion
Slide 30: Review of Preclinical Data in SMNΔ7 Mouse Models
30 Review of Preclinical Data in SMN Δ7 Mouse Models *muSRK - 015P is the parental clone of SRK - 015 on a mouse IgG1 framework Preclinical data published Nov 2018: Long, K., O’Shea, K., Khairallah , R., et al. Specific Inhibition of Myostatin Activation is Beneficial in Mouse Models of SMA Therapy.
Slide 31: Phase 1 Trial Design
31 SRK - 015 Phase 1 Trial Design SINGLE - ASCENDING DOSE (SAD) MULTIPLE - ASCENDING DOSE (MAD) Design Subjects Dosing Double - blind, placebo - controlled 3:1 randomization 40 Adult healthy volunteers (Ages 18 - 55) Double - blind, placebo - controlled 3:1 randomization Single doses at: 1, 3, 10, 2
Slide 32: Preclinical and Phase 1 Data Support Evaluation in SMA
32 SRK - 015 Preclinical and Phase 1 Data Support Evaluation in SMA Preclinical and translational data support myostatin as a drug target in SMA • Confirmed presence of target in disease setting • Achieved multi - fold increase in serum latent myostatin levels indicating target engagement • Treatmen
Slide 33: Well Tolerated in Phase 1 Healthy Volunteer Trial
33 SRK - 015 Well Tolerated in Phase 1 Healthy Volunteer Trial • Well - tolerated with no apparent safety signals • No dose - limiting toxicities identified up to highest evaluated dose of 30 mg/kg - No discontinuations due to treatment - related adverse events (AEs) - No treatment - related SAE - N
Slide 34: Phase 1 Pharmacokinetic Data Support Infrequent Dosing
34 Phase 1 Pharmacokinetic (PK) Data Support Infrequent Dosing SRK - 015 Displayed Well - Behaved, Linear PK Profile • Minimal variability observed, consistent with that commonly observed with monoclonal antibodies • Dose - proportional serum drug exposure Half - Life Supports Infrequent Dosing • Se
Slide 35: Phase 1 Pharmacodynamic Data Demonstrate Robust and Sustained Target Engagement
35 Phase 1 Pharmacodynamic (PD) Data Demonstrate Robust and Sustained Target Engagement Robust Target Engagement Observed • Single dose of SRK - 015 led to marked increases in serum concentrations of latent myostatin • No meaningful change observed with placebo Evidence Supports Durable Target Satur
Slide 36: TGFβ1 Plays Central Role in Multiple Diseases with Unmet Need
36 TGF β1 Plays Central Role in Multiple Diseases with Unmet Need Oncology Fibrosis Immuno - Oncology Tumor - Directed Therapy Myeloproliferative Disorders Upfront cash and equity investment: $80 million* One - time preclinical milestone: $25 million Additional milestones across 3 programs: Up to $1
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