Slide 1: Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program
Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program Limb-Girdle Muscular Dystrophy Type 2E Cambridge, MA June 8, 2020 Exhibit 99.2 SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 1
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains "forward-looking statements." Any statements contained in this presentation that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends,"
Slide 3: Welcome and Introduction
Welcome and Introduction Doug Ingram President and CEO Sarepta Therapeutics, Inc.
Slide 4: Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program
Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program Limb-Girdle Muscular Dystrophy Type 2E Louise Rodino-Klapac, Ph.D. Senior Vice President, Gene Therapy Sarepta Therapeutics, Inc.
Slide 5: LGMDs Are Devastating Muscular Dystrophies
LGMDs Are Devastating Muscular Dystrophies Monogenic, rare neuromuscular diseases that affect hundreds of thousands globally LGMDs are progressive, debilitating muscle-wasting diseases with no therapies1,2 Affect males and females equally Affect skeletal muscle Affect cardiac muscle in some types El
Slide 6: LGMD Portfolio Addresses Monogenic Mutations Lacking Dystrophin-associated Proteins
LGMD Portfolio Addresses Monogenic Mutations that Result in the Lack of One of the Proteins Comprising the Dystrophin-associated Protein Complex ANO5, anoctamin-5; FKRP, fukutin-related protein; POMT, protein-O-mannosyltransferase; TRIM, tripartite motif. β-sarcoglycan (SGCB) Is the Fundamental Subu
Slide 7: LGMD2E Phase I/II Study
LGMD2E Phase I/II Study ClinicalTrials.gov Identifier: NCT03652259
Slide 8: LGMD Type 2E Open-label Trial Design
LGMD Type 2E Open-label Trial Design 6 subjects treated with systemic delivery of AAVrh74.MHCK7.SGCB† Cohort 1: 3 subjects; 5x1013 vg/kg Cohort 2: 3 subjects; 2x1014 vg/kg Inclusion criteria Subjects ages 4 through age 15, inclusive Beta-sarcoglycan (SG) DNA gene mutations at both alleles Negative f
Slide 9: Endpoints in the LGMD2E Study
Endpoints in the LGMD2E Study Primary endpoint Safety Secondary endpoints: b-sarcoglycan expression at week 8* Other endpoints: Decrease in CK Functional endpoints North Star Assessment for Limb-girdle muscular dystrophies (NSAD) • 100-meter walk/run (100MWR) • 10-meter walk/run (10MWR) Time to asce
Slide 10: Pre-clinical Models Correlated Expression and Function
Pre-clinical Models Correlated Expression and Function ≥20 percent expression leads to increased function Pretreatment Post Treatment Function WT BSG KO AAVrh74.hSGCB 5x1012 vg/kg 300 200 100 0 Specific Force (mN/mm2) SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 10
Slide 11: LGMD2E Study Day 60 Expression Results: Cohort 1
LGMD2E Study Day 60 Expression Results: Cohort 1 (n=3) SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 11
Slide 12: LGMD2E Subject Demographics at Baseline
Cohort 1 - LGMD2E Subject Demographics at Baseline1 Exons 3-6 encode for the extracellular domain of SGCB Mutations in these exons lead to complete absence of or severely reduced expression of SGCB, and a severe phenotype that includes cardiomyopathy2 Subject Age (years) Mutation Weight (kg)* CK Lev
Slide 13: Robust b-Sarcoglycan Expression in Muscle Biopsies at 5x10^13 vg/kg
Cohort 1 - Robust b-Sarcoglycan Expression in Muscle Biopsies in All 3 Subjects at a Dose of 5x1013 vg/kg Percentage of SGCB-positive Fibers Intensity Mean (n=3)* 51% 47% Normal Control Subject 2 Subject 1 Subject 3 Beta-Sarcoglycan Expression (IF) Post-treatment Pre-treatment *Values represent aver
Slide 14: Robust b-Sarcoglycan Expression in Muscle Biopsies at 5x10^13 vg/kg
Cohort 1 - Robust b-Sarcoglycan Expression in Muscle Biopsies in All 3 Subjects at a Dose of 5x1013 vg/kg Subject Percentage of SGCB-Positive Fibers Mean Intensity 1 63% 47% 2 49% 57% 3 42% 38% Mean 51% 47% β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any re
Slide 15: SGCB Expression Upregulated SGC Complex at 5x10^13 vg/kg
Cohort 1 - SGCB Expression Significantly Upregulated SGC Complex at a Dose of 5x1013 vg/kg Sarepta Therapeutics 2019. Data on file. Normal Control d a g b SGC Complex ANO5 DYSF Image adapted from Fairclough RJ, et al. Nat Rev Genet. 2013;14(6):373-378. Subject 1 Post-treatment Pre-treatment Subject
Slide 16: SGCB Expression Upregulated SGC Complex Protein at 5x10^13 vg/kg
SGCB Expression Significantly Upregulated SGC Complex Protein at a Dose of 5x1013 vg/kg Sarepta Therapeutics 2019. Data on file. Image adapted from Fairclough RJ, et al. Nat Rev Genet. 2012;14(6):373-378. b-sarcoglycan α-sarcoglycan Colocalization (Merge) d a g b SGC Complex ANO5 DYSF β-sarcoglycan
Slide 17: Detection of β-sarcoglycan Expression by Western Blot
Cohort 1 - Detection of β-sarcoglycan Expression by Western Blot Post-treatment in All 3 Subjects Sarepta Therapeutics 2019. Data on file. The gene transfer delivers full-length SGCB Subject Mean SGCB Expression vs Normal 1 34.7% 2 39.2% 3 34.5% Mean 36.1% β-sarcoglycan gene therapy is investigation
Slide 18: b-Sarcoglycan Expression Supported by Vector Genome Counts
Cohort 1 - b-Sarcoglycan Expression is Supported by Vector Genome Counts Percentage of Beta-Sarcoglycan-positive Fibers Intensity Mean (n=3) 51% 47% Percent of Normal Mean (n=3) 36.1% Vector Copies/μg DNA Copies per Nucleus Mean (n=3) >E04 0.60 Beta-Sarcoglycan Expression (IF) Vector Genome Number B
Slide 19: Safety Review (Cohort 1)
Cohort 1 - Safety Review (n=3) 2 subjects had elevated liver enzymes, 1 of which was designated an SAE, as the subject had associated transient increase in bilirubin Both events occurred when the subjects were tapered off oral steroids Elevated liver enzymes returned to baseline and symptoms resolve
Slide 20: LGMD2E Study One Year Functional Results: Cohort 1
LGMD2E Study One Year Functional Results: Cohort 1 (n=3) SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 20
Slide 21: Summary of Functional Data at 1-Year
Cohort 1 - Summary of Functional Data at 1-Year ALL SUBJECTS SHOWED IMPROVEMENT IN ALL FUNCTIONAL MEASURES Subject Assessment NSAD* Time to Rise (sec) 4 Stairs Up (sec) 100 MWR* (sec) 10 MWR (sec) 1 Baseline 40 5.0 2.4 52.0 5.0 Day 270 41 4.1 2.3 47.7 4.5 1-year 44 3.8 2.2 48.4 4.5 Change from Basel
Slide 22: Mean Change from Baseline in NSAD
Cohort 1 - Mean Change from Baseline in NSAD β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any regulatory authority. ClinicalTrials.gov Identifier: NCT03652259. Mean (SD) Change From Baseline in NSAD 10 8 6 4 52 0 -2 -4 -6 -8 -10 0 30 60 90 120 150 180 210 24
Slide 23: LGMD2E Study Day 60 Expression Results: Cohort 2
LGMD2E Study Day 60 Expression Results: Cohort 2 (n=3) SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 23
Slide 24: LGMD2E Subject Demographics at Baseline
Cohort 2 - LGMD2E Subject Demographics at Baseline1 Exons 3-6 encode for the extracellular domain of SGCB Mutations in these exons lead to complete absence of or severely reduced expression of SGCB, and a severe phenotype that includes cardiomyopathy2 Subject Age (years) Mutation Weight (kg) CK Leve
Slide 25: Robust b-Sarcoglycan Expression in Muscle Biopsies at 2x10^14 vg/kg
Cohort 2 - Robust b-Sarcoglycan Expression in Muscle Biopsies in All 3 Subjects at a Dose of 2x1014 vg/kg Percentage of SGCB-positive Fibers Intensity Mean (n=3)* 72% 73% Normal Control Subject 5 Subject 4 Subject 6 Beta-Sarcoglycan Expression (IF) Post-treatment Pre-treatment *Values represent aver
Slide 26: Robust b-Sarcoglycan Expression in Muscle Biopsies at 2x10^14 vg/kg
Cohort 2 - Robust b-Sarcoglycan Expression in Muscle Biopsies in All 3 Subjects at a Dose of 2x1014 vg/kg Subject Percentage of SGCB-Positive Fibers Mean Intensity 4 65% 55% 5 77% 67% 6 75% 97% Mean 72% 73% β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any re
Slide 27: Robust a-Sarcoglycan Expression Upregulated Sarcoglycan Complex at 2x10^14 vg/kg
Cohort 2 - Robust a-Sarcoglycan Expression Significantly Upregulated Sarcoglycan Complex at a Dose of 2x1014 vg/kg Sarepta Therapeutics 2020. Data on file. Normal Control d a g b SGC Complex ANO5 DYSF Image adapted from Fairclough RJ, et al. Nat Rev Genet. 2013;14(6):373-378. Subject 4 Post-treatmen
Slide 28: Detection of β-Sarcoglycan Expression by Western Blot at Day 60
Cohort 2 - Detection of β-Sarcoglycan Expression by Western Blot Post-treatment in All 3 Subjects at Day 60 The gene transfer delivers full-length SGCB Subject Mean SGCB Expression vs Normal 4 53.0% 5 63.1% 6 70.3% Mean 62.1% β-sarcoglycan gene therapy is investigational and has not been reviewed or
Slide 29: b-Sarcoglycan Expression Supported by Vector Genome Counts
Cohort 2 - b-Sarcoglycan Expression is Supported by Vector Genome Counts Percentage of Beta-Sarcoglycan-positive Fibers Intensity Mean (n=3) 72.3% 73.1% Percent of Normal Mean (n=3) 62.1% Vector Copies/μg DNA Copies per Nucleus Mean (n=3) >E05 4.2 Beta-Sarcoglycan Expression (IF) Vector Genome Numbe
Slide 30: 89.1% Mean Reduction of Creatine Kinase Levels
Cohort 2 - 89.1% Mean Reduction of Creatine Kinase (CK) Levels Observed with b-Sarcoglycan Gene Therapy Subject Age (years) CK Levels at Baseline (U/L) CK Levels at Last Visit (Day 90) (U/L) 4 11 6320 852 5 11 8938 498 6 8 5743 776 89.1% Mean Reduction in CK at Day 90 β-sarcoglycan gene therapy is i
Slide 31: Comparison of Expression Results from Cohort 1 and Cohort 2
Comparison of Expression Results from Cohort 1 and Cohort 2 Cohort Dose IF % Positive Fibers (% of NC) Mean Intensity (% of NC) Western Blot (% of NC) qPCR (copies/nucleus) 1 (n=3) 5x1013 vg/kg 51% 47% 36.1% 0.60 2 (n=3) 2x1014 vg/kg 72% 73% 62.1% 4.2 β-sarcoglycan gene therapy is investigational an
Slide 32: Safety Review of Cohort 2
Safety Review of Cohort 2 (n=3) Majority of patients had AEs mild/moderate in severity, which resolved One SAE observed Dehydration resulting from vomiting 3 days after infusion which resolved in 2 days with ondansetron, promethazine and IV fluids No stopping/discontinuation rules were triggered by
Slide 33: Summary
Summary Data reflects optimized LGMD2E construct design AAVrh74 efficiently transduces all muscle types MHCK7 promoter allows for cardiac and skeletal transgene muscle expression Low pre-existing immunity for AAVrh74 Preliminary clinical results Increased beta-sarcoglycan expression across all patie
Slide 34: Next Steps for Clinical Development
Next Steps for Clinical Development AAVrh74.MHCK7.SGCB (SRP-9003) β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any regulatory authority. ClinicalTrials.gov Identifier: NCT03652259. Sarepta Therapeutics 2020. Data on file. Final dose for registration trial wi
Slide 35: Sarepta's Current Clinical Programs in LGMD
Vector AAVrh74 Promoter MHCK7 FULL LENGTH b-sarcoglycan Vector AAVrh74 FULL LENGTH Dysferlin Promoter MHCK7 Vector AAVrh74 FULL LENGTH γ-sarcoglycan Promoter MHCK7 Vector AAVrh74 FULL LENGTH α-sarcoglycan Promoter tMCK Vector AAVrh74 FULL LENGTH Anoctamin-5 Promoter tMCK LGMD2E LGMD2D LGMD2B LGMD2C
Slide 36: Questions & Answers
Questions & Answers SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 36
Slide 37: SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED.
SAREPTA THERAPEUTICS, INC. 2020. ALL RIGHTS RESERVED. 37