Slide 1: Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program Functional Data
Louise Rodino-Klapac Senior Vice President, Gene Therapy Sarepta Therapeutics, Inc. October 4, 2019 Clinical Update: srp-9003 Beta-Sarcoglycanopathy Gene Therapy program Limb-Girdle Muscular Dystrophy Type 2E FUNCTIONAL DATA Exhibit 99.2
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains "forward-looking statements." Any statements that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “believe,” “anticipate,” “plan,” “expect,” “will,” “may,” “intend,” “prepare,” “look,” “potentia
Slide 3: LGMDs Are Devastating Muscular Dystrophies
LGMDs Are Devastating Muscular Dystrophies monogenic, rare neuromuscular diseases 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 Elevated creatine kinase (CK) levels Symptoms
Slide 4: LGMD Portfolio
LGMD Portfolio Sarcoglycans prevent muscle damage during contraction All 4 functional sarcoglycans must be present to form a functional sarcoglycan complex (SCG) b-sarcoglycan (SRP-9003) a-sarcoglycan (SRP-9004) g-sarcoglycan (SRP-9005) Sarcoglycan deficiency leads to dystrophin deficiency Dysferlin
Slide 5: LGMD Portfolio Addresses Monogenic Mutations
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 6: Pre-clinical models correlate 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) *
Slide 7: LGMD2E Phase I/II Study: Cohort (n=3)
LGMD2E Phase I/II Study: Cohort 1 (n=3)
Slide 8: LGMD Type 2E Open-label Trial Design
LGMD TYPE 2E Open-label Trial Design Up to 6 subjects with LGMD Cohort 1: 3 subjects; 4-15 years of age, 5x1013 vg/kg AAVrh74.MHCK7.SGCB systemic delivery Inclusion criteria A confirmed SGCB mutation in both alleles Negative for AAVrh74 antibodies >40% of Normal 100 meter walk test 60-day needle mus
Slide 9: Outcome measures
Outcome measures Primary endpoint ≥ 20% b-sarcoglycan expression Safety Secondary endpoints, including: Decrease in CK Functional endpoints North Star Assessment for LGMD (NSAD) 100m 10m 4 stairs Time to rise
Slide 10: LGMD2E Study Expression Results: Cohort (n=3)
LGMD2E Study Expression RESULTS: Cohort 1 (n=3)
Slide 11: LGMD2E Subject Demographics at Baseline
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 Levels at Basel
Slide 12: Robust b-Sarcoglycan Expression in Muscle Biopsies in All Subjects
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 (IHC) Post-treatment Pre-treatment
Slide 13: Robust b-Sarcoglycan Expression in Muscle Biopsies in All Subjects
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%
Slide 14: SGCB Expression Significantly Upregulated SGC Complex
SGCB Expression significantly upregulated sgc complex at a dose of 5 x 1013 vg/kg β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any regulatory authority. Sarepta Therapeutics 2019. Data on file. ClinicalTrials.gov: NCT03652259. Normal Control d a g b SGC Comp
Slide 15: SGCB Expression Significantly Upregulated SGC Complex Protein
SGCB Expression Significantly Upregulated SGC Complex protein at a Dose of 5x1013 vg/kg β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any regulatory authority. Sarepta Therapeutics 2019. Data on file. ClinicalTrials.gov: NCT03652259. Image adapted from Faircl
Slide 16: Detection of β-sarcoglycan Expression by Western Blot
Detection of β-sarcoglycan Expression by Western Blot Post-treatment in All 3 Subjects at Day 60 β-sarcoglycan gene therapy is investigational and has not been reviewed or approved by any regulatory authority. Sarepta Therapeutics 2019. Data on file. ClinicalTrials.gov Identifier: NCT03652259. The g
Slide 17: b-Sarcoglycan Expression is Supported by Vector Genome Counts
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) 8.4E04 0.60 Beta-Sarcoglycan Expression (IHC) Vector Genome Number Beta-Sarc
Slide 18: LGMD2E Study Functional Data Summary: Cohort (n=3)
LGMD2E Study Functional data summary: Cohort 1 (n=3)
Slide 19: Natural History Data, Nationwide Children's Hospital
NATURAL HISTORY DATA generated by linda lowes & LINDSAY ALFANO at Nationwide Children’s Hospital 54 48 42 36 30 24 18 12 6 0 Age (years) + Duration of Follow-Up 0 2 4 6 12 16 14 8 10 18 North Star Assessment for Limb Girdle Muscular Dystrophies (NSAD) All Subjects North Star Assessment for Limb Gird
Slide 20: Creatine Kinase Levels Are Reduced with b-Sarcoglycan Gene Therapy
Creatine Kinase (CK) Levels ARE reduced with b-Sarcoglycan GENE Therapy ClinicalTrials.gov Identifier: NCT03652259 CK Levels (U/L) Subject Age (years) Baseline Day 30 Day 60 Day 90 Day 180 Day 270 1 13 10,727 619 2257 1135 1553 2300 2 4 12,826 4795 910 2159 5070 2665 3 13 10,985 687 2061 2392 10,055
Slide 21: Summary of Clinical Data: All Subjects Showed Improvement in All Functional Measures
SUMMARY OF CLINICAL DATA AT 9 MONTHS ALL SUBJECTS SHOWED IMPROVEMENT IN ALL FUNCTIONAL MEASURES Subject Assessment NSAD Time to Rise (sec) 4 Stairs Up (sec) 100 m (sec) 10 m (sec) 1 Baseline 40 5.0 2.4 49.3 5 Day 270 41 4.1 2.3 43.2 4.5 2 Baseline 48 1.5 1.6 59.3 3.4 Day 270 54 1.2 1.3 48.4 3.2 3 B
Slide 22: Summary of Clinical Data: All Subjects Showed Improvement in All Functional Measures
SUMMARY OF CLINICAL DATA AT 9 MONTHS ALL SUBJECTS SHOWED IMPROVEMENT IN ALL FUNCTIONAL MEASURES Subject Assessment NSAD Time to Rise (sec) 4 Stairs Up (sec) 100 m (sec) 10 m (sec) 1 Baseline 40 5.0 2.4 49.3 5 Day 270 41 4.1 2.3 43.2 4.5 2 Baseline 48 1.5 1.6 59.3 3.4 Day 270 54 1.2 1.3 48.4 3.2 3 B
Slide 23: Baseline Demographics of Age-Matched Natural History Control Group
Baseline Demographics of age-matched natural history control group (4-15 years) Subject Age (years) 1 5 2 12 3 10 4 9 5 9
Slide 24: Age-Matched LGMD2E Natural History Cohort Mean Change in NSAD
age-matched LGMD2E Natural history Cohort Mean Change from Baseline in North Star Assessment for Limb Girdle Muscular Dystrophies (NSAD), Subjects with Baseline Ages 4 to 15 Mean (SD) Change from Baseline in NSAD 8 6 4 2 0 -2 -4 -6 -8 -10 Natural History (n=5) Baseline 30 DAYS 60 DAYS 90 DAYS 180 DA
Slide 25: SRP-9003 Treated LGMD2E Patients Mean Change in NSAD
SRP-9003 treated LGMD2E patients (Low dose cohort 1) Mean Change from Baseline in North Star Assessment for Limb Girdle Muscular Dystrophies (NSAD), Subjects with Baseline Ages 4 to 15 Mean (SD) Change from Baseline in NSAD 8 6 4 2 0 -2 -4 -6 -8 -10 Baseline 30 DAYS 60 DAYS 90 DAYS 180 DAYS 270 DAYS
Slide 26: Patient 1: 100m Running
PATIENT 1: 100M RUNNING 100 m baseline running Limited hip extension/flexion SSAREPTA THERAPEUTICS, NC 100 m 9 months post gene therapy Good hip extension/flexion; faster speed =
Slide 27: Patient 2: Trunk Control
PATIENT 2: TRUNK CONTROL Ba 9 months Post Gene Therapy Poor Trunk Control @ it SSAREPTA THERAPEUTICS, NC
Slide 28: Patient 3: Getting Up from Sitting
PATIENT 3: Getting up from Sitting
Slide 29: Safety
Safety TO Day 270 (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 resolved withi
Slide 30: Summary
Summary Construct optimized for use in LGMD AAVrh74 efficiently transduces all muscle types Low pre-existing immunity for AAVrh74 MHCK7 promoter allows for cardiac and skeletal transgene muscle expression Preliminary clinical results Widespread beta-sarcoglycan expression across all patients at a sy
Slide 31: Future Clinical Development: Dose Escalation to Identify Registrational Trial Dose
Future Clinical Development: Dose Escalation to Identify Registrational Trial Dose Next Steps: Dose Escalation: 4-fold increase Final dose for registration trial will be selected from 2 doses studied Engagement with global regulatory agencies to discuss pivotal trial designs AAVrh74.MHCK7.SGCB (SRP-
Slide 32: Sarepta's Current Clinical Programs in LGMD
LGMD2E LGMD2D LGMD2B LGMD2C LGMD2L Program SRP-9003 SRP-9004 MYO-201 SRP-9005 SRP-9006 Target Function Stabilizes DAPC, prevents muscle damage during contraction Stabilizes DAPC, prevents muscle damage during contraction Muscle membrane repair Stabilizes DAPC, prevents muscle damage during contracti
Slide 33: Questions & Answers
QUESTIONS & ANSWERS = Gsanepra 7] THERAPEUTICS
Slide 34: Clinical Update: SRP-9003 Beta-Sarcoglycanopathy Gene Therapy Program Functional Data
Louise Rodino-Klapac Senior Vice President, Gene Therapy Sarepta Therapeutics, Inc. October 4, 2019 Clinical Update: srp-9003 Beta-Sarcoglycanopathy Gene Therapy program Limb-Girdle Muscular Dystrophy Type 2E FUNCTIONAL DATA