Sarepta Therapeutics, Inc. · NASDAQ:SRPT
Sarepta Therapeutics — Investor Day (June 2018)
56 slides from Sarepta Therapeutics's investor day presentation, Jun 19, 2018
Slide 1: Jerry Mendell, MD and Louise Rodino-Klapac, PhD
Jerry Mendell, MD Center for Gene Therapy Nationwide Children’s Hospital Columbus, OH Louise Rodino-Klapac, PhD Sarepta Therapeutics Cambridge, MA
Slide 2: Today's Presentation
Today’s Presentation • DMD background and the engineering of micro-dystrophin • Micro-dystrophin preclinical data • Evidence of gene therapy efficacy from SMA • Clinical data of micro-dystrophin gene therapy for DMD SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 2 DMD, Duchenne muscular dystrophy; SMA, spi
Slide 3: DMD: Our motivation
DMDOur motivation SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 3 Picture of DMD • Most common life-threatening childhood patient taken by Duchenne (1863) muscular dystrophy • Devastating disease —Boys are wheelchair-dependent by 12-13 years old • Patients die in early 20s-30s from pneumonia and/or cardio
Slide 4: Dystrophin-associated Protein Complex (DAPC)
Dystrophin-associated Protein Complex (DAPC) • Dystrophin is a core component of the DAPC • Functions as a “shock absorber” during muscle contraction • Loss of dystrophin causes disassembly of the entire DAPC • Normal muscle contraction in DMD causes chronic muscle breakdown • Restore the DAPC compl
Slide 5: AAV Is a Delivery Vehicle for Dystrophin
Receptor uncoating nuclear penetration ssDNA dsDNA • “Mini” chromosome • Does not integrate into host genome AAV particle Muscle Cell Adeno-associated Virus (AAV) Is a Delivery Vehicle for Dystrophin 5 DNA, deoxyribonucleic acid; dsDNA, double-stranded DNA; ssDNA, single-stranded DNA. SAREPTA THERAP
Slide 6: AAV Is a Delivery Vehicle for Dystrophin
REP CAP ITRs 145 bp Packaging signal ~5 kb Adeno-associated Virus (AAV) Is a Delivery Vehicle for Dystrophin • ssDNA virus • Does not cause disease in humans • Long-term persistence in cells 6 Open reading frames of AAV kb, kilobase; nm, nanometer. AAV Capsid SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 7: AAV Is a Delivery Vehicle for Dystrophin
REP CAP ITRs 145 bp Packaging signal ~5 kb cDNA cassette pA Pro Adeno-associated Virus (AAV) Is a Delivery Vehicle for Dystrophin • ssDNA virus • Does not cause disease in humans • Long-term persistence in cells • Gene therapy requires replacement of viral genes with gene of interest 7 Structure of
Slide 8: Pathogenesis of DMD: Dystrophin domains
Domain Dystrophin encodes a protein with 4 domains Pathogenesis of DMD 8 • Dystrophin is the largest gene in the human genome at 2.6 Mb —Poses a critical obstacle for molecular manipulation CR, cysteine-rich; CT, carboxy-terminal; H, hinge; Mb, megabase; N, amino-terminal; R, spectrin-like repeat. N
Slide 9: How Do We Decrease the Size of the DMD Gene?
How Do We Decrease the Size of the DMDGene?Birth of the mini-dystrophins 9 R2 and R3 critical for force production. R16 and R17 are required for the association of nNOS with the DAPC. Not present in this patient. 1. England SB, et al. Nature. 1990;343(6254):180-182. 2. Wells DJ, et al. Hum Mol Genet
Slide 10: How Do We Decrease the Size of the DMD Gene?
How Do We Decrease the Size of the DMDGene?Birth of the mini-dystrophins 10 “Mini”-dystrophin2 (6 Kb) 1. England SB, et al. Nature. 1990;343(6254):180-182. 2. Wells DJ, et al. Hum Mol Genet. 1995;4(8):1245-1250. N H1 R1 R2 R3 H3 R20 R21 R22 R23 R24 H4 CR CT • Clinical observations paved the way for
Slide 11: Challenge: Modify Dystrophin to <5 Kb to Fit AAV
DG Challenge: Further Modify Dystrophin to <5 Kb So That It Can Fit in AAV Particle 11 N H1 R1 R2 R3 R4 R5 R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 H3 H2 R20 R21 R22 R23 R24 H4 CR CT 14-240 241-336 337-447 448-556 557-667 718-828 829-934 935-1045 1046-1154 1155-1263 1264-1367 1368-1453 14
Slide 12: AAVrh74.MHCK7.Micro-dystrophin
AAVrh74 AAVrh74.MHCK7.Micro-dystrophin • MHCK7 promoter enables robust dystrophin expression in heart and skeletal muscle • AAVrh74 provides broad distribution to allmuscle types, including the heart and diaphragm 12 ITR, inverted tandem repeat; SR, spectral-like repeat. MHCK7 PROMOTER INTRON MICRO-
Slide 13: Strong Profile for AAVrh74
Strong Profile for AAVrh74 • Demonstrated efficacy — Ideal systemic biodistribution vs other vectors in preclinical testing — Widespread high-level gene expression after IV infusion in preclinical animal models — Gene expression in Phase 1 trials across multiple diseases by IM and IV delivery* — Low
Slide 14: Definitive Preclinical Studies of Systemic Delivery in mdx Mice
Definitive Preclinical Studiesof Systemic Delivery of Micro-dystrophin in mdxMice
Slide 15: Preclinical IV Study Design
Preclinical IV Study Design for the Delivery of AAVrh74.MHCK7.Micro-dystrophin 15 2 x 1012 vg total dose (8 x 1013 vg/kg) 6 x 1012vg total dose (2 x 1014vg/kg) 1.2 x 1013vg total dose (6 x 1014vg/kg) qPCR, quantitative polymerase chain reaction; vg, viral genomes. SAREPTA THERAPEUTICS, INC. 2018 R&D
Slide 16: Reassembly of the DAPC With Micro-dystrophin
Reassembly of the Dystrophin-associated Protein Complex With Micro-dystrophin 16 Image adapted from Fairclough RJ, et al. Nat Rev Genet. 2013;14(6):373-378. Dystrophin and BSG Expression (IHC) BSG, β-sarcoglycan; IHC, immunohistochemistry; LR, locoregional. Schematic of the DAPC SAREPTA THERAPEUTICS
Slide 17: Widespread Expression After Micro-dystrophin Gene Delivery
Widespread Expression After Micro-dystrophin Gene Delivery 17 Dystrophin Expression (IHC) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY WT, wild-type.
Slide 18: Widespread Expression After Micro-dystrophin Gene Delivery
Widespread Expression After Micro-dystrophin Gene Delivery SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 18 Dystrophin Positive-Fibers (%) 0 50 100 Tibialisanterior Gastrocnemius Quadriceps Psoas Triceps Diaphragm Gluteus Wt 1 x 1013vg 6 x 1012vg 1.2 x 1012vg Fiber Expression (%)
Slide 19: Reduced Fibrosis Accompanies Functional Improvement in the Diaphragm
Sirius Red-Diaphragm * 0 10 20 30 Collagen (%) Reduced Fibrosis Accompanies Functional Improvement in the Diaphragm 19 0 100 200 300 Specific Force (mN/mm2) Specific Force-Diaphragm Fibrosis, Sirius Red staining. Muscle, fast green staining. Evaluation of Fibrosis in the Diaphragm (IHC) WT mdx-LR 2
Slide 20: Histological Improvement in Treated Muscles
Fiber Diameter (μm) **** 0 5 10 15 20 25 Wildtype mdx-LR 2e12 vg 6e12 vg 1.2e13… Tibialis Anterior Fiber Diameter (μm) **** Diaphragm 0 10 20 30 40 50 Wildtype mdx-LR 2e12 vg 6e12 vg 1.2e13 vg Fiber Diameter (μm) **** Triceps 0 10 20 30 40 50 Wildtype mdx-LR 2e12 vg 6e12 vg 1.2e13 vg AAV.microdys MD
Slide 21: CK Reduction, Muscle Strength, and Stamina Improvement in mdx Mice
0.6 0.7 0.8 0.9 1.0 1.1 1 2 3 4 5 0 100 200 300 SpecificForce (mN/mm2) * 0 200 400 600 800 1000 CK Levels(U/L) CK Reduction, Muscle Strength, and Stamina Improvement in mdxMice Treated With AAVrh74.MHCK7.Micro-dystrophin 21 Force (Fraction oF First Contraction) EccentricContraction(CycleNumber) Wt m
Slide 22: Widespread Biodistribution Across 8 Muscle Groups in mdx Mouse
Hrt Lng Liv Kid Spl Gon Dia Pso Tri Qd Gas TA Widespread Biodistribution Throughout 8 Different Muscle Groups With Systemic Delivery of Micro-dystrophin in the mdxMouse Model 22 2 x 1012vg 6 x 1012vg 1.2 x 1013vg Vg copies per μg Total DNA Dia, diaphragm; Gas, gastrocnemius, Gon, gonadal; Hrt, heart
Slide 23: Micro-dystrophin With FLAG Tag in NHPs
Micro-dystrophin With FLAG Tag Will Reveal Transgene Distribution in Nonhuman Primates (NHPs) 23 MHCK7 PROMOTER INTRON MICRO-DYSTROPHIN pA ITR 145 bp 795 bp 97 bp 3,591 bp 53 bp 145 bp DYKDDDDK FLAG ITR (FLAG epitope) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 24: Endogenous Dystrophin and Micro-dystrophin.FLAG Colocalize in NHPs
Endogenous Dystrophin and Micro-dystrophin.FLAG Colocalize to the Sarcolemma in NHPs SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 24
Slide 25: Widespread Biodistribution With Systemic Delivery in NHPs
GLUT DIA LMG QD TRI HAM TA GAS Widespread Biodistribution With Systemic Delivery of Micro-dystrophin in NHPs 25 FLAG H & E GAPDH, glyceraldehyde 3-phosphate dehydrogenase; H & E, hematoxylin and eosin; HAM, hamstring; LMG, left adductor magnus. Micro-dystrophin Tissue Expression (IHC) Micro-dystroph
Slide 26: No Abnormal Immunological Responses in NHPs
0 100,000 200,000 300,000 400,000 500,000 BL 2 4 8 12 No Abnormal Immunological Responses Were Observed With Systemic Delivery of Micro-dystrophin in NHPs*† 26 BL, baseline; CBC, cell blood count; ConA, concanavalin A; ELISpot, enzyme-linked immunospot; DMSO, dimethyl sulfoxide; IFNγ, interferon gam
Slide 27: Conclusions
Conclusions Construct optimized for use in DMD • AAVrh74 efficiently transduces all muscle types • Low pre-existing immunity for AAVrh74 • MHCK7 promoter allows for cardiac and skeletal transgene muscle expression Preliminary preclinical results • Widespread micro-dystrophin expression across all mu
Slide 28: Evidence From Spinal Muscular Atrophy
Evidence From Spinal Muscular Atrophy
Slide 29: AVXS-101: Survival Data
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Age (months*) AVXS-101: Survival Data (as of Feb 2018) 29 Cohort 1 6.7 x 1013 vg/kg Cohort 2 2 x 1014vg/kg PNCR Natural History Study1: 75% event-free 50% event-free 25% event-free 8% event-free PNCR, Pediatr
Slide 30: AVXS-101: Motor Milestones
AVXS-101: Motor Milestones Two children are able to crawl, pull to a stand, and stand and walk independently 30 Cohort2 2 x 1014 vg/kg Age at gene therapy (months) Motor MilestoneAchievement Brings hand to mouth Head control Partial roll* Roll† Sitting with assistance Sitting Unassisted ≥5 seconds‡
Slide 31: Gene Transfer at Weeks
Gene Transfer at 4 Weeks 31 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 32: Gene Transfer at Weeks
Gene Transfer at 4 Weeks 32 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 33: Phase 1/2 Clinical Trial
Phase 1/2 Clinical Trial AREPTA NATIONWIDE THERAPEUTICS “= CHILDREN'S
Slide 34: Open-label Trial Design
Open-label Trial Design • 12 subjects with DMD –open trial — Cohort A: 6 subjects; 3 months-3 years of age — Cohort B: 6 subjects; 4-7 years of age • Inclusion criteria — Confirmed DMDmutation between exons 18-58, inclusive — Negative for AAVrh74 antibodies SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 34
Slide 35: Cohort B Endpoints
Cohort B (4-7 years of age) Endpoints • Primary endpoint: — Safety • Secondary endpoints: — Change in micro-dystrophin expression pre-vs post-treatment — Decrease in CK — 100-meter timed test (100m) — North Star Ambulatory Assessment (NSAA; 10-meter timed test included) — Timed Up and Go (TUG) — Asc
Slide 36: Clinical Study Results From Cohort B
Clinical Study Results From Cohort B
Slide 37: Subject Demographics at Baseline
Subject Demographics at Baseline SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 37 Subject Age (years) CKLevelsat Baseline (U/L) 1 5 20,691 2 4 23,414 3 6 34,942 4 4 29,210
Slide 38: Robust Micro-dystrophin Expression in Gastrocnemius Fibers
Robust Micro-dystrophin Expression in Muscle Fibers from the Gastrocnemius 38 Subject 2 Subject 1 Subject 3 Post- Treatment Pre- Treatment Normal Control Micro-dystrophin expression (IHC) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 39: Robust Micro-dystrophin Expression in Gastrocnemius Fibers
Robust Micro-dystrophin Expression in Muscle Fibers from the Gastrocnemius 39 Subject Mean Intensity Percentage of Dystrophin-Positive Fibers 1 82.0 % 78.0 % 2 59.0 % 73.5 % 3 83.0 % 77.0 % Mean 74.5 % 76.2 % SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Slide 40: Detection of Micro-dystrophin Expression by Western Blot
Detection of Micro-dystrophin Expression by Western Blot Post-Treatment Full-length Dystrophin Micro-dystrophin Actinin Subject 3 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 40 80 Subject 2 Standard Curve (% NC pool) 40 20 10 5 Post Pre Post Pre DMD Subject 1 80 Block 1 40 20 10 5 Post Pre Post Pre DMD
Slide 41: Detection of Micro-dystrophin Expression by Western Blot
Detection of Micro-dystrophin Expression by Western Blot Post-Treatment Full-length Dystrophin Micro-dystrophin Actinin Subject 3 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 41 80 Subject 2 Standard Curve (% NC pool) 40 20 10 5 Post Pre Post Pre DMD Subject 1 80 Block 1 40 20 10 5 Post Pre Post Pre DMD
Slide 42: Vector Genome Copy Number Is >1 Copy Per Nucleus
Subject VectorCopies/μg DNA Copies per Nucleus* 1 >105 1.7 2 >105 1.3 3 >105 1.9 Vector Genome Copy Number Is >1 Copy Per Nucleus, Consistent With Micro-dystrophin Expression Levels 42 *1 vector copy per nuclei translates to ~50% micro-dystrophin positive fibers SAREPTA THERAPEUTICS, INC. 2018 R&D D
Slide 43: Creatine Kinase (CK) in DMD
Creatine Kinase (CK) in DMD • Increased permeability of the sarcolemma leads to the leakage of CK from muscle fibers • Increased serum CK values are the hallmark of muscle damage, and are elevated in DMD (and other muscle diseases) — Markedly elevated CK values are diagnostic of DMD • Peak serum CK
Slide 44: Creatine Kinase (CK) in DMD
Creatine Kinase (CK) in DMD • Increased permeability of the sarcolemma leads to the leakage of CK from muscle fibers • Increased serum CK values are the hallmark of muscle damage, and are elevated in DMD (and other muscle diseases) — Markedly elevated CK values are diagnostic of DMD • Peak serum CK
Slide 45: Creatine Kinase (CK) in DMD
Creatine Kinase (CK) in DMD • Increased permeability of the sarcolemma leads to the leakage of CK from muscle fibers • Increased serum CK values are the hallmark of muscle damage, and are elevated in DMD (and other muscle diseases) — Markedly elevated CK values are diagnostic of DMD • Peak serum CK
Slide 46: CK Levels Dramatically Reduced with Micro-dystrophin Therapy
0 10,000 20,000 30,000 40,000 0 1 2 3 4 5 6 7 8 9 10 11 12 CK Value (U/L) Months Post-Treatment Subject 1 Subject 2 Subject 3 Subject 4 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 46 CK Values Over Time* 87% decrease from Day 0 (n=3) CK Levels Are Dramatically Reduced with Micro-dystrophin Therapy
Slide 47: Micro-dystrophin Gene Therapy Upregulates DAPC Proteins
Micro-dystrophin Gene Therapy Upregulates DAPC Proteins α-Sarcoglycan β-Sarcoglycan Normal Control Pre-treatment Expression of DAPC Proteins in Muscle Fibers from the Gastrocnemius of Subject 2 (IHC) Post-treatment SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 47
Slide 48: Patient Videos
Patient Videos a ¢ SAREPTA » NATIONWIDE THERAPEUTICS CHILDREN'S
Slide 49: Patient Home Video: Stair Climbing
Patient Home Video: Stair Climbing 2 days post-treatment 60 days post-treatment SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 49
Slide 50: Patient Video Post-treatment
Patient Video SAREPTA THERAPEUTICS, INC. R&D DAY 2018 Post-treatment 50
Slide 51: Patient Home Video: Days Post-Treatment
Patient Home Video: 90 Days Post-Treatment SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 51
Slide 52: SAREPTA » NATIONWIDE
SAREPTA » NATIONWIDE THERAPEUTICS CHILDREN'S
Slide 53: Safety (n=4)
Safety (n=4) • No Serious Adverse Events (SAEs) in this study • 2 subjects had elevated GGT that resolved with increased steroids within a week and returned to baseline levels • No other clinically significant laboratory findings • Patients had transient nausea generally within the first week coinci
Slide 54: Adaptive Clinical Study Design
Adaptive Clinical Study Design
Slide 55: Cohort C: Addition of Placebo-controlled Study Cohort
Cohort C (4-7 years of age): Addition of Placebo-controlled Study Cohort 55 Subjects • Treatment arm, n=12 • Placebo arm, n=12 —Crossover at 1 year Endpoints • Primary: —Safety —Demonstration of micro-dystrophin protein expression • Secondary: —Decrease in CK —Time to rise —Ascend 4 steps —NSAA —10-
Slide 56: Summary
Summary Preliminary Clinical Results • Consistent with preclinical results • Widespread micro-dystrophin expression • Upregulation of the DAPC complex • Reduction in CK is unprecedented • Vector genome copy levels (>1 copy/nucleus) are consistent with robust micro-dystrophin protein expression • Use