UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): June 19, 2018
Sarepta Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
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Delaware |
001-14895 |
93-0797222 |
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(State or other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
215 First Street
Suite 415
Cambridge, MA 02142
(Address of principal executive offices, including zip code)
(617) 274-4000
(Registrant’s Telephone Number, Including Area Code)
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instructions A.2. below):
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Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
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Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
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Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
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Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Indicate by check mark whether the registrant is an emerging growth company as defined in as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 7.01.Regulation FD Disclosure.
On June 19, 2018, Sarepta Therapeutics, Inc. issued a press release announcing that at its first R&D Day, Jerry Mendell, M.D. presented positive preliminary results from the first three children dosed in the Phase 1/2a gene therapy micro-dystrophin trial to treat patients with Duchenne muscular dystrophy. A copy of the press release and the presentation of Jerry Mendell, M.D. and Louise Rodino-Klapac, Ph.D. are furnished as Exhibits 99.1 and 99.2, respectively, and are incorporated herein by reference.
The information in this report furnished pursuant to Item 7.01, including Exhibits 99.1 and 99.2 attached hereto, shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section. It may only be incorporated by reference in another filing under the Exchange Act or the Securities Act of 1933, as amended, if such subsequent filing specifically references the information furnished pursuant to Item 7.01 of this report.
Item 9.01.Financial Statements and Exhibits.
(d) Exhibits.
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Exhibit Number |
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Description |
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99.1 |
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99.2 |
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Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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Sarepta Therapeutics, Inc. |
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By: |
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/s/ Douglas S. Ingram |
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Douglas S. Ingram |
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President and Chief Executive Officer |
Date: June 19, 2018
Exhibit 99.1
Sarepta Therapeutics Announces that at its First R&D Day, Jerry Mendell, M.D. Presented Positive Preliminary Results from the First Three Children Dosed in the Phase 1/2a Gene Therapy Micro-dystrophin Trial to Treat Patients with Duchenne Muscular Dystrophy
-- Biopsies performed at Day 90 showed robust micro-dystrophin expression in muscle measured by all methods and observed in all three patients --
-- Significant decrease in levels of serum creatine kinase (CK), an enzyme biomarker strongly associated with muscle damage caused by Duchenne muscular dystrophy --
-- No serious adverse events (SAEs) observed --
CAMBRIDGE, Mass., June 19, 2018 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases, announced that at the Company’s R&D Day, Jerry Mendell, M.D. of Nationwide Children’s Hospital presented positive preliminary results from its Phase 1/2a gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with Duchenne muscular dystrophy (DMD). Dr. Mendell presented the following preliminary data on the first three patients enrolled in the study:
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All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry. Mean gene expression, as measured by percentage of micro-dystrophin positive fibers was 76.2% and the mean intensity of the fibers was 74.5% compared to normal control. |
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All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 38.2% compared to normal utilizing Sarepta’s method, or 53.7% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue. |
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A mean of 1.6 vector copies per cell nucleus was measured in patients, consistent with the high micro-dystrophin expression levels observed. |
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No serious adverse events (SAEs) were observed in the study. Two patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week and returned to baseline levels. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing. |
Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empirically optimized the AAVrh74.MHCK7 specifically for DMD:
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The AAVrh74 vector can be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat neuromuscular diseases. |
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As a rhesus monkey-derived AAV vector, AAVrh74 appears to show lower immunogenicity rates in existing early-stage clinical studies than expected with other human AAV vectors. |
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The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with DMD, who typically die from pulmonary or cardiac complications. In preclinical models, micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels observed in skeletal muscles. |
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The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be important for maintaining the protective functional characteristics of dystrophin. |
“As a genetic medicine company, our goal is to work with the world’s leading clinicians and scientists to advance scientific discoveries to the clinic and, ultimately, to therapies that profoundly improve and extend the lives of those living with Duchenne muscular dystrophy and other rare, fatal diseases,” stated Doug Ingram, Sarepta’s president and chief executive officer. “Since the discovery of the dystrophin gene in 1986, scientists, clinicians, patient advocates and the biotech ecosystem have tirelessly searched for ways to restore or replace dystrophin and rescue boys with DMD from the damage and early death. Dr. Mendell’s results, if confirmed in additional patients, studies, measures and time points, represent a monumental leap forward in the direction of our goal.”
Dr. Mendell added, “I have been waiting my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin. Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD. I look forward to treating more patients in the clinical study to generate the data necessary to bring this therapy to patients with DMD, with the goal of dramatically changing the course of the disease.”
“For years, PPMD has been interested in the potential of gene therapy as a treatment for Duchenne. At a critical moment in development in early 2017 – with the help and support of our amazing community – we were thrilled to be able to fund this important project of Drs. Mendell and Rodino-Klapac. To have reached this moment today is incredible and we are grateful to Sarepta for their investment and partnership in moving this therapeutic approach forward. While these are early days and work remains to fully understand the full potential of gene therapies, these first signals are encouraging. We remain hopeful that this will lead to a viable treatment for Duchenne,” stated Pat Furlong, Parent Project Muscular Dystrophy’s (PPMD) founding president and chief executive officer.
PPMD committed $2.2 million to the trial, with support from additional Duchenne foundations and families.
About Sarepta Therapeutics
Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying Duchenne muscular dystrophy (DMD) drug candidates. For more information, please visit www.sarepta.com.
Forward-Looking Statements
This press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements regarding the design and potential benefits of the AAVrh74 vector, including its ability to systemically and robustly being delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier and its potential to show lower immunogenicity rates; the ability of the
MHCK7 promoter to robustly express in the heart; the potential of the transgene to maintain the protective functional characteristics of dystrophin; Sarepta’s goal to work with the world’s leading clinicians and scientists to advance scientific discoveries to the clinic and, ultimately, to therapies that profoundly improve and extend the lives of those living with DMD and other rare, fatal diseases; and the potential of Dr. Mendell’s results to represent a monumental leap forward in the direction of Sarepta’s goal, an unprecedented advancement in the treatment of DMD and dramatically change the course of the disease.
These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta’s control. Actual results could materially differ from those stated or implied by these forward-looking statements as a result of such risks and uncertainties. Known risk factors include, among others: success in preclinical testing and early clinical trials, especially if based on a small patient sample, does not ensure that later clinical trials will be successful, and initial results from a clinical trial do not necessarily predict final results; Sarepta’s ongoing research and development efforts may not result in any viable treatments suitable for commercialization due to a variety of reasons, some of which may be outside of Sarepta’s control, including the results of future research may not be consistent with past positive results or may fail to meet regulatory approval requirements for the safety and efficacy of product candidates, possible limitations of Company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, and regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover Sarepta’s product candidates; and even if Sarepta’s programs result in new commercialized products, Sarepta may not achieve any significant revenues from the sale of such products; and those risks identified under the heading “Risk Factors” in Sarepta’s most recent Annual Report on Form 10-K for the year ended December 31, 2017 and most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.
Any of the foregoing risks could materially and adversely affect the Company’s business, results of opera-tions and the trading price of Sarepta’s common stock. We caution investors not to place considerable reli-ance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.
Internet Posting of Information
We routinely post information that may be important to investors in the 'For Investors' section of our website at www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.
Source: Sarepta Therapeutics, Inc.
Media and Investors:
Sarepta Therapeutics, Inc.
Ian Estepan, 617-274-4052
iestepan@sarepta.com
or
W2O Group
Rachel Hutman, 301-801-5540
rhutman@w2ogroup.com
Exhibit 99.2
Jerry Mendell, MD Center for Gene Therapy Nationwide Children’s Hospital Columbus, OH Louise Rodino-Klapac, PhD Sarepta Therapeutics Cambridge, MA
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, spinal muscular atrophy.
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 cardiomyopathy • Incidence of 1:3500–5000 male births worldwide • Elevated CK levels CK, creatine kinase.
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 complex –restore function 4 DG, dystroglycan; nNOS, neuronal nitric oxide synthase. Image adapted from Fairclough RJ, et al. Nat Rev Genet. 2013;14(6):373-378. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 THERAPEUTICS, INC. 2018 R&D DAY
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
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 typical AAV construct with gene of interest cDNA, complementary DNA; kb, kilobase; pA, polyadenylation signal; nm, nanometer; Pro, promoter sequence. AAV Capsid SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 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 Domain Central Rod Domain (24 spectrin-like repeats, 4 hinges) Domain SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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. 1995;4(8):1245-1250. • Clinical observations paved the way for mini-gene therapy •61-year-old ambulatory patient with Becker muscular dystrophy had 46% of dystrophin coding region deleted (Del 17-48)1 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 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 mini-gene therapy •61-year-old ambulatory patient with Becker muscular dystrophy had 46% of dystrophin coding region deleted (Del 17-48)1 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 R2and R3critical for force production. R16and R17are required for the association of nNOS with the DAPC. Not present in this patient. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 1454-1568 1569-1676 1677-1778 1779-1874 1875-1991 1992-2101 2102-2208 2209-2318 2319-2423 2424-2470 668-717 2471-2577 2578-2686 2687-2802 2803-2931 2932-3040 3041-3112 3090-3360 3361-3685 2 3 4 5 6 7 8 1 10 11 12 13 14 15 16 9 17 50 51 52 53 54 55 56 57 58 59 60 69 65 66 67 68 70 71 72 73 74 75 76 77 78 79 61 62 63 64 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 NH3+ COO- H1 H2 H3 H4 CR Rod ⍺1- ST ß1- ST SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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-DYSTROPHIN pA ITR ITR 145 bp 795 bp 97 bp 3,591 bp 53 bp 145 bp ABD 1 SR1 SR2 SR3 2 SR24 4 CR 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 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 pre-existing immunogenicity:Nonhuman serotype guards against pre-existing immunity (still under evaluation; currently <15%) • Demonstrated safety — No observed adverse effect level (NOAEL) in primates and mice • GLP toxicity studies: IM, n=5; ILP, n=3; IV, n=2 — 14 human subjects dosed (IM, n=4; IV, n=10) without vector-related adverse effects — 6 approved INDs 13 GLP, good laboratory practice; ILP, isolated limb perfusion; IM, intramuscular; IND, investigational new drug; IV, intravenous. *Unpublished data based on screening of approximately 70 patients with Limb girdle muscular dystrophy (LGMD) or DMD. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Definitive Preclinical Studiesof Systemic Delivery of Micro-dystrophin in mdxMice
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 DAY Assess efficacy and safety 12 weeks after gene delivery •Transgene expression and biodistribution •Western blot and qPCR •Histological analysis •Functional benefit •Safety and toxicity
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, INC. 2018 R&D DAY
Widespread Expression After Micro-dystrophin Gene Delivery 17 Dystrophin Expression (IHC) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY WT, wild-type.
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 (%)
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 x 1012vg 6 x 1012vg 1.2 x 1013vg Effective Doses mN, milliNewtons. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY P<0.05 P<0.01
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 MDX-LR Wildtype Diaphragm Tibialis Anterior Triceps Histological Improvement in Muscles Treated With AAVrh74.MHCK7.Micro-dystrophin 20 Pathologist Conclusions Efficacy • Injection of mdx mice with the test article substantially reduced in a dose-dependent manner the skeletal myopathy that developed in vehicle-treated, age-matched mdx mice Safety • The test article AAVrh74.MHCK7.Microdystrophin (administered at 2 x 1012, 6 x 1012, or 1.2 x 1013 vg total dose by IV injection at 4-6 weeks of age) did not induce anatomic lesions in muscles of male mdx knockout mice at 12 weeks after administration SAREPTA THERAPEUTICS, INC. 2018 R&D DAY P<0.05 P<0.05 P<0.05
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 mdx-LR 6e12 vg 1.2e13 vg Specific Force in TA Eccentric Contractions CK •No difference in fatigue in the 6 x 1012vg and 1.2 x 1013vg doses SAREPTA THERAPEUTICS, INC. 2018 R&D DAY P<0.01 P<0.01 P<0.05
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; kDA, kilodaltons; Kid, kidney; Liv, liver; Lng, lung; Pso, Psoas; Qd, quadriceps; Spl, spleen; Tri, triceps, WB, Western Blot. MHCK7 promoter expresses micro-dystrophin in muscle (WB) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 1.2 x 1013vg 1.2 x 1013vg 6 x 1012vg 6 x 1012 vg Micro-dystrophin Micro-dystrophin α-actinin γ-tubulin MHCK7 promoter does not express micro-dystrophin in off-target organs (WB)
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
Endogenous Dystrophin and Micro-dystrophin.FLAG Colocalize to the Sarcolemma in NHPs SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 24
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-dystrophin Tissue Expression (WB) Micro-dystrophin (138 kDa) GAPDH (37 kDa) • NHPs were treated with 2 x 1014vg/kg with AAVrh74.MHCK7.Micro-dystrophin SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 gamma; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cells. *CBC/Chemistries Performed at Charles Rivers and histopathology formally reviewed by a veterinary pathologist (GEMpath Inc.). †Systemic delivery of AAVrh74.MHCK7.micro-dystrophin did not induce any anatomic lesions. Serum (1:X Dilution) Weeks from gene transfer Anti-AAVrh74 Antibodies Day-7 2 4 8 12 SPC/106PBMCs 100 0 200 300 400 2500 3000 3500 4000 4500 500 IFNγELISpot of AAVrh74 and Micro-dystrophin Peptide Responses Weeks from gene transfer DMSO (Negative Control) ConA(Positive Control) AAVrh pool 1 AAVrh pool 2 AAVrh pool 3 micro-dystrophin pool 1 micro-dystrophin 2 micro-dystrophin 3 micro-dystrophin 4 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 muscle types • Reduction in CK • Improved functional measures • No toxicity SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 27
Evidence From Spinal Muscular Atrophy
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, Pediatric Neuromuscular Clinical Research Network. *Month defined as 30 days. 1. Finkel RS, et al. Neurology. 2014;83(9):810-817. Cohort Current Median Age (Survival) (months*) 1 47 2 33 2 years Outcome: death or >16 hr/day of ventilator dependence for ≥2 weeks Construct: AAV9 serotype SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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‡ ≥10 seconds§ ≥30 seconds∥ E.04 6 ✓ ✓ ✓ ✓ ✓ ✓ E.05 4 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.06 2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.07 4 ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.08 8 ✓ E.09 5 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.10 1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.11 2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.12 3 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.13 1 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.14 4 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ E.15 2 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ *Bayley Scales of Infant and Toddler Development, item #20, rolls a minimum 180o from back in only one direction. †Bayley Scales of Infant and Toddler Development, item #20, rolls a minimum 180o from back to both left and right. ‡Sitting unassisted for ≥5 seconds is in accordance with the criteria of item 22 in the Bayley Scales of Infant and Toddler Development – gross motor subtest and surpasses the 3-second count used as a basis for sitting (test item 1) in the Hammersmith Functional Motor Scale – Expanded for SMA (HFMSE). §Sitting unassisted for ≥10 seconds is in accordance with the criteria in the World Health Organization – MultiCentre Growth Reference Study. ∥Sitting unassisted for ≥30 seconds defines functional independent sitting and is in accordance with the criteria of item 26 in the Bayley Scales of Infant and Toddler Development – gross motor subtest. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Gene Transfer at 4 Weeks 31 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Gene Transfer at 4 Weeks 32 SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Phase 1/2 Clinical Trial
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
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) — Ascend and descend 4 steps — Hand-held Dynamometry (HHD) — Cardiac MRI (at 1 year) SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 35 MRI, magnetic resonance imaging.
Clinical Study Results From Cohort B
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
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
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
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 Block 2 Standard Curve (% NC pool)
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 Block 2 Standard Curve (% NC pool) Western quantitation method Mean micro-dystrophin expression compared vs normal Sarepta 38.2% (not adjusted for fat and fibrotic tissue) Nationwide 53.7%(adjusted for fat and fibrotic tissue)
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 DAY
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 values are usually observed in patients with DMD who are between the ages of 2 to 5 years1 43 1. Zatz M, et al. J Neurol Sci .1991;102:190–196. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 values are usually observed in patients with DMD who are between the ages of 2 to 5 years1 • After the age of 7 years, serum CK values decrease with time and clinical progression — Serum CK values decline at a rate of ~8% per year in patients who are >7 years of age 44 1. Zatz M, et al. J Neurol Sci .1991;102:190–196. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 values are usually observed in patients with DMD who are between the ages of 2 to 5 years1 • After the age of 7 years, serum CK values decrease with time and clinical progression — Serum CK values decline at a rate of ~8% per year in patients who are >7 years of age • The rate of serum CK values decrease is impacted by the extent of disease progression — The serum CK values of wheelchair-dependent patients, and patients with advanced muscle loss, decrease more slowly than other DMD patients 45 1. Zatz M, et al. J Neurol Sci .1991;102:190–196. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 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 values are usually observed in patients with DMD who are between the ages of 2 to 5 years1 • After the age of 7 years, serum CK values decrease with time and clinical progression — Serum CK values decline at a rate of ~8% per year in patients who are >7 years of age • The rate of serum CK values decrease is impacted by the extent of disease progression — The serum CK values of wheelchair-dependent patients, and patients with advanced muscle loss, decrease more slowly than other DMD patients 45 1. Zatz M, et al. J Neurol Sci .1991;102:190–196. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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
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
Patient Videos
Patient Home Video: Stair Climbing 2 days post-treatment 60 days post-treatment SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 49
Patient Video SAREPTA THERAPEUTICS, INC. R&D DAY 2018 Post-treatment 50
Patient Home Video: 90 Days Post-Treatment SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 51
Safety
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 coincident with increased steroid dosing — Did not correlate with liver enzyme elevations or any other abnormality 53 GGT, gamma-glutamyl transpeptidase. SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
Adaptive Clinical Study Design
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-meter timed test —100-meter timed test SAREPTA THERAPEUTICS, INC. 2018 R&D DAY
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 of the MHCK7 promoter will significantly alter DMD disease course in the heart • New placebo-controlled study design could serve as the basis for registration SAREPTA THERAPEUTICS, INC. 2018 R&D DAY 56