UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 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): January 9, 2015
Sarepta Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 001-14895 | 93-0797222 | ||
| (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 Instruction A.2. below):
| ¨ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ¨ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ¨ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ¨ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Item 2.02 Results of Operations and Financial Condition.
Chris Garabedian, President and Chief Executive Officer of Sarepta Therapeutics, Inc. (the “Company”), will be conducting meetings with several investors attending the 33nd Annual J.P. Morgan Healthcare Conference (the “Conference”) in San Francisco from January12, 2015 through January 15, 2015. At these meetings, Mr. Garabedian will disclose that the Company had cash and other investments of $211 million as of December 31, 2014 (unaudited).
Item 5.02 Departure of Directors or Certain Officers; Election of Directors; Appointment of Certain Officers; Compensatory Arrangements of Certain Officers.
On January 9, 2015, after a tenure of more than a decade on the Company’s Board of Directors (the “Board”), John Hodgman notified the Company that he will be participating in an extended religious mission and, as result, has decided to resign from his positions as Director, Interim Chairman of the Board, Chairman of the Audit Committee and member of the Board’s audit and compensation committees effective on the date of the next annual meeting of stockholders, which the Company anticipates will be held in June of this year. There were no known disagreements between Mr. Hodgman and the Company or any officer or director of the Company which led to Mr. Hodgman’s resignation.
“We at Sarepta value John’s sage advice and will miss his insightful guidance as a director and in his role as interim chair. We thank him for more than a decade of service to the Company and wish him all the best in his missionary assignment and future endeavors” said Chris Garabedian, President and Chief Executive Officer of the Company.
Item 7.01 Regulation FD Disclosure.
The disclosure in Item 2.02 above is hereby incorporated by reference into this Item 7.01.
As part of the meetings at the Conference, on January 15, 2015, Mr. Garabedian will deliver the slide presentation attached to this report as Exhibit 99.1, which is incorporated herein by reference.
The information in this report and Exhibit 99.1 to this report is furnished pursuant to Items 2.02 and 7.01 and shall not be deemed “filed” for the purposes of Section 18 of the Securities and 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 Items 2.02 and 7.01 of this report.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits. The following exhibit is furnished as part of this report.
| Exhibit |
Description | |
| 99.1 | Sarepta Therapeutics, Inc. slide presentation to be presented at the 33rd Annual J.P. Morgan Healthcare Conference on January 15, 2015. | |
SIGNATURES
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.
| Sarepta Therapeutics, Inc. | ||
| By: | /s/ Christopher Garabedian | |
| Christopher Garabedian | ||
| President and Chief Executive Officer | ||
Date: January 12, 2015
| Exhibit 99.1
|
Exhibit 99.1
REALIZING THE POTENTIAL OF RNA-BASED TECHNOLOGY
JP MORGAN HEALTHCARE CONFERENCE
JANUARY 15, 2015
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FORWARD LOOKING STATEMENTS
This presentation contains forward-looking statements. These forward-looking statements generally can be identified by the use of words such as “believes or belief,” “anticipates,” “plans,” “expects,” “will,” “intends,” “potential,” “possible,” “advance” and similar expressions. These forward-looking statements include statements about our use of unique PMOs to develop treatments in areas of high unmet need; our plans to continue advancing eteplirsen towards regulatory approval and moving follow-on exons into human clinical trials; the potential broad application of our chemistries and technolog ies across a variety of disease areas; our strategic research focus and plans to continue advancing our chemistry platform and technologies, including our To ll-like Receptor Antagonist Program, into additional indications in rare or other diseases and against antibiotic-resistant bacterial infections, including through collaborations; our capitalization status; the potential market for eteplirsen and follow-on exon skipping drugs; our plans and ability to comply with the U.S. Food and Drug Administration (FDA) requirements to consider a new drug application (NDA) submission for eteplirsen complete; our plans and ability to successfully initiate and complete additional clinical trials for eteplirsen and other follow-on product candidates in Duchenne Muscular Dystrophy (DMD) and providing additional data, analysis and other information requested by the FDA and potential timing of the same; the potential of and timing of an NDA submission by us, which will continue to be evaluated based on FDA discussions and as additional data become available, and a potential filing and acceptance of an NDA for eteplirsen by the FDA on an accelerated or other pathway; our continuing discussions with the EMA regarding a potential approval pathway in Europe; our beliefs regarding the potential of and safety and efficacy of our product candidates, chemistries and technologies in DMD, rare and infectious diseases and other disease areas; and the timing of and the expected or planned research, development, clinical and regulatory progress for our product candida tes. Forward-looking statements also include those made during the presentation regarding future business developments and actions and the timing of the same, including our ability to establish and protect intellectual property rights and potentially commercialize our product candidates without claims of infringement.
Each forward-looking statement contained in this presentation is subject to risks and uncertainties that could cause actual resu lts to differ materially from those expressed or implied by such statement. Applicable risks and uncertainties include, among others: we may not have sufficient funds to execute our business plans; our product candidates and or the use of or application of our chemistries and technology may fail in the research, development or commercialization process for various reasons; we may not be able to comply with all regulatory requests and requirements for the research, dev elopment and commercialization of our product candidates; the FDA may determine that substantial additional data is required for accelerated or other approv al of eteplirsen or that our potential NDA submission for eteplirsen does not qualify for filing, even with additional information; the results of our ongoing research and development efforts and clinical trials may not be positive or consistent with prior results or demonstrate a treatment benefit ; there may be delays in timelines or we may not make an NDA submission orsuccessfully initiate, conduct or complete clinical trials, or make eteplirsen or any of our product candidates, chemistries or technologies commercially available for regulatory or other reasons; we may not be able to manufacture sufficient drug supply for our studies or commercialization; agency or court decisions with respect to our patents or those of third parties may negatively impact our business; and those risks identified under the heading “Risk Factors” in Sarepta’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 filed with the Securities and Exchange Commission (SEC), and Sarepta’s other filings with the SEC, which we encourage investors to review at www.sec.gov for a more detailed discussion on risks and uncertainties relating to our business.
Any of the foregoing risks could materially and adversely affect Sarepta’s business, results of operations and the trading price of Sarepta’s common stock. We caution investors not to place considerable reliance on the forward-looking statements contained in this presentation. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.
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SAREPTA THERAPEUTICS
CORPORATE HIGHLIGHTS
Sarepta is a late-stage development company utilizing RNA-based technology with unique phosphorodiamidate morpholino oligomers (PMOs) to develop treatments for areas of high unmet need
Priority remains on DMD – advancing eteplirsen towards regulatory approval, moving follow-on exons into human clinical trials
Differentiated PMO chemistries with broad application across variety of disease areas
Significant progress made advancing chemistry platform into additional indications in rare diseases and against antibiotic-resistant bacterial infections
5 DMD clinical trials underway
More than 10 new research programs underway
2 Chemistries tested in humans (PMO & PMOplus®)
Well-capitalized with ~$211 million in cash and other investments as of 12/31/2014
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DUCHENNE MUSCULAR DYSTROPHY
DEVASTATING RARE DISEASE WITH SIGNIFICANT UNMET NEED
Affects approximately 1 in 3,5001 boys worldwide
25,000- 30,000 patients in the U.S. and Europe
Sarepta’s lead program (Exon 51) estimated to target ~13% of DMD patients2
Follow-on Exon-Skipping Drugs have potential to treat 60-80% of DMD patients
National Human Genome Research Institute
Percent of DMD boys amenable to skipping each exon listed. Source: Annemieke Aartsma-Rus, et al. Hum Mutat. 2009 Mar;30(3):293-9.
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DMD COMPARED TO BECKER MUSCULAR DYSTROPHY (BMD)
ANY SHIFT FROM DUCHENNE TOWARDS BMD WOULD REPRESENT A MEANINGFUL DIFFERENCE IN PATIENT LIFE SPAN AND QUALITY OF LIFE
BMD is a milder phenotype with a more gradual progression1
The majority of patients with BMD remain ambulant significantly longer than patients living with DMD1
Typically between ages 5-10 as development is slow. Some patients are asymptomatic and diagnosed through abnormally
Diagnosis
high CK readings.
Difficulty Walking
Patients can often run into 20’s and may retain ability to walk through majority
Loss of Ambulation
ECKER of life through use of canes. Loss of ambulation typically occurs during 30’s.
B Lung Function Decline Generally mild. Trouble coughing and some difficulty breathing.
Cardiac Function Decline Generally mild, severe cases can lead to mortality in early 20’s.
Death
Childhood Adolesence Early Adulthood Adulthood Late Adulthood
1. Muscular Dystrophy Association
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REGULATORY UPDATE
DMD GLOBAL CLINICAL AND REGULATORY UPDATE
168 Week Data Released
All evaluable patients remained ambulant
Continued decline across all patients from week 144
Ongoing stability of respiratory function
NDA still planned for mid-2015
NDA Submission will continue to be evaluated based on FDA discussions and as additional data become available
FDA Feedback Received on Dystrophin Reassessment Protocol
Rescoring of Dystrophin-Positive Fibers by 3 Independent Pathologists Underway
FDA Feedback Received on Master Protocol for Exon 53 and Exon 45 Drugs
Agreement to proceed with primary endpoint of 6MWT in combined population
Placebo-controlled study with SRP-4045 and SRP-4053 to begin dosing patients with 30mg/kg in 1H2015
FDA communicated additional data requirements for NDA submission now planned for mid-year 2015
168-week clinical data from study 201/202
Safety data in newly exposed eteplirsen patients (subset with at least 3-month safety data); Dosing expected in 12-24 pts this month
Results from 4th Biopsy are expected for subset of patients in Study 201/202; Scheduling of biopsies underway
Dystrophin Rescore underway
Patient level natural history data being collected
EMA Update
Meeting in December provided preliminary guidance that additional clinical data will be needed for conditional approval
EMA encouraged continued discussions as additional data is compiled from current and new studies
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DMD CLINICAL PROGRAM STATUS (US AND EU):
ETEPLIRSEN AND FOLLOW-ON EXON-SKIPPING DRUGS (EXONS 45 AND 53)
Duration Exon Target
Study US/EU n Status DMD Population
(weeks) Treatment
4658-33 Single Dose EU 7 Completed Exon 51 10-17 yrs, non-amb
4658-28 12 EU 19 Completed Exon 51 5-15 yrs, amb
4658-201 28 US 12 Completed Exon 51 7-13 yrs, amb
4658-202 2401 US 12 Data through 168 Weeks Exon 51 7-13 yrs, amb
4658-301 48 US 120 Dosing Exon 51 7-16 yrs, amb
4658-204 96 US 20 Dosing Exon 51 7-21 yrs, non-amb
4658-203 96 US 20 Dosing 1Q2015 Exon 51 4-6 yrs, amb
4053-101 48 EU 36 Dosing Jan 2015 Exon 53 6-16 yrs, amb
4045-301 TBD EU/US 90 TBD Exon 45/53 7-16 yrs, amb
1. 212 weeks in extension phase for a total 201/202 duration of 240 weeks.
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DMD PIPELINE UPDATE
SAREPTA’S EXON SKIPPING PLATFORM FOR DMD
CLINICAL PROGRAMS DISCOVERY PRE-CLINICAL CLINICAL DEVELOPMENT
DMD Eteplirsen (AVI-4658)
DMD SRP-4053
DMD SRP-4045
DMD SRP-4050
Rare Disease DMD SRP-4044
DMD SRP-4052
DMD SRP-4055
DMD SRP-4008
DMD Clinical Development Status
PROMOVI 4658-301 – 39 Sites
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of 2 Surgical Sites fully initiated |
11 of 14 Hub Sites fully initiated
18 of 39 Infusion Sites fully initiated
Partially enrolled with patients receiving eteplirsen
Data potentially available late 2016 – early 2017
4658-204 – 4+ Sites
Sites enrolling
4658-203 – 7 Sites Selected
Enrolling Q1 2015
4053-101 (Europe) – 4 Sites
Sites enrolling
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PMO FOR THE TREATMENT OF DMD
CHRONIC LIFELONG THERAPY DEMANDS SAFETY
>2080 doses, representing ~50 patient years across all studies
Given to DMD boys with doses up to 50 mg/kg/wk for more than 3 years without clinically-significant treatment-related adverse events, dose-limiting toxicities or discontinuations
Does not activate innate immune system through Toll-like receptor (TLR) binding*
Charge neutral PMO chemistry minimizes protein binding to prevent off-target effects*
Plasma half-life of 3 to 5 hours*
Cleared through the kidney*
Sequence-specific binding to pre-mRNA directs alternative splicing*
*Sarepta internal data on file
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ETEPLIRSEN PHASE IIb STUDY DESIGN
STUDY 201: RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 202: OPEN-LABEL, LONG-TERM SAFETY AND EFFICACY
Study 201: Double-blinded, Study 202
Placebo-controlled Phase IIb Open-label, Long-term Safety and Efficacy Study
30 mg/kg/wk
n=4 n=4 n=4
50 mg/kg/wk
R
n=4 n=4 n=4
30 mg/kg/wk
Placebo * n=2
50 mg/kg/wk
n=4 n=2 n=2
n=2
*Placebo-controlled group rolled over onto open-label eteplirsen.
24 weeks 24 Weeks Ongoing Extension
Muscle biopsy: baseline Muscle biopsy: 12 weeks Muscle biopsy: 24 weeks Muscle biopsy: 48 weeks
Screening/Eligibility R Randomized SRP-4658 (Eteplirsen) Placebo
KEY INCLUSION CRITERIA
Out-of-frame deletion(s) that may be corrected by exon 51 skipping
Between the ages of 7 and 13 years
Between 200 and 400 meters (±10%) on 6MWT at Baseline
Receiving treatment with a stable dose of oral corticosteroids for at least 24 weeks before study entry
KEY ENDPOINTS
6MWT2
% Dystrophin positive fibers1
Pulmonary function tests3
Safety and tolerability
PK
1 Primary Endpoint (201/202); 2 Primary Endpoint (202) & Secondary Endpoint (201); 3Exploratory Endpoint
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PATIENT CHARACTERISTICS AT BASELINE
STUDY 201: RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 202: OPEN-LABEL, LONG-TERM SAFETY AND EFFICACY
Cohort N Age (yrs) Weight Height BMI 6 MWT
mean (kg) (cm) (kg/m2) (m)
mean mean mean mean**
mITT† Eteplirsen 6 9.4 29.4 122.2 19.5 388.6
(n=10)
PBO/Delayed-Tx* 4 8.8 30.7 119.3 21.5 380.3
ITT 30 mg/kg 4 9.8 34.9 130.5 20.3 347.3
(n=12)
50 mg/kg 4 9.1 29.1 121.3 19.6 384.8
Total 12 9.3 31.5 123.7 20.5 370.8
(Min, Max) (7.3, (22.1, (116, 138) (16.4, 25.6) (259, 437)
11.0) 39.8)
* Placebo/delayed-treatment cohort at 36 weeks had mean age of 9.5 years and mean 6MWT of 327.5 meters.
** 6MWT baseline values per patient were collected on 2 consecutive days, mean is based on average of both values.
† The Modified-Intent-To-Treat (mITT, n=10) patient population excluded two patients in the 30-mg/kg eteplirsen treated cohort who showed rapid disease progression upon enrollment and lost ambulation proximate to Week 24.
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ETEPLIRSEN STUDY 201/202 DESIGNED TO ENROLL MORE ADVANCED PATIENTS (EXPECTED TO DECLINE WITHIN 48 WEEKS)
Healthier Patients Evaluation Time
STUDY Baseline Age Baseline 6MWT <7 Excluded
Excluded Period
Eteplirsen 201/202 >440m
9.3 371 Yes 3.2 Years
Phase I/II (400 + 10%)
DMD114117
(DEMAND II) 7.3 409 No No 48 Weeks
Phase II
DMD114876
No
(DEMAND V) 7.8 409 No 25 Weeks
Phase II
DMD114044
(DEMAND III) 8.2 341 No No 48 Weeks
Phase III
Ataluren Phase IIb 8.5 357 No No 48 Weeks
Selected for an enriched population of patients expected to decline over 48 weeks
Study screened out healthier subjects (defined by >440 meters at baseline)
Controlled/prospective study in DMD without any treatment interruption or dose adjustment
* Per sponsor clinical study reports
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SIX MINUTE WALK TEST (6MWT) IS A WELL ESTABLISHED OUTCOME MEASURE
NATURAL HISTORY SHOWS PROGRESSIVE DECLINE IN PATIENTS OLDER THAN 7 YEARS
6MWT is an integrated assessment of cardiac, respiratory, and circulatory functions along with muscular capacity
Natural history studies indicate progressive functional decline in boys over 7 years of age1,2
“Those above the age of 7 years showed a progressive deterioration that was much more marked with each increasing year after baseline” 3
“The sharper progression with each found in our cohort, especially in the older boys >7 suggest that the relatively stable results on these measures over two or three years, as reported in some of these studies, may be related to the beneficial efficacy of the drug as this is not common in untreated boys“3
36MWT, 6-minute walk test; DMD, Duchenne muscular dystrophy. Mercuri E, et al. 13th International Congress on Neuromuscular Diseases (ICNMD), July 5-10, 2014, Nice, France. Note: Study imputed zero values for patients who lost ambulation during follow up periods
INCLUDED AS FUNCTIONAL ASSESSMENT IN MANY APPROVED DRUGS
Included as a functional assessment in multiple clinical trials4
Aldurazyme® for MPS I (Hurler, Hurler-Scheie)
Elaprase® for MPS II (Hunter Syndrome)
Myozyme® for Pompe disease
Vimizim® for MPS IVA (Morquio A Syndrome)
Served as the basis for regulatory approval of drugs for a number of rare diseases, with mean changes ranging from 23 to 44 meters5,6,7,8
Note: Aldurazyme and Myozyme are registered trademarks of Biomarin/Genzyme LLC. Elaprase is a registered trademark of Shire Human Genetic Therapies, Inc.
1McDonald, Henricson, et al 2013
2Mazzone, et al 2013
4Information obtained from www.clinicaltrials.gov on 24Sep2014
5Muenzer et al 2006 8van der Ploeg et al,2010
6Rubin et al, 2002 7Wraith et al 2004
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LESS THAN 80 METERS LOST OVER 3.2 YEARS IN CONTINUOUS ETEPLIRSEN COHORT (mITT; n=6)
LESS THAN 80 METERS LOST OVER 2.5 YEARS IN PLACEBO/DELAYED ETEPLIRSEN COHORT FROM LAST TIME POINT BEFORE DYSTROPHIN CONFIRMED (n=4)
METERS
=65m*
LAST TIME POINT
*p ? 0.017
BEFORE DYSTROPHIN
PRODUCTION
CONFIRMED
After general stability on the 6MWT through 120 weeks, similar declines of walking distance were observed from week 120 through week 144 with 61 meter and 63 meter declines in the continuous eteplirsen and delayed eteplirsen treatment groups, respectively
All patients showed declines in walking distance from week 144 to 168, including one patient in each arm that declined by more than 75 meters (highest 6MWT performer in continuous group; lowest 6MWT performer in delayed group)
After 3.2 years of therapy the mean age of the boys in the continuous eteplirsen arm (mITT) was 12.6 years (median age 12.9)
After 168 weeks of continuous eteplirsen treatment the mITT cohort (n=6) walked an average of 323 meters
Note: Note: Statistical analysis based on modified Intent-To-Treat (mITT, n=10, excludes two patients who experienced rapid decline and lost ambulation early in the study) Population using MMRM Test
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PATIENTS MAINTAINED AVERAGE 6MWT DISTANCE OF MORE THAN 300 METERS THROUGH 168 WEEKS IN CONTINUOUS ETEPLIRSEN COHORT (mITT n=6)
PLACEBO-DELAYED PATIENTS DECLINED AT SIMILAR RATE AFTER DYSTROPHIN CONFIRMED
Age at Baseline (yrs):
Mean
9.1
Age at WK 168 (yrs):
Median
9.3
Mean
12.4
Median 12.5
399.7m
323.0m
327.5m
254.5m
6MWT is a measure of total endurance and how well the entire body accomplishes the task. It is a test to help measure not only how muscles perform, but also lungs, and heart.
Note: Note: Statistical analysis based on modified Intent-To-Treat (mITT, n=10, excludes two patients who experienced rapid decline and lost ambulation early in the study) Population using MMRM Test
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AFTER > 2.5 YEARS OF THERAPY (WEEK 36 – 168), THE OBSERVED TREATMENT DIFFERENCE BETWEEN PLACEBO-DELAYED AND CONTINUOUSLY-TREATED ARM REMAINS INTACT (mITT n=10)
6MWT CHANGE FROM BASELINE TO WEEK 168 IN STUDY 201/202
Short Term
Treatment Benefit
METERS
WK 36: 56 Meters
Long Term
Treatment Benefit
WK 168: 65 Meters
WEEK
After 3.2 years of therapy the mean age of the boys in the continuous eteplirsen arm (mITT) was 12.6 years (median age 12.9)
Baseline ambulation for the continuous eteplirsen treatment cohort (mITT) was 399.7 meters and the placebo rollover cohort was 394.5 meters using maximum score of two measures
DATA BASED ON MAXIMUM 6MWT SCORE WHEN TEST WAS REPEATED
Note: Note: Statistical analysis based on modified Intent-To-Treat (mITT, n=10, excludes two patients who experienced rapid decline and lost ambulation early in the study) Population using MMRM Test
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WALKING DISTANCE IN POPULATION ABOVE AND BELOW 350 METERS FROM LAST TIME POINT BEFORE DYSTROPHIN CONFIRMED (WEEKS 36-168), mITT
POPULATION (n=10)
DATA BASED ON MAXIMUM 6MWT SCORE WHEN TEST REPEATED, ALL SUBJECTS > AGE 7 AT BASELINE
Eteplirsen 6MWT <350M and >350M Once Dystrophin Observed (132 Weeks)
Last Timepoint Before Confirmation of
Dystrophin in All Subjects
Baseline/Wk36 Distance > 350M
The study group which walked <350m at week 36 (n=5) lost 61 meters in ambulation from the potential time of dystrophin production (Week 36) through Week 168 compared to loss of 68 meters in >350m group.
Note: Mean age: 9.8 years at week 36; 12.4 years at Week 168; Includes modified Intent-to-Treat (mITT) Population *n=4 at week 84 due to a patient recovering from a broken ankle who was unable to participate at this time point excludes two patients who experienced rapid decline and lost ambulation early in the study) Population using MMRM Test
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Baseline/Wk36 Distance < 350M
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ETEPLIRSEN TREATED BOYS FUNCTION STATUS AT WEEK 168 (n=12)
SIX BOYS AGED 10-12 (AVG. AGE 11.5) AND SIX AGED 13-15 (AVG. AGE 13.4) AT WEEK 168 (n=12) NATURAL HISTORY SUBJECT STUDY ON GC-TREATED VS. GC-NAÏVE PATIENTS* (n=347)
*Henricson, et al. 2013
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PULMONARY STABILITY AS AN OUTCOME MEASURE IN DMD
PULMONARY FUNCTION TESTS: PHASE IIB EFFICACY ENDPOINTS
RESPIRATORY FUNCTION DECLINE IN DMD
Respiratory decline begins early in DMD leading to a high morbidity and mortality in late-stage DMD
Majority of respiratory failures due to ineffective cough and impaired airway clearance
MAXIMUM INSPIRATORY AND EXPIRATORY PRESSURE (MIP AND MEP) AND FORCED VITAL CAPACITY (FVC)
Sensitive measures of respiratory muscle strength well characterized in the disease natural history
FVC has been shown to decline at an average rate of 8 to 8.5 percent per year after 10 to 12 years of age
Declines in MIP and MEP correlate with decreases in voluntary cough capacity
Diaphragm
2’OMe
PMO
SHORT LONG
LONG
Significant increase of dystrophin expression achieved in diaphragm muscle of mdx mouse following PMO dosing
Braverman et al; Smith et al, 1987; Galasko et al, 1992; Hahn et al, 1997; Kang et al, 2000; Phillips et al, 2001; McDonald et al, 1995
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STABILITY OF PULMONARY FUNCTION IN ETEPLIRSEN-TREATED PATIENTS (ITT n=12)
MIP & MEP RESPIRATORY FUNCTION DECLINES IN DMD ACCORDING TO NATURAL HISTORY
Age at Baseline (yrs):
Age at WK 168 (yrs):
Mean
9.3
Mean
12.5
Median
9.7
Median 12.9
NATURAL HISTORY SHOWS DECLINES OVER TIME IN FVC, MIP & MEP % PREDICTED IN BOYS LIVING WITH DMD
FVC % Predicted
MIP % Predicted
MEP % Predicted
Age Ambulation Lost
Below 8
Ages 8 – 11
Ages 11– 16
Humbertclaude et al. European Journal of Pediatric Neurology 16(2012) 149 e160
* Wilson et al. 1984 equations
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ETEPLIRSEN SAFETY PROFILE
SAFETY PROFILE OF ETEPLIRSEN FOR LONG TERM USE
No clinically significant treatment-related adverse events observed through 168 weeks
– One treatment-unrelated serious adverse event: distal femur fracture
– Two instances of changes to coagulation due to thrombosis in device: port not flushed adequately of heparin
– Reported cases of transient urine protein elevation resolved without intervention and resulted in no clinical symptoms or other laboratory kidney marker changes
No clinically significant treatment-related changes detected on any monitored safety laboratory parameter
– Liver-specific enzymes, kidney function, coagulation profiles, or platelet counts
No hospitalizations, discontinuations, or treatment interruptions
Well tolerated with >1890 doses (~50 patient years) administered in studies 201/202
– No subject missed more than two consecutive doses
Missed doses primarily due to vacation and/or summer camp
– PBO/Delayed-Tx cohort (n=4) completed on average 142.3 out of 144 possible doses
– Eteplirsen cohorts (n=8) completed on average 165.9 out of 168 possible doses
No signs or symptoms of immune activation, including lack of infusion reactions, lack of treatment related hypersensitivity, and no flu-like symptoms
– Only one instance of injection site pain reported over greater than three years of weekly infusions
– No reported incidents of erythema, induration or discoloration at injection sites
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LONG-TERM SAFETY PROFILE OF ETEPLIRSEN (168 WEEKS)
SAFETY RESULTS OBSERVED WITH >1,890 DOSES OF ETEPLIRSEN (~50 PATIENT YEARS) ADMINISTERED in 201/202
PLACEBO
ETEPLIRSEN ETEPLIRSEN ETEPLIRSEN
TREATMENT-
FOR
FOR
FOR
FOR 168
EMERGENT
24 WKS
24 WKS
144 WKS
WKS
ADVERSE EVENT
n=4 (%)
n=8 (%)
n=4 (%)
n=8 (%)
Procedural pain
3 (75)
4 (50)
1 (25)
6 (75)
Vomiting
0
3 (38)
2 (50)
4 (50)
Hypokalaemia
2 (50)
4 (50)
0
4 (50)
Cough
2 (50)
2 (25)
1 (25)
3 (38)
Back pain
2 (50)
1 (12)
1 (25)
4 (50)
Fall
1 (25)
1 (12)
0
1 (12)
Headache
2 (50)
1 (12)
4 (100)
4 (50)
Balance disorder
0
3 (38)
0
4 (50)
Diarrhoea
1 (25)
1 (12)
1 (25)
2 (25)
Dermatitis Contact
0
2 (25)
0
3 (38)
Pyrexia
2 (50)
1 (12)
0
1 (12)
Haematoma
1 (25)
2 (25)
0
2 (25)
Abdominal pain
2 (50)
0
1 (25)
1 (12)
Nausea
1 (25)
1 (12)
2 (50)
1 (12)
Rhinitis
1 (25)
1 (12)
0
1 (12)
Polyuria
0
1 (12)
0
1 (12)
Muscle Spasms
0
1 (12)
2 (50)
1 (12)
Musculoskeletal Pain
0
1 (12)
1 (25)
1 (12)
Proteinuria†
1 (25)
0
1 (25)
5 (62)
Injection Site Pain
0
1 (12)
0
1 (12)
Through 168 weeks, 97% (590/609) of assessments of protein in urine were negative
3% total positive assessments through 168 weeks (includes placebo)
1.1% of all assessments for subjects on eteplirsen (6/565) classified as proteinuria
– Majority of cases determined unrelated to treatment†
– Cases mild and transient
2.3% (1/44) of assessments exhibited background proteinuria in subjects on placebo
Only one subject reported injection site pain over 168 weeks of treatment
†5 of the 7 cases of proteinuria were determined to be unrelated to treatment
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PRECLINICAL SAFETY PROFILES IN NON HUMAN PRIMATES IN FIRST THREE PMO DRUG CANDIDATES
NO ADVERSE EFFECTS IN REPEAT DOSE TOXICITY EVALUATIONS UP TO 320 MG/KG
STUDY
DRUG
SPECIES
ROUTE/DOSE
N
RESULTS
GENOTOXICITY
Bacterial Reverse
Eteplirsen
Negative: mutagenic potential,
Mutation
SRP-4045
N/A
N/A
N/A
induction of chromosomal aberrations,
Chromosomal Ab.
SRP-4053
induction of micronuclei
Micronucleus
Cynomolgus
SAFETY
Eteplirsen
IV, SC : 0, 40, 160, 320 mg/kg
6
PHARMACOLOGY
Monkey
No biologically relevant findings on vital signs,
Vitals
Cynomolgus
SRP-4045
IV: 0, 40, 160, 320 mg/kg
4
CNS, or cardiopulmonary activity
CNS
Monkey
Pulmonary
Cynomolgus
SRP-4053
IV: 0, 40, 160, 320 mg/kg
4
Cardiac
Monkey
REPEAT DOSE
Cynomolgus
Eteplirsen
IV weekly: 0, 5, 40, 320 mg/kg
6
NOAEL= MFD; 320 mg/kg
TOXICITY
Monkey
Kidney Pathology
Cynomolgus
SRP-4045
IV weekly for 12 weeks: 0, 5, 40, 320 mg/kg
9
NOAEL= MFD; 320 mg/kg
Cardiovascular
Monkey
Reproductive
Cynomolgus
Immunotoxicity
SRP-4053
IV weekly: 0, 5, 40, 320 mg/kg
9
NOAEL= MFD; 320 mg/kg
Complement Activation
Monkey
Toxicokinetic Profiles are comparable following the first and last weekly dose of 5, 40, or 320 mg/kg
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RESEARCH PIPELINE
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2014 ACCOMPLISHMENTS: PROGRESS TOWARDS BUILDING A FULLY INTEGRATED COMPANY
SETTING A STRONG FOUNDATION TO BUILD UPON IN 2015
204 enrollment
IND Opened for Exon 45
Initiated
Pompe research initiated
CTA Opened for Exon 53
301 enrollment
Myostatin research initiated
Initiated
Lupus research initiated
JAN
DEC
Additional research programs initiated
IND Opened for Exon 53
Sarepta’s research
labs open in
Manufacturing plant purchased in Andover, MA
Cambridge
Corporate
Small scale to mid scale manufacturing
DMD Development
transition successful
Research
TLR sequences licensed for research purposes
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WHAT MAKES ETEPLIRSEN DIFFERENT
SEQUENCE, CHEMISTRY AND DOSE ARE ALL IMPORTANT FACTORS
DMD EXON-SKIPPING CHEMISTRIES
PHOSPHORODIAMIDATE
MORPHOLINO OLIGOMER (PMO)
2’-O-METHYL
PHOSPHOROTHIOATE
SEQUENCE
Drug-specific optimized sequence
Charge neutral
Charge negative
CHEMISTRY
Plasma half-life of 2-6 hours
Plasma half-life of 19-56 days
DOSE
Up to 50 mg/kg intravenous
Up to 9 mg/kg subcutaneous
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DIFFERENTIATED CHEMISTRY AND SEQUENCE POTENCY FOR ETEPLIRSEN
CHEMISTRY, SEQUENCE, AND SAFETY ADVANTAGES IN DMD
LEIDEN RESEARCHERS SHOWED THAT PMO CHEMISTRY HAS UP TO 10-FOLD HIGHER DYSTROPHIN PRODUCTION
IN A MDX MOUSE MODEL ACROSS VARIOUS MUSCLE GROUPS
Source: Heemskerk, et al, 2009
CYTOKINE SCREENING DEMONSTRATED CLEAR DIFFERENTIATION
BETWEEN PMOS AND 2’OME CHEMISTRIES
Source: Sarepta Internal Data
SAREPTA COMPARISON STUDIES OF ETEPLIRSEN SEQUENCE VS
PRO051 SEQUENCE SHOWED UP TO 10-FOLD HIGHER
EXON-SKIPPING ACTIVITY
Source: Sarepta Internal Data
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NUMEROUS CHEMISTRIES CURRENTLY BEING TESTED IN MULTIPLE RESEARCH PROJECTS
POTENTIALLY ENHANCED TISSUE TARGETING, INTRACELLULAR DELIVERY AND DRUG POTENCY
NEXT GENERATION PMO CHEMISTRIES
PMO-X® PMOplus® PPMO VERSATILITY
PMOs are highly adaptable molecules and, minor modifications, potentially can be rapidly designed to target specific tissues, genetic sequences, or pathogens
SPECIFICITY
PMOs are charge neutral which may limit interactions with proteins in the body other than the target RNA*
STABILITY
PMOs are highly resistant to degradation by enzymes, potentially enabling drug activity*
A UNIVERSE OF POSSIBILITIES WITH PMO-BASED RNA MODULATION
| * |
|
Hudziak, et al. 1996 |
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PMO-BASED CHEMISTRY PLATFORM CLINICALLY EXPERIENCED
SAREPTA HAS MULTIPLE RESEARCH PROGRAMS IN HIGH VALUE DISEASE STATES
HUMAN SAFETY DATA GENERATED IN 2 CHEMISTRIES (PMO AND PMOPLUS®)
Promising chemistry platform—exon skipping & inclusion approaches in cell, animal, and humans
| 2 |
|
unique chemistries dosed in humans |
PMO program: >3 years of dosing demonstrate that PMO is safe and well tolerated
PMOplus: dosed up to 112mg/kg/week with no observed adverse events
Ongoing evaluation in multiple research programs
Opportunity to upregulate or downregulate proteins via exon skipping or exon inclusion
SAREPTA’S PMO PLATFORM HAS DEMONSTRATED:
Inhibition of mRNA function (Antisense, RNAi)
Inhibition of miRNA or lncRNA function (Antagomirs)
Control of mRNA function (Splice switching)
Alteration of mRNA function (mRNA Re-Engineering)
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STRATEGIC AREAS OF RESEARCH FOCUS
SAREPTA FOCUSING ON A REPRODUCIBLE PATH WITH A VISION OF CREATING RNA
THERAPEUTICS IN RARE GENETIC, ANTI-INFECTIVE, NEUROMUSCULAR, AND CNS DISEASES
RESEARCH MOVING FORWARD IN 2015
7 Research collaborations with universities in Rare Genetic, CNS, NM or Infectious Diseases outside of DMD using PMO, PMO-X or PMOplus 6 internal research programs ongoing outside of DMD (CNS, NM, RGD) In vitro data complete in 5 collaborations, patent applications filed, moving into animal studies
Multiple opportunities for data generation and research progress in 2015
Rare Genetic Disease Neuromuscular/CNS Anti-Infective
High unmet needs in focused Augment our DMD pipeline Multiple indications
areas Potential for single therapy to High unmet medical need
Validated using exon address multiple indications Opportunity to reverse resistance
skipping/inclusion approach IV dosing IV dosing; inhaled dosing
IV dosing Genetically validated targets Defined opportunity
Sarepta or strategic partner to Sarepta or strategic partner to Opportunity for a strategic
commercialize globally commercialize globally partner
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10 NEW RESEARCH PROJECTS STARTED IN 2014
SAREPTA IS MAKING CONSIDERABLE PROGRESS APPLYING PMO TECHNOLOGY IN ADDITIONAL THERAPEUTIC AREAS
CLINICAL PROGRAMS DISCOVERY PRE-CLINICAL CLINICAL
DMD Exon 51 Eteplirsen (AVI-4658)
DMD Exon 53 SRP-4053
DMD Exon 45 SRP-4045
DMD Exon 50 SRP-4050
DMD Exon 44 SRP-4044
DMD Exon 52 SRP-4052
Rare Diseases DMD Exon 55 SRP-4055
DMD Exon 8 SRP-4008
DMD & Becker MD Myostatin Inhibition
Progeria Progerin
Adult Onset Pompe Disease Alpha-glucosidase
Lupus & Graft vs. Host Disease Toll Like Receptors (TLR)
Marburg Virus AVI-7288
Ebola Virus AVI-7537
Influenza AVI-7100
Drug-Resistant Bacteria Burkholderia Cepacia
Infective Drug-Resistant Bacteria Pseudomonas Aeruginosa
-
Anti Drug-Resistant Bacteria Klebsiella pneumoniae
Drug-Resistant Bacteria Acinetobacter baumannii
Drug-Resistant Bacteria Staphylococcus aureus
Drug-Resistant Bacteria Neisseria gonorrhea
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MYOSTATIN INHIBITION
APPROACH PROVIDES SAREPTA MULTIPLE OPPORTUNITIES IN DISEASE STATES OUTSIDE BECKER AND DMD
SPLICE-ALTERING APPROACH UTILIZED TO INHIBIT MYOSTATIN PROTEIN PRODUCTION AT THE mRNA LEVEL
Inhibition of myostatin at the pre-mRNA level potentially allows increased muscle mass and strength
Different MOA utilized than other approaches which had off target effects
Research ongoing using PMOplus®, PMO and PMO-X®
PMO’s restored mdx weight to normal mouse levels in a 10 week mouse model
Sarepta PMO’s designed to inhibit myostatin lead to increased mobility in mdx mouse model
PMO’s IN DEVELOPMENT GENERATING HIGH LEVELS OF
EXON SKIPPING IN CELL MODELS
Myostatin Exon Skipping %
AONs Proprietary Various
RATIONALE FOR SAREPTA’S APPROACH IN MYOSTATIN
INHIBITION
Sarepta’s PMO chemistry has demonstrated affinity to penetrate muscle cells
Sarepta technology has demonstrated exon and inclusion skipping in cells, animals, and humans
PMO or PMOplus® chemistries provide a shorter regulatory path due to human safety data
SEVERAL POTENTIAL INDICATIONS – HIGH UNMET
MEDICAL NEED IN MUSCLE WASTING DISEASES
Duchenne and Becker Muscular Dystrophy
Muscle loss caused by ALS, SMA, etc.
Cachexia caused by Cancer, HIV/AIDS, MS, etc.
Open to collaborations
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ADULT ONSET POMPE DISEASE
POTENTIAL STAND-ALONE OR COMBINATION WITH EXISTING ENZYME REPLACEMENT
THERAPIES – RESTORES BODY’S ABILITY TO PRODUCE ACID ALPHA-GLUCOSIDASE
SAREPTA’S TECHNOLOGY SUCCESSFULLY ABLE TO INDUCE EXON INCLUSION AND GENERATE ENZYME ACTIVITY
Exon inclusion approach restores read-through: up-regulating enzyme production
Sarepta’s technology has demonstrated utility as an exon inclusion approach
Approach similar to DMD with multiple underlying mutations requiring unique exon-inclusion drugs
PMO or PMOplus chemistries provide a shorter regulatory path due to existing human safety data
Adult onset Pompe Disease, while rare, is an established market
Has potential to provide benefit that exceeds currently-marketed enzyme replacement therapy
Enzyme replacement could restore ability to produce enough alpha-glucosidase to become asymptomatic
Demonstrated partial restoration of enzyme production compared to no enzyme production in Pompe wild type cells
33
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TOLL-LIKE RECEPTOR (TLR) ANTAGONIST PROGRAM: LICENSED IN 2014
SUPPORTS PIPELINE APPROACH BEYOND RARE DISEASE AND OPEN TO PARTNERSHIPS
Sarepta has proprietary rights to AONs that antagonize TLR 7/8/9 with a high degree of activity compared to potentially competing AONs
Research program initiated in Lupus and GvHD
Provides Sarepta targets in multiple other disease states
TLR program may be applicable in a number of conditions that involve an innate immune response or a Th1-like immune response
TLR program can be used in the prevention of autoimmune disorders, an airway inflammation, inflammatory disorders, infectious diseases, skin disorders(e.g. psoriasis), allergy, and asthma
TLR signaling has also been linked to neurogenesis and was found to be involved in the pathogenesis of neurodegenerative diseases and could be used to prevent or treat neurodegenerative diseases
IP position established based on novel AONs; long lifecycle potential
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PPMO RESTORES ANTIBIOTIC SUSCEPTIBILITY IN RESISTANT STRAINS AND INHIBITS BIOFILM PRODUCTION (2 UNIQUE POC APPROACHES CONFIRMED)
OPPORTUNITY TO CAPITALIZE ON EMERGING ANTIBACTERIAL DATA
Sarepta is focused on infections of highest medical need and large hospital-based opportunities
Six programs identified and underway
NDM-1 PPMO’s can be used in combination with carbapenem to kill carbapenem-resistant bacterial pathogens
This is a new strategy to combat pathogens that express NDM-1
PPMO’s that target the cepl and acpP genes of Burkholderia cenocepacia J2315 were able to both prevent biofilm formation and breakdown existing biofilm
Broad commercial applicability
Opportunities for partnerships
Colistin, Meropenem, and Tobramycin susceptibility restored with co-administration of PPMO in A.Baumannii3
PPMO inhibits bacterial biofilm production and kills organism4
CDC; Antibiotic Resistance Threats in the United States, 2013
EMA and ECDC; The Bacterial Challenge: Time to React, 2009
Harbour L, et al. ICAAC 2014. Washington, DC; Abstract F-1553
Smith B, et al. ICAAC 2014. Washington, DC; Abstract F-1552
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FINANCIAL OVERVIEW
SHARES OUTSTANDING 41.3 million
RECENT CLOSING PRICE $14.93 as of 1/7/15
1.5 million shares daily
TRADING VOLUME
(90 day average volume)
MARKET CAPITALIZATION ~$617 million
CASH & OTHER INVESTMENTS
~$211 million as of 12/31/14
(UNAUDITED)
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Thank you