Sarepta Therapeutics Announces a Continued Benefit on Walking

Sarepta Therapeutics Announces a Continued Benefit on Walking Test
Through 62 Weeks in Phase IIb Open-Label Extension Study of
Eteplirsen in Duchenne Muscular Dystrophy 
Data to Be Presented at European Neuromuscular Centre Workshop 
CAMBRIDGE, MA -- (Marketwire) -- 12/07/12 --  Sarepta Therapeutics
(NASDAQ: SRPT), a developer of innovative RNA-based therapeutics,
today announced updated data from Study 202, its open-label, Phase
IIb extension study of eteplirsen for the treatment of Duchenne
muscular dystrophy (DMD). Patients treated with eteplirsen for 62
weeks and evaluable on ambulatory measures (modified Intent-to-Treat
population) maintained a statistically significant clinical benefit
on the primary clinical outcome measure, the 6-minute walk test
(6MWT), compared to patients who received placebo for 24 weeks
followed by 38 weeks of eteplirsen treatment. As reported previously,
Study 202 met its primary endpoint of increased novel dystrophin as
assessed in muscle biopsies at week 48 and is now in the long-term
extension phase in which patients continue to be followed for safety
and clinical outcomes. 
In the modified Intent-to-Treat (mITT) population, which includes
evaluable patients from both the 30mg/kg and 50mg/kg dose cohorts,
patients treated with eteplirsen for 62 weeks demonstrated a
statistically significant benefit of 62 meters over the
placebo/delayed-treatment cohort using a mixed-model repeated measure
statistical test. The mITT consisted of 10 of the enrolled 12
patients (4 eteplirsen-treated patients receiving 50 mg/kg weekly, 2
eteplirsen-treated patients receiving 30 mg/kg weekly, and 4
placebo/delayed-treatment patients), and excludes two patients who
showed signs of rapid disease progression and lost ambulation by week
24. The eteplirsen treatment cohort (n=6) continued to show disease
stabilization and the cohort has shown less than a 5% decline in
walking distance on the 6-minute walk test from baseline. The
placebo/delayed-treatment cohort (n=4) also demonstrated stability in
walking distance from week 36 through week 62 with a less than 10
meter change over this timeframe, the period in which dystrophin was
likely produced, with confirmation of significant dystrophin levels
at week 48 through analysis of muscle biopsies in these pat
"We are excited to see continued stability on the 6-minute walk test
with more than a year of follow-up where we would otherwise predict a
significant decline," said Chris Garabedian, President and CEO of
Sarepta Therapeutics. "Furthermore, the placebo / delayed treatment
group has shown stability over the last 26 weeks of treatment, the
period in which we would expect to see dystrophin levels translate to
clinical benefit. These clinical data support our belief that the
dystrophin levels we observed at 48 weeks are potentially an
important surrogate marker in assessing disease progression in
Duchenne and renews our commitment to advance this program forward as
we prepare our primary 48 week dataset for discussion with the FDA."  
The safety profile of eteplirsen was evaluated across all patients
through week 62 and there were no clinically significant
treatment-related adverse events, no serious adverse events, and no
discontinuations. One patient had a laboratory treatment-related
adverse event, a transient elevation of urine protein on a urine
dipstick test, however this elevation was not observed on a 24-hour
urine protein measurement and resulted in no clinical symptoms or
interruption of treatment. This patient did not show elevations of
the specific renal markers of cystatin C or KIM-1. Across both the
treatment and placebo/delayed treatment cohorts there is evidence of
continued stabilization on pulmonary function tests, echocardiogram,
muscle strength and clinical laboratory tests over the 62 weeks. 
Results from the mITT population, which combines the evaluable
eteplirsen-treated patients across the 30mg/kg and 50mg/kg cohorts,
have previously been reported and will be used as the primary
assessment of ambulatory clinical measures for the remainder of Study
202. Given there was no significant difference between the 30 mg/kg
and 50 mg/kg arms on the production of dystrophin through 48 weeks,
this mITT population is the most appropriate to assess dystrophin
production and its potential predictive benefits on ambulatory
clinical outcomes, such as the 6MWT.  
Summary of Additional 6MWT Analyses 
As pre-specified in both the Study 201 and Study 202 protocols and
statistical analysis plans, the 6MWT was evaluated on two consecutive
days at time-points that coincided with a muscle biopsy procedure,
namely the baseline visit, and weeks 12, 24, and 48. The maximum
distance walked of the two measures on any such visits representing
the "best effort" score was prospectively defined for inclusion in
the statistical analysis. These data were used to represent the
primary clinical endpoint in these studies, however only a single
measure of the 6MWT will be captured for each timepoint beyond week
48 in which this test is taken.  
The 6MWT data were also evaluated through week 62 using the various
methods of using the repeated test results including assessments of
minimum values, average values, and the day 1 (first measure) values
in assessing changes in 6MWT distance from baseline. Given the
inherent variability in an effort-dependent outcome, such as a
single-measure 6MWT, the robustness of the treatment effect seen with
the prospectively specified analysis was confirmed with these
additional analyses.  
Summary of 6MWT: Eteplirsen versus Placebo/Delayed-Treatment to Week

Results by Type of      Baseline    Adjusted   Estimated Treatment  p-value 
Analysis on Repeated    6MWT Value  Mean 6MWT  Benefit (Eteplirsen          
6MWT values             (meters)    Change     minus                        
                                    from       Placebo/delayed-Tx)          
Maximum Score            399.7      -15.6      61.9 m               less 
Eteplirsen (n=6)                                                    than or  
----------------------------------------------                      equal to
Maximum Score            394.5      -77.6                           0.007   
Placebo/delayed Tx (n=4)                                                    
Mean Score               388.6      -4.2       59.5 m               less     
Eteplirsen (n=6)                                                    than or 
----------------------------------------------                      equal to
Mean Score               380.3      -63.8                           0.012   
Placebo/delayed Tx (n=4)                                                    
Minimum Score            377.5      +7.1       57.1 m               less    
Eteplirsen (n=6)                                                    than or 
----------------------------------------------                      equal to
um Score            366.0      -50.0                           0.021   
Placebo/delayed Tx (n=4)                                                    
Day 1 Score              379.7      +4.7       59.6 m               less    
Eteplirsen (n=6)                                                    than or 
----------------------------------------------                      equal to
Day 1 Score              371.5      -55.0                           0.018   
Placebo/delayed Tx (n=4)                                                    

* Note: All analyses are based on Mixed Model Repeated Measures test 
Principal investigator, Jerry R. Mendell, M.D. of Nationwide
Children's Hospital, will present this data via an oral presentation
at the European Neuromuscular Centre (ENMC) Workshop today, December
7, 2012 at 4:20 p.m. UTC/GMT +1 hours/10:20 a.m. EDT. Dr. Mendell's
presentation will be posted on the Sarepta website in the "Events &
Presentations" section after the session is completed.  
About Study 201 and Study 202 (Phase IIb Eteplirsen Study)  
Study 4658-US-201 was conducted at Nationwide Children's Hospital in
Columbus, Ohio. Twelve boys meeting the inclusion criteria being
between 7 and 13 years of age with appropriate deletions of the
dystrophin gene that confirm eligibility for treatment with an
exon-51 skipping drug, received double-blind IV infusions of placebo
(n=4), 30 mg/kg of eteplirsen (n=4), or 50 mg/kg of eteplirsen once
weekly for 24 weeks (n=4). Muscle biopsies for evaluation of
dystrophin were obtained at baseline for all subjects, and after 12
weeks for patients in the 50 mg/kg cohort and after 24 weeks for
patients in the 30 mg/kg cohort. Two placebo patients were randomized
to the 30 mg/kg cohort and two placebo patients were randomized to
the 50 mg/kg cohort. This study design allowed Sarepta to investigate
the relationship of dose and duration of eteplirsen treatment on the
production of dystrophin over the course of the 24-week study. 
Study 4658-US-202 is the extension study to 201 and continues to
assess the long-term safety and efficacy of open-label eteplirsen.
The four placebo patients were rolled over to open-label eteplirsen
at week 24, with six patients on 30 mgs/kg, and six patients on 50
mgs/kg. Third biopsies occurred at 48 weeks in the original Study
201-treated patients, and at 24 weeks, the same time point, in the
original placebo patients. 6MWT was performed at 32 weeks, 36 weeks,
48 weeks and will continue to be performed every 12 weeks going
About Dystrophin 
Dystrophin, a large structural protein, is critical to the stability
of myofiber membranes in skeletal, diaphragmatic and cardiac muscle,
protecting muscle fibers from contraction-induced damage. Loss of
functional dystrophin destabilizes the dystroglycan protein complex,
impairing its localization to the muscle membrane, and compromising
the integrity of the membrane structure. The absence of functional
dystrophin results in muscle membrane breakdown with muscle fibers
being replaced by adipose and fibrotic tissue. 
About the 6-Minute Walk Test  
The 6-minute walk test (6MWT) was developed as an integrated
assessment of cardiac, respiratory, circulatory, and muscular
capacity (American Thoracic Society 2002) for use in clinical trials
of various cardiac and pulmonary conditions. In recent years the 6MWT
has been adapted to evaluate functional capacity in neuromuscular
diseases and has served as the basis for regulatory approval of a
number of drugs for rare diseases, with mean changes in the 6MWT
ranging from 28 to 44 meters (Rubin 2002, Wraith 2004, Muenzer 2006).
Additionally, published data from longitudinal natural history
studies assessing dystrophinopathy, a disease continuum comprised of
DMD and Becker muscular dystrophy, support the utility of the 6MWT as
a clinically meaningful endpoint (McDonald C, et al, Muscle & Nerve,
December 2010) in DMD. These data show that boys with DMD experience
a significant decline in walking ability compared to healthy boys
over one year, suggesting that slowing the loss of walking ability is
a major treatment goal. 
Modified Intent-to-Treat (mITT)  
The 6MWT results were analyzed using the mITT population which
excluded two patients who were randomized to the 30 mg/kg weekly
eteplirsen cohort who showed signs of rapid disease progression
within weeks after enrollment and were unable to perform measures of
ambulation beyond 24 weeks. This mITT population consisted of 10
patients (4 eteplirsen-treated patients receiving 50 mg/kg weekly, 2
eteplirsen-treated patients receiving 30 mg/kg weekly, and 4
placebo/delayed-treatment patients).  
About the Statistical Methodology 
The Mixed Model Repeated Measures (MMRM) test was used for all
statistical analyses of the 6MWT results, including for all
subgroups. Analysis of Covariance (ANCOVA) for ranked data was used
when the assumptions of normality of the dependent variable (the
change in 6MWT distance from baseline) were violated. Baseline 6MWT
scores and duration since diagnosis were included as covariates. 
About Duchenne Muscular Dystrophy and Eteplirsen 
Duchenne muscular dystrophy (DMD) is an X-linked rare, degenerative
neuromuscular disorder causing severe, progressive muscle loss and a
premature death. One of the most common fatal genetic disorders, DMD
affects approximately one in every 3,500 boys worldwide. A
devastating and incurable muscle-wasting disease, DMD is associated
with specific errors in the gene that codes for dystrophin, a protein
that plays a key structural role in muscle fiber function.
Progressive muscle weakness eventually spreads to the arms, neck and
other areas. Eventually, this progresses to complete paralysis and
increasing difficulty in breathing due to respiratory muscle
dysfunction requiring ventilatory support, as well as cardiac muscle
dysfunction leading to heart failure. The condition is terminal, and
death usually occurs before the age of 30. 
Eteplirsen is Sarepta's lead drug candidate that is designed to
address the underlying cause of DMD by enabling the production of a
functional dystrophin protein. Data from clinical studies of
eteplirsen in DMD patients have demonstrated a broadly favorable
safety and tolerability profile and restoration of dystrophin protein
expression. Eteplirsen uses Sarepta's novel phosphorodiamidate
morpholino oligomer (PMO)-based chemistry and proprietary
exon-skipping technology to skip exon 51 of the dystrophin gene
enabling the repair of specific genetic mutations that affect
approximately 13 percent of the total DMD population. By skipping
exon 51, eteplirsen may restore the gene's ability to make a shorter,
but still functional, form of dystrophin from messenger RNA, or mRNA.
Promoting the synthesis of a truncated dystrophin protein is intended
to improve, stabilize or significantly slow the disease process and
prolong and improve the quality of life for patients with DMD.  
Sarepta is also developing other PMO-based exon-skipping drug
candidates intended to treat additional patients with DMD. 
About Sarepta Therapeutics 
Sarepta Therapeutics is focused on developing first-in-class
RNA-based therapeutics to improve and save the lives of people
affected by serious and life-threatening rare and infectious
diseases. The Company's diverse pipeline includes its lead program
eteplirsen, for Duchenne muscular dystrophy, as well as potential
treatments for some of the world's most lethal infectious diseases.
Sarepta aims to build a leading, independent biotech company
dedicated to translating its RNA-based science into transformational
therapeutics for patients who face significant unmet medical needs.
For more information, please visit us at 
Forward-Looking Statements and Information  
This press release contains forward-looking statements. These
forward-looking statements generally can be identified by 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 the development of eteplirsen and its efficacy,
potency and utility in the treatment 
of DMD and the potential for the
creation of novel dystrophin to lead to significant clinical benefit
over a longer course of treatment. 
Each forward-looking statement contained in this press release is
subject to risks and uncertainties that could cause actual results to
differ materially from those expressed or implied by such statement.
Applicable risks and uncertainties include, among others: subsequent
clinical trials may fail to demonstrate the safety and efficacy of
eteplirsen or replicate results; treatment of patients with DMD using
eteplirsen over a longer duration may not lead to significant
clinical benefit; any of Sarepta's drug candidates, including
eteplirsen, may fail in development, may not receive required
regulatory approvals, or be delayed to a point where they do not
become commercially viable; and those identified under the heading
"Risk Factors" in Sarepta's Quarterly Report on Form 10-Q for the
three months ended September 30, 2012, and filed with the Securities
and Exchange Commission. 
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. For a detailed description of risks and
uncertainties Sarepta faces, you are encouraged to review the
Company's filings with the Securities and Exchange Commission. We
caution investors not to place considerable reliance 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. 
Sarepta Investor and Media Contact:
Erin Cox 
Press spacebar to pause and continue. Press esc to stop.