Sarepta Therapeutics Reports Long-Term Outcomes Through 144 Weeks from Phase
IIb Study of Eteplirsen in Duchenne Muscular Dystrophy
CAMBRIDGE, Mass. -- July 10, 2014
Sarepta Therapeutics, Inc. (NASDAQ:SRPT), a developer of innovative RNA-based
therapeutics, today announced data through Week 144 from Study 202, a Phase
IIb open-label extension study of eteplirsen in patients with Duchenne
muscular dystrophy (DMD). After nearly three years of follow up, results on
the 6-minute walk test (6MWT) showed a decline in walking ability at a rate
slower than would be expected based on available DMD natural history data. In
addition, a continued stabilization of respiratory muscle function was
observed, as assessed by pulmonary function tests. As previously reported,
Study 202 met its primary endpoint of increased novel dystrophin as assessed
by muscle biopsy at Week 48 and is now in the long-term extension phase in
which patients continue to be followed for safety and clinical outcomes.
At Week 144, patients in the 30 mg/kg and 50 mg/kg eteplirsen cohorts who were
able to perform the 6MWT (modified Intent-to-Treat or mITT population; n=6)
experienced a decline of 33.2 meters, or about 8.5 percent, from baseline in
walking ability. A statistically significant treatment benefit of 75.1 meters
(p≤0.004) was observed for the mITT population compared with the
placebo/delayed-treatment cohort (n=4), which initiated treatment at Week 25
following 24 weeks of placebo. After experiencing a substantial decline of
68.4 meters from baseline to Week 36, the placebo/delayed-treatment cohort
demonstrated a decline of 39.0 meters in walking ability from Week 36 through
Week 144, the period from which meaningful levels of dystrophin were likely
produced. These analyses were based on the maximum 6MWT score when the test
was performed on two consecutive days.
“The long-term clinical data for eteplirsen showing a slowing in the decline
of walking ability in a population now on average 12 years old are very
encouraging, particularly when compared with the growing body of DMD natural
history data which clearly show that similarly aged patients typically
experience an increasingly rapid decline in walking ability and lose
ambulation in their early teen years,” said Jerry Mendell, M.D., director of
the Centers for Gene Therapy and Muscular Dystrophy at Nationwide Children's
Hospital and principal investigator of the Phase IIb study.
“We now have nearly three years of treatment experience with eteplirsen from
our Phase IIb clinical study program and, based on guidance from the U.S. Food
and Drug Administration earlier this year, we plan to submit these results
along with additional data and analysis as part of a New Drug Application for
eteplirsen by year-end,” said Chris Garabedian, president and chief executive
officer of Sarepta Therapeutics.
Respiratory muscle function from baseline through Week 144 in the
Intent-to-Treat population (n=12), as measured by maximum inspiratory and
expiratory pressure (MIP and MEP), showed a 14.7 percent mean increase in MIP
and a 12.8 percent mean increase in MEP. Analyses of MIP percent predicted
(MIP adjusted for weight) and MEP percent predicted (MEP adjusted for age)
demonstrated a mean change from 91.7 percent at baseline to 93.9 percent at
Week 144 in MIP percent predicted, and a mean change from 79.3 percent at
baseline to 75.7 percent at Week 144 in MEP percent predicted. In addition,
there was a mean increase in forced vital capacity (FVC), a measure of lung
volume, of 11.0 percent. FVC percent predicted (FVC adjusted for age and
height) was maintained above a mean of 90 percent at Week 144, with 101.3
percent at baseline and 90.9 percent at Week 144.
“We are encouraged to see continued stability on measures of respiratory
muscle function in patients treated with eteplirsen for nearly three years,
particularly as declines in MIP and MEP are often the first signs of pulmonary
dysfunction in DMD,” said Edward Kaye, M.D., senior vice president and chief
medical officer of Sarepta Therapeutics. “As we prepare to submit a New Drug
Application for eteplirsen including these data, we are also on track to
initiate in the coming months several new clinical studies of eteplirsen in a
broader patient population to further characterize the drug’s safety and
Through 144 weeks, eteplirsen was well tolerated and there were no reported
clinically significant treatment-related adverse events and no
treatment-related serious adverse events. In addition, there were no
treatment-related hospitalizations or discontinuations.
Summary of 6MWT: Week 144 Treatment Results*
6MWT Estimated Treatment
Analysis of Baseline Change Benefit (Eteplirsen
Repeated 6MWT from Minus P-Value
6MWT Values† (meters) Baseline Placebo/delayed-Tx)
Maximum Score 399.7 -32.2
Maximum Score 75.1 0.004
Placebo/delayed-Tx 394.5 -107.4
Mean Score 388.6 -27.5
Mean Score 73.1 0.006
Placebo/delayed-Tx 380.3 -100.7
Minimum Score 377.5 -22.9
Minimum Score 70.8 0.010
Placebo/delayed-Tx 366.0 -93.8
Day 1 Score 379.7 -13.2
Day 1 Score 76.5 0.005
Placebo/delayed-Tx 371.5 -89.7
* All 6MWT analyses are based on a Mixed Model Repeated Measures test.
† All 6MWT analyses include the mITT population
‡ The pre-specified primary analysis of the 6MWT results was based on the
Patients performed two 6MWT evaluations on consecutive days at time points
coinciding with a muscle biopsy procedure at baseline and Weeks 12, 24 and 48.
Two 6MWT evaluations were also performed at Weeks 120 and 144, and will be
performed at all future functional assessment visits. All other evaluations
were a single 6MWT. The pre-specified primary analysis included the maximum
distance walked at those clinic visits where repeated tests were taken. Other
analyses of the repeated 6MWT results assessed mean, minimum, and Day 1 (first
measure) scores. Results from these additional 6MWT analyses confirm the data
observations in the primary analysis.
Summary of Pulmonary Function Tests: Week 144 Treatment Results
Pulmonary Function Test Mean Baseline Mean Week % Change from
(PFT)* PFT Value 144 Value Baseline†
Maximum Inspiratory 63.1 cm HO 72.4 cm +14.7%
Maximum Expiratory 68.1 cm HO 76.8 cm +12.8%
Forced Vital Capacity 1.73 liters 1.92 liters 11.0%
Forced Vital Capacity % 101.3% 90.9% -10.3%
Maximum Inspiratory 91.7% 93.9% +2.4%
Pressure % Predicted
Maximum Expiratory 79.3% 75.7% -4.5%
Pressure % Predicted
* All PFT analyses include the ITT population (N=12)
All Week 144 data were not statistically significantly different from
† baseline, except for a statistically significant increase & decrease in
FVC & FVC % Predicted, respectively (using one-sample t-test).
Summary of Additional Exploratory Efficacy Endpoints
Results through Week 144 for other exploratory efficacy endpoints, including
timed function tests (e.g., Gowers’ maneuver, 10 meter run/walk and timed
4-step test) and the North Star Ambulatory Assessment have shown continued
declines compared to baseline, though at potentially slower rates as compared
to the limited available natural history data. These endpoints are less well
characterized in DMD patients than the 6MWT and pulmonary function tests and
have more inter- and intra-patient variability, although they may be
predictors of decline at various stages of this disease. All patients
evaluable on measures of ambulation (modified Intent-to-Treat, or mITT
population) are still able to perform these tests including the 10 meter
run/walk and 4-step test, with the exception of two patients who are no longer
able to perform the Gowers’ maneuver.
About the Phase IIb Eteplirsen Program (Studies 201 and 202)
Study 201 was a randomized, double-blind, placebo-controlled clinical study
conducted at Nationwide Children’s Hospital in Columbus, Ohio. Twelve boys
aged 7 to 13 years with a confirmed genotype amenable to treatment with an
exon-51 skipping drug were randomized to one of three cohorts: 30 mg/kg (n=4),
50 mg/kg (n=4), and placebo/delayed treatment (n=4). Eteplirsen and placebo
were administered weekly by intravenous infusion.
At Week 25, all patients rolled over to Study 202, a long-term open-label
extension study, and placebo-treated patients initiated eteplirsen treatment
at 30 mg/kg (n=2) or 50 mg/kg (n=2).
The primary efficacy endpoint in Study 201 and Study 202 was the increase in
novel dystrophin as assessed by muscle biopsy at Weeks 12 and 24 and at Week
48, respectively. The primary clinical endpoint was the 6MWT, a well-accepted
measure of ambulation and clinical function in DMD. Long-term follow up in
Study 202 continues to evaluate safety and clinical outcomes including the
About the 6-Minute Walk Test (6MWT)
The 6-minute walk test (6MWT) was developed as an integrated assessment of
cardiac, respiratory, circulatory, and muscular capacity for use in clinical
trials of various cardiac and pulmonary conditions.^1 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.^2,3,4 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 in DMD.^5 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.
About the 6MWT Statistical Methodology and the Modified Intent-to-Treat (mITT)
The Mixed Model Repeated Measures (MMRM) test was used for all statistical
analyses of the 6MWT results. Baseline 6MWT scores and duration since DMD
diagnosis were included as covariates.
The mITT population used in the 6MWT analyses consisted of 10 of the 12
enrolled patients, including 4 patients in the 50 mg/kg cohort, 2 patients in
the 30 mg/kg cohort and 4 patients in the placebo/delayed-treatment cohort.
Two patients in the 30 mg/kg cohort showed rapid disease progression upon
enrollment and lost ambulation by Week 24, and thus were excluded since they
were no longer evaluable for the 6MWT. All other data were analyzed for all 12
About the Pulmonary Function Tests (PFTs)
Progressive respiratory muscle dysfunction in patients with DMD typically
leads to ventilation assistance and respiratory failure, and may ultimately be
a significant factor in patient mortality.^6 Measurements of respiratory
function are important for tracking the course of the disease, as well as the
evaluation of potential therapeutic interventions. Maximum inspiratory
pressure (MIP), maximum expiratory pressure (MEP) and forced vital capacity
(FVC) were included in the Phase IIb clinical studies of eteplirsen as
exploratory clinical outcome measures.
MIP and MEP measure the highest level of pressure a person can generate during
inhalation and exhalation, respectively, and are the most sensitive measures
of respiratory muscle strength.^7 Specifically, MIP is a sensitive measure of
diaphragm muscle weakness. In addition, DMD natural history studies have shown
a decline in MEP before changes in other pulmonary function tests, including
MIP and FVC, suggesting MEP is an early indicator of respiratory
dysfunction.^8 FVC measures the total volume of air expelled during forced
exhalation after maximum inspiration. In DMD, FVC increases concomitantly with
physical growth until the early teens. However, as growth slows or is stunted
by disease progression, and muscle weakness progresses, the vital capacity
enters a descending phase and declines at an average rate of about 8 to 8.5
percent per year after 10 to 12 years of age.^8,9 MIP percent predicted (MIP
adjusted for weight), MEP percent predicted (MEP adjusted for age) and FVC
percent predicted (FVC adjusted for age and height) are supportive analyses.
About Duchenne Muscular Dystrophy
DMD is an X-linked rare degenerative neuromuscular disorder causing severe
progressive muscle loss and premature death. One of the most common fatal
genetic disorders, DMD affects approximately one in every 3,500 boys born
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 in the lower limbs spreads to the arms, neck and other areas.
Eventually, increasing difficulty in breathing due to respiratory muscle
dysfunction requires ventilation support, and cardiac dysfunction can lead to
heart failure. The condition is universally fatal, and death usually occurs
before the age of 30.
About Sarepta’s Proprietary Exon-Skipping Platform Technology
Eteplirsen is Sarepta's lead drug candidate and is designed to address the
underlying cause of DMD by enabling the production of a functional internally
deleted 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 an internally deleted dystrophin protein is intended to 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 www.sarepta.com.
Forward-Looking Statements and Information
This press release 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 the development of eteplirsen and its
efficacy, potency and utility as a potential treatment for DMD, the potential
for the ongoing creation of novel dystrophin and its ability to lead to
significant clinical benefit, including as measured by the 6MWT and
exploratory measures such as pulmonary function tests, over a longer course of
treatment; the potential timing of an NDA submission for eteplirsen in the
treatment of DMD; the potential filing and acceptance of an NDA for eteplirsen
by the FDA; the timing and submission of additional data, analysis and other
information to the FDA necessary for the FDA to make regulatory
determinations; the timing and design of and ability to initiate additional
studies for eteplirsen; the potential regulatory approval of eteplirsen and
the confirmatory trials that may be required in connection with such approval.
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 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, including as measured by the 6MWT and
exploratory measures such as pulmonary function tests; any of Sarepta's drug
candidates, including eteplirsen, may fail in development, may not receive
required regulatory approvals, or may not become commercially viable during
projected time frames or at all due to delays or other reasons; we may not be
able to comply with all FDA requests; the FDA may determine that substantial
additional data is required for accelerated or other approval of eteplirsen or
that our NDA submission for eteplirsen does not qualify for filing, even with
additional information; the results of our ongoing and new clinical trials may
not be positive; there may be delays in timelines relating to an NDA
submission, initiating clinical trials, or making a product commercially
available for regulatory or internal reasons; we may not be able to
manufacture sufficient supply for clinical trials or commercialization; Agency
or court decisions with respect to our patents may negatively impact our
business; and those identified under the heading “Risk Factors” in Sarepta’s
Quarterly Report on Form 10-Q for the quarter ended March 31, 2014 filed with
the Securities and Exchange Commission (SEC), and Sarepta’s other filings with
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 press release. Sarepta does not
undertake any obligation to publicly update its forward-looking statements
based on events or circumstances after the date hereof.
^1 ATS Committee on Proficiency Standards for Clinical Pulmonary Function
Laboratories. ATS statement: guidelines for the six minute walk test. Am J
Respir Crit Care Med. 2002 Jul 1;166(1): 111 7.
^2 Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan
therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar
21;346(12):896 903. Erratum in: N Engl J Med. 2002 Apr 18;346(16):1258.
^3 Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al.
Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double
blinded, placebo controlled, multinational study of recombinant human alpha L
iduronidase (laronidase). J Pediatr. 2004 May;144(5):581 8.
^4 Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM et al.. A
phase II/III clinical study of enzyme replacement therapy with idursulfase in
mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006 Aug;8(8):465 73.
Erratum in: Genet Med. 2006 Sep;8(9):599.
^5 McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, et
al. The 6 minute walk test in Duchenne/Becker muscular dystrophy: longitudinal
observations. Muscle Nerve. 2010b Dec;42(6):966 74.
^6 Finder J.D., D. Birnkrant, J. Carl, et al. Respiratory care of the patient
with Duchenne muscular dystrophy: an official ATS consensus statement. Am J
Respir Crit Care Med. 2004; 170: 456–65.
^7 Lynn, D. J., R. P. Woda and J. R. Mendell. Respiratory dysfunction in
muscular dystrophy and other myopathies. Clin Chest Med. 1994; 15(4): 661-674.
^8 Hahn, A., J. R. Bach, A. Delaubier, et al. Clinical implications of maximal
respiratory pressure determinations for individuals with Duchenne muscular
dystrophy. Arch Phys Med Rehabil. 1997; 78(1): 1-6.
^9 McDonald, C. M., R. T. Abresch, G. T. Carter, et al. Profiles of
neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil.
1995; 74(5 Suppl): S70-92.
Media and Investors:
Sarepta Therapeutics, Inc.
Jim Baker, 617-274-4010
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