Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in
precision genetic medicine for rare diseases, today shared new
results from the ongoing study of SRP-9003 (rAAVrh74.MHCK7.hSGCB),
the Company’s investigational gene therapy for limb-girdle muscular
dystrophy Type 2E (LGMD2E). In the first look at expression data
from biopsies taken two years after a single administration of
SRP-9003, results found sustained protein expression in muscle
tissue. In functional outcomes assessments taken two years
following treatment in Cohort 1 (low-dose cohort) and one year
after treatment in Cohort 2 (high-dose cohort), patients continued
to demonstrate stability in their NSAD (North Star Assessment for
Dysferlinopathies) total score and improvements on timed function
tests. Results are being presented today at the 2021 Muscular
Dystrophy Association (MDA) Annual Clinical and Scientific
Conference.
SRP-9003 is in development for the treatment of
LGMD2E (also known as beta-sarcoglycanopathy and LGMDR4), a
devastating monogenic neuromuscular disease caused by a lack of
beta-sarcoglycan (beta-SG) proteins. SRP-9003 is a gene therapy
construct that transduces skeletal and cardiac muscle, delivering a
gene that codes for the full-length beta-SG protein, the absence of
which is the sole cause of the progressive degeneration and a
shortened lifespan characterized by the disease.
“This data is the first look at longer-term
expression data with any gene therapy for muscular dystrophy. The
meaningful and sustained levels of beta-sarcoglycan protein
expression at two years and continued strength of the functional
outcomes measured are tremendously positive and support continued
advancement of this investigational treatment for patients,” said
Louise Rodino-Klapac, Ph.D., executive vice president and chief
scientific officer, Sarepta Therapeutics. “In Cohort 2, we also saw
strong expression of delta-sarcoglycan and gamma-sarcoglycan
proteins in addition to beta-sarcoglycan, which suggests that
SRP-9003 is working to restore the dystrophin associated protein
complex, or DAPC, which provides biological support for the
sustained functional benefits observed in both cohorts. LGMD2E is
one of the most severe forms of LGMD and causes significant
disability in children while frequently leading to early mortality
and the data continue to suggest this treatment could bring much
needed hope to these patients.”
Efficient transduction in skeletal muscle and
robust beta-sarcoglycan protein expression were seen in both dose
cohorts following infusion with SRP-9003, and significant creatine
kinase (CK) reductions were observed.
Cohort 1 (Dosed at 1.85×1013 vg/kg), 24 months
following treatment:
- As measured by western blot, mean
beta-SG of 54% at 24 months of normal control, compared to 36%
measured at Day 60.
- Percent immunofluorescent (IF)
positive fibers was 48% compared to normal control, compared to 51%
at Day 60.
- Participants showed a mean
intensity of 35% of transduced beta-SG, properly localized to the
muscle sarcolemma, as measured by IF, compared to 47% at Day
60.
- The mean NSAD improvement from
baseline of 5.7 points at 18 months was sustained through 24
months.
- All three participants demonstrated
continued improvements from baseline across all functional
measures, including time-to-rise, four-stair climb, 100-meter walk
test and 10-meter walk test.
Cohort 2 (Dosed at 7.41×1013 vg/kg), 12 months
following treatment:
- At Day 60, the expression of
beta-SG (72% mean positive fibers and 73% mean intensity) resulted
in increased expression of delta-sarcoglycan, with 65% mean
positive fibers and 103% intensity, and gamma-sarcoglycan, 60% mean
positive fibers and 97% intensity. These results suggest treatment
with SRP-9003 demonstrates reconstitution of the DAPC, which could
lead to improved membrane integrity and thus improved clinical
motor outcomes measures.
- All three participants demonstrated
improvements from baseline across all functional measures,
including the NSAD, time-to-rise, four-stair climb, 100-meter walk
test and 10-meter walk test.
- The mean NSAD improvement from
baseline was 4.0 points at one year, compared to 3.7 at 6
months.
In an exploratory evaluation of all SRP-9003
treated patients compared to a natural history cohort; patients
treated with SRP-9003 demonstrated significant improvements in
functional outcomes after 24 months. The mean decline in total NSAD
score for patients in the natural history cohort was 4.6 points
while SRP-9003 treated patients demonstrated a mean improvement of
4.6 points for a clinically meaningful difference of 9.2
points.
Since the last update from this study in October
2020, there have been no new drug-related safety signals observed,
and no decreases in platelet counts outside of the normal range and
no evidence of clinical complement activation observed in either
dose cohort.
About SRP-9003 and the
StudySRP-9003 uses the AAVrh74 vector, which is designed
to be systemically and robustly delivered to skeletal, diaphragm
and cardiac muscle, making it an ideal candidate to treat
peripheral neuromuscular diseases. AAVrh74 has lower immunogenicity
rates than reported with other human AAV vectors. The MHCK7
promoter has been chosen for its ability to robustly express in the
heart, which is critically important for patients with limb-girdle
muscular dystrophy Type 2E (LGMD2E), also known as
beta-sarcoglycanopathy and LGMDR4, many of whom die from pulmonary
or cardiac complications.
This open label, first-in-human study is
evaluating a single intravenous infusion of SRP-9003 among children
with LGMD2E between the ages of 4 and 15 years with significant
symptoms of disease. The SRP-9003 study has two cohorts, each
studying a different dose-per-kilogram based on the weight of the
patient. Three participants in the low-dose cohort (Cohort 1) were
treated with a one-time infusion of SRP-9003 dosed at 1.85×1013
vg/kg and an additional three participants in the high-dose cohort
(Cohort 2) received a one-time infusion dosed at 7.41×1013 vg/kg
based on linear standard qPCR titer method. The six participants
were between the ages of 4 and 13. Post-treatment biopsies were
taken at 60 days.
Sarepta has exclusive rights to the LGMD2E gene
therapy program initially developed at the Abigail Wexner Research
Institute at Nationwide Children’s Hospital.
About Limb-girdle Muscular
DystrophyLimb-girdle muscular dystrophies are genetic
diseases that cause progressive, debilitating weakness and wasting
that begin in muscles around the hips and shoulders before
progressing to muscles in the arms and legs.
Patients with limb-girdle muscular dystrophy
Type 2E (LGMD2E) begin showing neuromuscular symptoms such as
difficulty running, jumping and climbing stairs before age 10. The
disease, which is an autosomal recessive subtype of LGMD,
progresses to loss of ambulation in the teen years and often leads
to early mortality. There is currently no treatment or cure for
LGMD2E.
Sarepta has five LGMD gene therapy programs in
development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B
and LGMD2L, and holds an option for a sixth program for LGMD2A.
About Sarepta
TherapeuticsAt Sarepta, we are leading a revolution in
precision genetic medicine and every day is an opportunity to
change the lives of people living with rare disease. The Company
has built an impressive position in Duchenne muscular dystrophy
(DMD) and in gene therapies for limb-girdle muscular dystrophies
(LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth
(CMT), and other CNS-related disorders, with more than 40 programs
in various stages of development. The Company’s programs and
research focus span several therapeutic modalities, including RNA,
gene therapy and gene editing. For more information, please
visit www.sarepta.com or follow us
on Twitter, LinkedIn, Instagram and Facebook.Forward-Looking
StatementsThis 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, SRP-9003 being the ideal candidate to
treat peripheral neuromuscular diseases; the potential benefits of
SRP-9003, including its potential to restore the dystrophin
associated protein complex (DAPC); the potential benefits of MHCK7
and the AAVrh74 vector, including its potential to be systemically
and robustly delivered to skeletal, diaphragm and cardiac muscle;
and potential market opportunities.
These forward-looking statements involve risks
and uncertainties, many of which are beyond our control. Known risk
factors include, among others: success in preclinical trials and
clinical trials, especially if based on a small patient sample,
does not ensure that later clinical trials will be successful; the
data presented in this release may not be consistent with the final
data set and analysis thereof or result in a safe or effective
treatment benefit; different methodologies, assumptions and
applications we utilize to assess particular safety or efficacy
parameters may yield different statistical results, and even if we
believe the data collected from clinical trials of our product
candidates are positive, these data may not be sufficient to
support approval by the FDA or foreign regulatory authorities; if
the actual number of patients suffering from LGMD is smaller than
estimated, our revenue and ability to achieve profitability may be
adversely affected; we may not be able to execute on our business
plans and goals, including meeting our expected or planned
regulatory milestones and timelines, clinical development plans,
and bringing our product candidates to market, due to a variety of
reasons, some of which may be outside of our control, including
possible limitations of company financial and other resources,
manufacturing limitations that may not be anticipated or resolved
for in a timely manner, regulatory, court or agency decisions, such
as decisions by the United States Patent and Trademark Office with
respect to patents that cover our product candidates and the
COVID-19 pandemic; and even if Sarepta’s programs result in new
commercialized products, Sarepta may not achieve the expected
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, 2020 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 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 SEC filings made by Sarepta. 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.
Internet Posting of
InformationWe 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.
Sarepta Therapeutics, Inc.
Investors:Ian Estepan,
617-274-4052iestepan@sarepta.com
Media:Tracy Sorrentino,
617-301-8566tsorrentino@sarepta.com
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