Duchenne muscular dystrophy ((
)) is the most common type of dystrophy in children, with a
prevalence of approximately 1 in 3,500 to 1 in 4,700 male births[1,
2]. Despite extensive genetic characterization of the disease,
survival remains limited to the second and third decades of
life. Briefly, DMD results from mutations in the dystrophin
gene. The dystrophin gene is responsible for the production of a
protein, "Dystrophin," which is found in both muscle cells
(skeletal and cardiac cells). Dystrophin plays a role in the normal
function of muscle fibers. DMD patients have deletions or mutations
of the dystrophin gene, which ultimately leads to the synthesis of
an abnormal dystrophin protein. Production of abnormal dystrophin
leads to formation of abnormal muscle fibers and ultimately leads
Advances in treatment have improved the survival rates of DMD
patients, however the mean age of survival remains low
(approximately 25 years). While current treatments may slow
disease progression, new therapies have the potential to improve
quality of live and improve survival rates. One such therapy
involves "exon-skipping" technology. Exon-skipping is an
RNA-targeted therapy; meaning that the therapy targets the
messenger RNA (mRNA; think of messenger RNA as the intermediate
between a gene and it corresponding protein). Exon-skipping
therapies are designed against a specific region of an mRNA that
harbors a disease-causing mutation. The exon-skipping therapy
prevents the disease causing exon from contributing to the final
protein sequence. Although the disease causing mutation is present
in the mRNA sequence, the exon with the mutation is "skipped"
during the translation of the mRNA into a protein, theoretically
leading to synthesis a viable/functional protein.
Sarepta Therapeutics ([[SRPT]]; formally AVI BioPharma), is
currently evaluating an exon-skipping drug, eteplirsen (formally
AVI-4658), for the treatment of patients with DMD. Biochemical data
from a Phase IIb extension study indicates that eteplirsen
treatment increases the amount of Dystrophin positive muscle fibers
in DMD patients. While the biochemical data suggest that eteplirsen
can alter dystrophin production, more information is required to
determine if the change in dystrophin expression will produce a
clinically significant improvement in patients with DMD. Although
eteplirsen may provide a new therapy for DMD, it is important to
look more closely at the trial and the subsequent data (see below
Background: SRPT Jumps Following Phase IIb Data
SRPT stock closed at $14.84 on Oct. 2, 1012. Following the
release of 48-week data, SRPT jumped to $44.93 on October 3rd. If
eteplirsen eventually receives FDA approval, SRPT could be worth
significantly more than the share price in October 2012. However,
investors may want to approach SRPT long positions with caution.
While SRPT made significant gains following data from the Phase IIb
study, it is important to note that the trial only enrolled 12
patients. Investors may find it useful to closely examine the trial
design/data to determine if the results from the Phase IIb study
justify the current SRPT valuation.
The Phase IIb trial provides biochemical validation that
eteplirsen can restore some level of dystrophin. The clinical data
indicate that eteplirsen may prevent a decrease in clinical
performance (6 minute-walk test), but it is uncertain if eteplirsen
can improve clinical performance (compared to baseline).
Additionally, it is important to note that 2 of the 10 patients
from the Phase IIb study were excluded from the clinical analysis
due to rapid progression of DMD during the treatment.
The Phase IIb eteplirsen data is intriguing, but is important to
note that the Phase II trial consists of only 12 patients.
Initially 8 patients received eteplirsen and 4 patients received
Initial Trial Design:
- *Eteplirsen 30 mg/kg/wk; n=4
- *Eteplirsen 50 mg/kg/wk; n=4
- *Placebo/delayed treatment; n=4 (at week 24, Placebo patients
switched to Eteplirsen: 30 mg/kg/wk; n=2, 50 mg/kg/wk; n=2)
To be included in the trial patients must "Achieve an average
distance within 200 meters and 400m ±10% (i.e. within 180m and
440m) while walking independently over six minutes". If a
patient's walk score was greater than 440m, then the patient did
not qualify for the trial. SRPT has noted that the trial was
designed to target patients that would likely decline over a
48-week period, therefore the trial did not allow "healthier
patient based on higher 6-minute walk test at screening."
Biochemical Measure of Dystrophin:
The Phase IIb trial provides data on impact of eteplirsen on
dystrophin production (as tested by immunofluorescence) and a
clinical performance (6-minute walk test). While the eteplirsen
Phase IIb trial undoubtedly provides clinically relevant data in
the realm of DMD treatment, more clarity is needed before
eteplirsen will garner approval from the FDA. For example, the
dystrophin production data is measured by the "mean change from
baseline in % of dystrophin positive fibers"(primary study
At 48 weeks, the eteplirsen 30 mg/kg/wk cohort(n=4) had a 52.1%
mean change in dystrophin positive fibers, whereas the 50 mg/kg/wk
cohort(n=4) had a 41.7% mean change in dystrophin positive fibers.
However it is important to note the amplitude of changes in
dystrophin expression for subjects in each treatment cohort. The
change in dystrophin positive fibers ranged from approximately
40-60% in the 30 mg/kg/wk cohort, whereas the amount of dystrophin
positive fibers ranged from approximately 30-60% in the 50 mg/kg/wk
cohort. In terms of dystrophin expression, it appears that the 30
mg/kg/wk and 50 mg/kg/wk dose provide a similar impact on
It is also noteworthy that two patients (monozygotic twins) in
the 30 mg/kg/wk cohort displayed increased dystrophin expression at
24 and 48 weeks, but they became non-ambulatory by 24-weeks and
therefore were unable to conduct the 6-minute walk test.
Clinical measure: 6-minute walk test
The 6-minute walk test (6MWT) is a secondary study endpoint, and
the primary clinical endpoint (the primary study endpoint is the
biochemical measurement of dystrophin). The 6MWT is an exercise
test that is used to periodically evaluate exercise tolerance in
patients with cardiac, pulmonary, and neuromuscular disease
At 36 weeks, the eteplirsen-treated cohort (n=4) walked
approximately 15 meters less than their baseline 6MWT. At 36 weeks,
the delayed treatment cohort (24 week placebo, followed by 12 weeks
of eteplirsen) walked approximately 70 meters less than their
baseline. At 48 weeks, the eteplirsen-treated cohort (n=4) walked
approximately 8 meters more than their baseline 6MWT. At 48 weeks,
the delayed treatment cohort (24 week placebo, followed by 24 weeks
of eteplirsen) walked approximately 61 meters less than their
baseline. The 48-week 6MWT data indicated that the eteplirsen
treatment may improve 6MWT compared to baseline. However, by 62
weeks the 6MWT had returned to the levels observed in week 36. At
62 weeks, the eteplirsen-treated cohort (n=4) walked approximately
16 meters less than their baseline
6MWT. At 62 weeks, the delayed treatment cohort (24 week placebo,
followed by 38 weeks of eteplirsen) walked approximately 78 meters
less than their baseline.
Analysis of 6-minute walk test data
While the data may indicate that eteplirsen impacts the 6MWT
performance, the inconsistency between 6MWT data between 36, 48 and
62 weeks makes data more difficult to interpret. For example, does
the increase in the increased 6MWT performance at 48 weeks
represent a true clinical improvement, or is a result of
experimental variation that is inherent to the 6MWT? The 6MWT
appears to be somewhat reproducible in a clinical setting, but
several factors may impact performance (test administrator, course
length, course memory) . For example, patients can make a
clinically significant improvement in the 6MWT between the 1st and
2nd attempts on the same day. Given the small sample size, it
is difficult to know if the improvement of the 6MWT at week 36 is
directly related to eteplirsen treatment or experimental variation.
An n=4 for the contented eteplirsen cohort may limit the
conclusions that can be drawn regarding an increase in performance
During the conference call to discuss the 48-week data, Chris
Garabedian, CEO, remarked that "Of the 50 milligram per kilogram
eteplirsen patients, all of the patients saw an increase in their
6-minute walk test distance from 36 weeks and three of the four
showed improvement, which we are defining as more than 10 meter
increase in meters walked from the 36-week time point." SRPT has
elected to administer two different 6MWT at each time point but
they select the highest 6-minute walk score for every time point.
It would be interesting to know if the patients would still display
a "³ 10m" increase in walking distance. Since SRPT has defined 6MWT
"improvement" as "³ 10m" increase, it would also be useful to know
the score for the replicate walk test. For example, are there
examples where patients displayed more than a 10m change between
replicate 6MWTs administered on the same day?
Overall, the Phase IIb eteplirsen data indicates that eteplirsen
may offer a clinical benefit to a cohort of DMD patients. However,
a lager trial is required to more accurately determine the clinical
benefit of eteplirsen treatment. As with any clinical trial, sample
size is extremely important to demonstrate reproducibility and to
identify both efficacy/side-effects. A small trial may not provide
an accurate summary of a drug profile and a small trial may not
have the power to capture the genetic variation that may actually
occur in the real-world patient population. It is important to note
that patient germline genetic variation can impact the
efficacy/toxicity of a drug response.
Other Considerations: Safety
To date, eteplirsen has been well tolerated (no treatment
related adverse advents).
Eteplirsen relies on a morphilino-based system for
"exon-skipping." Despite the fact the eteplirsen is well tolerated,
more studies will be required to assess the long-term effect of a
therapeutically relevant dosage. While eteplirsen does not appear
to cause any serious adverse advents, it is important to note that
eteplirsen is based on morpholino chemistry, and morpholinos have
been shown to cause off target effects/toxicity. Clearly,
eteplirsen was selected for its efficacy and relative lack of
toxicity, but it will be interesting to determine if
therapeutically relevant doses of eteplirsen produce unwanted
side-effect in a larger/longer trial. For example, are there any
long-term toxicities related to
the morpholino chemistry
(ex. The morpholine subunits)?. Alternatively, are there any
non-specific targets of the anti-sense technology (i.e. Does
eteplirsen bind to/interact with DNA or RNA molecules other than
the dystrophin mRNA?).
Future value drivers for SRPT: Progression of eteplirsen to a
Phase III trial and/or a partnership deal with big biotech/pharma.
Given the hype surrounding eteplirsen , any positive news may move
SRPT to higher levels. SRPT will likely to continue to make gains
as it moves to Phase III trial however, long-term investors should
wisely consider trial design and results from the Phase IIb study.
If the eteplirsen data is not reproducible in a larger (Phase III)
trial, or if the data reveal any severe adverse reactions, SRPT
shares may take a significant hit. Remember that even promising
drugs fail during a late stage trial. Buyer beware…
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I have no positions in any stocks mentioned, and no plans to
initiate any positions within the next 72 hours. I wrote this
article myself, and it expresses my own opinions. I am not
receiving compensation for it. I have no business relationship with
any company whose stock is mentioned in this article.
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