Chimera Research Group
Duchenne's Muscular Dystrophy [DMD] is a genetic disorder that
afflicts approximately 1 out of every 3,600 male infants. The
inherited disease is caused by mutations in the gene for
dystrophin- a muscle protein- resulting in muscle weakness at an
early age that quickly worsens over time. Breathing difficulties
and heart disease typically begin in the early twenties, eventually
leading to death.
Sarepta Therapeutics (
), formerly Avi BioPharma, has developed an RNA-based therapy
designed to allow DMD patients with specific deletions in the
dystrophin gene to produce active forms of the protein. Genes are
comprised of exons and introns; during the translation process from
DNA to protein, pre-mRNA is assembled, introns are removed and
exons are spliced together to form mRNA, which is then used as a
template to create proteins.
In patients with DMD, the errors can lead to what's called an
out-of-frame, or frame-shift deletion. Cells read the genetic code
in sets of three nucleotides. If an exon deletion causes this set
of three to become out of step, every subsequent read will be
incorrect and no protein will be made. Sarepta's exon-skipping
technology can correct the reading frame, allowing functional
protein to be produced. The company's lead compound eteplirsen
(AVI-4658) enables the skipping of exon 51. Additional compounds
targeting other exons are also in development.
Earlier in the year, Sarepta presented short-term data for
Eteplirsen. Long-term safety and efficacy results were presented
this Saturday at the WMS Congress in Persh, Australia. We had
already learned from a press release of top-line results October
3rd that results were positive: 50mg/kg treated patients remained
stable- perhaps improved on the 6MWT- and treatment delayed
patients appeared to have stabilized; dystrophin expression
improved across all cohorts. While there are still questions
remaining, the overall picture from Saturday's presentation appears
positive. It is unfortunate we were unable to attend or view the
The primary endpoint is percent dystrophin positive fibers, with
a clinical outcome measured by the 6-minute walk test (6MWT). The
three original cohorts have become two active treatment arms of
either 30mg/kg or 50mg/kg Eteplirsen. It is important to note many
later analyses exclude two patients from the 30mg/kg arm due to
their initial rapid deterioration. As it turns out, the two are
identical twins. The boys remain on study and continue to receive
drug as well as monitoring. Pulmonary function of both subjects
have remained stable through the 48-week extension.
Below is a key piece of data describing individual dystrophin
levels showed robust data. Increase in dystrophin positive fibers
occurred in all 12 patients in a clear, time-dependent manner. No
dose-response is apparent.
Additional measures including immunofluorescence, western blot,
and RT-PCR all confirmed production of new dystrophin. A bit of
fuss was made over the apparently low level of protein seen in the
western blot and low RNA in the PCR assay.
My only critique is Sarepta's poor labeling; the Normal Control
lane in this Western Blot, appears to be in the far left. Also,
Mandys106 is an antibody for the detection of dystrophin. For those
who want a bit more detail, Actin acts as a "loading control" to
help normalize each lane for analysis- lots of actin means large
amounts of protein was loaded in the lane and needs to be accounted
for. In this blot, even the small amount of dystrophin is more than
it appears compared to normal control. But this does not mean
insufficient amounts of dystrophin is being made. For one thing
Mandys106 is designed to bind normal dystrophin, it is uncertain
how well it binds to the truncated form created by an exon skipping
If we take a look at PRO051 from Prosensa, which is partnered to
), we can see that similarly low amounts of dystrophin are
detected. This blot is from patient samples taken at 24 weeks.
Notice the high amounts of protein loaded in each lane for patients
compared to control.
What's lacking are individual 6MWT scores, but this is because
data is still being collected in the trial and the company is
attempting to limit bias from parents influencing their children's
performance . The apparent improvement from 36-week to 48-week for
both the 50mg/kg and treatment-delayed arms may simply be a blip
and require further assessment. We have the mean data, now it is
important to know if some boys fare much better, or worse, than
others. The company will need to be more forthcoming with this. In
particular, why is the 30mg/kg arm completely absent? Why isn't the
delayed treatment arm broken into 30mg/kg vs. 50mg/kg? It would be
fantastic to see curves for each of the 12 patients. Unfortunately,
we will likely have to wait to see these results.
In the end, Eteplirsen maintains its crucial safety profile.
There are no signs of kidney, liver, muscle, cardiac, or other
measured toxicities. But as with any treatment where new proteins
are introduced into the body, Eteplirsen can potentially elicit an
immune reaction. For this reason, all study participants had been
tested for immunogenicity against dystrophin. Steroids taken by
most DMD patients also appear to lessen the risk of a reaction.
The big question now is whether Sarepta will be able to secure
an Accelerated Approval path for Eteplirsen. The need is compelling
and the results look good, but was the trial "adequate and well
controlled"? This is the subject of heated debate. On the one hand,
there is no arguing Eteplirsen is active; it induced dystrophin
formation in 100% of treated patients. And amazingly, the course of
disease appears to have changed for the four delayed treatment
patients. Yet of 8 patients who received drug for the entire
48-weeks, only 4 stabilized (that's assuming all 4 boys in the
50mg/kg arm did well). And within this small group, evidence from a
slew of family videos show boys previously limited by their disease
to be thriving.
Later this week we hope to learn substantially more in a couple
investor calls hosted by Wedbush with DMD expert Dr. David McDonald
on Wednesday October 17, and CEO, Chris Garabedian, and Ed Kaye,
CMO on Thursday October 18.
While investors agonize over the trial results, manufacturing of
Eteplirsen is becoming increasingly important. A contract
manufacturer has been brought in to assist with scaling up
production to commercial levels. Any details of Sarepta's
manufacturing capabilities would be welcome.
Perhaps the most important upcoming event will be Sarepta's post
Phase II meeting with the FDA either late this year or early 2013.
Management will press their case for a quick path to market; with
in months, we will know if the FDA is in agreement. Accelerated
approval would be unprecedented for a trial of this size. The
Agency will be under enormous pressure from advocacy groups as well
as politicians to make the drug available. At the same time, it is
tasked with ensuring the public's safety. As of right now, with
such a small number of test subjects, AA is certainly not a
slam-dunk proposition. The end of Phase II meeting will provide
clarity on this crucial matter.
An additional set of 6MWT data may also become available in
December- this one at 60 weeks. With few patients, every data point
bares increased importance. The 60-week time-point has the
potential to confirm what appears to be a reversal in declining
6MWT scores of the delayed treatment cohort. In our view, this
would demonstrate an amazing clinical benefit. The test can also
confirm early signs of improvement in the 50mg/kg group; taken
together, they have the potential to offer strong support for
There is a lot to look forward to in the ensuing months. We
remain bullish on Sarepta
and believe it is undervalued relative to peers.
I am long [[SRPT]]. 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
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