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Sarepta Therapeutics, Inc. (NASDAQ:SRPT)

Sarepta DMD Development Program Update

October 17, 2013 12 PM ET


Chris Garabedian - President and CEO

Ed Kaye - Chief Medical Officer


Marissa Penrod - Duchenne Alliance

Debra Miller - CureDuchenne

Jane Larkindale - Muscular Dystrophy Association

Sharon Hesterlee - Parent Project Muscular Dystrophy


Welcome to the Sarepta DMD development program update. My name is Brendan and I will be the operator for today. At this time, all participants are in a listen-only mode. Please note that this conference is being recorded.

I will now turn it over to Chris Garabedian, President and CEO of Sarepta. You may begin sir.

Chris Garabedian

Good morning, everyone. We, at Sarepta, are very pleased and excited to give an update to the community on our Duchenne Muscular Dystrophy and our activities related to eteplirsen. There has been a lot of communications related to exon skipping in recent weeks and we thought it was a good time to reiterate our commitment to our DMD clinical development program and our plans to pursue approval of eteplirsen in the U.S. within NDA submission in the first half of next year.

An NDA submission is the first step in the process to pursue a drug approval of eteplirsen. As a reminder, our drug eteplirsen is a drug that has designed to treat only those patients that have genotypes or dystrophin gene deletions that are amenable to an exon 51 skip. We have a lot to discuss today and we are also leaving some time for a Q&A session with some of the larger DMD advocacy organizations based in United States.

Joining me on this call is Ed Kaye, our Chief Medical Officer, and he and I will be providing an update on a lot of the activities going on currently. But I would also like to welcome the following organizations to our call and thank them for participating today. These organizations include the Muscular Dystrophy Association or MDA represented by Jane Larkindale, Parent Project Muscular Dystrophy or PPMD represented by Sharon Hesterlee and Holly Peay, Duchenne Alliance represented by Marissa Penrod and CureDuchenne represented by Debra Miller.

Before we open the call to Q&A, both Ed Kaye and I will be providing an update on various activities, including an overview of our clinical program with eteplirsen, our plans for a confirmatory study with eteplirsen, an introduction to a new genetic testing program that Sarepta is supporting in collaboration with PPMD who will administer the program, an overview of our new online resource center for the broader DMD community and healthcare professionals who treat DMD which is called Let's Skip Ahead and can be found at, and finally our plans for streamline development of follow-on exon skipping drugs to treat other DMD genotypes and our pursuit of an eventual class approval where we hope to make available more than 20 drugs that will be required to treat all of the out-of-frame deletions that are amenable to exon skipping technology.

I will be making some forward-looking statements, so I would like to read a statement that indicates that this presentation includes forward-looking statements, including statements about the development, regulatory approval process and clinical status of Sarepta’s product candidates and the potential benefit of such product candidates to Duchenne muscular dystrophy patients.

These forward looking statements involve risks and uncertainties, many of which are beyond Sarepta’s control. Any such risks can materially and adversely affect the business, results of operations and the trading price of Sarepta's common stock. For a detailed description of risks and uncertainties we face, we urge you to review Sarepta’s official corporate documents filed with the Securities and Exchange Commission, including the risks and uncertainties disclosed in Sarepta’s latest report or Form 10-Q. We do not undertake any obligation to publicly update these forward-looking statements based on events or circumstances after the date hereof.

So now I would like to provide a brief overview on the activities we have planned in the next six to nine months with the eteplirsen.

I described our goals for today that outlined in this slide. On the next slide is an overview of our activities that we plan over the next six to nine months. For the rest of this year, we have several FDA update meetings. This month we will be having a manufacturing or CMC, which stands for Chemistry, Manufacturing Controls to discuss what are the requirements that are needed to submit as part of our New Drug Application in the first half of next year.

Again that meeting will take place this month and we will have more clarity and guidance in terms of what would be required in an NDA submission next year. In November, we have a follow-on meeting to discuss some of the clinical issues that was described previously in discussions related to our confirmatory study and study design as well as what will be needed to go into our NDA in the clinical sections in our NDA submission in the first half of next year.

We should have more information on our midscale production batches later this year and we hope to provide a manufacturing update on how that's going by the end of the year. And as I mentioned, we do plan to submit our New Drug Application for eteplirsen to the FDA in the first half of 2014.

Concurrently, we are focused on our clinical development activities of which Ed will describe in more detail later in this call. But we're going to be doing a lot of this setup for our confirmatory trial with eteplirsen for the remainder of this year, all to be on track for first patient dosing in the first quarter of 2014.

Before I turn the call over to Ed Kaye to provide the latest clinical data with eteplirsen and our plans for our confirmatory study, I'd like to highlight the strong data set related to our technology and the proof of concept that we are producing meaningful levels of dystrophin and that the doses we are studying in the clinic are producing the desired effect in support of our drug mechanism of action and our ability to produce the essentially protein dystrophin that is lacking in patients with Duchenne and the root cause of the disease.

To be clear, we are producing a truncated version of dystrophin that is the same length of dystrophin that is absorbed (inaudible) muscular dystrophy, a mild muscular dystrophy that is not characterized by the progressive decline and early loss of ambulation in depth observed in Duchenne.

Our mechanism of action is exon skipping that has been widely described and this slide shows you the eteplirsen chemical structure which has very favorable drug like characteristics and is very differentiated from other technologies used in exon-skipping and in the RNA space.

Our mechanism of action of exon-skipping is described in this next slide. What we are doing on this slide is an example of how we're restoring a DMD patient’s ability to overcome the genetic deletion that they may have by skipping over the exon that is causing the messenger RNA to be out-of-frame. By skipping over this problem area in this case we're skipping over exon 51, we allow the patient to produce a functional truncated form of this essential dystrophin protein.

The example on this slide is a patient from one of our studies that has a deletion of exon 49 to 50, and by skipping over exon 51 you can see we turn an out-of-frame deletion in the messenger RNA to an in-frame deletion that can produce a shorter but functional dystrophin protein.

On this next slide we highlight our data using RT-PCR. This is an essay that produces an analysis to demonstrate that our drug is acting by the mechanism of which we purported to act. That is producing exon-skipping and producing an appropriate length messenger RNA of the truncated dystrophin protein that we're intending to produce.

This slide shows that we've been able to show exon-skipping in a 100% of all patients that have been evaluated both in our previous study of 19 patients that was conducted in lower doses over 12 weeks of which 17 received biopsies and all 17 of which showed evidence of exon skipping by RT-PCR analysis.

We also showed exon skipping was achieved in all patients and at all time points evaluated post treatment in our Phase IIb study evaluating doses of 30 and 50 mg/kg again using RT-PCR analysis.

On the next slide we show data on our primary endpoint. The percentage of dystrophin-positive fibers that were observed compared to pre-treatment biopsies. And you can see that all patients were producing high levels of dystrophin with an average of approximately half of muscle fibers counted showing a positive for the dystrophin protein after 48 weeks of treatment.

We've presented the slide numerous times and have shown that we reach statistical significance on this primary outcome measure and we see consistent high levels across all of the patients including those who received 24 weeks of treatment.

Importantly at 12 weeks, we did not see increases of dystrophin in the muscle biopsies, despite the fact that a 100% of the patients showed exon skipping by RT-PCR. This means that our mechanism is working, but it takes anywhere from 12 to 24 weeks to see the requisite dystrophin in the muscle biopsies again of which we've shown at 24 weeks and beyond.

In addition to evaluating dystrophin-positive fibers, which is described on this slide and these were based on an evaluation by a trained neuropathologist under controlled and blinded conditions. We also used a computer-generated quantification methodology that looked at dystrophin signal intensity by immunofluorescence.

In this analysis we observed dystrophin intensity levels of more than 25% on average after 48 weeks of treatment and more than 15% absolute increases on average after 48 weeks of treatment. The absolute increases are based on the change from the baseline signal intensity that we had in the pre-treatment biopsies.

In the placebo patients who crossed over to eteplirsen treatment, we observed dystrophin intensity levels of more than 20% on average after 24 weeks of treatment and more than 10% absolute increases on average after 24 weeks of treatment. Again the 10% plus absolute increases on average were based on the change from baseline signal intensity in those patients who were treated for 24 weeks.

These were statistically significant changes and were also correlated with statistical significance to the increases observed in dystrophin-positive fibers demonstrating a consistency in the trained pathologist findings and a computer-generated assessment of the same biopsy samples.

Only two patients did not observe an increase in dystrophin signal intensity of more than 10% after 24 and 48 weeks of treatment. And these were the two non-ambulant twins. These twins also had the lowest observed dystrophin-positive fibers after 24 weeks of treatment which had been previously reported.

Importantly we achieved statistical significance when comparing patients dystrophin intensity versus placebo at 24 weeks and also in all patients at 48 weeks compared to baseline. As I mentioned, we evaluated the correlation between dystrophin signal intensity that was generated objectively by computer with the dystrophin-positive fibers that were assessed by a trained neuromuscular pathologist under controlled and blinded conditions and there was a strong correlation with a statistically significant P value which underscores the robustness and consistency of our dystrophin analysis and the collaboration between objective computer generated measure and one to write by a trained expert pathologist under blinded and controlled conditions.

These dystrophin data support the biochemical affect of eteplirsen across our patient population and across genotypes, five genotypes studied and explain the positive clinical outcomes and stability that we are seeing in our clinical study results that Ed Kaye will describe.

With that I will turn the call over to Ed Kaye, who will describe our recent clinical findings through 96 weeks.

Ed Kaye

Thank you very much, Chris. What I’d like to do is really talk about our 96 week data that we recently announced at the World Muscle Society a few weeks ago and then I’ll transition into our proposed plans for our confirmatory study.

So to remind you, on this slide, I just want to point out a few details about the study that we’re trying to do to make it as robust as possible. The first part of the study was, which we refer to as Study 201 was a six month placebo controlled blinded study. And we really wanted to look at the difference between 30 milligrams and 50 milligrams. So patients who were at 50 milligrams were biopsied at the three month time and then the 30 milligrams dose biopsied at the six months interval. Everyone then in Study 202 at 48 weeks was biopsied and all of the patients at that point were on therapy.

Also, we tried to get as homogenous a group as possible. The boys just to remind people who were over 7 years of age, on average were 9 years of age at the beginning of the study. And again with the expected to deteriorate while the study was progressing. The endpoints were safety primarily, clinical and laboratory measures, but also there are primary efficacy endpoint was a number of percent of positive dystrophin fibers and the clinical endpoint was a 6-Minute Walk Test.

On the next slide, we have the results of our 6-Minute Walk Test and this was again change from baseline to week 96. And yes, and here we are, I have it on the slide. So I think this is the mean change which was our pre-specified endpoint. I also like to point out that this was done in 10 out of the 12 patients, this is our modified Intent-to-Treat to the boys stop walking before dystrophin was expected to be positive based on our results of the biopsies. And only those boys 10 out of the 12 boys who were able to perform the 6-Minute Walk Test were evaluated here.

And two I think important aspects is that at week 96 we saw again very little change from baseline in the boys who were treated continuously on eteplirsen and also again show stability up to week 96 on the boys who had been changed from placebo and were now on treatment.

If we look at the next slide, it goes into a little bit more detail in regards to the individual patient. Of note, all of the patients except for one had less than a 10% change if we look from week 36, which was the last time point before dystrophin confirmed in our placebo girls to week 96. It was only one child who had a broken distal tibia that was not allowed him to perform the test, the 6-Minute Walk Test at week 84, but he was able to perform it at 96, but he was rehabbing from his fracture and he was able to walk again after that. That’s the only patient that declined, but on average all of the boys again remained stable through week 96. And again this is in contrast of what we we’re going to expect it based on the natural history studies.

On the next slide, just to talk about the safety through 96 weeks and we have all of the groups’ patients treated for eteplirsen both for 96, 72 weeks in our original placebo arm. And in summary, there was only one unrelated serious adverse event and that was the distal femur fracture that was seen secondary to a car accident and there was no hospitalization or discontinuations. We saw two cases of transient protein elevation that were not associated with any clinical side effects and also had no other laboratory parameters and these were only intermittent and result spontaneously without having to discontinue therapy. And then just on the next slide we just have a summary of the safety results, and again we have the unrelated serious adverse event and the only adverse event of special interest was related to this transient protein area.

And finally just to in the next slide, just to summarize the eteplirsen data through 96 weeks, we didn't have any clinically significant treatment related adverse events in all of the boys remained on therapy and there were no discontinuations. As Chris pointed out we had on average a 47% of normal dystrophin positive fibers which was specifically significant. And then if we look at the patients in the eteplirsen treated evaluable group on the six minute walk test, they lost less than 5% of their walking ability from baseline to week 96. And also we saw a stability in the previous placebo group that were placed on therapy.

So what I'd like to do next in this next slide is to really talk about our potential confirmatory study design. The one important caveat is that we have not had a final decision from the FDA, we're still in discussion with them.

So this is what we have proposed and we hope by the end of this year, to have a final protocol design. So this study will be an open label with one arm containing 60 treated patients approximately, the other group will be an untreated group. But they won't have the same entry criteria, but they will be patients who would be amenable to exon skipping, through exon 44, 45, 50 and 53 and again that would be approximately 60 patients.

We would do biopsies, but what we've tried to do is to reduce the burden to patients and the families so we would plan on doing muscle biopsies that would be randomized to a biopsy schedule in 40 of the patients rather than all of the patients, with 10 of the boys receiving biopsies at week 24 and 20 receiving biopsies at week 48 and the final 10 would have muscle biopsies during the extension phase. Again, this is so that would allow us to compare the dystrophin data to what we learned in the initial Phase IIb study and to confirm what we saw now in the confirmatory study.

So in the next slide, just to summarize the potential study endpoints. As we had performed in the Phase IIb we would do the six minute walk test which in our experience has been the most sensitive endpoint to-date, also we would have key secondary efficacy endpoints, again would be the dystrophin positive muscle fibers and do this in a very similar fashion to what was done in the Phase IIb. We would obviously have a number of safety and laboratory endpoints and then we are looking at some exploratory endpoints.

In the next slide we have the potential eligibility criteria, this again, will be finalized when we have the full discussions with the FDA. These would ambulatory boys, greater than seven years of age. We would confirm an auto frame deletion that could be corrected by exon 51 skipping. And in our untreated group, again these would be boys who could be corrected by exon 44, 45, 50 and 53. They would all be required to be on a stable regiment of corticosteroids and obviously there would some other additional criteria that would be included.

Now just on the next slide, we'd just like to demonstrate to what is involved in participating in a clinical trial for those people who have never participated in a clinical trial. The first point which we are in now is really contacting the clinical site to see if patients are available. And these clinical sites eventually will be posted on and then families then can reach out to the site to schedule a screening visit to see if their child will be eligible.

Once the patient is screened, the clinical investigator then determines whether or not the patient is eligible for the study. Once eligibility is determined, there is the inform consent and the investigator goes through with the patient and the family, really to talk about what are the potential risks and benefits and why they should or should not participate in the clinical trial.

Finally the patients enrolment study, baseline assessments are obtained and then there are weekly infusions which are done under the supervision of the clinical investigator at the site. And obviously there is a lot of in the study, there are study assessments that are conducted periodically and then patients may receive weekly infusions in the clinic visits at a local infusion center.

And finally, just in the final slide, just I want to talk about some of the preparations that we are undergoing to initiate those into the first quarter of next year. We are having discussions with the FDA to finalize the study design. We will be looking at sites in the United States and in Canada. We are selecting and on boarding the clinical research support vendors and this is well on its way.

We also plan to post the study design and all the eligibility criteria on once they are finalized. And again, we hope to initiate dosing patients in the first quarter of next year.

So, at this point, let me turn back the discussion to Chris Garabedian, who is going to talk about our Let's Skip Ahead program.

Chris Garabedian

Thanks Ed. And before I move on to the describing our Let's Skip Ahead website, I wanted to address the question that has come up a lot over the last few weeks. As it relates to the failed drisapersen studies and what it means to our program.

While the failed studies with drisapersen were a disappointment to the DMD community. We believe it underscores how important it is to have a chemistry that is not have dosed related toxicities that may prohibit a dose that is active enough to produce a clinical effect. Eteplirsen uses a very different chemical structure as what we call the drug's backbone and this unique chemistry allows us to achieve doses in our studies that are five to eight fold greater than those doses studied in the drisapersen trials.

And the dystrophin dataset, I described earlier, underscores the importance of achieving a dose that produces the type of robust and consistent response that we have seen in our studies. We understand the disappointment of the drisapersen trial participants particularly those who are discontinued from drisapersen treatment upon the announcement of the failed clinical trials.

While we understand this disappointment, we are exploring the feasibility addressing these patients who are in the drisapersen trials. While we are facing some patent challenges in Europe that provide challenges to offering drug to patients from the EU drisapersen sites and drug supply and regulatory issues that limit our ability offer drug to patients outside of Europe. We are exploring the feasibility of including drisapersen trial participants from any drisapersen studies in which patients were enrolled at U.S. or Canadian sites. While there maybe some patients who were in the U.S. drisapersen study, this was referred to as DEMAND V also referred to as the 876 study.

For those patients in DEMAND V or 876 who were randomized to a placebo arm and never received drisapersen in an extension study, they may qualify for our eteplirsen treated arm in our confirmatory study.

We do not have plans at this time to include drisapersen treated patients in this arm of our confirmatory study. However we are exploring the feasibility of including an additional cohort of patients in an eteplirsen treated arm for those patients who participated in drisapersen trials. Again this would be from sites in the U.S. and Canada.

We will be prioritizing dosing for our eteplirsen treated cohort in our confirmatory study, so the availability of drug for the drisapersen patients maybe delayed and we think the earliest dosing of such a drisapersen-treated arm might occur is by the end of the second quarter of next year.

While there are no guarantees at this point, as we've just begun to explore the feasibility of such an arm, we would hope to extend this to drisapersen trial participants regardless of ambulatory status and would also extend this to patients who participated in the original drisapersen non-ambulant study that was conducted in the U.S.

In a moment, I will describe the best way for drisapersen trial participants to alert Sarepta of interest in participating in eteplirsen cohort or any patients who are interested in Sarepta DMD clinical trial as we’ve developed a website, Let’s Skip Ahead at that allows patients or family members to sign up and alert us to interest and to provide information that can help us determine if a patient may qualify for current or future clinical trials.

Let me now describe some more details about our Let’s Skip Ahead website and I encourage all of you to check it out and sign up at

This slide describes the Let’s Skip Ahead online resource center. And this is designed for patients with DMD, their families and healthcare providers who treat DMD patients. We provide information and resources on exon skipping, genetic testing and clinical trials. It’s an opportunity to sign up for updates as I just described about upcoming clinical trials and other important information from Sarepta. To get information and updates, please sign up at

The next slide shows a feature of the resource center, which is an exon mapping tool. And this is an easy-to-use tool to help patients or family members understand exon deletions and exon skips and how they may be linked. This information may be helpful when speaking with your healthcare provider.

The next slide again shows you where you can join Let’s Skip Ahead and this online community. And we encourage you to sign up it’s a very simple sign up form requesting the basic information so we can provide you information necessary with updates from Sarepta and information about clinical trials.

Additionally, Sarepta announced this morning in collaboration with Parent Project Muscular Dystrophy, PPMD that we are supporting a genetic testing program that will be administered by PPMD to ensure that DMD patients have their genetic information to determine which drug technologies they may benefit from in the future or what clinical trials they may qualify to participate in. We have now included information about this Duchenne program on our Let’s Skip Ahead website under the site menu labeled Genetic Testing and under the subhead titled Access to Genetic Testing, with a little key picture icon next to it.

To describe more details about this program, I would like to turn the call over to Holly Peay of PPMD who will be over seeing the program for PPMD. Operator, if you can open up the line for Holly Peay please.


Yes. Holly, your line is now open.

Holly Peay

Great. Thank you, Chris. Can you hear me well?

Chris Garabedian

Yes, we can hear you.

Holly Peay

Excellent. Okay, so I am Holly Peay, PPMD’s Vice President of Education & Outreach and I am the Director of the Duchenne Connect Registry. And at Duchenne Connect and in PPMD we are grateful to announce the Decode Duchenne Project. And as Chris described, this is our new genetic testing program that allows patients for Duchenne and Becker to have access to genetic testing.

Through the registry and through PPMD, we know there is a need for this program and that there is a small but significant minority of people who are unable to have genetic testing because it denies on insurance or because they don’t have insurance coverage. So we are delighted to providing support to all families who need access to genetic testing services can get access.

This program is expected to launch before the end of 2013 for Duchenne Connect. And to participate patients need to have a confirmed diagnosis or be suspected of having Duchenne or Becker muscular dystrophy. There you need to have not previously had genetic testing or they need to actually need additional genetic testing as determined by the Duchenne Connect coordinator.

They need documentation to confirm the patient’s lack of insurance coverage, insufficient coverage or denial and they need to be citizen or legal residence of United States. And in addition people must register on Duchenne Connect to have access to the program. So we encourage you to learn more about the program by going to Duchenne Connect’s at And all registrants will get information from us on how to apply for the program once it launches. So please make sure you are titled or you are registered on Duchenne Connect so you can access the program.

And again we would like to thank Sarepta for supporting this important initiative that will allow access to individuals who have not been able to benefit from genetic testing. Thank you, Chris.

Chris Garabedian

Thank you, Holly. And again, we are really excited about PPMD's willingness to help us with this program and to allow this service to the patients who need it. Lastly, I would like to describe Sarepta's plans for follow-on exon skipping drugs for DMD and our plans for an eventual what we hope to be a class approval. We understand that eteplirsen treats a subset of the DMD patients in the U.S. only about 13% of the total and a fraction of the patients who could benefit from exon skipping technology.

At this time, we are hopeful that the success we have seen with eteplirsen will be evident as we develop the same technology to treat other DMD genetic subtypes. And we are committed to pursuing the possibility that all of the Duchenne patients who can benefit from exon skipping might someday have drug available for treatment in the future.

This slide describes the four follow-on exon skipping drugs that we are planning to have ready for clinical trials in the future. Specifically we've included patients amenable to all of these exon skipping drugs in our eteplirsen confirmatory study in the untreated non-exon 51 amenable patient cohort.

The hope is, is that after the year is over a follow-up in this untreated cohort that we may have open INDs on some or all of these drugs and may have drug available to roll those patients over on to a study drug so that we can start evaluating the utility of all of these follow-on exons in which we would capture a dystrophin through biopsies and follow them for safety and clinical efficacy.

We believe this study design and plans for rollover is the fastest way to accelerate the development of these follow-on exon targets. We’ve communicated previously that we expect to have an open IND on at least one of these drugs by mid next year and on at least two of the drugs by the end of next year again with the hope that in 2015 when these patients are coming off of the untreated cohort, we might have open INDs and drugs available to roll all of these patients over into a clinical study.

The next slide really just shows the challenge of drug development in Duchenne. In that, after you move beyond the most amenable exon, exon 51 it becomes very challenging to enrol enough patients in any of these other exon targets to power it sufficiently for six minute walk test and to have a robust dataset. So what we've done is we've combined four additional exons and we believe that cohort of four follow-on drugs could provide the confirmatory evidence to what we're seeing with eteplirsen both safety and in terms of dystrophin and clinical evidence.

We know that it's infeasible to expect that we can enrol enough patients for clinical trials beyond those I've mentioned. And so this will require a unique a regulatory strategy that we describe as class approval.

On the next slide, we describe as we have previously, our path to a potential class approval. And that is first and foremost we build a strong foundation with eteplirsen on both the clinical utility and safety database, our preclinical evidence of safety and dystrophin that we have described on today's call that would be accepted as a surrogate marker in the hopes that we can accelerate development on the follow-on exon skipping products.

Step two is to demonstrate comparable safety and efficacy with those follow-on exon skipping products that I described, exon 45, exon 53, exon 50, and exon 44. We will be developing in vitro data to support the optimized sequence that we're using on those follow-on exons. And that is the basis of which we think we can claim a class approval or ask the FDA to consider that where we would be using the same manufacturing process, a standard dose with the same drug components that we are using with the eteplirsen and the follow on exon targets. And we would be using the same methodology to optimize the lead sequences for those rare exons or what might be more than 20 additional drug candidates where we could not enroll patients for each of those and clinical studies that just are added in our patients. So that would be step three to supplement all of the clinical data on a eteplirsen and our follow on exons with in vitro data that supports this class approval.

So, in summary we have a lot going on for the remainder of this year and for the next six to nine months. As we have several FDA meetings we are currently putting together sections of our NDA and planning for an NDA submission in the first half of 2014 and clarifying exactly what needs to go into that NDA with the FDA in these subsequent meetings. We are in parallel as Ed described already planning and working on the activities to prepare for our confirmatory study of which we expect first patient to be dosed in the first quarter of 2014 and as I have described on today's call providing an update that we are looking into the feasibility of including the drive the person trial participants from the U.S. and Canada sites in another cohort of patients that would be treated with eteplirsen.

And as a reminder for any patients who were not exposed in the U.S. study to drive the person did not roll over to the extension and we are in the placebo arm, they may qualify for our eteplirsen confirmatory study treatment on.

The next slide highlights the FDA process, so what does it mean that they we're submitting a new drug application in the first half of next year. These are the steps that are part of the pathway between submitting a new drug application or NDA and the potential drug approval.

After we submit our NDA, then in 60 days the FDA tells us, if they have accepted the NDA for review. If we are granted a priority review, there would be an additional six months or review time in which the FDA would be making a decision on whether eteplirsen is approved.

There are couple steps between the NDA acceptance off review and an approval. There is a Day 74 letter as is described which determines whether there will be an advisory committee and if they will go what they call the panel, in which they ask an independent outside group of advisers to recommend if the drug should be approved or not. These are typically public forums that also allow for patient participating and representation.

With that I would like to open up the question and answer and I just want to highlight that we also can entertain any additional questions from any patients or family members out there and they can submit those through email at or through toll free number. But we have asked each of the DMD advocacy organizations to compile the most salient and common questions they get and we have time for two questions from each organization.

So with that operator, we'd like to open up the line for the first two questions from Debra Miller of CureDuchenne.

Question-and-Answer Session


Okay. Actually don't show Debra Miller on our call at this time. (Operator Instructions).

Chris Garabedian

Okay. With that operator, why don't we move while Debra tries to sign on, to Marissa Penrod of Duchenne Alliance.


Okay. And Marissa your line is open.

Marissa Penrod - Duchenne Alliance

Thank you so much. Thanks Chris and Ed. And one of the questions we have was about the confirmatory study protocol. We think you have covered that pretty thoroughly, do you have anything else you want to add or I'm going to go ahead and move on to another question.

Ed Kaye

Well, the only thing I can add Marissa is the, we plan to have a meeting with the FDA in November and hope to have some type of agreement by the end of the year as far as the clinical trial protocol. And that's probably currently what our plan is.

Marissa Penrod - Duchenne Alliance

Okay, great. Thank you.

Chris Garabedian

Let me just add to what Ed described. We have communicated previously that the FDA had raised the question of a placebo control arm, we have highlighted in previous communications that we believe that a placebo arm maybe infeasible, it could significantly impact our ability to enroll the study and get through IRB approvals and possibly to get patient consent, it has risk in patient dropout if eteplirsen were to be approved. And so we continue to have those discussions with the FDA, the feasibility or infeasibility of including a placebo-controlled arm in that study. I just wanted to highlight that, but Marissa, you can go to the next question.

Marissa Penrod - Duchenne Alliance

Okay, great thanks. How does the regulatory path for eteplirsen impact the clinical development of the next exon-skipping drug candidates in the pipeline?

Chris Garabedian

Sure. Marissa I'll take that one. So as I just described recently, we have a progressive approach to the next exon-skipping drug candidates. Ed and I here from patients and family members almost weekly of other exon targets that are needed and when could drugs be made available. And so what we've tried to shape is a reasonable, but very accelerated development and regulatory pathway of which at this point we don't have complete agreement from regulators, but this is the path that we will pursue, which is if we can gain the establishment of dystrophin as a surrogate based on the eteplirsen studies both the current one, which we think we have good evidence of dystrophin as a surrogate in our current study, but we'll also be capturing more dystrophin data in our confirmatory study to add further evidence. Then if at that point dystrophin is accepted as a surrogate, it may mean that these other exon-skipping targets that I described 45, 53, 50 and 44 could be submitted for approval based on, let's say, a 24 week dystrophin dataset and that would be the fastest path as we see it to a drug approval. So your question is a good one in that to be eteplirsen dataset serves as the foundation that could build upon accelerated development of the other exons. Of course we will continue to follow all the patients for the other exons for safety and efficacy even if we were to get approval on a dystrophin endpoint. And again, we also need the regulators to agree that a standard dose using the same manufacturing process as eteplirsen is acceptable to streamline development and not require the same expectations of dose ranging, finding, studies, et cetera. We believe the in-vitro evidence with the standard dose should be sufficient to identify the right dose for the subsequent exons.

Marissa Penrod - Duchenne Alliance

Okay. Great thank you so much. Thanks for the detail. Can you tell us about your primary method of detecting dystrophin and how that relates to what other people on the field are using?

Chris Garabedian

So Ed would you like to describe that?

Ed Kaye

Certainly. So I think this is obviously a very important endpoint and something that we spend a great deal of time on. And I think the field in general has really focused on immunofluorescence and at the current time our belief is that that’s the most sensitive method of detection. And I think what we've tried to do is really to demonstrate that in our 24 weeks, we had a blinded study that we were able to have the neuropathologist and also confirmed by the computer images looking at intensity and then also looking at 40 week data showing an increase in dystrophin.

So I think this is very consistent to what has been done in the past using the immunofluorescence. It gives us a great deal of information using this type of technique because not only can we demonstrate the present positive fibers with dystrophin, but we also have the ability to confirm that the dystrophin associated glycoprotein is like alpha and gamma cycle glycen also connect. And so it allows us a great deal of information to look not only are we getting the percent correct, but we can also look at the intensity and look at other information related to this. So this is going to remain for the next study on our preferred method of detection for the dystrophin-positive fibres.

Marissa Penrod - Duchenne Alliance

Okay, great. Thank you so much.

Chris Garabedian

Thank you, Marissa. Operator was Debra Miller of CureDuchenne available? Did she join the line?


Yes she did. I have her line open.

Chris Garabedian


Debra Miller - CureDuchenne

Hi. Can you hear me?

Chris Garabedian

Yeah Debra we can hear you fine.

Debra Miller - CureDuchenne

Okay great. Thanks so much. And first a big thank you to Chris and Ed for hosting this webinar, we really appreciate it and I think I speak for the entire Duchenne Community and thanking you for your dedication and we’d be still happy to have this program with you. My first question and you’ve touched on it quite a bit, but what I am speaking on behalf of all these families that have sons that are not amenable to Exon 51. And is it possible to give any more of a definitive timeline both for the next four exons that you would be working on and then beyond?

Ed Kaye

Yeah Debra I think what we talked about is that we do currently have programs for 44 and 45, 50 and 53. We had a discussion for one of our programs or pre-NDA meeting at the FDA and we find to have another discussion for pre-NDA meeting at the end of this year. So we’ll have two programs that are on development. Exon 53 is currently in development in Europe. And I think in a way to try to expedite the program, as Chris has mentioned previously, in our controlled group, this turns out to be the appropriate controlled group in the eteplirsen confirmatory study, we will have patients who are amendable to 44, 45, 50 and 53. And after the first year we would again that gives us valuable information in regard to those patients about the natural history hopefully that will expedite our trial design for these boys. And then we can also, if drug is available we plan to try to roll these boys over after the first year that they’ve been studied in the open-label untreated arm to try to get them on therapy as soon as possible.

So and as I think you heard from Chris, we have plans for well over 20 different drugs and we’re trying to put them online as quickly as possible and try to use really the knowledge information that we’ve gained from the eteplirsen data to try to link that and bring that to a platform approval to try to get as many of these drugs online and in patients as soon as possible.

Debra Miller - CureDuchenne

Okay. And then my next question is, you talked a little bit about the confirmatory trial, but moving forward into these subsequent exons, will you be including non-ambulatory patients in all of these trials?

Ed Kaye

That’s really a good question, Debra. I think one of the limitations right now of course is that we are focused on the reason for focusing on the 6-Minute Walk Test is that that's currently considered the most sensitive and has been validated in other indications for regulatory approval. And as you probably know, a lot of the outcome measures for the upper extremity haven't been validated or shown to be as sensitive. So initially we are focusing on especially for our confirmatory study for Exon 51 on the 6-Minute Walk Test.

I think as we gain more information about how to look at upper extremity function, certainly that’s something that we would consider to look at the non-ambulatory boys once we have a better understanding of how best to study and to show an effectiveness and safety related to our therapy.

Chris Garabedian

Yeah. And let me add to that Ed. So first we do have two non-ambulant boys in our current extension trial that both showed dystrophin production at 24 weeks and 48 weeks in two different muscle groups. They continue, although they lost ambulation early in the study and essentially couldn't complete the 6-Minute Walk at the time point we did finally show dystrophin in a muscle biopsies, they have stabilized on pulmonary function and other measures and seem to be doing quite well still on the drug and taking it safely.

So we think that is some further evidence of our drug utility in the non-ambulant population. And we do think, because there aren't good validated outcome measures in the non-ambulant population. We expect to appeal to the FDA that a broad label is appropriate and that a non-ambulant population should not be denied eteplirsen upon approval based on what we understand about the mechanism, the ability to produce dystrophin in a non-ambulant population and that we would expect some benefit conformity if we can’t measure those invalidated non-ambulatory measures.

I also described that we are exploring the feasibility of the drisapersen trial participants. As you know, there were numbers that were not ambulant both in the drisapersen-treated arm and the placebo arm until we would open up if we do, do such a cohort of eteplirsen-treated patients that would open up possibility to see our drug safety and utility in a non-ambulant.

Also I mentioned the untreated Exon 51 cohort that we’d have to rollover after a year if we had an open IND study drug. Even if those patients did not participate in our ambulatory study of those other exon targets, we would not deny providing the drug to the non-ambulant population because we would still follow them for safety and other outcomes outside of the powered study again referring to the exon 45, 53, 50 and 44 population.

So we think we are showing our commitment over the long-term of the program to understand safety and utility in the non-ambulant population. And we don’t think the regulators or the FDA would deny access or approval in that population based on the evidence we're seeing with eteplirsen.

Debra Miller - CureDuchenne

Okay. Thank you.

Chris Garabedian

Okay. Thank you, Debra. Operator now I’d like to open up for two questions from Jane Larkindale of the Muscular Dystrophy Association.


And Jane your line is open.

Jane Larkindale - Muscular Dystrophy Association

Hi as everybody else said, thank you very much for this really informative webinar and community really like, I’d like to hear where you are in eteplirsen dialog. We have a number of questions related to the GSK data announcement. And I was wondering if you would be able to address some of the verifications from that data announcement. How would you think that large trial will impact your chances of getting accelerated approval? And how do you and do you still think the 6-Minute Walk Test is going to be the best endpoint to your larger studies?

Chris Garabedian

Yeah. So Ed why don’t you address the 6-Minute Walk Test, vis-a-vis the drisapersen sales studies and then I can address the accelerated approval question?

Ed Kaye

Sure. Jane I think, obviously we really can’t comment on the drisapersen study because we were not participants and not really understand all the aspects of that. But I think it has caused concern about whether the 6-Minute Walk Test is an appropriate clinical test for DMD boys. And I think the short answer is we still firmly believe that it is a good test. And our review of all the data and certainly the data in our hands we found it to be the most sensitive endpoint.

I think an important aspect that we focused on is really the patient selection to use this endpoint, because eteplirsen is really focused on maintaining the 6-Minute Walk Test distance. We are not improving on the 6-Minute Walk Test, but we are trying to keep the boys stable and preventing further deterioration.

So it’s really important to have a cohort that we would expect to deteriorate during the time of the study until we focus on the over seven and there has been a number of natural history studies just this year alone that have confirmed that boys over seven years of age really do continue to deteriorate on average 40 to 80 meters. And even in the recent drisapersen study the boys who were over seven years of age deteriorated on average between 75 and 82 meters. So I think by having a very homogeneous population that should decline during the focus that we can demonstrate that these boys are stable than that I think should be a good study design.

And Chris I will let you comment further.

Chris Garabedian

Great. Yeah. So Jane on your question related to accelerate approval, we believe these two drugs are very different. So in terms of will the FDA look differently upon our NDA submission in light of the drisapersen data, again we think our data set is very differentiated as I described earlier with our dystrophin analysis, that's because they are very different chemical entities. Our drug chemistry backbone is very different. And we think the data will standalone and stand on its own in front of the FDA and won't confuse our clinical data set because again we had a dose that was five to eight fold higher with a different drug chemistry so we do not think that the failed studies of drisapersen are an enditement at all on exon-skipping or our drug's ability to see that exon skipping as we demonstrated 100% of our patients.

So with that, again our plans are intact to submit an NDA. And we will have obviously continue to follow these 12 patients still plan to enroll our confirmatory study. And of course we are disappointed that a potential treatment has been hampered and may affect the timing or even the possibility of pursuit for an approval of that drug. And so we think there is even more urgency on Sarepta's part to do everything possible to make eteplirsen available as soon as possible through whatever mechanism the FDA allows through the NDA process.

Jane Larkindale - Muscular Dystrophy Association

Okay. Great.

Chris Garabedian

Thank you, Jane, I appreciate your participation. And operator, if we can now open up the last two questions to Sharon Hesterlee of Parent Project Muscular Dystrophy.


And Sharon, your line is now open.

Sharon Hesterlee - Parent Project Muscular Dystrophy

Okay. Thank you. And as others have said thank you very much for arranging this conference and webinar and we are so pleased to be partnering on the Decode Duchenne project. My first question has to do with cardiomyopathy. As we know that most of those Duchenne will eventually develop cardiomyopathy, can you tell me eteplirsen any benefit that you have seen on cardiac measures, and what would be your expectation for intact on cardiac functions?

Ed Kaye

Okay. Sharon, how are you?

Sharon Hesterlee - Parent Project Muscular Dystrophy


Ed Kaye

I think obviously that is a very important question, because know that cardiomyopathy is an important component of the disease. The way our study was designed however is we chose boys who were younger and were in healthier condition and did not have cardiomegaly or cardiac problems at the outside of the trail.

So we have all of the boys by recurrent ECGs and echo's and today we haven't seen any changes, but again all boys were normal to begin with in regards with their cardiac functions.

So I think right now we plan to continue to follow these boys long term to appoint where perhaps they might develop any cardiac symptoms and will be able to know at that point. But I think at the current time, we really can't say too much about the effect on heart until we have more information.

Sharon Hesterlee - Parent Project Muscular Dystrophy

Okay. Would you anticipate that you would see an impact?

Ed Kaye

Well, I think we know that there is a small amount eteplirsen and get into the cardiac muscle and I think whether or not it's going to have a clinical effect, it's little too early to tell.

Sharon Hesterlee - Parent Project Muscular Dystrophy

Okay. So then a question on different topic that I think a lot of people are concerned about. Do you have plan to address patients for duplications or patients who may require multiple exon to be skipped with your technology. For example on the Let's Skip Ahead tool you can't put it duplications.

Chris Garabedian

Yeah. So Sharon let me address that. So first of all obviously we are in a regulated industry. So what we put on a website, it needs to be rooted in our current development program. So, clearly we do not have a product or effort in place to have a drug to treat duplications or double skips at the point. So, please understand, we're in a regulated environment and it limits what we can ultimately communicate to the community directly.

But regarding the duplications or double skips. So first our initial focus which is not a small feet, which use to have every patient with deletions that could benefit from our technology to have a drug available to them. That is going to take a heroic effort and lot of thought with the regulators to allow that class approval.

We are very connected to the research community. We know there is some work going on to look into the feasibility of applying exon-skipping or this type of technology to duplications. And we're in communication, we continue to follow that. And at a point that we believe that there is an application, we will explore that and determine the feasibility of pursuing that in clinical studies and what a regulatory pathway might look like with that.

So again, there is a lot of hope and promise with this technology but it does take time to do the appropriate experiments and to make sure we have confidence that this technology can be applied.

As it relates to double skips, if we get class approval and let's say we have 25 or so drugs on the shelf and a patient required two of those exon-skips to be pulled off the shelf at the pharmacy. This is a -- obviously the physician would be able to make that determination.

The FDA in terms of approval or reimbursement is another issue and question. And we think the real question there is safety and if you combine for example two drugs at 30 mg/kg per week that would be a dose of 60 mg/kg per week of which we have not studied in human subjects. So that's something that we'd have to figure out and explore with the regulators at the time that we have a class approval of the feasibility of double skip. So again we're very committed to our DMD program and if our technology can be applied to treat all the patients, we will be looking into that, but at this time it's just premature to suggest how and when that might occur.

Sharon Hesterlee - Parent Project Muscular Dystrophy

Okay. Thank you.

Chris Garabedian

Okay. Thank you all, to the DMD advocacy organizations for participating in this. Thanks to PPMD for describing the genetic testing program, we are very excited about that. And again for all of you listening The Skip Ahead website is a great resource. If you sign-up, we can provide updates as the company gets it. And for those patients or families who are interested in clinical trials either now or in the future sign-up, provide the requisite information. And we can reach out if we believe you qualify for clinical studies that we're planning for next year or beyond.

Another question we often get from the community is, what can we do to help, is there anything we can do to help. And I would say reaching out to any of the organizations that were represented on this call is a good start, visit their websites, learn more about those organizations, offer them help and assistance. That is their existence, that's what they are there for is to align with industry, with regulators, with the community and make sure that the community is doing everything possible to help which drug approvals gaining access et cetera. You will see many of the Sarepta employees at a lot of these conferences that are attended by the community, family members, patients themselves and we're always accessible. And again you have another forum through to reach out directly to the company, through email or through our toll free if you have any specific questions or interests in talking to the company directly.

So with that I just want to reiterate our commitment to our DMD program. We believe in our technology and we are doing everything to get eteplirsen approved as soon as possible. And to do everything to accelerate development of the follow on exons and even the class approval that would allow drugs to be treated for the rareage of exon deletions that exist in the DMD community.

So thank you all on behalf of Ed, myself and the Sarepta team, thank you for your time. And look forward to the next call.


And this concludes today's conference. Thank you for joining. You may now disconnect.

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