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Sarepta Therapeutics (NASDAQ:SRPT)

Update on FDA's Consideration of Accelerated Approval for Eteplirsen After Further Review of Data on Dystrophin and Clinical Outcomes

April 15, 2013 05:00 PM ET

Executives

Erin Cox - IR

Chris Garabedian - President and CEO

Ed Kaye - CMO

Analysts

Bill Tanner

Robyn Karnauskas

Christopher Marai

Ritu Baral

Liisa Bayko

Brian Skorney

Joseph Schwartz

Tim Lugo

Reni Benjamin

Debojit Chattopadhyay

Tedd Tenthoff

Operator

Welcome to the Sarepta Therapeutics Corporate conference call. My name is Joe and I will be your operator for today’s call. At this time, all participants are in a listen-only mode. Later and we will conduct a question-and-answer session. Please note that this conference is being recorded.

Joining us on today’s call are Chris Garabedian, Sarepta’s President and Chief Executive Officer; and Ed Kaye, Sarepta’s Chief Medical Officer. I will now turn the call over to your host Erin Cox. Erin, please go ahead.

Erin Cox

Thank you, Joe, and thank you for joining today’s call. Earlier today, we issued a press release providing an update on our end of phase 2 meeting with the FDA last month. The press release is available on the news and event section of the Investor Relations portion of our website at www.sareptatherapeutics.com.

As mentioned joining me on the call today are Chris Garabedian, Sarepta’s President and CEO; and Ed Kaye, our Chief Medical Officer.

I would like to note that during this call, we will make a number of statements that are forward-looking, including statements about the developments and clinical status of Sarepta's product candidates and the potential efficacy, safety and clinical results from ongoing or future studies involving product candidates. the potential and timing for regulatory review and approval of Sarepta's product candidates, the potential use of the accelerated approval pathway for eteplirsen, the potential for dystrophin as a surrogate marker, the amount and type of data that will be necessary for the FDA’s regulatory determinations, the impact of manufacturing and development activities and NDA submission timeline, the potential pricing and market opportunity for our product candidates, our ability to manufacture candidates, our ability to protect our intellectual property rights, future financial performance including revenues, expenses and financings, potential funding from the governments and other sources, and collaboration and partnering opportunities.

These forward-looking statements involve risks and uncertainties, any of which are beyond Sarepta’s control. Any such risks could 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, you are encouraged to review the company's official corporate documents filed with the Securities and Exchange Commission.

With that, let me turn the call over to Chris Garabedian, Sarepta’s President and Chief Executive Officer. Chris?

Chris Garabedian

Thank you, Erin. And before I begin, I would like say that we here at Sarepta as we sit here in Cambridge across the river from Boston are quite shaken up the explosions that occurred at the finish line of Boston Marathon. Today is Patriot’s Day, a local holiday and we had one of our employees in the race and had confirmed that she is okay.

On behalf of all of our employees, our thoughts and prayers go out for those who were injured and their families and I would like to pause for a brief moment of silence.

We are proud members of the Boston community and we care deeply about our employees, their families, our colleagues and our neighbors throughout the region. While we would rather choose not to have to release data on a day like today, we are obligated to release material nonpublic information in a timely manner and this is why we decided to proceed with an announcement this afternoon about the regulatory path forward for eteplirsen, our drug for the treatment of Duchenne muscular dystrophy and provide the appropriate context for what was in the press release. We will be archiving this call and it can be accessed on our website.

As you all know we met last month with the FDA's division of neurology products in a type B, end of phase 2 meeting to discuss the eteplirsen clinical and preclinical data sets. Specifically two primary objectives of the meeting would again feedback on the feasibility that the data from our eteplirsen clinical program would meet the requirements for a sub part H accelerated approval NDA filing. To be clear sub part H is a name for the section of FDA regulatory code 20 CFR 314 that describes an accelerated approval pathway for new drugs for serious and life threatening illness for a drug that and I’ll read from the code, 'has an effect on a surrogate end point that is reasonably likely based on epidemiologic, therapeutic, pathophysiologic or other evidence to predict clinical benefit on the basis of an effect on a clinical end point other than survival, or irreversible morbidity'.

We have received the FDA's meeting minutes and have a better understanding of what the FDA needs in order to indicate to us the acceptability of an accelerated approval filing. Specifically the division of neurology products requested two summaries from our existing data set, and I quote - a coherent and comprehensive summary to support distrophen as a surrogate and a detailed discussion of all clinical outcomes in the eteplirsen study. We are encouraged that the meeting minutes contained the following statement. The agency stated that they had not made a final decision regarding acceptability of the proposed sub part H, accelerated approval, NDA filing and that the agency would consider the additional data submitted by sponsor before making a final decision.

The FDA is approaching the question of distrophen as a surrogate that is reasonably likely to predict clinical benefit in the thoughtful manner we expected and is requesting more information about distrophen and potentially more evidence supporting the notion that the distrophen we're seeing in the muscle biopsies is functional and is likely to predict clinical benefit particularly with our supporting data on the six minute walk test. The more detailed discussion on clinical outcome should help to further illustrate data that may support the distrophen as quote, 'reasonably likely to predict the clinical benefit.

While we explained a number of these topics in the briefing documents, during the FDA meeting we described our understanding of dystrophin and the methodologies that are used to measure it in much greater detail than was provided in the briefing document. This was information that they wanted to better understand and requested that we capture a more comprehensive summary in a follow-up document. Likewise, we discussed more detail about the clinical outcome in response to questions in the meeting that was outlined in the briefing document and they wanted a separate summary to put all of our clinical data in the proper context. Make no mistake we had a lengthy and detailed amount of information in the briefing document and in most cases these documents provide sufficient information to allow the FDA to make an informed decision. But it is clear that the FDA recognizes that a decision to accept a surrogate endpoint for approval that has not yet been used for a drug approval is an important matter and needs to be considered with a fuller understanding of our data set.

We believe that eteplirsen will be held to the same standard as any drug if the FDA were to accept a Sarepta NDA submission to file under the accelerated approval regulatory path and would go through a detailed review of the entire Eteplirsen dataset in an independent review of our Phase 2b study but it appears that the FDA would like to more fully understand our data set prior to making the decision whether an NDA submission would be acceptable for filing.

Since our meeting with the FDA took place last month, we requested transfer of our 74 week data set from the CRO to evaluate Eteplirsen’s continued effect on clinical outcomes. We shared this in a press release earlier this month on April 5th and will incorporate this 74 week data set into the clinical outcome summary that the FDA requested which we did not have for inclusion in the briefing document which was compiled and submitted earlier in the year.

We have begun compiling these summary reports on dystrophin and clinical outcomes and are taking a thoughtful approach and a more extensive review of the literature to establish our strongest support possible for dystrophin as a surrogate marker and for the eteplirsen clinical data set to suggest that the dystrophin we are producing is reasonably likely to predict the clinical benefit based not only on how our six minute walk test results showed a statistically significant benefit in our treated patients versus placebo but also how the literature or the natural history of the disease might support that the stabilization we see in both arms is not expected to occur off of treatment, particularly when we selected a patient population that was older than seven or almost nine years on average and capped based on 6-minute walk distance so we would not enroll too healthy a population.

As a reminder, the 6-minute walk test resulted 74 weeks support a continued stabilization of patients in both the early treatment and placebo delayed treatment cohort. The continued performance on both of these arms in our valuable modified intended treat population suggested in our original or early treatment cohort that we could maintain ambulation in a population that was above 350 meters on average that base fine, over nearly a year and a half. But more importantly our placebo cohort which had an average of less than 330 meter on their 6-minute walk test at 36 weeks, the last time point that we would not have expected dystrophin production also stabilized between weeks 36 and 74 or over a 38 week or nearly nine month period.

The stabilization of this placebo delayed treatment cohort in which we changed the trajectory of the decline on six-minute walk test between weeks one and 36, the period they declined, the literature on the 6-minute walk test suggested those who are walking less than 350 meters or less than 330 meters depending on which paper you reference are at much greater risk to rapidly decline or lose ambulation.

We are planning to submit these reports to the FDA in the coming weeks and will request a follow-up meeting to take place in the next few months or later this quarter. We do not anticipate that this request for information by the FDA nor the delay of a few months on a definitive decision on the acceptability of an accelerated approval submission will have any impact on our ongoing activity as we will continue to move our manufacturing and clinical activities on a critical path.

As we once again feedback on the feasibility of a potential accelerated approval filing, we would still like to have our CMC meeting with this feedback and we’ll now expect to have our end to phase II meeting with to discuss CMC issues in the third quarter of this year.

While we will need the FDA’s feedback on what they will need in a CMC section of a potential accelerated approval NDA submission if we decide to pursue this pathway, we are maintaining all critical path activities related to manufacturing that we believe we would need for such an NDA submission.

In summary, we are encouraged by the FDA’s meeting minutes and believe we can provide the information they need on dystrophin in clinical outcomes so that they could make an informed and appropriate decision on the acceptability of dystrophin as a surrogate marker that is likely to predict clinical benefit in its devastating progressive and irreversible disease.

Let me, in my prepared comments with highlighting how collaborative the FDA has been in providing clear feedback and direction in their communication. They seem to understand that this decision is important and that time is up in the essence for the families affected by DMD, who may benefit from such a treatment.

Furthermore, we believe the division of neurology products is approaching this decision with careful thought and the appropriate standards as they consider the risk-benefit profile of this rare disease where there are no currently approved treatments.

We have heard the remarks recently from Dr. Margaret Hamburg and Janet Woodcock and Robert Temple; they have all highlighted the flexibility afforded the FDA in considering approval of drugs for serious life-threatening disease for which there are few or no treatment options available. We believe Duchenne fits into this category.

Lastly, it is not lost on Sarepta that many efforts by parents of the DMD boys that might benefit from our treatment along with other advocates in the DMD community are having an impact and we thank them for their commitment and sense of urgency in highlighting the practical realities of this disease and how quickly this disease can progress without an opportunity to reverse loss of function.

Operator, that concludes my prepared remarks, and we can open up the call to questions.

Question-and-Answer Session

Operator

Thank you, we will now begin the question and answer session. (Operator Instructions). We are now standing by for questions. It looks like we have Tedd Tenthoff on line with the question. Go ahead Tedd.

Tedd Tenthoff

Two questions, if I may. How quickly do you think you can actually get this data pulled and put together in a report and resubmitted to the FDA? And is there a specific timeline in terms of how long they would have to respond following that kind of resubmission?

Chris Garabedian

Tedd, it’s a good question. So again, we are preparing these documents and in the coming weeks, we believe they will be ready for submission. One thing that we were encouraged by was there was a seeming willingness to be flexible around the timing of the follow-up discussion related to these documents. So, what would normally be a 60 day to 75 day meeting request, we may be able to work with them to accelerate that timing. It's premature to speculate if that's the case and how quickly we could calendar that. But typically the FDA likes sometime to read, review and discuss those documents. So, to some degree it will be based on how much time they need and also calendaring can be challenging at times as well. So, again where we sit today we don’t have enough information to guide more specifically on that timing. But that's why we hope, as we stated in my comments that it would occur by the end of the quarter.

Tedd Tenthoff

Yes perfect that’s helpful now other quick question if I may just from your response there and in your prepared remarks, you have talked about this flexibility on the part of the FDA and we have heard different commentary from Dr. Temple and other people within the agency. Maybe you can give us kind of a high level view of; you have given us the update today, you have given us feedback from the minutes but maybe you can give us a higher level view of really where the FDA was. I mean was this a collaborative meeting? Was this something where they seemed, pretty interested around this and just needed additional information? What other color can you give us around how the FDA meeting went?

Chris Garabedian

I think any company or CEO would hesitate trying to speculate and make comments on the FDA. But what I will say is that we believe this is getting the attention that it deserves. We believe that they are engaged in this; in the way we would like to see them engaged asking very good questions, being again as I mentioned in my comments very thoughtful and thorough. And yes, I believe we are getting the attention at all levels throughout the FDA, that this program deserves and we recognize that this is a decision that they are going to ensure that they are thoughtful about because there maybe people paying attention beyond those interested in Sarepta on a decision around this. So again, I think we're believing that they are engaged and involved at all levels of the FDA around this decision.

Operator

Our next question comes from Bill Tanner. Go ahead Bill.

Bill Tanner

Thanks for taking the question, Chris. Just looking at one of the quotes from you in the press release, you said that you're confident about the method in which you've collected dystrophin. I'm curious if you can respond has the FDA questioned anything about the methodology of that or is it more about just trying to determine as to whether or not it's functional dystrophin protein?

Chris Garabedian

Well, the way I would say and the reason we provided those detail is because when you are dealing with a surrogate like dystrophin of which you know we believe that it’s the best surrogate for Duchenne, it’s the inability of these boys to produce dystrophin and that’s what our drug is trying to do working with their genetic machinery to produce a Baker-like dystrophin. And so what we are trying to do is cover every aspect of this, right, so part of that will be what’s characterized in the literature around the dystrophin that, what the dystrophin itself in let’s say in normal population, what we know about the dystrophen is produced in Baker that were trying to mimic with our drug technology and of course there is other factors, the methodology that’s used and the various pros and cons of those methodologies and we do several to collect data and we picked one particular for our primary endpoint that we believe we have a good reason which shows that and which is similar from other companies that have attempted to go down this pathway. But to make a decision to say this surrogate is now acceptable as under an accelerated promo pathway we understand they need to understand everything about it. How we collected? What levels are we seeing, the consistency of those levels. Is there other evidence like restoration of the Dystroglycan complex that can supportive to suggest it’s functional. So all of these things, we again are confident in how we collected it, the levels that we are seeing, the consistency we are seeing across the samples within a patient and across the patients, the other supporting evidence we have whether that be evidence that we’re restoring the dystroglycan complex even from other studies that have been published along with dystrophen intensity and other supportive data.

So, again all I’m trying to do is characterize the fact that this is going to be a thorough approach we’re taking and that we’re confident in all the aspects of the dystrophen that we’ve produced and that’s the all reason the quote was highlighting some of the specific aspect.

Bill Tanner

Okay that’s helpful and then as it relates to it sounds like this is going to go on for maybe a little bit longer that what it had been initially contemplated as it relates to division director changes, I mean how do you see that or do you see that having an impact in a positive or negative I guess in the process?

Chris Garabedian

Again, I can’t speculate as far as I know, there is no formal changeover of any division director etc. that’s been mapped out obviously those who are reviewing these documents, those who have prepared the meeting minutes, those who were participating in the actual meeting, they are becoming the experts on our program and we don’t believe that we’re going to lose any continuity and that the FDA will do what’s necessary to ensure that we don’t lose the learnings and the education and the engagement and the exchange that we’re having with the division and even outside of division of members of sitters and throughout the hierarchy of the FDA.

So I mean I think you know from that vantage point we don’t view that as a particular concern and we’re doing the best we can to make the case so that anybody who could pick up these documents could have a tutorial and believe strongly in this surrogate.

Operator

And our next question comes from Robyn Karnauskas. Go ahead Robyn.

Robyn Karnauskas

I’ve got two quick ones, so can you give a little bit more color about what in the clinical outcome summary is typically included and how is this different from maybe what was presented and maybe more specifically with individual patient data and dystrophen data presented at the meeting?

And then second question, just to follow up on your comments regarding dystrophen collection, I was just wondering if the FDA asked more specifically about how comfortable you were with dystrophin production given it takes time for dystrophin production to be even throughout the patient and your biopsies are from specific locations, I was wondering if that came up at all? Thanks.

Chris Garabedian

Yes, thanks Robin. So the first question on the clinical outcomes, so we did share a fair amount of data including, the FDA had individual patient data prior to our meeting but it was not a full data set. As you know we anticipate that when we file our NDA, they are going to have the entire data set and they'll be able to do as detailed and deep an analysis and summary on their own and we would expect that they would use the same standards they would apply to any drug that they're considering for approval.

I say what surprised us was that we had a lot of information in the briefing document that we believed was sufficient to make the decision of whether or not the data set. The overall size of the data set, what type of data we collected, would be enough to allow them to make a decision of whether the submission would be acceptable for filing. It seems that they want a higher degree of assurance before they send a signal that they say yes, this is an acceptable submission for filing, to find out later that maybe some of the more detailed supported data would make it more difficult to approve the drug, right.

So again, we believe the briefing document reflected the totality of the data set but didn't have all of the details and I’ll say that the FDA has in the past and maybe looking in this case, the idea that it may just be some supportive data on a patient or two that makes them more comfortable that there is some evidence that the distrophen that's been produced is having an effect on clinical outcome, but even if that's in a subset of patients or a handful of patients. So I think we look at this as them wanting to better assess the likelihood that they can look at this, I am trying to be careful with my words, to look at this as a way where they have a higher degree of confidence before they accept the submission.

Robyn Karnauskas

Just a follow up with that answer, you know given that the FDA may by the end of the year or maybe next year have more data for Prosensa which is a similar technology it may give them a lot of data on the correlation, did that come up at all, do you think that the FDA may want to wait to see even more data knowing that’s coming correlating dystrophin with walk?

Chris Garabedian

Yes we do not believe that to be the case, we have got no indication of that at all. There is not really much precedents for that as far as I am aware and again we believe that they are evaluating this drug on its own merit. They are looking at our data set, safety efficacy biochemically and clinically, we've said that from the beginning we stand by that and we have been given no indication that they are applying a different standard on our data because of what our competitor may or may not be able to produce at some point in the future, whether that’s near-term or long-term. So again, we've had no indication of that.

The dystrophin question you asked Robyn again, look there is a lot of representatives and division and there is a lot of people involved in this process and we really appreciate it the time that the division gave us to have a really thoughtful measured discussion around dystrophin, how we have collected it, the delay of the dystrophin and the fact that we did not see it at 12 weeks but saw it very robustly and consistently after 24 weeks of treatment and even more so after 48 weeks of treatment. So, we believe that whatever they did not glean from the briefing documents, they understood following the meeting and I believe that it was a result of the very deep detailed discussion we had in the meeting that led them to say let’s capture that Sarepta in a nice what I would almost describe as a white paper of a dystrophin, tell us about this you told us a lot in the meeting, we would love to have that in greater detail in a nice as they described comprehensive summary.

So, again it was not driven in our mind by concerns about the consistency across the samples or the fact that we took biopsy sample from a particular location. they know we can’t treat these patients as guinea pigs and start making multiple surgical incisions to try to see how diffusive it is across the musculature. So, again we think they understand the complexities and challenges and that we have to work with what we have given the human subjects.

Operator

All right and we now have Christopher Marai online with a question. Go ahead Christopher.

Christopher Marai

I think you touched upon this just briefly in your response to the last question but it's obvious that this is a rapidly changing field and that much of this might be an education process for the FDA, could you give us an idea about how to speed the FDA was on the latest scientist research in the field, specifically around dystrophin as a surrogate marker as well as natural history (inaudible) with respect to the clinical outcomes? Thanks.

Chris Garabedian

The FDA has a lot of smart people and they understand how to ask questions very directly very well. However, they have a live preview, alright. They’ve got to consider, I mean just take each division, division of neurology and how many disease areas they have to maintain a level of expertise on.

So, we would not expect them to be as expert and detailed as a company that’s at this point largely focused and from a proprietary development standpoint singularly focused on the Duchenne muscular dystrophy and dystrophin, right. So, we always expect that there is an exchange, a deeper understanding and we believe that happened with our briefing document, we believe it happened even further in our meeting and we believe it’s going to happen further after we submit this summary document.

So, again we understand the onus is on us to make sure we have the most comprehensive and detail view of dystrophin, our data sets and of course we work with experts in the field, outside of the company to gain a better understanding ourselves so we can represent the literature, the findings in the field, what’s emerging in the best way we know how.

So, we do believe that the onus is on us to make the most compelling case that pulls in and ties in the latest research, the latest literature. But I can tell you, it’s a very smart lot and they get up to speed very quickly.

Christopher Marai

And just a follow up, if you decide to pursue this pathway, what are we thinking in terms of timing for filings?

Chris Garabedian

We have not wavered from our comments that we really need to get our CMC feedback to really understand. So there is a couple of ifs here, okay. The first if is if they give us a signal that they will accept the submission for filing under accelerated approval, okay. The second one is we need to wait until we get the feedback on CMC for what is required under an accelerated approval filing in the CMC section. Now, we have said we believe they have shown flexibility in cases like these where there is a rare disease, there is an urgency of getting drug to patients and again, let’s take the topic of stability, right.

We know as we're trying to ramp up supply, this is unlikely to be a drug that's going to be sitting on the shelf for more than weeks, let alone months. So we need to have that discussion with the FDA about how flexible they are on stability data, on comparability when we are scaling up, process validation if we move from mid-scale to large scale. How quickly can we bring these other scales of manufacturing into the market? Again, these are really only issues under the scenario of an accelerated approval and that’s why we need to get their read on that first. Then we need to have the CMC section. But again all of that activity is continuing to take place. And it's just a matter of how we compile it, what data they need, and what time point we would have that, and then we can guide more specifically on the timing of a filing in an accelerated approval.

Operator

We have another question here from Ritu Baral, go ahead Ritu.

Ritu Baral

But did you guys cover the design of the pivotal trial coming up during this meeting? Specifically any thoughts as to what randomization could be or whether it could be a historical control? And then I have a follow-up.

Chris Garabedian

Yes, we did have a brief discussion around the confirmatory trial design. Frankly, there was a lot to cover on the topic of accelerated approval and dystrophin and also to make sure there was a clear understanding of our phase II B design, right, and the delay of the dystrophin that we learned about in the placebo part of the study where we didn’t see dystrophin at 12 weeks but then we did see it consistently and robustly after 24 weeks of treatment. So, they were very generous with their time but there was still a limited amount of time to cover everything we would have liked to. They were very gracious to offer, subsequent meetings as needed to get all the information we needed to keep this program moving forward and on a critical path. So, we got some feedback but we really need to re-visit this and they were suggesting that it was premature in that we needed to get our hands around whether this would be a scenario if we were feeling a little bit accelerated approval in which a commercial drug might be made available right during the confirmatory study.

And so, I think we need to have further discussion and we expect to have further discussion with them about the confirmatory study, once we get a better handle on the feasibility of a Subpart H filing. So that's all we have to say right now but we do have a good idea of a lot of the elements and our clinical activities are proceeding as you know to the final protocol really becomes important when you are about to submit to your IRB. So, we believe we have time to finalize that protocol, it’s not stopping us from identifying sites, considering identification of patients, preparing everything we need to, to make sure we don’t delay the timeline and we are not at this point delaying anything with our expectation of starting dosing in the first quarter of next year.

Ritu Baral

Does the request by the, also encompass some of the other proteins that are part of the complex, some of the ones that you reported on in your Phase 2a, like the Dystroglycan, Sarcoglycan, the functionality of that complex?

Chris Garabedian

Yes it did and that is; I think it’s fair to say that one of the areas that they seem to be very interested in hearing more about and is one of the things we are going to make sure is included in the summary that we are putting together because I mean honestly this is unprecedented in terms of looking at this surrogate and considering it as a base of approval and so to some degree and we believe we have the most robust data set that’s been produced of all of the drugs that have attempted to show dystrophin production. So this is new ground for them and again, we believe that they heard a lot that they wanted to have us capture in a summary document. But we see you head on one area that was definitely discussed in the meeting and that they stated they wanted to hear more about and of course we have a published paper from our initial study with the eteplirsen, we collected additional glycoprotein data from (inaudible) from our current and we believe that that could be an important consideration of supporting the function of the dystrophin that we are producing.

Operator

We have another question here from Liisa Bayko, go ahead Liisa.

Liisa Bayko

First question is, can you may be describe the other clinical outcomes that that you did collect, besides 6-minute walk test? It seems from the commentary here that FDA is interested in exploring those as well. Thanks

Chris Garabedian

We collected a lot and we also were able to describe some of the outcomes in the two (inaudible) we had. For example pulmonary function, quantitative muscle testing, nine hole Peg Test, etc. So one thing that we are pleased that we were able to do was even though these two twins became non-ambulant, before we started the extension study, we are able to continue to collect safety and efficacy data in these two boys. And so I think there was interest in understanding that as well as the ambulant boys, the idea that you know we collected a lot. I think there was a good discussion about the variability of some of these other tests like Gower maneuver and four stair climb test and North Star ambulatory scoring, and so while there was an acknowledgment, there was also a feeling that there may be some insights in looking at the individual patient data that might not be seen in a cohort analysis. So if a cohort may not be supportive but a patient or two may be very supportive, right, the clinical benefit or a signal that would be reasonably like to predict clinical benefit.

So you know again, there is a voluminous amount data and I think what they’re saying is acknowledgement is you know what let see it, let see that data, and summarize it in the best way you know how and we’d like to consider that before make our final decision. So again, we collected a lot cardiac data as well which again we said we didn’t expect that to decline in the placebo patients because with more of safety market, but I just described a lot of the secondary exploratory outcome that we collected.

Liisa Bayko

Chris, there was a lot of discussion after the meeting last week at Cold Spring Harbor about natural history and just the context of that I mean how much of your discussion with FDA were evolved around the natural history and obviously there is a sort of four ways look at it, one is by age, one is by certain walk distance 320 or 350 whatever 330 whatever it is, can you maybe talk about FDA sort of feeling about that?

Chris Garabedian

You know, it is great question Liisa. So I mean look, I talked to people all the time about this right and there is still confusion right about what point is the progression really start and what are the right age groups and what are the different cutoffs for 6-minutes' walk. So definitely we highlighted some of this in our meeting and again I think there was an appreciation of our understanding of the natural history and our selection of the patient population, right.

I think, it’s wrong to try to draw to comparison of what happened in our study to you know we know in other company had a larger dataset that they brought to the FDA that included five and six year old. We know the data that was presented last week at Cold Spring Harbor was another study that included five or six years old on the average age skewed much younger almost a year and half younger to our patient population.

We know that other studies they don’t cap the 6-minute walk test and so tend to enroll patients who have a healthier baseline. So we did have an opportunity to explain that the selection of patients here would lead to a more progressive decline than you would see in a general natural history paper. But that’s again, an area that we have an opportunity to clarify even further in words that we were able to highlight in the meeting and that’s going to be something that we also incorporate in our clinical outcome summary. So again a good question you’re hitting at some of the things that would give them some more comfort around our data set by providing them the proper context in which to view it.

Liisa Bayko

Okay, I have two more questions for you, the first one probably pretty easy. Have you thought at all, now at this point about the breakthrough status and whether or not something would help you at this point and is that something you intend to do?

Chris Garabedian

As I mentioned we said we would make a decision on our strategy as it relates to breakthrough by the end of the second quarter, so that continues to be our guidance on this. What I would say, and I've said this prior but I believe it more even now, is that we have a specific task in hand which is to get feedback on the feasibility of you know an accelerated filing if we submit an NDA on this current data set. And we are getting the feedback we need the responsiveness we would expect and we think we can achieve what we need with the communication, with the meetings that we may need in follow up to clarification point, you know this has the attention of the people that we need at the FDA, we will make a decision as a company and we're going to learn a lot, you can imagine about how they view our data set in this process to give us the understanding of their sentiment as it relates to whether or not this is a breakthrough therapy.

So again, stay tuned on that, we’ll have our strategy outlined by the end of the second quarter.

Liisa Bayko

Okay and then just final is a point of clarification, you will submit and request at the same time, so you'll submit your sort of responses, this request and then request a meeting with them and this will all happen this quarter so you'll have the meeting next quarter.

Chris Garabedian

We hope, again the meeting is not calendared, they've suggested, they have some flexibility to move more quickly than their standard timelines potentially, so this is speculative but we still believe that we can submit these documents, request the meeting and have it calendared by the end of the second quarter.

Liisa Bayko

So calendared means completed or you'll just have it on the books at that time?

Chris Garabedian

Yes, again, our goal, our hope is that we can have the meeting by the end of the second quarter. Now, again that may be some follow up minutes et cetera, and so communication around that may not occur until after that, but again it's premature to guide on time but then again we're just stating our goal. The CMC meeting again, we want a signal on this accelerated approval question and so we are suggesting that the CMC meeting will now have to happen in the third quarter.

Operator

And we have a question here from Brian Skorney. Please go ahead Brian.

Brian Skorney

Thanks for taking the question. I guess I just wanted to kind of get a little color on the part of the press release where you said the agency agrees to file Subpart H NDA submission with additional safeties reported from the first few months of the pivotal confirmatory study; I guess can you give us any sense of what, or how much additional safety data the FDA is looking for I mean did they kind of quantify it in patient years or they are looking for something very specific to kind of de-risk the safety profile off of the confirmatory?

Chris Garabedian

Yes I think what we provided in the press release is the best way we can characterize it. if I were to give additional color, I would say you read that closely, okay. And the reason, I say that is that there and I will just read it. So in the event it agrees to file that the agency agrees to file Subpart H NDA submission. So again for those I believe all of you understand the vernacular that the FDA uses. We submit an application, the FDA files it. So the sponsor does not file the FDA files it. The sponsor just submits the application. So in the event the agency agrees to file the NDA submission, additional safety data to support approval could come from the first few months of the pivotal confirmatory study. So what they are saying is that if it’s likely that an NDA would be submitted and we were collecting additional safety data for the first few months of our pivotal confirmatory trial that we could supplement right that NDA filing with some additional data if they felt they needed that to support approval again reading from the sentence. Again, this is one of the things you can look at things and read too much into it not enough but this is the statement that we believe captured their comment on safety the best and that’s why we included it in the press release.

Brian Skorney

I mean I guess I was trying to gain more of the scale of the pivotal confirmatory study based on the commentary, I mean the difference…

Chris Garabedian

Yes. There was no suggestion that there needed to be a certain number of patients. I think we described which I’ve described previously the size of the treated number of patients to be in their ballpark of 60 to 80, so they know that they know enroll doesn’t happen all on day one, they know. So again, they were aware of when we would start dosing and you know again, suggested that the first few months, it is what it is. We’ve given a timeline and that’s as much as we have and that is as much as we’re ready to communicate based on that knowledge at this point.

Brian Skorney

Just a quick follow-up, I think, Chris, I just wondered if you could kind of give your thoughts on why these requests are being made by the agency, I mean it seems like these are usually review issues especially kind of the detailed discussion of clinical outcomes in this study of opposed to pre-NDA discussion. Why do you think the FDA…?

Chris Garabedian

Yes, in my earlier comments kind of alluded to this, it seems that they’re digging a little deeper here than they would normally and almost bridging it into a review of our data. And to some degree I’m not too surprised in that it’s a smaller dataset than they’re used to. 38 patients total, 12 patients in our ongoing extension study and for them to make a decision and as I mentioned, they may recognize that it’s possible that others are looking to them in this discussion and so they’re not going to make this decision without a lot of thought about truly understanding the data set and reviewing as much as they can before they guide positively.

So, it’s hard to agree more those are speculative comments that I’m making but we think they just want to better understand this before they send a signal that, yes we would accept this type of data base for an accelerated approval filing.

Operator

We have question here from Joseph Schwartz. Go ahead Joseph.

Joseph Schwartz

I was wondering if you were able to get a sense about how the FDA views your MITT analysis and how they felt about the two patients that received drug who saw a decline in 6-minute walk and how you might be able to put that into context relative to the Dystrophin generation story.

Chris Garabedian

So and again I was alluding to this in earlier comments. We really appreciated the ability to describe for the division, our trial design, the delay of the dystrophin and how that had an impact on what we saw in the clinical outcomes. The ability to describe the two twins; and how rapidly they declined and how that was consistent with the delay of dystrophin in our inability to affect the slope of their decline on an ambulatory measure like 6-minute walk. So they were very generous with their time, to be able to really understand and hear this. I think the minute suggest a desire to have a lot of those discussions captured in a good summary. And so again we were very encouraged by the thoughtfulness, the intelligent questions; the openness of hearing what we understand the data to be telling us. But again this is worth sharing everything that we believe and worth hearing and so I can't make any more speculative comments beyond that. I think we will have to see.

Joseph Schwartz

And then did the FDA identify any particular review issues in you were able to show them to date?

Chris Garabedian

Well no, again, I don’t think it’s something they would comment on terms of review issues, right at this point, because, again they are pretty good at sticking to the task at hand, and what we are requesting. But I can give you my opinion. There is nothing that came out of the discussion that would lead me to believe that, it’s going to be, how the data sets panned up. We expect them to review the data set, they way they would any NDA and we all know they do a good job with that. They analyze it in great detail. They do their own independent review and analysis. They will put their own presentation together, we'll have an opportunity to sponsor to do the same and we hope that we come to the same conclusion but to speculate that there may be reviewed, I think it’s premature.

Operator

Tim Lugo is online with a question. Go ahead Tim.

Tim Lugo

Thanks for taking the question. Within the language you recited earlier regarding the first few months of data from the pivotal confirmatory study, why would the FDA not also want to see efficacy data from that study in addition to safety data? And I guess, in general, I'm trying to figure out how comfortable they were with the open label nature of data produced after 24 weeks in the Phase 2b?

Chris Garabedian

Yes well so first of all the whole crux of our question around accelerated approval is do they need additional efficacy data, right? I mean, the whole basis of the question is, believing that this is an urgent enough disease to consider approving it before we have confirmatory efficacy evidence to support it, right? So, the whole question is based on not having additional efficacy data beyond our extension study. Because obviously that will push out the timeline quite a bit if they wanted efficacy data and in the short-term, the first few months we know we will unlikely be even producing dystrophin, let alone to see an impact potentially on efficacy. Regarding the open label nature, again I'll just repeat we were very pleased with their willingness to hear and understand our trial design, right? And the delay of the dystrophin and we did explain that I have explained previously that although it was an open label study from week 25 on, that this was not unblinded until after week 32 the company didn't even know the data, until after the week 32 assessments and the patients and staff at Nationwide Children’s didn't know whether they were on placebo or treatment until after week 36.

So, we were able to explain that these patients and staff were still blinded beyond the time point in which we would have expected dystrophin in the placebo control arm. So we did have an opportunity to explain this in great detail. Again, this is something we will make sure is made clear. We believe we did a good job with the briefing document, but now with a more detailed context, we will make sure that’s reinforced.

Again, there weren’t any particular concerns raised related to that because we had an opportunity to explain the rollover and when the patients were employed at.

Tim Lugo

Understood. And within this whitepaper, which you will be submitting, will you argue a specific percent Dystrophin increase, which will be tied to clinical, what you view as clinically meaningful? I believe you mentioned 10% in the past based on pre-clinical data. But is there -- are you trying to define a response rate, essentially?

Chris Garabedian

Yes, well again, we have said we believe that the levels we were seeing in terms of dystrophin-positive fibers are above the threshold and so we did explain that. You are already working with a sample of the musculature and you are trying to derive a correlation to clinical outcome of which we think you know one when you are above the threshold you are going to see a variability based on phenotypes and stage of disease and where they were at baseline 6-minute walk and things that would be more impactful on outcome than the level of dystrophin potentially. And we would never expect a tight correlation there, okay 35% dystrophin-positive fibers, one that a 10 meter benefit but 38% will give you another 2 meters and these are efforts depend in test, you have got a single biopsy that you are extrapolating. I think they get it, I think they know that you are unlikely to see this very tight correlation and that there is threshold effect. And yes we are combing through all the literature and pulling all of the evidence we have that would be supportive of this endpoint as meaningful.

Tim Lugo

One last question, you mentioned in the past submitting PMO backbone data from other indication previous to DMD, is that still the intent?

Chris Garabedian

Yes, we did discuss with them the experience of our PMO chemistry and the fact that this is the same backbone that has been dosed in the clinic for over a decade, all of those clinical studies that we have been doing from West Nile virus to polycystic kidney disease to coronary artery disease, these are on file at the FDA, right. For many of these we had summary reports that were submitted et cetera. So they again were acknowledging that that would be a consideration again I don’t want to overstate it. it’s just something that we were able to talk about and they acknowledged that would be a consideration but again we put the caveat's on it that these are in different patient population, these are lower doses than we’re looking DMD that they were shorter durations than what we’ve seen in our current study. So with all the caveats right, you have to weigh that evidence appropriately versus our seeking an approval for a chronic treatment at a dose that’s higher than it’s ever been test et cetera. So again we were encouraged that they would consider this past experience on the backbone but I wouldn’t elevate it to the critical decision point.

Operator

Our next question comes from Reni Benjamin. Go ahead Reni.

Reni Benjamin

Thanks for taking the question, Chris. Just very quickly, can you just help us understand why the FDA maybe concentrating on the dystrophin level instead of what I consider another surrogate endpoint to 6-minutes' walk test which is ultimately a surrogate to survival, is there no way to refocus the discussion to the 6-minutes' walk test results?

Chris Garabedian

Look, I took 6-minutes' walk test was – our primary clinical measure and that we had predefined in our SAP in our extension at 48 weeks. So we believe it the important clinical outcome and we believe they see it as the most important outcome. Again, I think they are just trying to do have fuller understanding of everything else. I think we and one of the other analyst said (inaudible) sounds like they’re doing kind of many review I think to some degree that looks like what they’re trying to deal with is just let us have a better understanding of this fuller dataset before we send the signal that it is acceptable.

But again I think we’re most encouraged by is that they’re going to be consider a filing and accelerated approval NDA submission after review of these summary papers, so we think this is a very encouraging sign and but again it’s still too early to draw conclusions at this point. We have request, we need to submit what they've asked for and request a follow up meeting and that's what we have to do at this point, that's the task at hand.

Reni Benjamin

And just maybe a follow up from a previous question, is it, are you looking more at biopsy specific distrophen levels and then extrapolating that, or are you looking more to correlate distrophen levels and the clinical benefit that you're seeing, what is it, or is the FDA focusing on both and everything.

Chris Garabedian

I think we're starting to split hairs here a little bit. I mean look, distrophen, they want to understand that distrophen and any evidence that we have that the distrophen we're producing is functional, that we can some level of confidence in it, that might allow the FDA to look at the clinical outcomes and whatever might be favorable, our 6-minute walk date or anything else that might look favorable even in a patient or two, to look at that through the appropriate lens once they feel that there's an understanding of the distrophen that we're producing.

Obviously if we had a clear correlation and there was no question about our clinical benefit we would be talking about full approval not accelerated approval, so this is something that we believe we're approaching it the appropriate way, thoughtfully and again I can't get inside the minds of everybody at the FDA who's involved in this. We just respond to what they are asking and try to interpret what that means in terms of what's important for them to make their decision.

Operator

Our final question comes from Debojit Chattopadhyay, go ahead Debojit.

Debojit Chattopadhyay

Thank you for taking the question, in your prepared remarks and on some of the analysts' questions the age of the patients between your trial and (inaudible) trial have been brought about. Specifically in your trial most of the patients would have been on the negative slope of the inverted U curve, right, given the age of the patients. But that is comparing with historical data and does that correlate to the use of steroids in this population because, what would you normally expect with steroids, would you expect a plateauing in or a decline in the 6-minute walk test.

Chris Garabedian

So what we've basically stated is that there's a variety of natural history studies that have been done that have various ranges some that includes steroids, some that don’t some that have varying degrees of steroids, different doses of steroids, different lengths of time that the patients were followed right. And so what we believe is that there is a range of decline that you would expect in the (audio gap) burden approved that this is not likely to occur in this population based on again the general natural history, I will ask Ed to comment and support that.

Ed Kaye

Yes I know, I think one of the things that were important in choosing this particular design and the criteria was that boys with steroids do have some delay in the fall off but once they begin to decline the steroids does not reverse it, it really delays the loss of ambulation but it doesn’t reverse the disease process. So I think, what we saw in our study is very consistent with what you would see on a large population of boys on steroids and then once that decline does start it’s not reversed by steroids.

Chris Garabedian

Yes and it probably did not reverse but the slope of the curve of the decline is pretty consistent it’s just shifted out a bit with steroids. So, again the slope of the decline is generally consistent even if the steroid is able to push out the degree of ambulation out a little bit.

Debojit Chattopadhyay

And one last question. Is there any plan to have any additional biopsies in the ongoing study then I mean do you expect kind of a plateauing dystrophin based on the deficient defendant mechanism of action or the majority of the patients now that that they are much older?

Chris Garabedian

Yes so look it was difficult to ask these boys and the parents of these boys to require them to go through a third surgical biopsy but we felt it was important to understand this drug and its effect on dystrophin overtime and the accumulation. We were very pleased that we were able to demonstrate between weeks 24 and 48 that we saw increased dystrophin levels and may not be at a plateau with continued treatment. At this point, we are not planning to ask for a fourth surgical biopsy to prove this now for follow-up studies under longitudinal studies with this drug, we may consider longer time points but it’s premature to speculate on that. At this point, it’s hard to predict. We do know that in animal studies you can get too much higher levels of dystrophin, positive fibers and dystrophin intensity and dystrophin in general in these animal models and we know that even with our own conjugated morpholinos you can see almost normal levels of dystrophin in let say in MDX mouse. So, there is nothing to believe that we can continue to get our drug in that it wouldn’t produce more dystrophin.

But again, we probably will not have that answer in the near term but we’re very encouraged by what we produced today.

I think that again, we’ve run long time so operator, I believe we’ll have to cup that off but let me just summarize that again, we are very encouraged by the FDA’s responsiveness or the willingness to understand our data set fully and understand this dystrophin marker before they make a formal and final decision on the acceptability of that under the accelerate approval guidelines. We are pleased that they have given us an opportunity to even further characterize our clinical outcomes that again might be supportive that the dystrophin we’re producing is reasonably likely to predict clinical benefit.

Of course, it’s still too early to draw conclusions or to put probabilities on whether this will be a go or no go on accelerated approval filing but again we sit here encouraged that we have an opportunity to makeup even more stronger, more detailed case with more information.

So, I’ll just thank everybody for listening and the interest and the questions and we appreciate again. We are saddened by what’s occurred here in the Boston area and again we put our presence thoughts to all the families affected by any people harmed or injured in the explosion.

So, thank you very much everybody for dialing in and enjoy the evening.

Operator

Thank you, ladies and gentlemen. This concludes today’s conference. Thank you for participating. You may now disconnect.

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Source: Sarepta Therapeutics CEO Discusses Update on FDA's Consideration of Accelerated Approval for Eteplirsen After Further Review of Data on Dystrophin and Clinical Outcomes (Transcript)
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