Good day, ladies and gentlemen, and welcome to the Sarepta Therapeutics First Quarter 2019 Earnings Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will be given at that time. [Operator Instructions] As a reminder, today's program is being recorded.

And I would like to introduce your host for today's program, Ian Estepan, Senior Vice President, Chief of Staff and Corporate Affairs. Please go ahead..

Thank you, Valerie, and thank you all for joining today's call. Earlier today, we released our financial results for the first quarter of 2019. The press release is available on our website at www.sarepta.com and our 10-Q was filed with the SEC earlier this afternoon.

Joining us on the call today are Doug Ingram; Sandy Mahatme; Bo Cumbo; Gilmore O'Neill; and Louise Rodino-Klapac. After our formal remarks, we'll open the call up for Q&A. I'd like to note that during this call, we'll be making a number of forward-looking statements.

Please take a moment to review our slide on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, any of which are beyond Sarepta's control.

Actual results could materially differ from these forward-looking statements and any such risks can materially and adversely affect the business, results of operations, and trading prices of Sarepta's common stock.

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q filed with the Securities and Exchange Commission as well as the company's other SEC filings.

The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projections provided today based on subsequent events or circumstances. With that, let me turn the call over to Doug Ingram, our CEO, who will provide an overview of our recent progress.

Doug?.

Thank you, Ian. Good afternoon and thank you all for joining Sarepta Therapeutics on its 2019 first quarter results and corporate update conference call. In 2017 and 2018 we defined our ambition and then gathered the tools necessary to achieve that ambition. Our vision was audacious, but also very specific.

As a fully integrated commercial stage biotechnology company with a multi-platform approach, we attend on being among the world's leaders in precision genetic medicine.

For our RNA platform, that means advancing our PMO technology to treat greater segments of the patient population with our exon skipping therapies, advancing our next generation PPMO technology which if successful could be a significantly more efficient version of our PMO technology, and bringing our RNA platform and expertise to new therapeutic diseases that could benefit from our [steroid] [ph] blocking technology.

And for our gene therapy platform, it means building out our durable gene therapy model by focusing on two interrelated exercises; one, advancing our multi-therapeutic gene therapy engine, already producing the broadest late-stage gene therapy pipeline in biotech; and two, advancing our hybrid manufacturing model with the goal of having the most robust capacity available in gene therapy, coupled with the ability to quickly transition constructs from proof of concept to commercial process supply.

The elements we built in 2017 and 2018 to fuel that vision are these. First, pipeline. Through internal development and external collaborations, we built what is currently a 26-program pipeline second to none. That includes 11 gene therapy programs, 14 RNA programs and a gene editing collaboration.

It also includes multiple therapeutic areas from Duchenne to 6 Limb-girdle diseases to Charcot-Marie-Tooth to MPS IIIA, multiple additional CMS applications, and the list goes on. Second, resources. We entered 2019 with $1.2 billion in cash.

And we raised another $375 million in the first quarter to ensure that we fuel our aspirations and we meet our very specific near-term goals. And third, talent. When I joined Sarepta, we had about 200 employees.

We have increased the number of employees, such as chemists, biologists, genetic experts, regulatory professionals manufacturing experts and the like, by some 300 - in fact, 300% since then. And we are in fact tracking to about 850 employees by the end of this year.

Moreover, the sophistication of our talent is second to none, including our gene therapy center of excellence in Columbus, Ohio, headed by Dr. Louise Rodino-Klapac and our very talented Head of R&D, Dr. Gilmore O'Neill.

When one assesses our ability to achieve our goals, it should be done in reference to the tools that we have gathered, and that's assets, our gene therapy manufacturing platform, our balance sheet and our talent.

Now, having gathered the tools to fuel our ambition, I noted at the inception of this year that 2019 would be the year of execution as it is our goal to build our reputation, not only on the breadth of our ambition and the quality of our science, but also on our operational excellence to drive performance and to execute.

And I am very pleased to say that in the first quarter, our team executed brilliantly. Let's start with our RNA franchise. In our third year from launch, EXONDYS 51 continues to perform, with sales standing at $87 million and quarter over same quarter last year growth of an impressive 35%.

In early 2018, I represented that we would build a positive relationship with the FDA and we would define an accelerated approval pathway for the bulk of our RNA platform.

I am pleased to say that in the first quarter of 2019, the FDA accepted our next PMO therapy, golodirsen, for filing, gave us priority review, set a PDUFA date of August 19, 2019, and informed us that they do not intend to empanel an advisory committee at this time.

In the first quarter of 2019, we announced positive results from our third PMO candidate, and that's casimersen. If successful, with golodirsen and casimersen, we will have three therapies serving the community by the first quarter of 2020, representing nearly 30% of the Duchenne population and more than doubling the coverage that we have today.

This is particularly impressive when one considers that in the entire history of biotech, there are less than 15 companies that have commercially launched three or more internally developed therapies. And we are progressing our next generation PPMO technology as well.

To remind you, our PPMO is a proprietary peptide conjugated version of our PMO RNA technology, which in animal models has robustly increased cellular penetration, greatly enhancing exon skipping and dystrophin production.

In the first quarter, we transitioned from our single-ascending dose study to our multi-ascending dose study for our first of 6 candidates, SRP-5051. We have screened our first patient in the study, and we should have insight on dosing levels by the end of 2019 to the first quarter of 2020.

Moving next to our gene therapy franchise, we have made very significant progress in the first quarter.

Having fulfilled our commitment to commence our placebo-controlled micro-dystrophin gene therapy trial by the fourth quarter of 2018, we have now made great progress on enrollment, having now dosed 18 patients thus far and we are comfortably on track to complete all dosing in the trial in this quarter, the second quarter of 2019.

And we are on track to commence a multi-center trial with commercial supply by year end. In the first quarter, we also announced very positive results from our first cohort of Limb-girdle 2E, that's our first program. Mean protein positive fibers was 51%, some 250% of the predefined milestone of success of 20% in the study.

Mean intensity was an impressive 47% and western blot quantification was a mean 36%. Creatine kinase enzyme, the marker of muscle damage, dropped by an unprecedented 90%. These results are particularly telling since they come at 0.25 of the dose of our micro-dystrophin program.

Given the lack of expression at another recent neuromuscular program in the stage at 5 times E13.

These results suggest the elegant design of our construct with potential positive read-through to all of the other Limb-girdle programs in our pipeline and also back to our micro-dystrophin gene therapy construct, which not only shares the same vector and promoter, but the same designer Dr. Louise Rodino-Klapac.

Commercial process supply for the Limb-girdle 2E pivotal trial will be available in the first-half of 2020. We have decided to use the available time to dose escalate the clinical supply from the Nationwide Children's facility. We plan to dose 3 patients in cohort 2 at 2E14.

This strategy will inform the dosing regimen not only for the 2E pivotal study, but it should also inform dose selection for all 6 of the Limb-girdle programs. We have planned to initiate dosing in this cohort in the middle of this year. Prior, as we announced earlier today, we continue to build out our gene therapy engine.

This time with an additional partnership with Nationwide Children's Hospital and Dr. Zarife Sahenk for our sixth Limb-girdle therapy, Limb-girdle 2A, otherwise known as calpainopathy. We are excited to deepen our relationship with Dr. Sahenk, the inventor of and the principal investigator for, our Charcot-Marie-Tooth program.

And we are pleased to add a gene therapy treatment for calpainopathy to our pipeline. Calpainopathy is an autosomal recessive Limb-girdle disease that results in very serious muscle degeneration and wasting. It is also the most prevalent form of Limb-girdle, accounting for about 30% of all Limb-girdle muscular dystrophy. Dr.

Sahenk's approach relies on rh74 and elegantly replaces the missing native protein from the calpain 3 gene, the root cause of the disease.

Going on, with our partner, Lysogene, in the first quarter, we commenced dosing in our Phase II/III gene therapy program to treat MPS IIIA, also known as Sanfilippo disease, a devastating neurological disease that often robs the life of children before the age of 15.

In the first quarter, we also made great strides toward the build-out of our gene therapy manufacturing plants. We are near completion of our process development and yield optimization efforts and have advanced our analytical development for our micro-dystrophin commercial process.

Our goal is to complete all process and analytical development, and to be in a position to commence our commercial process supply trial by year end. As many of you know, two of our CMOs were recently acquired in multibillion-dollar transactions.

Both of their investments further validate Sarepta's programs and our approach to manufacturing, in so far as we are the most significant long-term customer of both Brammer and Paragon.

Our hybrid manufacturing approach is a purposeful strategy designed to allow us control of the most differentiated aspects of the manufacturing process, while affording us the speed, the scale and the risk mitigation to match our goal of rapidly completing the safety and efficacy of our first program and bringing it to the community.

Our strategy includes building internal talent and ability around high-value differentiated process development, analytical development and early-stage manufacturing, and entering into long-term partnerships for large-scale supply. The goal then is to control the highly differentiated parts of manufacturers.

Those will allow us to move rapidly from conception to commercialization, and to partner and outsource those portions that will become the commoditized aspects of manufacturing.

For that end, we are near completion of a 75,000 square-foot dedicated Sarepta gene therapy manufacturing facility with Brammer Biosciences and its parent Thermo Fisher in Lexington, Massachusetts, targeted for commercial manufacturing beginning in late 2019 this very year. We also have dedicated supply with Paragon.

And as recently announced by Paragon and its parent, Catalent, we are in discussions for a deeper commercial supply relationship, including a second dedicated site for Sarepta supply. We set very ambitious targets for ourselves for 2019. And I am proud to say that the Sarepta team has so far in 2019 executed well against those targets.

And yet again, we must remind ourselves that there is much left to be done in 2019. And an enormous number of important milestones and inflection points left to achieve. We will complete dosing of our placebo trial for micro-dystrophin in 2019. We will dose additional Limb-girdle patients in 2019.

We will report out on progress of our first 2E cohort of patients later this year at a medical meeting or a scientific conference. We will continue the dosing of our trial for MPS IIIA or Sanfilippo disease. We will commence dosing of our first Charcot-Marie-Tooth gene-therapy cohort.

We intend to obtain our second PMO approval this time for golodirsen and to launch golodirsen in 2019. We expect to submit an NDA for casimersen in 2019. We will execute our multi-ascending trial for our next generation PPMO in 2019.

We intend to complete our process development, build commercial supply for micro-dystrophin and commence our commercial supply trial before the end of this year, 2019. And we will very likely find additional attractive assets to fuel our gene-therapy engine this year. The remainder of 2019 will be busy, but it will certainly be consequential.

If we achieve our goals, we will profoundly improve the lives of countless patients living with and otherwise dying very young from rare disease. We will build an enduring genetic medicine powerhouse designed to outlive all of us, and we will certainly create enormous shareholder value.

And with that, I will turn the call over to Sandy Mahatme to provide an update on the financials.

Sandy?.

Thanks, Doug. Good afternoon, everyone. We are pleased with our financial performance for the first quarter of 2019. Some of the highlights include $87 million of net product revenues, flat operating expenses compared to the prior quarter and approximately $1.4 billion in cash, cash equivalents and investments on hand as of March 31, 2019.

We continue to see attractive opportunities to expand our portfolio of products, leveraging our business development expertise to accelerate this expansion and augment our progress in internal research.

This is further evidenced by this morning's announcement around our agreement with Nationwide Children's Hospital that added a candidate for Limb-girdle muscular dystrophy type 2A to our pipeline.

We feel that with the capabilities and expertise we have internally and the directed nature of genetically targeted therapies, we can identify programs that have a high probability of success, that we have the expertise to efficiently move to clinical development, and that fit into our commercial portfolio.

Our recent Limb-girdle muscular dystrophy 2E clinical results provide additional support for the strategic path that we are on and solidify our position as the leading gene therapy company. This agreement brings our pipeline to 26 products in development, 11 of which are in gene therapy.

We expect to continue our current pace of expansion, maintaining our selective approach around both the science and financial metrics. Investments in developing our pipeline will grow in 2019 as we continue to add programs and invest programs from smaller early-stage trials into late-stage development.

We will also continue to invest in our Gene Therapy Center of Excellence in order to internally identify new targets for development. The expansion of our pipeline must be fully supported by investments in manufacturing capacity.

Shortly after Q1, we secured the remaining suites at Brammer Bio and, as a result, their site in Lexington, Massachusetts is not fully dedicated to Sarepta DMD therapy programs.

We also purchased more iCellis units at Paragon to build additional capacity for commercial supply in anticipation of commercial launches of both our micro-dystrophin and LGMD programs. From a cash perspective, we remain well positioned to execute our plan and invest in our business.

We maintain a very strong balance sheet, which allows us not only to invest appropriately in our current pipeline, but also to secure opportunities, such as the Limb-girdle muscular dystrophy 2A agreement that have a higher probability of success than traditional business development deals. Now moving to the financials.

This afternoon's press release provided details of the first quarter of 2019 on a non-GAAP basis as well as the GAAP basis. The press release is available on Sarepta's website. Please refer to our press release for a full reconciliation of GAAP to non-GAAP.

I'd like to add a quick reminder here that our 2019 non-GAAP financials exclude net interest expense, depreciation and amortization expense as well as one-time expenses and stock-based compensation. Net product revenue for the first quarter of 2019 was $87 million compared to $64.6 million for the same period of 2018.

The increase primarily reflects increasing demand for EXONDYS 51 in the United States. We reported a non-GAAP net loss of $53.8 million or $0.75 per share in the first quarter of 2019 compared to a non-GAAP net loss of $17.5 million or $0.28 per share in the first quarter of 2018.

In the first quarter of 2019, we recorded approximately $12.1 million in cost of sales compared to $5.6 million in the same period of 2018. The increase was driven by higher inventory costs and royalty payments to BioMarin, primarily related to increasing demand for EXONDYS 51 in 2018 and into 2019.

On a GAAP basis, we recorded $90 million and $46.2 million of R&D expense for the first quarter of 2019 and 2018, respectively, which is a year-over-year increase of $44.4 million.

The year-over-year growth in GAAP R&D expenses was driven largely by increased manufacturing activities related to gene therapy, increased patient enrollment in our early- and late-stage clinical trials as well as higher employee-related costs due to significant hiring in 2018 and into 2019.

On a non-GAAP basis, the R&D expenses were $81.4 million for the first quarter of 2019 compared to $43.3 million for the same period of 2017, an increase of $38.1 million. Turning to SG&A.

On a GAAP basis, we recorded $60.6 million and $43.3 million of expense for the first quarter of 2019 and 2018, respectively, a year-over-year increase of $17.3 million. On a non-GAAP basis, the SG&A expenses were $47.8 million for the first quarter of 2019 compared to $33.7 million for the same period of 2018, an increase of $14.1 million.

The year-over-year increase was primarily driven by continued expansion to support our commercial launch plans globally and 20 therapies in various stages of development across our therapeutic modalities.

On a GAAP basis, we recorded $200,000 in net interest expense for the first quarter of 2019 compared to $4.5 million of net interest expense for the same period of 2018.

The decrease in interest expense is primarily driven by payoff of certain debt instruments during the first - fourth quarter of 2018 as well as high return on investments over the first quarter of 2019. We ended Q1 with approximately $1.4 billion in cash, cash equivalents and other investments.

This was an increase of $175 million in our cash positions from the prior quarter and was driven primarily by the equity raise of $365 million net cash, offset by $54 million related to manufacturing initiatives and other net cash from operations. With that, I'd like to turn the call over to Bo for our commercial update.

Bo?.

Thank you, Sandy. Good afternoon, everyone. As you can see from our revenue of $87 million from Q1 of 2019, physicians continue to be committed to helping patients start and stay on EXONDYS 51. Duchenne patients and the Duchenne community continue to be core of who we are and what we do.

Our work will not be complete, and we will not rest until we've helped the broadest number of Duchenne patients in the quickest amount of time, providing a clear path to access for these potential life changing treatments. We continue to focus on genetic testing and enhance our efforts on identifying new patients.

As you know, we have a very successful program with Decode Duchenne, established in conjunction with PPMD many years ago, which focuses on the U.S. patient populations. Since then, Decode Duchenne has genotypes more than 1,000 DMD patients. And as a result, patients got into care or on a treatment or into clinical trials.

We have now started supporting genetic testing in other areas around the world, and we'll continue to bolster opportunities to help the community by supporting genetic testing in certain regions. Rounding out our RNA franchise, our two other chemo-based therapies for Duchenne currently in development, golodirsen and casimersen.

As Doug mentioned, the FDA granted golodirsen priority review status with a PDUFA date of August 19, 2019. In response, we will be ready to launch golodirsen later this year. The foundation of our plan will be tailored to reaching those individuals, the Duchenne community, who are exon 53 skip amenable.

We will leverage our knowledge and expertise in EXONDYS 51 to assist patients accessing this medication as fast as possible. Sarepta's commercial and medical teams are prepared for the potential approval of golodirsen. We remain on track to submit our NDA for casimersen in 2019 with a target approval in the first quarter of 2020.

If approved, casimersen will serve approximately another 8% of the Duchenne community. With that said, our goal by early 2020 is to have three approved drugs borne out of our RNA platform for individuals living with Duchenne.

While the majority of the commercial and medical teams are focused on EXONDYS 51 and ready for the potential launch of golodirsen, we have already begun planning for a successful launch with micro-dystrophin.

As part of that plan, we've already begun to build out our four micro-dystrophin launch team and are preparing for commercial site readiness to ensure multiple clinics, not only in the U.S., but globally in identify and treat patients safely with our micro-dystrophin gene therapy, if approved.

While the core of the company is focused on Duchenne, the science continues to lead us into other therapeutic areas of need. As Doug mentioned, we are excited about the addition of our Limb-girdle 2A program. Based on our market research, Limb-girdle muscular dystrophy 2A has the highest frequency in the United States, Europe and Brazil.

We're excited to have this opportunity to partner with a new community, where there's such a high unmet need. In support of the immense opportunity for us, we started meeting with the leading KOLs around the world to have a deeper understanding of the Limb-girdle muscular dystrophy disease state.

We will continue our educational initiatives at global conferences to build a foundation of knowledge on how vectors, promoters and RNA chemistries fit into various disease states. In the coming quarters, we will report on the progress we've made on these initiatives.

In addition, we recently hired genetic testing professionals, who have a background in rare disease and will focus on our six Limb-girdle muscular dystrophy programs as well as our many other gene therapy programs, such as MPS IIIA and a few other programs yet to be named.

We're also thoughtfully building out our global infrastructure to enable us to launch RNA therapies, if we have approvals in other regions or prepare for potential launch, global launch, in the coming years with our micro-dystrophin and Limb-girdle muscular dystrophy programs.

With the hope of gene therapies before us, we must ensure access and reimbursement is top of mind. There are structural hurdles to access on reimbursement of a single-dose transformative gene therapy.

And as a leader in genetic medicine, Sarepta is working to play a leading role in resolving those hurdles, so that if our therapy is approved, patients can rapidly benefit from them. As we consider access, reimbursement and affordability, we do not believe that the primary impediment will be price.

For life changing single-dose therapies that can improve and extend the life of those with devastating rare genetic disease, even the most conservative cost-effectiveness models will support a multimillion-dollar proposition.

Pfizer itself has noted, health technology assessment models can often justify prices for gene therapy in the $20 million to $25 million range, far above the actual price that an innovator would actually charge for therapy, which means the vast share of value will benefit society and patients.

A good example of this are the recent statements by Novartis that is SMA gene therapy, Zolgensma, is cost-effective at the price of $4 million to $5 million.

Now far from the issue of price, the fundamental issue is the structural impediments that come from the unintended consequences of a health care reimbursement system that has for many decades been built around chronic symptomatic therapies.

Sarepta has been in detailed engagement with private and governmental payors to find solutions that would provide early access to waiting patients, provide to the innovators the value that justify investment in gene therapy and that ensures that payors, both public and private, can absorb the cost of a transformative therapy without overwhelming the system.

For Sarepta, no solution is off the table. We are exploring payments over time, risk-based contracting so that Sarepta shares in the outcome and durability risk with payors, subscription models that can provide payors with more certainty and flat or a firm patient pricing over weight based pricing.

We're also working with those who are focused on legislative changes that would allow states and private payors to negotiate these sort of access, empowering relationships, and are beginning the process of working with CMS and state Medicaid to ensure that our therapies are equally available to private and Medicaid patients.

We have created a dynamic internal team made up of market access, government affairs, national accounts, distribution professionals and other key functions to collaborate with health care leaders and stakeholder groups to work together and truly address new models for reimbursement.

Sarepta has already initiated multiple exec-to-exec meetings with major commercial Medicaid healthcare leaders, in addition to influential stakeholders within the federal government or leading reimbursement working groups around the country.

To date, we've already held numerous meetings with key decision makers to help inform a path forward, so that the promise of gene therapies and new models around pricing and reimbursement can be realized.

Sarepta fully appreciates this goal in this conversation and that if we are to remain true to our mission of placing human health central to all that we do then we must, as innovators and drug developers, come to the table with not only solutions and ideas, but actual plans to execute on.

We appreciate all the payors and thought-leaders who are already engaging and partnering with us on these efforts. We look forward to finding a solution together. Our mission is to be the global leader in precision genetic medicine. It all started with EXONDYS 51.

We have broadly expanded our pipeline to potentially treat tens of thousands of patients in need and include have patients being dosed with gene therapies in Duchenne, Limb-girdle muscular dystrophy, MPS IIIA, and Charcot-Marie-Tooth as well as had two approved RNA therapies for Duchenne in the coming quarters.

This is truly an exciting time for all patients living with rare and debilitating diseases. All of us at Sarepta look forward to the future of precision genetic medicine. I will now turn the call back over to Doug..

Thank you, Bo, and with that, let's open up the line for questions..

Thank you. [Operator Instructions] Our first question comes from Alethia Young of Cantor Fitzgerald. Your line is open..

Hey, thanks for taking my question, guys.

I'm just curious, in light of attendance to the Pfizer data readout and, obviously, you guys have a lot of experience with gene therapy, can you talk about maybe potentially what you might expect to see what this data is at, at the current dose they're at? And just any other kind of observations from being NDA, just in and around the competitive landscape would be helpful as well?.

Okay. Thank you for that question, Alethia. So a couple of things, just to bring everyone up to speed, it's our understanding now that Pfizer has confirmed that it is going to do a data release at a patient advocacy conference in late June of this year at the PPMD conference. I believe it's down in Orlando.

So a couple of things, first, of course, we're very interested in seeing the data. We can't, obviously, speculate on what that data will look like in advance of the meeting. But we look forward to seeing it. We'll obviously be there. There are a couple of things, however, to consider as we wait for and review that data.

So, first of all, I think based on where we are in development and Pfizer's most recent public statements, we are in the lead on development. Our best guess is we're, as it stands right now, about a year ahead of Pfizer in our development program, I will remind you that, we will be done dosing our placebo controlled trial this quarter.

Obviously, that could change. But as it stands now, I think we're about a year ahead of Pfizer. There are some other things to consider as we consider what we'll see at PPMD. First, to evaluate the results, I think it's important to consider their dose. So, just so everyone understands, we use different titers.

So comparing dose requires some mathematical adjustment between us. Sarepta uses supercoiled GPCR. And we understand that they use something that's called linearized GPCR. And you have to do a conversion. And that conversion between those two titers, based on our analysis, is about 2 to 1.

That means that on an apples-to-apples basis, Pfizer's current dose is about 300% of our current dose, about 300%. Theirs is a truly staggering dose and an enormous viral factor burden for the patient.

So when one eventually sees their expression data, you will need to judge that expression data against the viral burden to which the patients are being subjected. And that does implicate safety not merely in those first three patients, but also in the patients across the entire spectrum of the disease, ages, weights and the like.

Obviously, we take no position on their dose selection, as we are not privy to their preclinical data or otherwise. But one would assume that in light of their dose selection, they will need to show a very impressive concomitant expression benefit to remain competitive.

In fact, at 300% or so of our dose, if they are unable to show expression levels that are greater than our expression, it raises at least the question whether they have a viable program from a risk-benefit perspective. But we'll see what they have when we see them in June. And there is one other thing.

It will be interesting to see how they quantify dystrophin. As you will recall, Sarepta was very transparent when we announced our data last year. First, of course, we provided quantification of dystrophin using western blot.

Western blot has been the gold standard and the only measure that the FDA has yet accepted as the basis of approval for a dystrophin-producing therapy. And second, we use immunohistochemistry. We did both dystrophin-positive fibers and we did intensity.

And we went so far actually just to show images, and we not only showed images for the immunohistochemistry, we actually showed images as well for western blot, so you could see we were essentially doing our math for you.

This is extremely important, immunohistochemistry, because all of the literature for now decades on Duchenne has been done on immunohistochemistry and dystrophin-positive fibers and intensity. So judging expression without IHC would be impossible. It would be impossible to make meaning of data.

And third, you will know we provided genome copies for nucleus, a very important metric for gene therapy coverage and transduction. Now, so we're clear, Pfizer is an incredible company.

And so, they should and we will assume they will transparently provide western blot dystrophin-positive fiber intensity and genome copy data for their data release, as they clearly should have this data. We know that they also looked at - they are looking now I believe at an experimental new measure using mass-spec that has never been used before.

But this cannot possibly take the place of the measures that allow for a meaningful analysis and a comparison of expression with reference to the great body of literature and the prior trials and the like, all of which rely on western blot and immunohistochemistry.

Transparency demands western blot dystrophin-positive fiber data, intensity data, genome copies. And the level of this transparency will become extremely important for a number of reasons. Obviously, it will be impossible for an investor, an analyst or a physician to make any meaning of their data in the absence of these measures.

But there's something far more important than this, and that is the issue of patients. Gene therapy is unique. It has a particularly [unforgiving] [ph] treatment in a sense, because it has unique bioethical considerations.

If a patient is given a gene therapy, they will likely be unable to get any other gene therapy literally for the rest of their lives unless the science on that changes. Patients choosing to participate in clinical trials and their physicians deserve accurate information that can inform that decision making.

Now, we're going to assume that Pfizer knows and understands that they will do the right thing. And we have no reason to believe they won't. But given that Pfizer has chosen to make the data disclosure at a Duchenne patients' conference, it would be particularly unconscionable for them to hide western blot and IHC data.

And we'll assume that will not occur. So I think we don't know the data. It'll be very interesting to see it in June. When we review the data, as everyone does, we'll need to review in the context of their dosing.

And we'll certainly like to take careful look at their western blot data, their immunohistochemistry data, dystrophin-positive fibers and intensities, so that we can make meaning of the data that we see in Orlando..

Thank you. Our next question comes with Ritu Baral of Cowen. Your line is open..

Hi, guys. Thanks for taking the question. A question for Bo, you mentioned that you're putting together your strategy for the micro-dystrophin gene therapy even now.

What are your high-level thoughts on treating the prevalent population? How are you looking at the low-hanging fruit age-wise, mutation-wise, baseline function-wise? What percentage of that prevalent population is an ideal candidate out of the gates, especially with how you're thinking about pricing?.

Well, I mean, currently, we think that the entire population based off the clinical trial design that Gilmore and the team is putting through will be eligible. So if there's not a, quote unquote, low-hanging fruit. I think both combined there's going to be a mad rush coming in.

Now, that when you start talking to physicians and [John] [ph] sort of mentioned this on clinical trial improvement, about how his patients are literally trying to bang down the doors to get in.

If you start thinking about clinical - I mean commercial readiness, the physicians are telling me that patients are already lining up, they're already trying to identify whether they're going to be eligible or not.

So, really, it's about site readying, just making sure that we have enough sites that can dose the drug immediately after approval, making sure that they're up to speed and safely administer the therapy in a very quick time.

I think the biggest thing that I want to do beforehand is work on access and reimbursement, making sure any sort of - as I said in the speech, making sure that the system is ready for these once-in-a-lifetime transformative therapies, and that we can get to the patients as fast as possible.

So I'm putting a lot of emphasis on access reimbursement and site readiness over the next couple of years. And this will be globally, especially not only in the U.S., but some of our large markets such as Brazil, Germany, et cetera..

Thank you. Our next question comes from Brian Abrahams from RBC Capital Markets. Your line is open..

Hey, guys. Congrats on all the progress, and thanks very much for taking my question. I have a question on the Limb-girdle 2E program.

Can you talk about how you chose, how you selected the dose that you're going to be moving to? Will you be doing any additional monitoring or supportive treatment to monitor for LFTs and manage LFT elevations? And then, can you talk about the type of patients that you're going to include in this next cohort? Should we assume these are going to be patients with the more severe phenotypes, mutations and exons 3 and 4, just to enable the most apt comparison to the low dose? Thanks..

I will turn the question to Dr. Louise Rodino-Klapac..

Sure. The dose selected was based on our non-clinical data. It was predesigned in the protocol already for dose escalation. We will be enrolling a population as in the same first cohort of 4 to 15 years of age for continuity between them. And I think there was one more question, sorry..

So I think exons, included in those, just to make sure that there's an apples-to-apples comparison..

Right, yeah. So that represents a majority of the population anyway between these exon 3 to 6..

And the one thing I would just remind is that we're in a luxury position in one sense. We've seen great results thus far with our first cohort, but to get to commercial supply, which we will need to do to our pathway to getting to the community, we have some time, where over a paradigm working on that as we speak.

And so, we should dose escalate during this period of time and test a higher dose and see if that higher dose provides a better benefit to safety perspective than our current. But the good news is we're already sitting at a really good position.

To remind us, on protein positive fibers, we were at 51%, which is 2.5 times higher than what the predefined level of success was for the trial. So, we're already in a good position and now we have the luxury of dose escalating without having to worry about any kind of delay..

I think there was another part to the question as well. Let me answer. This is Gilmore O'Neill speaking. You had asked also about monitoring liver functions. And we are, obviously, keeping a close eye on that. It is our working hypothesis now.

And I think supported by the data we've seen to date, that these liver enzyme changes are amenable to prednisone management. And we are continuously updating, and amending, and adjusting or optimizing our steroid regime.

So we will be keeping a close eye on that, but our hypothesis is that we will be able to control that well with steroid use during that initial dosing period, right..

Thank you. Our next question comes from Tazeen Ahmad, Bank of America. Your line is open..

Hi, good afternoon. Thanks for taking my question. I'm wondering if you could give us a little bit more color on LGMD2A.

How does that compare pathologically to the other subtypes that you studied? And seeing that you're adding, presumably you've mentioned another 30% of LGMD patients, how does that change any manufacturing constraints for Paragon? Thanks..

Well, let me - a couple of thoughts and then I really should turn this over to Dr. Louise Rodino-Klapac. I've gotten a good primer on it, so you're at serious risk of me just answering the question, all right. So under this the manufacturing issue first.

We really are in the process of [guess] [ph] charting out the pathway on manufacturing and clinical program perspective across all of these Limb-girdle programs. As you rightly know, we now have six Limb-girdle programs and little to no competition here.

Notwithstanding the fact that we have little to no competition, we need to move with enormous sense of urgency to bring these therapies forward. We're really excited about 2A. I think we mentioned earlier this is about 25% or 30% of the Limb-girdle community.

That means that we are just about - there is some error margin around this, that probably 70%, 80 - higher than 70%, 80%, maybe even 80% of the Limb-girdle patient population that could be served by our 6 programs.

And then, as Louise will tell you about this, obviously, given that this largest one, this presents itself a little later, because it relates to essentially an issue associated with the inability to properly repair a muscle as it gets damaged as opposed to what things like sarcoglycan does and micro-dystrophin program does.

But with that said, I'll turn this over to Louise to answer it properly..

Sure. I think Doug set it up well. If you think about our Limb-girdle programs, they roughly fall into two buckets which is the sarcoglycan and as well as now calpain fits in quite nicely with our Dysferlin and Anoctamin 5 programs.

Just thinking about the mechanism of action of these important proteins, Calpain as well as dysferlin and anoctamin 5 are involved in the repair and generation process in muscle. And that's generally why you see a slightly later onset in the mid-teens for these.

So as far as the mechanism, over time, you'd just lose that regenerative capacity and that leads to this really devastating disease. As far as read-through, we're using the same rh74 vector as we are for the other 5 programs.

We're using the same promoter, the tMCK promoter that we're using in two of our other programs, such as LGMD2D and LGMD2L or anoctamin 5. So there has been a lot of shared learnings. We've obviously had to collaborate with Dr. Sahenk over the years. And there was shared development of these programs.

So, we're really excited to be continuing to work with her and move these programs forward..

Thank you. Our next question comes from Matthew Harrison of Morgan Stanley. Your line is open..

This is Maxwell Skor on for Matthew Harrison. Just a quick question on the progress you're making on manufacturing. I believe you've executed tech transfer from Nationwide. But have you started to produce vector at any of Brammer's facilities? And can you comment on how many lots you'll need to produce of GMP vector? Thank you..

So, this is Doug. I can give you the broad strokes, but thank you for asking about manufacturing. It gives me an opportunity to mention something that I had intended to mention in the opening, I didn't. I would like to brag a little bit about what we're - the people at Sarepta, I mentioned that we have Dr. Louise Rodino-Klapac and Dr.

Gilmore O'Neill, and we have lot of great folks.

But as you think about our hybrid model, just so you're talking about that, one of the things we're doing is gathering - to gather at Sarepta expertise around process development and analytical development in an early GMP manufacturing, if that is going to allow us to hold all of this differentiating aspects of manufacturing, and also, as we keep bringing in assets to move them rapidly through the preclinical to the clinical stage to the commercial stage.

And I'm really proud in relation to that to talk about Dr. Reed Clark. Dr. Reed Clark, who is now a Sarepta employee, is a pioneer in the field of process development and AAV biology. He actually is the person that developed Nationwide Children Hospital's manufacturing process, and he actually collaborated with Dr.

Louise Rodino-Klapac on early development of the micro-dystrophin and Limb-girdle programs. Every time I mention his name, Louise smiles, so I know it's positive. We are building under Dr. Clark, a formidable team focused on process and analytical development.

Just that we understand what that all means, by the end of 2019, we will have 200 employees dedicated to manufacturing at Sarepta, and that's manufacturing, process development, analytical development, technical operations, quality control, quality assurance, regulatory CMC operations. We have folks in Cambridge, in Burlington.

We have a 30-acre facility in Andover that we own. And of course, we have our Gene Therapy Center of Excellence and some manufacturing down in Columbus, Ohio. And we'll be spending $600 million to $650 million on manufacturing in just the next 15 months or so to make sure that we're ready to fully serve this community.

Now, where are we with micro-dystrophin. Yeah, we certainly have some time to do tech transfer over to the Brammer facility from the - from Nationwide Children's Hospital. As we stand right now, in the broadest of strokes, we are in the latter stages of process development.

We are just about done on yield optimization and we are deeply in analytical development. There's going to be a lot of assay work that has to get done in the next couple of months, but we are deep in that as well, and we are very fortunate to have Dr. Reed Clark on top of that as well. So we're in good shape right now.

We have done runs, I'm not going to give you the number of that, but we have done runs. We have iCellis units up and running. We've done some early runs, and we've got good data from that. We're tracking. And our goal now, there's a lot of work to be done, but we are on track as it stands today to meet our goal.

Our goal is to have our next commercial supply trial fully embedded with the agency, and then our commercial process fully embedded with the agency and to commence our commercial supply trial before the end of 2019..

Thank you. Our next question comes from Debjit Chattopadhyay of H.C. Wainwright. Your line is open..

Hey, good afternoon.

So given the price point that you mentioned and reappears you're alluding to, how are you thinking about non-ambulant patients, especially in the commercial supply study in the micro-dystrophin program? Also, have you had any additional dialogue with the agency regarding the design for that study?.

We have not had direct discussions - further discussions with the agency on the design. Obviously, we're tracking to do that in the near-term. We will be burdening the agency with a lot of discussions across our programs over the course of 2019 and that will be one of them.

The short answer on non-ambulatory patients is that there is no way that Sarepta is leaving them behind.

This - just to remind us of where we are, the vector that we have not only robustly expresses in skeletal muscle and cardiac muscle, it actually over expresses by about 120% in cardiac muscle, which means that there should be no child or young adult, who is beyond the ability - beyond the place where our micro-dystrophin program, if it is successful, could help them and benefit them and extend and improve their lives, so we don't want to leave them behind.

And we will ensure that the design of our next trial includes sufficient focus on older and non-ambulatory patients that we will not only get a label for that, which of course, is our big goal, but also puts us in a place where we can get, to the fullest extent possible, rapid access post-approval from payors..

So just as a follow-up on the PPMO program. Again, given the investment that you're seeing from peers, how important is this PPMO program to the overall franchise, especially focused on rescuing the non-ambulant patients? Thank you so much..

Yeah, thank you. Well, we're very excited about the PPMO program. We don't - we try not to talk a lot about it, because we don't want to pump it right now. We're in the middle of a multi-setting dose. We've had a very successful single-setting dose trial. We're starting our multi-setting dose at 4 mgs per kg. We need to get a lot higher.

We'd like to get a lot higher than that. But one of the things will be now we're in the PPMO is just to remind people - and I'll remind people once again that at this time people are otherwise unaware. The PPMO program, which is our RNA therapy, it is the same back-up as PMO.

We've conjugated a peptide that allows number one, candidates, the molecule then becomes positively charged, it allows much greater penetration into the cell. And in preclinical models, if we could get up to high enough doses, we can see as much as an order of magnitude, more expression and therefore, more benefit than our PMO technology.

So we're really focused on that. And so it is a very big part of our thesis. It's a big part of our thesis for patients with Duchenne muscular dystrophy, both frankly, ambulatory and non-ambulatory patients, and it will be an important part of our platform going forward, beyond Duchenne muscular dystrophy. One of the things that Dr.

O'Neill and his team in research are working on is target selection, both from our PMO, our PMO plus and our PPMO programs, that the target selection beyond Duchenne in the areas where our RNA technology would make brilliant stance, sometimes in ways that perhaps gene therapy couldn't actually address, places where, for instance, the gene is so large, it's not easily packaged in AAV biology.

So the PPMO program is important. We're tracking to get inside by the end of this year and in the first quarter of next year. We have six constructs in the PPMO program. They cover about 43% of the Duchenne community, and we'll certainly provide an additional update on that at the end of this year, early into 2020..

Thank you. Our next question comes from Christopher Marai of Nomura. Your line is open..

Hey, good afternoon. Thanks for taking the question. Just regarding your Limb-girdle 2A program, wondering if you could further elaborate on how you might be testing that in the clinic? It looks like patients with this disease express normal levels of the protein, if I'm not mistaken.

And I guess, there's another option perhaps, to measure something like proteolytic activity. How do you look to - I guess, to study this gene therapy relative to the others as it seems a little bit different? Thank you..

I'm dying to answer the question. There's a person who is much better than me at this so I'll let Dr. Rodino-Klapac to answer this question..

One thing I just want to clarify, there's a variety of mutations so you can have a complete loss of function, there's like a lot of other mutations that to your point, do lead to normal levels of calpain, but is non-functional.

This is an enzyme kind of lack of activities, to your point, measurements of the gene that we're transferring, the wild type version of the protein will be important. So that will be part of our development plan is to make sure that we are accurately measuring not only the quantity of the protein, but the wild type version that we are delivering..

And we will be - this is Gilmore. I mean, we are mapping that out, and we will actually be working on the design of these clinical programs, and we're finding them in parallel with the non-clinical work that we're undertaking right now..

But in some ways, this is Mike, although on the face of it, one might look at this and try to compare it for instance to dystrophin expression, wonder if you - if that's the way to look at it, maybe this will be challenging to be successful.

This actually might be easier in some ways, because an enzymatic activity might very well show a very strong direct correlation between proteolytic, enzymatic activity and genotype. So actually, in many ways, it may be more..

Yeah, it may be. But I think the key point that Louise has made also to support that is the fact that it is not universally expressed. Only some mutation association with a high level of protein expression, there are others which are associated with that. So just let me clear that, that nuance is correctly understood..

Thank you. Our next question comes from Martin Auster of Credit Suisse. Your line is open..

Hi. This is Mark on for Marty. Thanks for taking my question and congratulations on the progress. So with - Novartis' gene therapy is expected to be approved this month, at which time we would expect the company to announce its pricing scheme.

With payors you talk to, do they see your DMD gene therapy in a similar light as SMA gene therapy in terms of potential value to patients? And how should we think about potential read through from Zolgensma pricing?.

Well, we'll wait and see it before we can really comment on it, obviously. We're doing a lot of work. We haven't given precise information externally on the way we're looking at the pricing issue. We're dealing significantly with structural issues.

I think one of the things you hear - if you went and did a survey of payors right now, you'll hear a lot of payors talking very positively about Sarepta and this program in a couple of ways.

One, they'll just - I think, you'll hear from people because you can do a whole Google search, and I think you'll find people saying positive things about our proactive outreach. We - I think, more aggressively than most companies in gene therapy have been reaching out to payors and to begin a dialogue about the structural issues.

And I think they're also well aware of these early results that we've seen with our program and many of them have made the point that we have to find solutions together to ensure that patients get access and they see the value here.

So I do think - and I think if we don't really go into depth and compare and contrast with other programs, but I suspect that they're probably excited about SMA as well.

For a host of reasons, I think there may be reasons why our pricing model might be different than SMA kids, which are smaller kids, these are younger age than our program, but we're going to wait and see what - where this stands and then we'll look at it, come back at a later date and talk more about some of the structural issues and the work we've already that team are doing there.

And then we'll also, at some point, start talking about the pricing issues that we're a little premature on that right now..

Thank you. Our next question comes from Gena Wang of Barclays. Your line is open..

Thank you for taking my questions. I will follow Alethia's question regarding the Pfizer data. I know, Doug, you comment a lot on the biomarker data. Just wondering what would be your thoughts on the North Star data. I know, we all know their patient is slightly older than your patient.

How would that data read through to your program? And a quick follow-up question regarding the micro-dystrophin gene therapy 102 study.

For the three months biopsy data, of which if you complete enrollment in second quarter, then they should be ready by 4Q, so I know it is a placebo-controlled study, double-blind, but wondering, will you be able to see the data? What would be the earliest time you would be able to see the data?.

Well, a word now, well - so you've answered the question for me, I appreciate it. On the latter part, this is a placebo-controlled trial, we're not going to risk the lives. So you'll see the data, when all the patients have made it to one year so that's when we'll obviously see the data.

So we are really excited about the program, it's going really well from a dosing perspective. Dr. Jerry Mendell has been a real hero and the work he's done, he's our principal investigator and for this trial, sole investigator.

Going back to the Pfizer data, the thing - look, I have always been - or at least, I hope I've been careful in talking about the functional data for a few patients in an open label. We are very excited about what we're seeing, the signals that we're seeing from a functional perspective with respect to our micro-dystrophin program.

As I think everyone knows, we've seen very good results. All of the kids are improving on all the time points across all of the measures with very significant reductions in CK, which gives us a lot of hope. The danger in all that, of course, is that it's a small cohort and it's an open-label study.

What we really need to see there from a functional perspective is the results of a low controlled placebo controlled trial, and we're doing that right now and we feel confident about where we are, and where we're going to end up there.

So what I would say as we look across to the Pfizer data in June, I think you - it would be nice if they had some data and function that just said that there was some benefit that they might be seeing in kids, but we all understand together, that is open-label, that there's motivational issues associated with it as well, and who knows what they're looking at from a functional perspective.

And that the real thing that we all need to look for and the real thing we need to consider is expression level. What kind of expression are you getting? The biggest issue with these gene therapy constructs before we showed our data was whether we could actually do this.

Could you actually do full body confusions and get significant - first get significant transduction across the entire skeletal muscle and cardiac muscle. And then, could you create a gene construct that was clever enough to be able to show rate expression was there. That's the big question in these early studies.

Obviously, we're very excited about the fact that the answer was a resounding yes to both of those questions for us last year, and that's going to be the question that one needs to look to in June. And it may very well be the case that the answer is yes to those as well as with Pfizer.

But given the fact that it's 300% of our dose, I hope that will be resounding, yes, with a good quantification. And then on function, I think the answer is you're really just getting some comfort as you track into a better control study on function..

Thank you. Our next question comes from Brian Skorney of Baird. Your line is open..

Hey, good afternoon, guys. Thanks for taking my questions. I guess, just to start just jumping off of your answers to Alethia's questions on the upcoming Pfizer data.

Do you happen to know the tighter comparisons between their 3 to the 14 dose and Audentes' 3E to the 14 dose that they had just reported the other week? And is there anything you would read into the safety events from the Audentes program that you're seeing particular around the thrombocytopenia and cholestasis? And then just as a follow-up, I heard you said that you're pretty much done with the yield optimization for the commercial manufacturer.

Can you tell us what the downstream yield that you're getting on a single iCellis 500 run is? Thanks..

We're - I'll answer your last question, because it's a non-answer. We're not willing to give yield information yet so we're a little early on that. Going back on Audentes a couple of things, I don't know - we don't know enough about the tittering between the two to make brand comparisons between those two.

I will point out thing when you evaluate the safety issues associated with the Pfizer construct and the Audentes construct. Just remember that the Audentes patients - well almost all, not all of them, almost all of them viewpoint.

So while it is still a big dose, it's a big - it's not actual big aggregate dose, these were, I think the great majority of these were newborn, and then newborns and one year olds were almost all of them, and that's going to be very different, obviously than with muscular dystrophy.

And then of course, there are a lot of different things, different vector and different promoter..

Thank you. Our next question comes from Salveen Richter of Goldman Sachs. Your line is open..

Hi. It's Ross on for Salveen. Thanks for taking the question. I just have two. The first one on the Limb-girdle muscular dystrophy 2E program.

You're going to start the cohort two in the middle of this year, when could we expect an initial read on that data?.

Do we have an answer to that yet? We'll give you an update as we start getting in closer to dosing and we know the exact timing of the dosing, not attempting to be elusive here, but we don't have the full answer.

Your second question?.

Our next question comes from Vincent Chen of Bernstein. Your line is open..

Great. Thanks for taking the questions. A couple of quick ones for me. The first one is, given your commentary on Pfizer's dosing.

I was wondering, if you could comment on whether you have flexibility to go up on dose for your micro gene therapy? And whether you made plans to do so? Or if there are no plans, what do you might potentially choose to this depending on what you see from the Pfizer readout?.

Okay. So I'll answer that first. The preclinical perspective. So first, from a preclinical perspective, there is headroom on dose escalation for our construct. And certainly, in the first four patients that we've seen, there's nothing about that, that would contra - would be inconsistent with that viewpoint, actually.

And just to remind everyone, in the first four patients, it was very well tolerated. There was some mild nausea for a couple of days, and three of the four patients had elevated liver enzymes, but all of them rapidly responded to a bump up in steroids and resolved back to baseline very quickly. So we could dose up.

We don't currently have plans to dose up for the simple reason that we're seeing significant expression.

One of the things that - one reason we chose the dose that we chose is we do have a belief that it is inappropriate to under dose patients in gene therapy for all those biological reasons that we talked about earlier, we can't use children as guinea pigs, we've got to try to find a dose that provides efficacy benefit from the very beginning two times E to the 14 is frankly a fairly significant dose, even using supercoiled qPCR as a measure.

And then in the preclinical model as well, there was significant headroom, some significant headroom on the ability to dose up. When you see the kind of level we're getting here, 90% expression level on western blot, it isn't quite clear whether we would get a concurrent benefit from dosing up. So as it stands today, we are not considering dosing up.

We're very interested to see what Pfizer has, it's an interesting experiment to learn, we'll look at it when we see it. As it stands right now, we know where we're going..

Thank you. Our next question comes from Danielle Brill of Piper Jaffray. Your line is open..

Hi, guys. Thanks for the question. Just another quick follow-up on Pfizer's data. We also heard that they may present expression data measured by mass-spec.

I'm curious if you guys can generate a data using this just to allow personal level of comparison in the event that they don't provide western blot NIHB measurements?.

So we don't have any data on mass-spec. mass-spec has never been used, never been accepted by the agency as a measure for dystrophin quantification. It's an interesting experimental measure, and we certainly applaud them for thinking around the corner, but other interesting measures.

I know they are scalable MRI, cardiac MRI, a lot of other things people are thinking about.

But if one wants to try to find a way to make meaning of expression either against all of the literature that exists on dystrophin-positive fibers and correlating that with functional issues or looking at prior therapies or prior trials or other programs, what has to use a combination of western blot quantification, an immunohistochemistry quantification and localization, including dystrophin-positive fibers and intensity, and they have that data.

They might have that data. They certainly have done western blots and they certainly what would have done immunohistochemistry.

So while it might be interesting to see their mass-spec experiment, one would assume that they really want to be - if you want to have a meaningful discussion about their program, they're going to have to show western blot and IHC data. And genome copies per nucleus, which is also equally interesting..

Thank you. Our next question comes from Joel Beatty of Citi. Your line is open..

Hi. This is Shawn Egan on for Joel. Thank you for taking my question. Two for me today. The first on is kind of a high-level strategy question.

Kind of, as you consider building your gene therapy pipeline, now as an established vector promoter combo already in-house, can you help us understand kind of the factors that go into the decision process to either pursue an external partnership like the one that was announced today versus developing these in-house if the transgene is 100% homologous? And my second question is also on the kind of Pfizer competitor data, could help us frame how important the biopsy location is? I think you guys have kind of pulled from the gastro, while Pfizer is pulling from the upper Limb.

Is there a lot of difference between those muscles and how they could express the transgene?.

I'll let Louise answer the second question. I know, it's the first question here, we are - we will be - we are moving to the place, where we're going to be agonistic about pulling from external or developing internal.

So we are - Louise, when she came over to Sarepta, brought with her, I'm proud to say, I tried to get her entire map with her, and we're building from there.

I think, I mentioned before, we have about 80,000 square-foot facility in Columbus, Ohio, which is our Gene Therapy Center of Excellence, and we are listening to - we are in the middle of target identification, beginning to build constructs there.

We've got some pretty significant ambitions to - don't hold this to this, because, obviously, discovery process is as it is. But our goal is to look to identify and elevate as many as two targets a year internally over time and we're building that.

But at the same time that we do that, we're going to do externally as well, the 2A program is a perfect example of that. We have enormous regard for staying. That's one of the reasons to be headed into our agreement with Heron, starting where we do. She's advanced in this 2A.

And so the idea that we can work with her with 2A, take the construct that she's already built and advance it and accelerate the program is very meaningful. So we're going to be looking above an internal and external and frankly, we're - it's going to be, sort of the best athlete from a construct perspective is going to win out over time.

And then as it relates to the other question..

So your question based on upper limbs versus lower limbs. Speaking for our nonclinical data, we looked at every single muscle and we saw no significant difference in micro-dystrophin levels across those muscles, so whether it was triceps, biceps or lower limb like gastro [on FDA] [ph] there was no difference.

So theoretically, there should be no difference from where you take the bio piece that you should be consistent results..

Thank you. Our next question comes from Anupam Rama of J.P. Morgan. Your line is open..

Hi, guys. This is Tessa, filling in for Anupam this evening. Thank you for taking our questions and congratulations from us on all the progress.

One from us on what your latest thinking is on the commercial supply trial? And what the gating factors are to finalizing design here? What are the key components we should be considering? And how will that impact time line to market? Thanks so much, guys..

I'll answer the broad strokes and [indiscernible] as many of you know, the broad question is what are the gating factors and where are we with the commercial supply trial. So we are finalizing the trial and the arms on that trial. Even as we speak, we're pretty close to getting it done.

In broad strokes, it remains very similar to what we talked about before, which is it will be a trial that will ensure that we have good data from a commercial perspective, both on ambulatory and on non-ambulatory patients. You will have the largest breadth of - inclusion of EXONDYS is possible as well.

And we will have a multi-center - multisite trial, both in the United States and there will be some sites ex-U.S. as well, and it will be larger trial and placebo trial that we're doing. And it is the height of the numbers I've given before, kind of the $50 million, $60 million, $70 million, but we haven't nailed that all down yet.

So we're doing some work on that.

And now we're gaining items to that, obviously, one of the things that we're going to want to do is share our views with the agency, I'm sure the agency is in agreement with the path we're taking as the target profile that we would envision that path would get us, including a broad label across all age groups, for instance.

The other big gating items are manufacturers. So getting this, the manufacturing process up and done and getting all the analytical work done, the process development finally finished with - outpatient finally complete, getting the agency bought-in on all of that and then getting some runs done is a big gating item. But we're on track for all of that.

And our goal is to be replaced, as I said, that by the end of 2019, we'll commence that trial. And then one other feature of that trial, at least as we currently envision it is interim analysis on that trial on three months biopsy data.

So we have the opportunity with biopsy data on the interim basis, and compare that when we actually open our placebo trial, compare that to the expression levels we're seeing in the placebo trials so that we can confirm the comparability of our commercial supply to our clinicals.

If I missed anything features to add, Sandesh?.

No, I think you captured everything and obviously, the site engagement is something that we already. So the site engagement is something that we're actually already doing around the world, and obviously, talking not just to FDA, but other agencies around the world..

Thank you. Our next question comes from Liisa Bayko of JMP Securities. Your line is open..

Hi, there. Thanks for taking my question.

Perhaps, a simple question, perhaps one that's more complicated, but could you based on just your assumptions at this point, and I know there's a lot of details to be worked out, give us a sense of how many patients you think you'll be able to treat from a facility such as Brammer?.

We are - so I can give you broadest stroke answer, which is our goal is to be in a position that when we launch. So I want you to envision a world in which we could - is that everything works brilliantly be in position by the end of 2020 to launch it then. I would say, there's a lot of good reasons why I could slip.

So I don't want to envision that, that is some hard hand chart view, but you can imagine a world that would set the cadence. We are building commercial supply. We have the most aggressive assumption on launch cases, so that we're in a position if everything goes well on a launch then.

And if we did that, we want to be in a position that starting with our first commercial launch in the United States, and then moving rapidly ex-U. S., we can completely serve the community with therapy. So that's the short answer. And that's, we want to be in a position where we're able to robustly support the community.

And what that means is we're going to mention all of this gaining items to get the commercial supply ready for our commercial supply trial by the end of this year. And then what we're going to be doing once we get there is building supply and inventory over the course of 2020 in advance of the commercial launch of the therapy.

That's why we're spending in addition to everything else over $600 million in the next 15 months.

And as I said, I hope it didn't pass, I noted in my opening remarks, we have a 75,000 square-foot facility dedicated throughout - that we're building with Brammer Bioscience as a parent company, we feel about for sure, even as we speak, that's just about done in the next couple of months, it should be ready for commercial supply before, obviously before the end of this year, we will be using that supply to commence our trial..

Thank you. Our next question comes from Yun Zhong of Janney. Your line is open..

Hi. Thank you for taking the question. So the question is on the comparison between your micro-dystrophin program versus the other two.

And specifically, on patient enrollment criteria, I believe the initial Phase 1, 2 study had the specific requirement for patient to have prem shift or premature stop codon between exon 18 and 58, is the - does the 24 patient study still have that criteria? And if not, why was that removed? And what about the commercial scale of study?.

The short answer is that the current Study II has that exclusion in it out of an abundance of caution. There is good reason to believe that, that is overly abundance of caution and we are doing some works.

So the next trial we are expanding the inclusion criteria significantly, and we are removing the exclusions that are unnecessary and there are almost certainly many of the exclusions from an exon perspective are unnecessary.

So our goal is to get you as close as is possible without creating undue risk to be as close as possible to all of the exon mutations in the next trial..

And - okay.

And then on the age of the patient, the 24-patient study still have patients between the ages above four and seven?.

Right. Correct..

And that will be expanded in the commercial scale study as well?.

Yes. But they'll be more - they'll be other age tree as well. Now understand that there's been a bit of a - I think people - let me be very clear about this and I think it will come as a surprise to people. It is not our goal to have a therapy that works brilliantly for 7 year olds alone. That is not the reason we have, what is a fairly tight range.

The reason we have it is that across the journey of Duchenne muscular dystrophy, there is - your phenotype is going to change as you grow. And in fact, the measures won't even work. The [NSA eata] [ph] we're using in 4 to 7 year olds would be appropriate for younger children. We have to use something automatically.

And then when you get passed about seven, as [NSA] [ph] begins to become more difficult, we have start using some other functions like….

In fact, you're correct. You can actually use. The reasons that we have 4 to 7 year olds, because that's the point when they are gaining for the majority, they're coming to up to a plateau sort of around that age 6 to 7. But then after 7 years old, what you begin to see is those young boys are now in the stage to trying.

So combining with the same study, it actually creates the problems. So it is….

Wouldn't work, so the goal here is to show - the goal here is to confirm the fact there are small group of people. The next study he's going to have different arms. So we will explore dosing in older patients as well as we will be exploring dosing in even younger patients. It's very likely. So - and again, all of your - or two goals.

The goal number one is, of course, the label. We need a label as we launch this therapy that allows to fully serve the community across all age groups.

And of course, the second one is to ensure that we have a robust package right to reimbursement, so that one was therapy is available to the communities, patients can get it without having to wait any more in the balance of time..

Thank you. Our next question comes from Timothy Lugo of William Blair. Your line is open..

Oh, hi, Myles on for Tim. Thanks for taking the questions. Just back on the micro-dystrophin gene therapy, I'm wondering whether you do actually have internal data or this data out that suggests the expansion of the coverage of the exon mutations would actually be safe. You said it was overly cautious to exclude earlier.

But I'm wondering what's changed now.

And secondly, what's your advice to patients that you've currently screened that has an exon mutation outside of your current gene therapy programs? Did you tell them go to seek therapy? Do you go to another additional gene therapy program or standard of care? Let us know what your advice is for those patients? Thanks..

You answer the second one and then I'll have….

I'll answer the second one and I'll let Louise answer the first. So the point here is, right, we're not giving specific advice to patients, along this with the specificity that you're saying.

What we are saying and recommend to all patients is that they should actually pursue the standard of care, optimal standard of care, and should not be concerned about that, and its pursuit, while our trials are ongoing and being designed.

So we're actually quite frank about that advice to patients where comfortable standard of care is what they should pursue, whether or not they're eligible for studies or awaiting to see if they're eligible for studies. And then, what I have to do is, what's changed in our philosophy and….

One final thing just to be clear on that, particularly, as it relates to symptomatic therapies, steroids and our PMO and [indiscernible] therapies.

There's a different issue with respect to gene therapy, because as I said before and I'll let Louise talk about, often as a group, there is an unforgiving nature to gene therapies, you can't get multiple gene therapies. You can't even talk about it. The symptomatic therapies, you don't have an issue yet.

But one of the things you definitely do want to do is protect yourself. There are gene therapies coming. If these gene therapies are successful, there is a potential to have a transformative moment.

The likelihood that one can rescue and bring back a function that's long been gone, I think you can probably - a bridge too far, it's probably asking too much of a therapy. Protection is the biggest issue, which means you need to protect yourself while you're waiting for a therapy.

If you have an opportunity to protect yourself with an existing therapy and your physician agrees you should be on it. You should be fighting to stay on it, protect yourself while companies like Sarepta and Pfizer and others look like that to advance therapies that might be truly transformative and rescue you from future damage.

And with that, I would turn it over to Louise to answer the question about the exon..

Sure. Just to get back to the exon, Doug mentioned, this was really instituted as an overly abundant, with an overabundance of caution. It was really based on what I would call a case study in an earlier trial with a patient with a very large deletion and terminus.

And really, what it shows is there's a potential, theoretical potential to recognize that area of deletion. But really, the implications of that were unknown, whether there was even any consequence of that. So based on that, 18 to 58 mutations are not found within the micro-dystrophin transgene network, that's where the number came in.

So it's very conservative, and so we feel very good about expanding beyond that, just based on mutations that already have a normal amount of the - or trace amounts of the protein. So we are definitely expanding in a rational way. We think that we have a very good reason to do so..

Thank you. Our next question comes from Tim Chiang with BTIG. Your line is open..

Hey, thanks. Doug, when I was at the MDA conference, the [Technical Difficulty] Pfizer, they've gone up to 3E to the 14 on the dose, and then they had come back down to 2E to the 14 of the dose.

Is that something that you guys have heard as well? And then also on Limb-girdle 2A phenotype, Louise, could you compare and contrast 2A phenotype to 2B phenotype? I mean, are there very clear distinct differences? Obviously, a different gene you're delivering.

But I guess, what the 2B phenotype, it's a dual vector, could you just confirm is the 2A a single vector that you'd be delivering on the gene?.

Yeah, answer that one….

To answer your question, so with the LGMD2B, it's just for Limb - that's a dual vector. And the calcium program where within the calcium gene, that's a single vector. In both cases, we're delivering the full length gene. There are to your point similarities between the phenotype.

We know those interactions between the two proteins, so it's not surprising, but there are similarities in the disease..

Okay. And then so, let me answer on this. So to answer on - I'm really reticent to sort of pass along rumors, because there's been a lot of talk about this dropdown.

Just for those, to make sure we're on the same page, recently it revealed by Pfizer that they have a protocol, it's an interesting protocol, an unusual one I think, where their 1 times E to the 14, I'll remind you, it's probably about the same as our 2 times E to the 14, given the titers.

And then they chose to go to 3 times E to the 14, which again is probably something like 6 times E to the 14 using our measures. And then, they have what we recently discovered was - that we've discovered is that they have this constant dropdown where they could drop back down to some middle dose between the two, at their 2 times E to the 14.

It's again the [indiscernible] you get my point. I don't want to elaborate on that for you. Most recently, we heard that they are saying that they have not yet dropped down in between those two.

So what we're - what we're envisioning right now is we're going to see in June what we understand at least from the investors that we're going to see two cohorts. One cohort with 3 patients at 1 times E to the 14, and then one cohort of 3 patients at 3 times E to the 14. And then they only have to make a final decision about it, for your dropdown.

I will note that we're - we don't have anything like that. So, for instance, with respect to our 2E program, as we mentioned, our protocol provides that we dosed at 5 times E to the 13, and we are now going to dose at a higher dose to explore 2 times E to the 14.

And then as when we're done we're going to make a decision about the risk-benefit, and the efficacy and safety of those two doses and make a decision between the two. And the good news is that we've only got good expressions at 5 times E to the 13.

So we don't see a significant benefit for going higher, then obviously, we're not going to put these kids under unnecessary amount of viral....

So this is Gilmore here, again. I just wanted to follow-up one thing, you do ask the question or you talked about the two programs, the micro-dystrophin, our micro-dystrophin program and Pfizer.

I just want to follow up on the mass-spec question, because I know you're all sophisticated thinkers, and would be very careful about comparing apples and oranges, western versus mass-spec. I think there are certain things that you should like to look into methodology, very clear about the methodology being used.

Not these that which is that in the developing our western blot, we and Louise Nationwide, optimized that methodology to ensure that the western blot was measuring monomer.

The - is an issue potentially and you have to look at how mass-speced actually pulls down the peptide, because mass-spec doesn't actually use the full protein, it actually digests the protein and then actually measures peptide fragments, and then essentially computes them together.

So one has to be very careful in understanding how much or what's the specifically is of the mass-spec methodology for identifying and quantifying monomer.

So I think it will be very - it's very important for everyone who's looking at mass-spec to actually consider the methodology and the details of that and take - to be very cautious about comparing across methods..

Thank you. Our next question comes from Joseph Schwartz from SVB Leerink. Your line is open..

Hi, good afternoon. Thanks for taking our questions. This is Dae Gon dialing in for Joe, and congrats on all the progress. So I had two broad questions, one on manufacturing and one on the competitive landscape. And that's not that - I don't want to go into Pfizer data.

But briefly on manufacturing, the recent ASE-CT, there was a lot of presentations and talks on manufacturing and the various methods. So looking at the press release, you have the 75,000 square feet at Brammer.

And so I just wanted to get your take on question one, what kind of conversations or interactions and feedbacks have you received from the FDA with regards to systematizing multiple iCELLis units to make your material? And the second question is as it pertains to manufacturing, we've heard a lot about how the downstream and the analytical methods are a huge opportunity for optimization.

So can you briefly comment on where you stand with those analytical and downstream recuperation yield?.

So in the broadest of strokes where, there - just to remind everyone, we chose it, we're using clinical supply for Nationwide and that's an immunity adherent process in hyper stats. But it's not a very scalable process, because it's a two-dimensional process. iCELLis is very similar, it's an adherent process as well so [indiscernible] as well.

But it's a three-dimensional process, which allows for scale. We're on ongoing dialogue with the agency and on issues and questions relating to the iCELLis units and analytics and the like.

The good news is just so we're all clear, one comforting aspect of all this is that there is - and even though gene therapy is in many ways, nascent, there is good precedent for this one thing, which is moving from hyperstack to iCELLis units and system advise the iCELLis units.

And the reason for that is because this is exactly what Novartis is doing. And Novartis' program is a sister program in a sense to our program over at Nationwide Children's Hospital.

Their program started hyperstacks and [Remilion] [ph] and transitioned over to commercial supply at iCELLis units with the same [Remilion] [ph] here in process with iCELLis. So while there is a lot of work to be done, we're confident that the pathway has been trodden with Novartis, which as we understand should be getting approved soon.

So I think we're in a good shape there. We've got a lot of work we're doing on the downstream side. We've got a lot of work to do on the analytics side. And certainly, there is optimization to be done on the downstream side. The group's looking at that even as we speak and we're playing a big part of that as well..

Thank you. I'm showing no question at this time. I'd like to turn the conference back over to CEO, Doug Ingram, for any closing remarks..

Thank you very much. First, I want to thank everyone for joining us this evening for our conference call. Hopefully, you'll come away with the understanding first that at least so far this year, the team that I have gathered around me at Sarepta has been doing a very good job at executing. I'm very proud of all that.

And then, beyond that, one would understand that we have a lot more to execute on in 2019. And this will be very consequentially here, first, for patients, and then for Sarepta and our long-term goals, and certainly, if we're successful in all that, for our shareholders and the shareholder value.

And we look forward over the course of 2019, not only in executing, but bringing more updates to the investment community. So thank you and have a good evening..

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you for your participation. Have a wonderful day. You may all disconnect..