Good day, ladies and gentlemen and welcome to the Sarepta Therapeutics Third Quarter 2019 Earnings Call.

[Operator Instructions] After the speakers' presentation, there will be a question-and-answer session [Operator Instructions] And now, I'd 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, Michelle, and thank you all for joining today's call. Earlier today, we released our financial results for the third 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, Dr.

Gilmore O'Neill and Dr. Rodino-Klapac. After our formal remarks, we'll open up the call for questions. 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 and such risk can materially and adversely affect the business, the results of operations and the trading prices for 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. And with that, let me turn the call over to our CEO, Doug Ingram, who will provide an overview on our recent progress.

Doug?.

Thank you, Ian. Good afternoon and evening, and thank you all for joining us for Sarepta Therapeutics' third quarter 2019 conference call. Our ambitious strategy involving one of the deepest multi-platform genetic medicine pipelines in biotech has required focused execution over the course of 2019.

To remind you, we have more than 25 active programs across our RNA and gene therapy platforms, and we're either actively in or in early stage planning for some nine human clinical trials to advantage our clients.

I am pleased to say that over the course of 2019 and in the third quarter specifically, we have made very significant strides in advancing our programs and our strategic vision, and I'm excited to discuss those advancements. However, [indiscernible] I must also acknowledge what we all know, that we had a setback in the third quarter.

And rather than baring it among or after a discussion of our successes, I will begin by commenting our CRL disappointment that occurred in August.

Having worked diligently on our submission for VYONDYS 53, the generic name for that is golodirsen for well over a year, and based on all of our interactions with the division of neurology products, we were very confident that we would obtain an approval on our PDUFA date, which was August 19.

Instead, as you know we were surprised to have received a complete response letter, also known as the CRL, signed by the Office of Drug Evaluation I. Our disappointed extends beyond Sarepta to the 8% of exon 53 amenable DMD patients in the United States to generate every day, while they await access to this therapy.

When I joined Sarepta, I made some commitments externally and in the division of neurology we intended to build a positive relationship with the division of neurology, one founded on transparency and on solid evidence-based science.

And consistent with that commitment, we will work with the agency to address the reasons for the CRL and to turn in a pathway for a potential approval, if one is possible.

I've heard from those who would prefer that I speak more often more publicly on this issue, and/or that I would attempt to engage the patient community or others to assist, for instance, in applying external pressure to bring this therapy a lot faster. I have no intention of doing either of those things.

If we can win the day with this therapy and with this issue, we will have done so on the size and on the regulation and in collaborative evidence-based discussions with our reviewers at the FDA. Now I've also heard some speculation about the implications of this CRL. So let me take a moment to address these as well.

First, the VYONDYS CRL does have implications for our submission for our next PMO casimersen. As they are closely related, we will await clarity on the VYONDYS matter before we submit for casimersen in the United States. But let me disabuse anyone who might have concerns for our other programs.

The CRL does not have any read through to our microdystrophin gene therapy program. The CRL involved two safety signals in connection with an application for accelerated approval. Our microdystrophin program is overseen by a different part of the FDA, Sedar, and we are not seeking accelerated approval there.

There is simply no overlap in either substance or personnel. Second, to those may believe that the CRL suggest some sort of bias on behalf of the division of Neurology towards Sarepta, I would unequivocally and emphatically disagree.

Let me reiterate that I remain convinced that we were treated very fairly and professionally by the division of Neurology. Also, I am very proud of the Sarepta team and how they comported themselves during this review.

From my perspective, we have gone a long way in the last two-and-a-half years in forging a positive evidence-based working relationship with the division. We will work diligently to address the VYONDYS CRL. So with that, I do not intend to provide a prediction on outcome or on timing, or to provide interim views during the process.

However, I will provide an update to the patient, physician and investment communities, once we have definitive clarity on the outcome of those discussions. Now moving to our positive achievements in the quarter, we have made some enormous amount of progress in this third quarter.

EXONDYS continues to perform well with third quarter sales above consensus at $99 million. That is a 26% increase over the same quarter last year. Commenting for a moment on our confirmatory trial for EXONDYS. To remind you, this trial comprises three arms.

One with EXONDYS at 100 milligrams per kilogram and another at 200 milligrams per kilogram versus our current dose at 30 milligrams per kilogram. The trial design which was an FDA requirement, will answer whether higher doses of EXONDYS provides even more benefit than the currently approved dose.

Now since the confirmed -- the comparative arms involve higher doses than the currently approved dose, we were required to begin our confirmatory trial with a healthy human volunteer study. We have completed this trial and based on the results, we have initiated the main confirmatory trial. We will be begin dosing this quarter.

Staying on our RNA franchise, we have moved to our multi-ascending dose trial for our next generation RNA platform, the PPMO and we are dosing trial participants now. We will have safety and dosing insight in 2020.

If our PPMO shows encouraging results in addition to SRP-5051, that's the construct that we're currently in a multi-ascending dose regarding, we have five additional constructs that have already been built, which in total have the potential to treat as much as 43% of the DMD community.

We are also conducting research now on new therapeutic targets that could be served by our PPMO platform. Moving next to our gene therapy platform, as you know, we are expanding enormous resource and energy to build out our vision of an enduring gene therapy engine.

Between our research and clinical stage programs, we have more than 14 therapeutics candidates advancing through research and development.

We have made great progress thus far, this year and quarter, led by our most advanced program SRP-9001 for DMD, which at least to my knowledge, is the highest potential late-stage gene therapy program currently in biotech.

As you should be aware, our double-blind, placebo-controlled, SRP-9001 one microdystrophin trial, the trial that we call study II, was fully dose by mid-year.

But we took advantage of the availability of additional study material and previously announced that we had increased the study end from 24 patients to 40 patients, significantly increasing the study power and confidence in this study. In addition to our initial site with Dr.

Jerry Mendell at Nationwide Children's Hospital, we have added a second site at UCLA with Dr. Perry Shieh. I'm very proud to be associated with that clinician and investigator. Both sites are actively dosing patients and we remain on target to complete our dosing by year-end. Microdystrophin manufacturing is progressing well.

From a capacity perspective, Brammer has now completed the build-out of our single-use microdystrophin manufacturing facility in Lexington, Massachusetts. We also have dedicated suites with Paragon in Maryland.

with actually substantially greater capacity than our dedicated Lexington facility, which means we have robustly secured capacity well in advance of launch. Our analytical development work proceeds well, and we continue to make progress on process development and yield optimization.

Given our recent capacity, analytical development and process development progress, we remain on track to commence our next trial Study 301 with commercial development supply by mid-2020. Now Study II is being conducted with clinical material from Nationwide Children's Hospital.

Study 301 will be a multi-center, multi-country, placebo-controlled trial using commercial process material from our hybrid manufacturing model with Brammer and Paragon. The main study will include DMD patients ages four to seven, but we are also planning a separate study for older and non-ambulatory patients as well.

Commenting on a few of our other gene therapy programs. Following exceptional expression and biomarker results in our first three-patient cohort dose with our construct for limb-girdle 2E, in October we announced positive nine-month functional results in that same cohort.

Consistent with robust expression of the native beta-sarcoglycan protein that is the cause of the disease, all patients improved on every functional endpoint by the nine-month timeframe.

Consistent with the protocol, we will treat an additional three-patient cohort with a higher dose and then in early 2020, we will decide on the dose for what we hope to be in a pivotal trial. These results will help us form dosing not only of our 2E program, but also of the other limb-girdle programs in our pipeline.

We will also meet with the FDA in the near term, to discuss the development pathway for our limb-girdle programs, and informed by this and further work on manufacturing, we will provide an update on the clinical pathway and the timing for our limb-girdle portfolio in 2020.

Next, led by our partner Lysogene, the AAVance gene therapy study for MPS IIIA, also known as Sanfilippo Syndrome Type A is proceeding well with 13 patients having been dosed to-date.

MPS IIIA is a rare autosomal, recessive lysosomal storage disease that primarily affects the brain and the spinal cord causing severe cognitive decline, motor disease, behavioral decline, and unfortunately, death at young age.

AAVance is a single-arm trial evaluating the safety and efficacy of an [indiscernible] gene therapy to deliver the missing SGSH gene with the goal of robustly expressing the missing enzyme in the brain that is the cause of MPS IIIA. Moving to Charcot-Marie-Tooth or CMT, Dr.

Zarife Sahenk of Nationwide Children's Hospital intends to commence dosing of the proof-of-concept study for CMT 1A subject only to obtaining final release of trial material for that study. CMT is the largest inherited neuromuscular disease in the world. And CMT 1A, a devastating peripheral nerve disease is also the most prevalent form of CMT. Dr.

Sahenk's gene therapy is an AAV1 mediated construct to deliver the neurotrophin factor 3, NT3. In animal models, NT3 has been shown to promote nerve regeneration, improved motor function, histopathology and electrophysiology of the peripheral nerves.

And in early proof of principle studies, NT3 has shown markers of clinical benefits in patients with CMT 1A, when administered subcutaneously.

In summary, we have made great progress in the third quarter and over the course of 2019 toward our ambitions advancing our RNA and gene therapy platforms, advancing our many development programs, building out our gene therapy manufacturing capacity, and building out our town.

As with any ambitious strategy, our progress this quarter was met with an obstacle in the form of the VYONDYS CRL. The breadth of our ambition inevitably comes with challenges and obstacles to address and to overcome.

But to those who might at times, feel discouraged or disheartened by the need to overcome the occasional barrier, we should keep top of mind what we are doing with all of this.

If we are successful in our mission, we will not merely be among the most significant gene therapy and genetic medicine biotechnology companies in existence, but we will have more importantly extended, approved and saved the lives of countless patients who would otherwise have been left helpless.

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

Sandy?.

Thanks, Doug. Thanks, good afternoon, everyone.

Let me start by saying that we had another strong quarter, both in terms of financial performance and in progress towards the pipeline and manufacturing capabilities, with the current topline run rate approximately $400 million and a cash balance over $1 billion, we are in a strong position to continue to accelerate our strategic imperatives and invest in the growth of Sarepta.

Net product revenue for the third quarter of 2019 was $99 million compared to $78.5 million for the same period of 2018. The increase primarily reflects higher demand for EXONDYS 51.

On a GAAP basis, the Company reported a net loss of $126.3 million and $76.4 million or approximately $1.70 and $1.15 per share for the third quarter of 2019 and 2018, respectively. We reported a non-GAAP net loss of $84.4 million or $1.14 per share compared to non-GAAP net loss of $37.1 million or $0.56 per share in the third quarter of 2018.

In the third quarter of 2019, we recorded approximately $13 million in cost of sales, compared to $8.7 million in the same period of 2018.

The increase was primarily driven by inventory costs related to higher demand for EXONDYS 51, during the third quarter of 2019, as well as accrued royalty payments to BioMarin and the University of Western Australia.

On a GAAP basis, we recorded $133.9 million and $86.6 million of R&D expenses for the third quarters of 2019 and 2018 respectively, which is a year-over-year increase of $47.3 million. R&D expenses were $110.5 million for the third quarter of 2019 compared to $64.2 million for the same period of 2018, an increase of $46.3 million.

The year-over-year growth in non-GAAP R&D expense was driven primarily due to continuing ramp up of our microdystrophin program, our ESSENCE program and initiation of certain post-marketing studies for EXONDYS 51. Turning to SG&A.

On a GAAP basis, we recorded $75.4 million and $53 million of expenses for the third quarters of 2019 and '18 respectively, a year-over-year increase of $22.4 million. On a non-GAAP basis, the SG&A expenses were $59.6 million for the third quarter of 2019, compared to $42.5 million for the same period of 2018, an increase of $17.1 million.

The year-over-year increase was primarily driven by significant organizational growth and continued expansion to support our commercial launch plans globally and almost 30 therapies in various stages of development across several therapeutic modalities.

On a GAAP basis, we recorded $2.5 million in other expenses for the third quarter of 2019, compared to $7 million for the same period of 2018. The favorable change is primarily driven by the payoff of certain debt instruments during the third quarter of 2018, as well as a higher return on investments over the third quarter of 2019.

We had approximately $1.1 billion in cash, cash equivalents and investments as of September 30, 2019. With that, I'd like to turn the call over to Bo for a commercial update.

Bo?.

Thank you, Sandy. Good afternoon, everyone. To begin, we are pleased with the continued strong performance of EXONDYS 51 in the third quarter. Total revenues reached $99 million.

We were also pleased to be in a position to increase our 2019 revenue guidance range from $365 million to $375 million to a range of $370 million to $380 million for EXONDYS 51. Sales have increased quarter-over-quarter for over three years now. And we continue to see consistent demand for EXONDYS 51 as we speak today.

Compliance and adherence have remained high and stable since launch and to-date, continue to remain steady. It should be noted that in the past two years, we've experienced ordering volatility at the end of the year and suspect that we could see a change in ordering patterns with both Christmas and New Year's falling in the middle of week.

Internally, we are assuming the pattern from previous years could be more extreme this year due to both holidays falling mid-week. With that said, we feel comfortable with the guidance provided. The success we achieved this year reflects the impact EXONDYS 51 continues to have on patient lives.

We remain the leading voice with KOLs and payers across the world in support of Duchenne patients and are recognized as the leader in RNA and gene therapies within the Duchenne deal.

Our strategy to advance the very best science, build awareness, an appreciation for Duchenne and pave new pathways, so Duchenne patients gain access to therapy, have resulted in the successful trajectory of EXONDYS 51 since its approval just over three years ago, and will play a role for future therapies.

As for golodirsen, if approved, we will be ready to launch, leveraging our knowledge and experience to facilitate rapid access to individuals amenable to exon 53. Our work is focused in delivering and grounding us and how we do as the patient.

That journey begins with identifying patients in our core therapeutic areas, Duchenne, the limb-girdle muscular dystrophies and MPS IIIA. Patient identification will be central to the commercial organization for the balance of 2019 and leading into 2020 and beyond.

The genetic testing program decode Duchenne which we saw repeating many years ago consistently identifies patient. We are also in the process of building genetic testing programs for other disease states we're working on as well.

We believe patient identification will always be one of our primary commercial goals, and we will continue to place resources on these programs. Another important goal will be gene therapy site readiness.

We are already working on global site readiness for our DMD microdystrophin program and working with many of the Zolgensma and Spinraza sites treating SMA.

Based on the very strong results Novartis demonstrated with their recent launches of Zolgensma and understanding the label and the differences in patient population sizes between the two disease states, we believe having a strong network of sites ready in training to handle gene therapies will be critical.

We will continue to focus on this as we move through worldwide development, and if successful, commercialization. We also believe it's critical to focus on access reimbursement as early as possible. We're already speaking to and educating large-to-mid sized insurance plans, as well as CMS and Medicaid providers.

On the differences between chronic therapies and [Technical Difficulty] gene therapy and the importance of quickly gaining access through these therapies for diseases like Duchenne. We have built constructive relationships with payers over time and look forward to continuing to work with them to support broad access.

In the limb-girdle muscular dystrophy, we are focused on disease education in identifying patients. The limb-girdle muscular dystrophies are a family of diseases, about 30 subtypes and all. Therefore, patient identification is of critical importance.

Our plan is to leverage our knowledge and experience to ensure that we're able to serve these communities as we have in Duchenne.

We have already attended limb-girdle muscular dystrophy conferences, held educational symposiums at major neuromuscular conferences, held advisory boards to understand how our position to identify and treat patients and already have a digital presence within the community.

All of this will help us prepare for the potential to support multiple launches in the years to come. Sarepta's prospects to transform the lives of patients with rare diseases is unparalleled in the industry.

We have the largest neuromuscular RNA and gene therapy pipeline in the industry, and we understand the responsibility that comes with such an important mission. With that, I will turn the call back to Doug for closing remarks..

Thank you, Bo. So looking forward, we have a number of significant milestones to achieve for the rest of 2019 and through 2020. First, we intend to complete dosing of our SRP-9001 Study II, that's our microdystrophin study by year-end, with functional readout 48 weeks thereafter.

We still intend to complete our process development for SRP-9001, not manufacturing for purposes of conducting our next clinical trial, gain insight from the agency on CMC and on our trial itself, and then to commence Study 301 by mid-2020. We intend to dose an additional high-dose cohort for limb-girdle 2E and then make a dose selection.

We intend to gain regulatory and manufacturing insight and to present an update on the development pathway and timeline for our entire limb-girdle program in 2020. Dr. Sahenk intends to commence a proof-of-concept study for CMT gene therapy NT3 and we intend to obtain safety and dosing insight for our PPMO program in the first half of 2020.

So we, obviously, have a lot to do, but a lot of milestones as well over the coming months and quarters. Thank you all for joining us tonight, and I'll open up the lines for questions now..

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

Hey guys, thanks for taking my question and congrats on all the progress over the quarter. This may be a simple one, but I was just curious to get your perspective on Zolgensma on partial hold and like should we -- is there any -- are there any reads to potentially make seeing the other gene therapy program? Thanks..

Thank you for that question, Alethia..

Okay. So first, let me say this, let's make sure we're all on the same page. For those of you may be unaware, I suspect, everyone is aware, Novartis recently announced that their clinical trial or AAV9 mediated SMA gene therapy for intrathecal administration was placed on a partial clinical hold due to neurotoxicity that we've seen in animal models.

So first understand this. We do not have any unique insight into the Zolgensma clinical hold itself or the Zolgensma program. Certainly one should look to Novartis to gain accurate insight on that program and those issues. So with that said I should tell you, we see no read through to our program and there is a host of reasons for that.

First, understand that we are dosing peripherally with IV administration. We're not dosing intrathecally as what the issue as announced by Novartis regarding that partial clinical hold. And second of all, understand that we're not using a benign Dr. Louise Rodino-Klapac, he was with us tonight and Dr.

Jerry Mendell chose rh74 for a number of specific attributes. One of the significant ones was that rh74 unlikely benign as an example, does not promiscuously cross the blood-brain barrier. And unlike SMA, where that would be a value, there is absolutely no value to these microdystrophin constructs in the CNS at all.

They have promoters that wouldn't turn on in the CN -- CNS, so there would be no value there. So this seems to have been a very wise choice. I also know this, that we have enormous amounts of preclinical and animal model evidence with respect to rh74 and even at doses that are multiples higher than we're using in our clinical trial.

We have never seen signs of neurotoxicity as relates to AAVrh74..

Great, thanks..

Our next question comes from Whitney Ijem of Guggenheim. Your line is open..

Hey guys, thanks for taking the questions, and also congrats on all the progress. I'll ask a question on the origin for microdystrophin patients. Curious if we'll get an update on them in 2020, either an update from you or possibly a publication from Dr.

Mendell?.

Yes, thanks for that question. Thank you for your comments. So, yes document Dr. Mendell has always had a keen interest in publishing the one-year data on the four patients and he is working on the manuscript even as we speak. So I feel very confident that we'll have a publication in 2020 on the first four patients..

Great, thanks. And then maybe one quick follow-up. Thanks for your comments on golodirsen.

I guess, I'm just curious if you're willing to comment on the type of meeting you'll be having with the FDA and whether or not their timing is based on that?.

I missed the end of your question, but I still have the answer. The answer will be frustratingly -- I'm not going to provide updates. I -- as I said, we are going to work with the agency and if there is a rapid pathway, we'll work with the agency to see if there is one. What I would like not to do, is to provide interim comment.

So I don't want to provide an update along the way. There are meetings that we're having, pathways we are considering or the views of the agency, but I will make a promise to everyone.

When we have definitive clarity, I will very rapidly provide an update, not only to the investment community, but also obviously to the patient and the physician community as well. So thank you for that..

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

Hey, good afternoon. Thank you for taking the question. Really quickly maybe thinking about dosing of the items -- you said VYONDYS is being pushed into 2020 as we [indiscernible].

And then regarding the PPMO ongoing study, [Technical Difficulty] profile, would you consider modifying the division's headroom and is that [Technical Difficulty]? And then when do we see that update, it wasn't there in your prepared remarks? Thank you..

I have to really apologize, we were unable to hear your question.

I'll try to answer what I think may have been your question, and it was a question about limb-girdle dosing for the 2E program will be dosing patients over the course of this quarter, and we'll have that insight for the biomarker perspective early next year, and that's when we'll be able to make the decision.

If the question in part was, what are the choices in dosing? We dose -- our original dose is 5 times E to the 13. The protocol itself calls for a dose escalation to 2 times E to the 14, that's what we will be doing in the next three-patient cohort. We'll be getting that done very soon and we'll have that dosing insight early next year.

On [indiscernible] decision, we've seen great results in our 5 times E to the 13, to remind when we had expression levels of just over 50% and of course, we've seen very good signals, it's three patients, so I'm going to be careful. But we've seen very good signals of functional efficacy in these first three patients.

So we are in a good place now and then we'll compare both the tolerability and the safety profile for a higher dose as well as the expression levels from that higher dose and we'll make a decision regarding that. And then I think you asked a question about the PPMO. I'm going to apologize, I didn't get the first part of the question.

I think one of the question --part of the question may have been, when can we expect an update regarding the PPMO program. That will happen certainly before the middle of 2020. It should be actually significantly earlier than that hopefully. And what were you looking for there? Remember what the PPMO is.

Our current technology the PMO RNA technology that forms the basis of eteplirsen or EXONDYS and golodirsen and casimersen and alike, this morpholino technology, the PPMO is a peptide-conjugated version of that same technology.

The peptide, which is positively charged at least in animal models drags that therapy into the cell in much greater abundance then it should result if we can get to the right doses in much significant increases in both Exon skipping and then therefore dystrophin production and presumably additional functional benefits.

And so, by -- before the middle of next year, we're going to essentially get -- the one big question is, can we tolerably increased doses to significant level? So far things are going very well, but we have more work to do. So we'll be getting dosing insight and safety signals before the middle of next year.

So that will include things like tissue levels, skip levels and perhaps even dystrophin production levels. I'm getting a thumbs-up from our -- from Dr. O'Neill suggesting that I haven't made a mistake there. And we'll have that before the middle of next year.

I apologize if there are parts of the question that I was unable to hear and therefore I haven't answered..

Our next question comes from Brian Abrahams of RBC Capital. Your line is open..

All right. Thanks very much for taking my questions.

On microdystrophin, anything you're seeing so far with the additional cohort of patients to suggest that this new batch might be any different from the batch used to dose that first 24, I guess 12 patients perhaps, and with respect to manufacturing composition, the way the second center administers it or stability through transportation out to LA? And then secondarily, I recognize you're not giving play by play updates on your FDA feedback.

But we did see recently that Sedar is going to reorganize the office in neuroscience and other areas of the office of new drugs between now and year-end.

Just wondering if that might mean a change in leadership of the group that's responsible for the golo application or any other implications this might have for your ongoing dialog with the agency on golodirsen, casimersen and your future gene therapies? Thanks..

Taking the first question regarding microdystrophin, please understand this is a blinded placebo-controlled trial. So we'll await those results.

But with that said, also understand that the material for this trial is the same process and the same manufacturer, both in our clinical material coming from the same hyper GMP, hyperstack and adhering -- adherent process at Nationwide Children's Hospital.

So on the face of that, we have no concerns regarding material itself and we're very cognizant of things like the supply chain and the way it transports. So we're very confident on those regards. So, things are going well. I don't want to -- these are blended trials that will see the functional results and other related issues.

Once all the dosing is done, we unwind our portion at the end of 48 weeks but we certainly are very confident on the material itself and the process for trial both and with Dr. Jerry Mendell and also with Dr. Perry Shieh of UCLA.

Talking about the reorganization, the short answer on that is that we are not going to -- and I'm certainly not going to speculate on what that could mean for golodirsen at all. I will say this, we have had a very productive relationship, both with Dr. Billy Dunn and Dr. Bastings, both of whom we have considerable regard for us.

So we think this is certainly a good answer for those in neuroscience and neuromuscular across the industry..

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

Hey, good afternoon. So given the tools in the toolbox currently would you consider a vectorized exon skipping approach, or are you limited by manufacturing capacity as far as the vectorized exon skipping is concerned? And just a follow-up on the same question.

In terms of a comparability between wild-type dystrophin expression and microdystrophin, is there a correlation or conversion, say for example, if you have 8% wild-type expression, that should have the same kind of functional benefits as say at 30% on microdystrophin expression? Thank you so much..

So on the first question. We have significant programs focused on Duchenne muscular dystrophy both from RNA perspective as well a gene therapy perspective. Others have different approaches.

We are generally not focused on, nor do we intend to have a focus in anytime in the near future on the concept of using gene therapy to deliver exon skipping modality where it's not something we're interested as gene transfer therapy.

I should also note, however, that as it relates to CRISPR/Cas9 which itself is a form of exon skipping is not in the RNA side actually, it's directly at the genome itself. That is an approach that Dr. Charlie Gersbach is taking. He is taking a different approach than others in that regard.

His CRISPR/Cas9 approach actually does a fairly significant type and if it is successful, and this is a research program at this point, this is not a development stage program and we are seven ways away from a development stage program, but if that works, it would be an approach that could be available perhaps to as many as 50% of patients that have had DMD.

But that is a research program some ways out. As relates to the first -- the choice is a basic question about the concept of using an AAV-mediated approach through some other mechanisms, [indiscernible] mechanism would like to insert an exon skipping agent.

It isn't our focus and frankly, it isn't something that we are obviously excited about as an organization. On that second issue, I'll turn to Louise Rodino-Klapac who might have some views based on the animal modeling on the accords that one sees between expression in the microdystrophin and what one might see of expression wild-type dystrophin..

Right. Thank you, Doug. In our preclinical studies, we did an extensive dose escalation and we found that is as little as 20% dystrophin microdystrophin-positive fibers led to clinical benefit. And if you think about our clinical results that were about 80% microdystrophin-positive fibers, we were well beyond that level.

So we really based it on extensive efficacy studies in [indiscernible] Mdx Mouse Model for the disease..

[Operator Instructions] Our next question comes from Tazeen Ahmad of Bank of America. Your line is open..

Hi, good afternoon guys. Thanks for taking my question. Just wanted to get a sense thought about the timing of the readout for the confirmatory study that you're starting this quarter. I think on clinical trials, it has a 2024 date for readout, but just wanted to get some clarity, if that's round about the timeline you're expecting? Thanks..

We will come up with more clear -- we will provide an update in probably later in 2020 about timelines associated with the confirmatory trial. The good news on the trials is still we're on the same page, is that this was -- this was a little more complicated as the confirmatory trial that one might normally imagine.

This is not a trial with a placebo arm versus the approved dose. It was as I've noted in the -- my comments, it is a confirmatory trial that actually tests a different thesis, which is the current dose versus a significantly higher version of that dose. To do that, before you commence the main trial, you have to start with a healthy volunteer trial.

And we've done that, we've completed that, that's readout, that justifies moving to this higher dose study. As I said before, there really are three arms. There is the 30 milligrams per kilogram which is our currently approved dose.

There is an arm at a 100 milligrams per kilogram, there is a arm at 200 milligrams per kilogram and it gets a little bit more complicated than that over time. But that's essentially the study and that study is initiating now and we will be dosing now.

We can provide updates on that probably towards the end of 2020 or so, give you some additional updates on time wise..

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

Thank you for taking my questions. And the first one is ESSENCE trial, just wondering if you can remind us when the data will read out? And also, do you think FDA were -- wanted ESSENCE data in order to approve golodirsen and casimersen? And then my second question is very quickly regarding the one-year data for four patients.

Just wondering at what will be included in the one-year data update, would that include biomarker data to show like CT and the protein level as well as the functional data? Thank you..

So as relates to ESSENCE, ESSENCE will be -- will read out likely in August. We're recruiting now, that means we've recruited over 70%, so ESSENCE is coming along very well. We should have a readout in ESSENCE around 2023.

As I said, I'm not going to comment on the pathway for golodirsen until we have more clarity from the agency, and then I'll come back and provide definitive clarity. And then I think your second question was, as it relates to....

Dr. Mendell's one year....

Our one-year data will be inclusive of partial biomarkers safety. It will be inclusive of the data that he has on the first four patients at the one year mark..

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

Good afternoon. Thanks for taking my question.

So with regard to the gene therapy manufacturing, can you detail the progress you've made on yield optimization and assay work, essentially where you stand right now with overall tech transfer from NCH as you look to start the commercial grade pivotal trial?.

So let's go through a couple of things. There's been obviously elements in our [indiscernible] I won't provide numerically, but broadly speaking they are the following. First we long ago transferred the process from Nationwide Children's Hospital to us and to this hybrid approach we have.

So remember there really are a collection of three groups working our process development and analytical development mostly here and that is, we -- our own group, we've got a significant group, we've got 10 iCELLis units here actually and we've got our partners at Paragon and we got our partners at Brammer.

So we made a lot of progress, first, just on our pure capacity perspective, as I said, we have fully built with Brammer Biosciences a single-use facility in Lexington and it is done and ready to go. We have -- at Paragon we actually have even more significant -- well, that is significant capacity.

We have even more significant capacity at Paragon and that's -- the iCELLis units are there and getting ready to go as well. Led by Dr. Reed Clark at Sarepta who made great strides on assay development and as it relates to process development, we've made significant strides on our microdystrophin program.

We've actually made significant strides on some of our limb-girdle programs as well. In fact, as it relates to yields for the clinical trial, we will be locking -- I'm not going to give you exact date, but it will be in the near-term.

We will be locking process and beginning confirmation rights, so that we're in a position by the middle of 2020 to commence what we -- Study 301, which is our commercial process supply trial.

So all in all, I'd say we're making great progress around capacity and assay development and we're making good progress on process development and yield optimization as well.

We still have a lot left to do, but I think we started this process, we got ahead of this early -- got the capacity as soon as we realized the opportunity in front of us, and I think the team is very focused. We've got a lot of great expertise here and we're making good progress..

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

Hi guys, good afternoon. Thanks for the question. Doug, have you dosed any of the additional limb-girdle 2E patients? You said you'll have the dose selected by early next year. So, is it safe to assume that they will be dosed by the end of this year? Thanks..

They should be dosed by the end of this year. We have the material, the patients are all screened, so -- details on who's scheduled for when, but the three patients should all be dosed by the end of this year and we should have insight in it and it should be around the end -- before the end of the first quarter, we should have insight..

Yes..

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

Hi, thanks for taking the question. he question is on exon skipping agents, including your PPMO's and development as well as competing companies.

Is there an amount of dystrophin expression from those agents that kind of get so high that it would be competitive with the gene therapy agents in terms of competitive from a marketing standpoint, and if so, could you help characterize what that may be?.

Well, it's hard to judge right in advance. I will say that is an enormously high bar. So to remind one with respect to our microdystrophin program, we're seeing over 90% expression and as Dr. Louise Rodino-Klapac mentioned in response to a question earlier, you get transformative functional improvements in animal models at even lower than that number.

So we -- to ask whether there is possibility that the PPMO and I think it really would only be the peptide conjugated PMO, whether you could be in a place where it could actually be in some ways, competitive with a gene therapy, I think we'll await the results of our study in 2020, but that is a high bar.

I think the real interesting question for our PPMO program, assuming the success of our gene therapy is that if we got -- we had such significant and robust expression, and I will say at least in animal models and I don't -- we will await the data from our multi-ascending dose study, but within animal model getting to the right dose, you could have in order of magnitude more of exon skipping, more disciplined production and then significant increases in function.

The real question in that scenario, there's a number of questions. First is, is there a place for accommodative therapy of a very transformative gene therapy with a potential follow-on PPMO, and obviously there is also the opportunity of gene therapy successful for the PPMO for those patients who would otherwise screen out of the gene therapy.

And then the PPMO is again, let's say, let us wait for data before we get too far over our skis.

But in fact, PPMO data was able to get to very high doses and was significant, well tolerated and then obviously, the next question for us and we're looking at this right now is, what other areas should we take this therapy to provide benefits to patients who would benefit from steroid-blocking and significant doses..

[Operating Instructions] Our next question comes from Ritu Baral of Cowen. Your line is open..

Thanks for taking the question. So Doug, you mentioned that you have, I guess, locked in a placebo-controlled design aspect to the Phase III of the 301 trial.

Can you describe your current thinking on patient numbers, randomization? You didn't mention younger patients and it sounded like you said that you're sequestering older patients in a different study.

And just to clarify your answer to Salveen's question, so have you finished assay validation and if not, when do you think you might know that's down with FDA and start those engineering runs you mentioned?.

I'll answer the second question first. We still have work to do on assay validation, but we're making great progress under the guidance of Dr. Reed Clark, and obviously, our goal and target and every intention is to have that done well in advance of the commencement of our Study III which is going to start in the middle of 2020.

So obviously, we've made great progress so far in assay development. As we always do in our Study III, there are number of elements that we will disclose later as we have further discussions with the agency. So we're all clear about the goals of that study.

It's our intention in that study to have data results sufficient both from approval perspective, as well as from an access and reimbursement perspective to serve a broad population for Duchenne muscular dystrophy.

And by broad, of course, we think both in terms of age, we went from the youngest children to the oldest patients with DMD, and we also mean the broad in regard to mutations we want to ensure that patients across all mutations have an opportunity to benefit from this. And the studies that we're designing are designed with that intention.

Our main study is the study that was -- the primary study proposed for the functional results is the age four to seven-year olds, and that's a one-to-one placebo-controlled trial double-blinded etc., multi-site multi-country trial. But we have other studies as well.

We will have -- we will have some study for younger patients, to your very good question. Then we will have older patients and non-ambulatory patients as well in a separate study, and we're planning those as well. So that is our goal and our goal is to have this all commence by mid-2020..

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

Hey, good afternoon guys. Thanks for taking the call. So you said that you're on track for a mid-2020 start to Study III. But on last quarter's call, you guided for first half 2020. You actually said that you might do it as early in 2020 as possible, first quarter if possible.

So I'm just trying to square away if manufacturing is up online, Lexington facility is running, feeling good about your yields, what's sort of the change here between this quarter and last quarter, let's say, it's more mid-2020 as opposed to targeting the first quarter possibility?.

This is not -- so we're clear that you shouldn't read into my comments delay, there's no delay.

Just understand, our goal is to lock -- once one locks process development, then you have to go through an entire process of confirmatory runs and like just to be a in a position to commence the trial and then, of course, you got [indiscernible] IRB approval, so we've always guided to mid-2020, first half of 2020 to mid-2020 and that continues to be our plan.

So read my current statements as a positive development that we continue to make good progress on analytical development capacity and process development, so that we will be in a position to fulfill our goal of starting this trial by mid-2020..

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

Hi all, this is Tess [ph] in for Anupam tonight. Thank you for the update and for taking our questions. Just one from -- from the confirmatory commercial supply 301 trial.

I wanted to confirm that in SMB, there will be -- the FDA has agreed that there will be an interim analysis on microdystrophin expression in the study, but I think the intention was that this would readout in 2020.

I'm just wondering if you'd reached agreement on how many patients will be with it and within this? And then my second question if I could, on the Charcot-Marie-Tooth program.

Can you just remind us of timelines for dosing here? Really when they should -- when all the patient should be dosed? I'm just trying to think about potential timelines for data on that program. Thanks so much guys..

On the first question, we have meetings planned with the agency across a number of programs, including about CMC and the Study 301 design. We will have that done, certainly planned in time to commence Study 301 by mid-2020. On the --.

Just a second. Doug, sorry. To -- out of respect for every analyst trying to get a question on the call, we're asking everyone to ask only ask one question. So we're happy to follow up afterwards..

Our next question comes from Tim Lugo of William Blair. Your line is open..

Hi, this is John on for Tim. Thanks for the question.

I was just wondering if you can provide any additional details on the Sanfilippo program, maybe specifically around the commercial prospects or the safety expectations from dosing directly into the brand?.

Well, I guess, broadly speaking, I can turn to Louise to provide some insight on the second of the two questions. On the first of the two questions, it's obviously a very rare disease. But we're very excited to serve this community.

This is a devastating disease that historically has been bereft of any of these children to generate both cognitively, behaviorally and then neuromuscularly rapidly commencing in about four, five years old. And so there is option. But talking about it commercially, we're very excited about it for our mission.

And then as it relates to the safety and scientific issues, Louise if you have any insight into that?.

I would just add as we've mentioned, 13 patients have been dosed. This is direct delivery. The preclinical data is exceptional that supports this approach and that we are getting very robust delivery into the parts of the brain that are meaningful for biological and functional efficacy..

And this is Gilmore here. I think I can speak about the neurosurgical.

Out of the procedure for human patients so far, it seems, you kind of -- how should I say, it gives you [indiscernible] to think are about concepts of the injecting directly to the brain, this actually is an experience has been developed over many years in the context of many therapeutic interventions.

And it's being well tolerated to-date and we anticipate that the benefit risk is likely to be positive in the context of what is very serious disease..

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

Hi, thanks for taking my question. Just a couple that pertain to the model. So how many patients on therapy and what percentage do we think are genotype right now and then also, what's the growth in that? Thanks..

Well, So, we are not -- we don't typically provide -- typically we don't provide information on patients on therapy for the commercial product EXONDYS.

Sandy -- I assume Sandy you have a comment on gross to net?.

Well, we haven't provided specific guidance on gross to net either. I mean, when you look at our commercial and non-commercial split, it hasn't really changed in the recent past. But that's about all we have said so far on that topic..

We, obviously are very pleased with the performance of our products since its approval in 2016. As you saw we were continuing to grow in the last quarter, which means we're continuing to serve additional patients with EXONDYS or eteplirsen.

And I should note this, that people, I'm sure people know this, but to the extent you don't know this, we don't take price increases. I mean, we certainly haven't in the past. So what -- when you see growth on sales, you're obviously seeing additional patients being served by this therapy..

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

Hi, thank you very much for taking the question.

So, can you remind us your -- how you were going to leverage the data from the now 40-patient study to help you get FDA approval now that you have a placebo-controlled study plan to be initiated in mid-2020? Apparently you won't be able to see any data from the 40-patients study before you initiate the pivotal study..

Correct. So one possibility in this will require first, additional conversations with the agency and then obviously all of this will be considered in the context of the data when it actually develops. But again, we will be done dosing if all goes well, and things are going very well right now.

We will be done dosing what we call Study II, the 40-patients, placebo-controlled trial by the end of this year. We'll have a readout on that 48 weeks thereafter, which will provide both safety as well as functional benefits of our microdystrophin therapy.

Out of four that time, we will have expression-related information from the next study which is Study 301, which is our commercial supply trial.

At least we will have that in a significant subset of the 301 trial itself, which means that at the time that there is a readout from our Study II on function and safety, we will also have insight from both the CMC and from biopsy data on the comparability of our commercial supply and our clinical supply.

And certainly at that time, we will approach the agency and discuss the pathway for the fastest possible approval consistent with regulations and good signs and good safety..

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

Hi guys, this is Brian [ph] on for Vincent. I guess, I just have a clear [Technical Difficulty] the future manufacturing model for your gene therapy programs.

Is the goal eventually to bring some capacity in-house or is your sense that primarily relying on the CDMOs, the long-term strategy?.

Yes, I think it's a great question.

So, as you know, you can see through what we're doing from a platform perspective that as we stand here even now, I think we have one of it's not the deepest gene therapy specific pipelines and it's because we intend to be a durable enduring gene therapy biotechnology company treating rare disease for a long time, that means we're going to be looking at lots of things.

We are very excited and we're very pleased right now with our hybrid manufacturing model. It's allowed us to move rapidly to gain expertise quickly and to work with some of the best and brightest and we're pleased with that, and that's why we have great relationships with Aldevron and with the Brammer, now Thermo Fisher or Paragon or Catalent.

But we're looking at other things as well down the road. We will certainly do feasibility studies on whether additional capacity internally makes sense and we'll look at other modalities even beyond the approaches we're taking right now.

But as it as relates to our microdystrophin program and these limb-girdle programs that we're working on right now, this is the approach we're taking and it's working well for us..

Our next question comes from Tim Chiang of BTIG. Your line is open..

Hi, thanks. I don't know if you've mentioned the number of patients that are enrolled in Study II. I was just wondering if you had account of the 40-patients that you're targeting for that study? How many of them have already enrolled and then how many patients do you expect Dr.

Sahenk to enroll of the 40 patients?.

I don't have a details on the split between Dr. Mendell and Dr. Sahenk. I can tell you, there is a significant inventory of patients in both sides. So being able to fulfill our needs to get everyone dosed by the end of the year shouldn't be an issue. I don't have an update or count on the number of patients dosed.

We know that the first 24 patients were all dosed before the last time we spoke on our earnings call. We're dosing patients even as we speak. In fact, I don't want to get too over my skis on these things and a patient was dosed today. So we are on track to have everyone dosed by the end of this year..

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

Hi, good evening. Thanks for taking my questions. This is Dae Gon [ph] dialing in for Joe. So Doug, just, sorry if I missed this. Just thinking about the timeline going forward, I briefly caught you're talking about Study II being complete enrollment wise by the end of the year with 48-week data towards the year-end of next year.

So if we think about the calendar or the timeline of Study III, which was anticipated to study in mid-2020, are we, I guess, given the competitive landscape, some of the other guys that are using vector [indiscernible], so all it goes for example, as well as your commercial product and some of the other microdystrophin players also entering a larger Phase III trial in 2020, can you maybe talk about comfort level in terms of your enrollment? How many trial sites are you anticipating and what's your target enrollment here that could actually get you through to that year-end biopsy data to match the concurrent 48-week NSA data?.

Well, I'll say some broad stroke statements, and Dr. O'Neill may want to comment on things like trials sites, numbers related.

To just broadly understand the following, we don't take for granted the region we have, but we do have a read right now versus other folks and we've already -- by the end of this, we will have 40 patients dosed in our placebo-controlled trial, our proof-of-concept study with our first four patients.

Of course, we've done [indiscernible] data on those first four patients in publication in the near term. And we're very confident about the progress we're making towards Study 301.

We're very, very confident about where we'll be at the end of 2020 as we are reading out the functional data from Study II and the opportunity to have biopsy and CMC-related data from Study 301. But with that said, Dr.

Neill, if you want to make any additional comments?.

So, I would say is that we're very conscious of issues you've raised around competition or -- if that's not really right, we are putting ourselves up with patients actually trying to sites and [indiscernible] across different studies.

We are engaging -- we already obviously actively engaged with sites through our prior and ongoing efforts with our PMO programs, and we are actively engaged with sites around the world. You are looking at evaluating our interests, the competitive landscape and the capacity to participation.

So we're actually confident that we can actually enroll as is required to meet the timelines that we've got in line. But I'd say we are very conscious of these issues you raised and that's why we are being very careful and precise in how we evaluate engagements in sites around the world..

There are no further questions, I'd like to turn the call back over to Doug Ingram for any closing remarks..

Thank you very much and thank you all for joining us this afternoon and this evening for our update. We look forward to executing our plans for the remainder of 2019, and obviously providing a further updated our next conference call early next year..

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect..