Q2 2019 Earnings Call
Good afternoon, ladies and gentlemen, and welcome to the dentist Therapeutics second quarter 2019 earnings Conference call.
At this time all participants are in a listen only mode.
Later, we'll conduct a question and answer session and instructions will follow at that time.
If anyone should require operator, let's turn the call. Please press star and then zero on your Touchtone telephone.
As a reminder, this conference call is being recorded.
I would now like to turn the call over to Andrew Chang head of Investor Relations at a dentist. Please go ahead.
Just after market close today, we issued a press release with earnings and operating results for the second quarter 2019.
The press release and live webcast access are available on the investors and media section of the dentist website at Www Dot identity, TX Dot com.
The webcast link will be available for approximately 30 days.
Joining me on the call today are Matt Patterson, Chairman and Chief Executive Officer.
Natalie Hollis, President and Chief operating Officer.
And Tom Soloway, Executive Vice President and Chief Financial Officer.
Before we begin with prepared comments I'd like to remind callers that the information discussed on the call today is covered under the safe Harbor provisions of the private Securities Litigation Reform Act.
I caution listeners that the company's management will be making forward looking statements.
Actual results could differ materially.
From those stated or implied by our forward looking statements due to risks and uncertainties associated with the company's business.
These forward looking statements are qualified in their entirety by the cautionary statements contained in today's press release and the Companys SEC filings.
The content of this conference call contains time sensitive information that is accurate only as of the date of Thislife broadcast August six 2019.
Hi, dentist undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances. After the date of todays call except as required by law.
I would now like to turn the call over to Matt Patterson, Chairman and Chief Executive Officer.
Thank you Andrew and good afternoon, everyone. The first half of 2019 has been an exciting and busy time and we're pleased to share the progress we have made across our product portfolio.
As well as several important key milestones, we expect for the remainder of the year and into 2020.
We have a lot to cover so let's get started.
Beginning with 81 three to our lead product candidate for the treatment of X linked to Bill or my office C. R. XL MTM, we're pleased to announce that we recently initiated enrollment in what we're calling a pivotal expansion cohort in our Spiro studies to confirm the safety and efficacy profile of 80 132 at a dose of three times 10 to the 14th vector genomes per kilogram.
We have selected this as the optimal dose based on the safety and efficacy data collected to date and the input of our scientific and medical advisors.
We expect enrollment in the pivotal expansion to complete this fall and we believe the results will support the submission of a biologics license application for 80 132 in mid 2020, and an M.A. in Europe in the second half of 2020.
The decision to add a pivotal expansion cohort two as Spiro and its design were based on a series of productive interactions with the FDA on M&A over the past several months under armour and prime designations respectively.
The intent of these discussions was to collaborate with both agencies regarding how to rapidly advance 80 132 to license applications based on the medical need and existing clinical data.
The specifics of the conversations largely focused on how best to further establish the benefit risk profile. The T 132.
The three times 10 to the 14th dose with rigor and minimal subjectivity.
As always it's a dialogue and it's incumbent upon us as the sponsor to take the feedback and design a study that both meets the regulators objectives and allows us to move as efficiently as possible towards filing.
This new fields, particularly urgent and XL MTM, perhaps about half of these boys don't live to see their second birthday and there are currently no treatment options available.
We are confident that we have developed a plan that balances these needs and will support the filing of license applications in the U.S. and the E U.
Before sharing the details of our regulatory discussions lets first review the overall enrollment of a spiro today.
We started with cohort one at a dose of one times 10 to the 14th vector genomes per kilogram in which we enrolled six treated patients and one delayed treatment control.
We then escalated to cohort two at a dose of three times 10 to the Fourteens vector genomes per kilogram in which we have now also enrolled a total of six treated patients and one delayed treatment control.
However, it's important to remember that to date, we have only reported data from three patients treated at the proposed commercial dose three times 10 to the 14th.
So it was not surprising that a first recommendation of the regulators wants to see more data from additional patients treated at that dose prior to filing.
Beyond this request to increase the number of patients treated at the proposed commercial dose. The regulators feedback was focused in three main areas endpoint selection study design and duration of follow up post treatment.
I'll talk about how we've addressed each of these areas in turn.
Let's start with endpoint selection consistent with our expectations both agencies recommended focusing on endpoints that are clinically meaningful.
Based on our own work and other publications in the field, we know that reduction of ventilator dependence is considered to be closely correlated with morbidity and mortality outcomes and children living with neuromuscular disease, including XL MTM.
In addition, as you can imagine the decision to initiate and maintain young children on ventilator support is an important determinant of quality of life for both patients and their caregivers.
As such we have defined the primary efficacy endpoint for the pivotal expansion as the change from baseline in hours events, let torry support overtime through week 24 post treatment.
Both the FDA and EMA have agreed that this is a clinically meaningful efficacy assessment and importantly, the data we have generated to date give us confidence that we can meet this endpoint.
Recall as of the April 29, as Spiro data analysis, we saw sustained and meaningful reductions and ventilator support and all nine patients treated with four patients have successfully completely weaned off of mechanical ventilation.
So we believe we are on solid footing for the primary efficacy analysis.
Now, let's turn to the second main area of focus study design.
We have designed you spiro pivotal expansion cohort to enroll eight patients consisting of four age matched pairs defined as being within plus or minus six months of age of each other.
One patient from each pair will be randomized to receive a single dose of 80 132 or three times 10 to the 14th vector genomes per kilogram and the other will serve as a delayed treatment control.
Delayed treatment control patients will be administered 80 132 once the 24 week data are collected from the full pivotal cohort.
In discussing the ventilator support endpoint the regulators were focused on ways to reduce subjectivity and minimize potential bias in the decision making around ventilator waning.
As is usually the case the recommendation for US was to run a double blind placebo controlled study.
This was met with resistance from our investigators and data monitoring committee strongly questioned performing sham infusions in cereal muscle biopsies uncontrolled patients.
So balancing the two perspectives, we have introduced multiple elements of control to the design of the pivotal expansion to increase the overall rigor and objectivity of the efficacy assessment.
First we've gone from a three to one randomization any dose escalation cohorts to a one to one randomization, which amplifies the overall power to assess the treatment effect.
Secondly, weve age matched the one to one randomized pairs to control for any motor or respiratory functional changes that could be attributed to subjects age.
And thirdly, the ventilator Weaning protocol now includes a blinded review of all respiratory functional data by an independent panel of Pulmonologists to approve all ventilator support reductions.
The third point in particular, we view as critical as it enables blinding of the primary endpoint without requiring the placebo control.
We are confident that our approach to study design will enable the regulatory authorities to interpret the data from the primary efficacy evaluation as reliable and accurate.
Finally, turning to study duration the regulators were appropriately focused on assessing durability of benefit of 80 132 and as is always the case, the more data and the longer the follow up the better. The key question is when is the optimal time point to perform the data cut to support a filing.
Fear not surprisingly the FDA guided towards 48 week follow up.
As we have previously shared all patients in a spirit will be followed for safety and efficacy for five years.
Our plan is to submit our license application once we collect 24 week data from the pivotal expansion cohort by which time. The filing will also include over 24 months follow up data from patients in cohort one.
And approximately 12 to 24 months of data from patients in cohort two.
In total we plan to submit with data from 22 patients 18 treated 10 of whom will have been followed for 48 weeks or longer which we believe will strongly support the durability of benefit with a tier 132.
So in summary, we believe we have put together a robust plan that addresses the feedback of the regulatory authorities moves. This important program forward rapidly and in the end will demonstrate a positive benefit risk ratio and support a potential licensing approval for 80 132.
As I mentioned earlier, we have already initiated enrollment of the pivotal expansion cohort and plan to complete dosing by the fall.
And importantly, all other aspects of our preparation for license applications are proceeding well, including on the CMC side as Natalie will touch on in a moment.
Before we turn to the remainder of our pipeline I'd like to thank all of our partners and collaborators the ball team members, our scientific and medical advisors and of course, the XL MTM community has courage and strength or a constant reminder of our mission to bring 80 132 to patients as quickly as possible.
With that I will turn the call over to not only to walk through the rest of our pipeline and make a few wrap up remarks Natalie.
Thank you, Matt and Hello, everyone.
We've made tremendous progress on our pipeline programs in the past quarter and I'm pleased to walk you through the highlights of our recent work.
Starting with our upon pay program, we continue to advance our product candidates 88, fourfive towards 90 filing later this quarter. We've now completed our dose ranging and GLP toxicology studies and both the Tompane mouth and NHP is respectively.
And are in the process of finalizing the study reports and preparing the I'd submissions with an eye toward initiating clinical studies early next year.
Our expertise and still make administration of 88 to drive broad muscle tissue transduction, then transgene expression provides us with a highly differentiated approach in pompe disease.
We believe 88.5 is the only gene therapy in development today, which is delivering and expressing GA directly in the tissue is affected by the disease.
This potentially best in class approach stands in contrast to both enzyme replacement therapies.
And deliver direct to gene therapy candidates that rely on an inherently inefficient cellular uptake mechanism a GA from plasma to deliver the enzyme to an intra cellular side of action.
As such we avoid the need to engineer the GA transocean to optimize for CRM stability or cell circuits receptor binding affinity with this approach. We're excited to bring this program through the eye and the submission as we believe it has transformative potential for the treatment upon pay to see.
Turning now to our Duchenne muscular dystrophy program. We're excited about the rapid progress we've made since we announced our platform and pipeline expansion in early April .
As a reminder, in DMD. We are initially advancing three back to rise exon skipping product candidates, which we believe together have the potential to address more than 25% of the duchenne patient population.
87, no two which is the most advanced disease program is designed to treat DMD caused by duplications of Exxon Q or mutations and exxon's, one defied the dystrophin gene.
Nationwide children's hospital, our collaborator for this program plans to initiate patient dosing next quarter using their clinical material, which was manufactured at their facility.
We expect nationwide to dose one to two patients prior to the clinical program transitioning to our construct and clinical material early next year.
In parallel with the Nch work, we've successfully completed work to transition to you and manufacture our 87 I would to construct in house.
Dose ranging and toxicology studies are underway to support a 90 filing for the dentist product in Q1 of next year.
We expect that we expect to initiate a full phase one two study at 87 node to quickly once the i. indeed clear.
We took the time over the past few months to refine the nch constructs because we intend to use the backbone as a platform for rapid expansion of our Factorized exon skipping approach into additional DMD genotype and to get a fact.
We have achieved meaningful improvements in the manufacturing productivity and product quality in making the transition to our contract.
So importantly, as we did with XL MTM, we expect to initiate our duchenne clinical work with the commercial product and manufacturing process in place.
From here, we're well positioned to rapidly advance our preclinical work on 87 51, and 87 53 are additional product candidates designed to treat DMD patients with genotype amenable to skipping exon 51 and 53.
We expect to provide more refined timeline for moving these programs into the clinic and are coming update.
And Myotonic dystrophy sector screening studies for 80, 466 are underway and we plan to submit an i., Andy and 2020.
Well relatively early in its development. We are excited about the potential of this program.
As a reminder, we are evaluating both doctors that are in a knockdown and exon skipping a purchase.
Each of which have been Matt Mechanistically validated to block the accumulation of toxic are in a in effect itself. The key pathological mechanism in DM one.
We believe that by combining antisense with the delivery and tissue transduction powered Avi, we overcome the recognize limitations and make an antifungal and create the potential to provide transformational impact on this devastating disease, which affects more than 100000 people in the U.S. Europe and Japan.
So more to come here and we're certainly pleased with the early progress.
Turning to manufacturing, we continue to view our investment in our own internal large scale cgmp manufacturing operation as a key strategic value driver for the company.
It has enabled our rapid progress through clinical development towards the law and the M&A filings for 80 132 as not shared earlier and more recently has allowed for accelerated preclinical development of our pump pay to Sean and Myotonic dystrophy program.
Our current operations utilizing the Malians CRM free suspension culture production process at 1000 liter scale is expected to meet the anticipated global commercial demand for 18 months retail and the near term development needs for other product candidates.
Also in April we were pleased to announce our new state of the art Cgmp plasmid manufacturing facility.
We brought positive manufacturing in for reasons similar to our early decision to bring in Dr production.
To improve control over our supply chain reduce cost and accelerate production timelines for this piece starting material.
We expect this internal capability to take money off of our development timelines across the pipeline over time.
Leveraging all aspects of our Avi manufacturing leadership for rare neuromuscular diseases will continue to be a cornerstone of our strategy for long term value creation for our shareholders.
Finally, we continue to maintain a strong balance sheet with $378.6 million of cash cash equivalents and marketable securities as of June Thirtyth.
Our balance sheet strength positions us to make meaningful progress across our pipeline and were excited by the multiple upcoming milestones and look forward to sharing further updates over the coming months.
That concludes our prepared comments for today's call. Operator, you may now open the line for questions.
Ladies and gentlemen, if you have a question at this time. Please press the Star then the number one key on your Touchtone telephone.
If your question has been answered for you assure me for so from Hill. Please press the pound key.
Again that is star and then one to ask a question.
And our first question comes from.
Pam Rama with JP Morgan Your line is now open.
Hey, guys.
Thanks for taking my question and congratulations on all the progress just two quick ones for me.
For the patients in the pivotal.
Spiro cohort.
Patients all been identified I think you said enrollment would complete this fall and then.
A second question for the World muscle update later in the year, what additional analyses could be presented beyond kind of the endpoints. We already know and can you remind that duration of follow up we'll get at the conference. Thanks, So much.
Hi, Anna Farm, it's Matt Thanks for your question.
Those are pretty quick ones.
Eight patients indeed, our identified I can remind people that weve been continuing our insecticide natural history running and running study in the background alongside a spiro all along and so we've maintained a pool of patients that might be candidates for spiro should we need additional enrollment and so patients are identified and it's just a matter of working through the logistics of enrollment over the coming.
A couple of months here in the fall as we said so yes, we expect to complete enrollment this fall and.
Obviously, that's what helps us get that get us to the deal in mid next year.
WMS you know its a little fluid on a farm is the honest answer we certainly will have a data update.
But I'm not in a position today to articulate exactly how much additional data and exactly how many patients. The team is working on that and finalizing that plan right now.
At the same time, they're working on enrollment in the study and.
Preparation activities et cetera, So we'll have a little more color on that as best as we can here in the coming weeks, but I would say that I don't expect it is going to be quite as much of a data update as we had today as TCT it'll be a meaningful update but it probably won't be quite as much data as we had a day as TCT.
That's my initial read on it.
Awesome. Thanks for taking my questions and congrats again on all the progress.
Thanks, Jonathan.
Our next question comes from Chris Raymond with Piper Jaffray. Your line is now open.
Hi, This is Nicolas go Brzeski on for Chris Thanks for taking the question.
I guess I just had a quick one on 81 32.
So you guys have highlighted that you've used the same process and the same facility is at the same scale from preclinical anti enabling work all the way now almost a commercialization, but I was just curious.
Are you currently manufacturing or moving to manufacturing plasmid for 81 32 in house for the program prior to BLE filing and then also just wondering what the regulatory hurdles might be or if there are certain data you need to show efficacy to confirm that you have an equivalent product when you switch to plaza needed at a new production site and then just lastly does this have any impact on Sealy filing times at all for.
For the MPM program.
Hi, Nicole Thanks for the question.
A bit of a work in progress I would say, but.
Plasmid manufacturing up and running and going well I would say.
That our current vision.
Is to include it in the license application.
But we certainly want to make sure that that plan is comfortable to the agency and if there is any work to be done which in terms of comparability.
That we handle that our guess would be that animal data would be satisfactory for that frankly, but.
So thats a bit fluid and but I can assure you that we're in a position where it won't become rate limiting for the BLA filing and if for some reason we needed to do a little bit more work, we would file it as opposed approval change we're in a position to be able to be flexible in that regard.
So.
Certainly, we'll do our best to get it in and leverage it as much as we plan to but.
We won't let it delay any delay in filing.
Thank you.
Our next question comes from Joseph Schwartz with SVB Leerink. Your line is now open.
Great. Good afternoon. Thanks for taking my question. This is <expletive> on dialing in for Joe and congrats on all the progress.
So just two questions from me one on 81 32, and the second question on DMD.
Apologies if there are kind of two questions multipart questions, but I guess, starting with the 132 just wanted to get your take on.
Sort of that patient number I think you previously talked about enrollment expansion cohort enrolling three to five patients and we now have eight.
I understand that it's now randomized one to one so maybe it is just a symantec's kind of a thing where four patients does fit in with a three to five guidance you provided previously so any color there would be good.
Second question is on D.M.D.. So you mentioned that 72 will enter the clinical trial in one to two patients using the nch based material I'm, assuming that that shouldn't be system and you're working through the conversion to suspension base. So how many patients are you thinking in terms of phase one two and as we think about your subsequent programs and 51 and 53 any chance you could run a basket trial, especially since the 53 patients are somewhat of a small underrepresented genotype.
Operations. Thanks.
All right. Thanks, they're gone I took some notes hopefully I get these right, but check me if I don't so regarding the 81 through two yeah. So I tried to say it in the script, but let me just restate the patient numbers, because I understand that tent potential for a little confusion.
Cohort one we all agree and understand six patients were treated and there was one untreated control cohort to be first we treated three patients and we had an untreated control and then we announced that we were going to expand that to enroll another three to five today, we're announcing that we did enroll additionally, those three patients into that cohort.
So thats done that is in fact distinct and separate from the pivotal expansion cohort, which is eight patients.
For treated and for delayed treated.
So hopefully that's clear and that gets me to those numbers I mentioned in the script, which is that in the end the veolia would be filed on.
Number of 22 total number of patients 18, who have been treated 12 of them have been treated at the.
Proposed commercial dose of three times 10 of the 14 so.
Hopefully that makes sense.
And then on the DMD side, so yes so.
Look the program early research as everyone knows started a nationwide they're our partners on this they have done additional work to answer after you ask questions and get a trial started but indeed you're right.
It looks like they will get started with treating one or two patients with the material. They have made at nationwide with their version of the construct.
And that's on track to start here later that later this year as previously guided to.
But weve also chosen to.
Optimize the construct we're switching it to an 88 construct which of course is what we use in our other programs.
And as Natalie mentioned, we're pleased with how that has gone and that's going to result in our own.
Distinct I, indeed that we're going to file in Q1.
Which is for that optimize construct manufactured by our same in house.
Large scale serum free suspension culture system. So.
So thats the plan and so the vast majority of the clinical work will be from the adient as product.
And starting.
First half of next year.
Nch will get start with a couple of patients and we'll see what we learned from that as part of the program.
And then finally, but as far as specifics of the.
Clinical protocol for that I'll don't as I, India in Q1, and the number of patients and specific endpoints.
Don't have the detail to go into on that today, but I expect we'll have that information and more color to provide there later in the year.
It won't come as any surprise that we expect to evaluate a lot of the same assessments full thin tissue and clinical assessments that have been seen to date in the Duchenne community.
Which will probably also translate over to what we end up doing in the clinic for 51 and 53.
And finally your question about a basket I, India, a little early to say there were engaging with FDA, but you can bet that we are taking a creative approach to how to do this we have highlighted previously that we're optimistic about our ability to move this program as quickly.
Given the fact that it's the same.
Backbone same basic construct in each case, but for the specific anti sense sequence for each Exxon and so one can envision a scenario that's very logical incredible where you can rapidly move through preclinical development for future axons and even clinical if you can find ways to be creative and leverage experienced with various endpoints and designs to move the whole thing quickly. So.
But we expect to engage with the FDA in that sort of creative dialogue in the coming months as well as we have progress we'll keep you posted.
Our next question comes from Ritu Baral with.
Cowen Your line is now open.
Hey, guys. Thanks for taking the question.
On the pivotal cohort.
What are your powering assumptions around the one to one.
The eight patients randomized one to one you mentioned the primary endpoint is.
Reduction the hours of ventilator support through 24 weeks.
What.
What's your powering and what are your sort of placebo.
Assumptions not placebo, sorry delay treatment control assumptions for what's going to happen to the ventilator support.
Well no surprise the team's done a thoughtful analysis of this and reviewed.
All of the thanks for two sorry for the question.
No surprise teams done a.
Helpful Review of all the data we have today has gotten quite comfortable that.
Eight will power the study adequately to detect a statistic to determine a statistically significant difference.
And.
As far as the controls I mean, we have the benefit of having monitor the controls.
During the early part of the study and of course the data.
As well as anyone and we know that there were no changes in ventilator Tory status and to control patients and so of course, it's logical that one would expect the same.
In the control patients in this study so.
And.
So there is a lot of high degree of confidence about.
Eight as a number to achieve that goal and obviously that's why we settled on the plan and are optimistic about next steps.
Was that was that placebo started delayed treatment assumption was that powered at all by some of the instructor stations were just the.
Just the two patients in Europe .
I don't actually know the answer to that off the top of my head, but I'm not.
I could I'm, certainly happy to follow up and double check but.
Yes, so rather than speculate I guess I can follow up on it but there is no data in any of our.
Work, whether it's in septimus or.
Even where census, or natural history, our medical record review, we did a while back or of course, the ASCO data in those two controlled patients to suggest.
That any patient.
Wood, who would have that untreated without any other outcome, except us remaining on venturi support the whole time from baseline onward.
Got it and then just moving to your potential pump. They study can you just give us some broad strokes outline as to what you think that first clinical study will look like will you be and able to enter.
Pediatric patients immediately will there be.
A biopsy endpoint will there be functional endpoints and when.
Sure its a.
A little early to go into total detail, but I'll I'll share some introductory thoughts and our expectation would be to be able to articulate more details.
Once the Indy is in and cleared and we have any agency feedback so.
But that being said.
It's reasonable we believe to assume that this will be a study that.
More likely than not starts in adults.
But certainly we appreciate the importance of rapidly evolving the program to also treat patients who are suffering from infantile pumping disease, given the medical need so.
But we have a lot of experience and compare on the table. So we have some thoughts and how best to do that but I think starting in adults and no surprise the endpoints are likely to include both.
Biopsy based assessments.
Our ones looking at protein expression GA in this question and glycogen levels.
As well as relevant clinical endpoints, which are reasonably well established in the pump it community from various clinical studies have been done overtime.
A little bit distinct obviously between what one measures in the adult.
Population versus the infantile of course, and that's why those may very well be appropriately studied in separate protocols.
As has also been done in the past so.
So that's probably all I can do for today, but I'm happy to provide more details later in the year as we have any agency feedback on our plans.
Sounds good thanks for taking the questions.
Sure.
Our next question comes from Whitney Ijem with Guggenheim. Your line is now open.
Hi, guys. First question is just on DMD given the vector switch I guess just wondering what.
If any read through there or kind of how you guys are thinking about the read through through the first two MTGE patients that will be treated kind of whats the read through from the data you'll get there as we think about the data from your program and the second question was just going back to the plasma manufacturing.
Can you just kind of remind us the benefit there other than obviously, having control of your own supply are there any financial kind of benefits as we think about Cogs.
Sure Hi, Whitney.
You know I would say.
How we think about the nch versus our product is.
That the Nch data will be interesting and certainly will all take a look at it and learn what we can but in the end it will be a very low and you know it's going to be one or two patients and as Natalie articulated we've made what we feel are our powerful improvements to the construct for product quality.
And productivity in the manufacturing system.
And it sets us up for this template approach for future programs. So.
I would encourage people to think like we do which is that.
The key data to begin interpreting all data data from patients treated with the authentic product.
Over the course of next year.
If there is something interesting to be gleaned from the first couple of patients at nationwide Soviet and we'll talk about it but it feels a bit unlikely to me given the low and some of the product differences.
Sorry second half of the question on the plasma side, there's no question that it's multifaceted positive.
And remember this is particularly critical when you're working neuromuscular diseases and we're working with.
Larger doses of HIV and of course, as we expand into pumping Duchenne Myotonic are beginning to work with larger patient populations and patients who are heavier.
With per kilo dosing so.
The Plaza manufacturing is absolutely about control now we've seen some examples of setbacks for programs because there has been a quality question related to the raw material.
But it's absolutely also about cost.
And we believe this operation is going to pay for itself rapidly.
Given what we see as the cost of working with outside vendors in that arena. So far these days and finally I would say timelines I mean, it's.
It's a long lead time, it's just like trying to book space at a CMO for manufacturing your product and reserving a sweetens and spending money up front, and then hoping everything tracks, okay, and and that it works out to in this case.
It gives us much more certainty over our timelines and ability to hit our program development milestones. So it's really three it's really three things quality fast and confidence in our timelines.
That are behind that investment.
Our next question comes from Steve seat House with Raymond James Your line is now open.
Good afternoon. Thank you.
So given it sounds like the FDA requested a certain design for the 80 132.
Total expansion Gordon you settled on a bit different design details and duration of follow up I apologize if I missed this but I didnt hear what then was the FDA is response or receptivity to your Ultimate study design subsequent to the initial exchange do you have a written agreement on the final protocol or what's your level of confidence that the FDA is amenable to the.
The trial design details that you laid out.
Sure. Thanks, Steve for the question.
We had a whole series of back and forth interactions with both FDA and the European to European largely in the context of scientific advice procedure, but.
Both written and verbal exchanges that sort of guided us to where we landed.
I would say that.
Not surprising to us.
FDA is sort of final agreement to that one can file the BLM is something that they differ to the time when they have the full dataset.
And there is nothing surprising about that to US that's standard course of business for rare disease drug development in particular, where you have a relatively small number of trials and patients treated.
And so but in the end based on our digestion of their feedback through those multiple rounds, we feel very confident.
About our plan and that was part of what I was hopefully able to articulate in the script conversation. There are are written remarks.
That.
When you really dig in and you try to evaluate what the agency is looking for.
With their requests and it really does end up coming down too.
Getting some additional data at that dose studying a meaningful clinical endpoint.
Collecting data in just a reliable and meaningful way so they can.
Believe that it's real and accurate am and of course, they always say they'd like as much as possible. So we really worked very hard to to accommodate all those and so.
Through all that feel a high degree of confidence that in the end, we're going to strike a good we're going put together a big good presentation of data that produces a pottery positive benefit risk ratio, which is another important perspective to keep in mind. This is excellent monetizable or my office, the fatal disease with no treatment and so.
I think in the end, it's going to be a very compelling story and and likely to move forward in a positive manner.
Okay. Thank you and I wanted to ask about good considering the focus of the company now and neuromuscular disease and move into Factorized exon skipping pretty novel approach.
Given the success of Spinraza and SDMA saw Jens by showing that you can target with HIV and SNA pretty effectively and preclinical data that shows factorized Exxon inclusion in essence, they as possible.
Already collaborating with Nch has a history here is SM and appealing indication clinically to you and would there even be freedom to operate with a factorized Exxon inclusion approach there we're interested.
We're certainly excited to go into a vector rise exon skipping and and.
In addition to standard gene replacement as we've done historically and we find that there is a wealth of opportunities out there that are interesting.
But for now I would say that our focus in the near term remains on the pipeline that we've we've recently announced and and executing on pumping into Shannon Myotonic, there's a tremendous amount of opportunity.
Now we feel really good about the.
Progress, we can make and the value we can generate with MTM pump a and.
Duchenne and Myotonic, we're obviously in a position where were really.
Setting up for a very exciting.
2020 in particular.
With the BLM filing and MTM and and the potential for.
Proof of concept data in pump, a and duchenne in the 90 and Myotonic. So.
Plenty of work to do.
Thank you for the questions.
Thank you.
Again, if you have a question. Please press Star then one.
Our next question comes from Jeff.
She Chad Potter gay with H.C. Wainwright. Your line is now open.
Hey, good afternoon, and thank you for taking the questions I've got a couple so just could you walk us through your updated thoughts on the excellent TM addressable commercial opportunity and how do you think the label could play out given that you're enrolling patients primarily under the age of five and what fraction of patients.
Alive over the age of five thanks, so much.
Sure. Thanks for the question.
No meaningful changes from our previously stated commercial guidance, we think that the.
The.
Recent publications about MTM incidence and prevalence.
As well as our own data still guide us to a place where we believe that there was an incident population of several hundred patients in the markets, we would expect to pursue and prevalent population of.
Two or three times that.
And indeed, you're right that we are focused on enrolling patients who are.
Less than five years of age and but that doesn't does cover the majority of empty on patients that being said, we're taking a very thoughtful tied to our.
Commercial preparations and wanting to ensure we have a very.
Robust.
Package of information for future payers to ensure.
Patient access for our treatment access for all patients with NTM and so we're evaluating additional opportunities to.
Collect any data and.
Slightly older patients if that would be helpful to payers. So while we don't have a set plan on that today, but something certainly we're interested in but you can bet that.
As we're looking into next year, we're turning into a very commercial oriented company across the board and and.
And collecting data that supports that story is key to us as you know we've already historically done a lot of work in this regard largely focused on characterizing the burden of MTM.
Which we think will be critical to those future payer conversations and then you combine that with.
Incredible value that we believe are demonstrating with our clinical data both the patients and their caregivers and we feel very good about.
Commercial opportunity as it continues to mature.
And then on the 80 702 program I understand as shown in the clinic, yet, but based on the preclinical data up where do you think dystrophin expression should line up for you guys and given the relatively smaller opportunity the first broad program.
The regulatory path forward does that make the exon skipping approaches in terms of.
Dystrophin expression based.
Filing or the micro dystrophin gene therapy based approach is better it's more functional data. Thanks.
Well.
Seven or two program you know as we previously shared when we announced the program. We're extremely pleased with what was observed in terms of dystrophin expression.
Of.
40 to near normal levels of dystrophin expression across a range of muscle tissues that were sampled in animal studies and importantly, that's 40% to 100% of normal full length dystrophin, not 40% to 100% of a 30% size truncated form of dystrophin.
Which is what one mix with the micro dystrophin programs and that of course is the crux of why we believe we have the potential to be.
Superior safety and efficacy profile over time.
Now that our approach produces a full length or near full length version of the missing protein.
So we believe the preclinical data.
Track very positively and we look forward to studying that in biopsies in the clinical program as well and and sharing that information as soon as we can.
As far as the.
Regulatory approach and.
Template for future programs I mentioned earlier, we believe we can move very efficiently through the other exxon's as far as what endpoints are appropriate to study for approval I think this is a very fluid subject frankly in duchenne.
We read everything that everyone else reads, but.
I think it remains to be seen whether the agency.
I will support approval of these sorts of products on dystrophin expression alone or whether clinical data will be required.
It could actually very I think program to program.
Depending on.
Medical need even within given Exxon So we'll see about that so it's difficult to know, but right. Now we're just intent on finalize our clinical plan and coming up with a thoughtful approach to.
Generating positive safety efficacy data and differentiating our program overtime.
As we go.
Thank you so much.
Thank you.
Our next question comes from Raju Prasad with William Blair. Your line is now open.
Hi, there guys. This is Sammy honor for Raj Congrats on all the progress.
I had a question jumping off the commercialization strategy for 81, three Q are you guys looking to partner with any kind of specialist centres in order to recruit patients.
To sorry to recruit patients for.
Clinical work or.
Four to support commercialization I'm not sure I understood support commercialization.
You know I don't.
Have a good answer for that today honestly I think.
Commercial team is actively working on all the sort of key planning activities. So.
It's an interesting question I don't have a good answer for you today, but happy to talk more about it in the future in particular as the commercial team.
I'll begin to refine our strategy for ensuring.
Rapid penetration of the market no surprise.
Things are moving quickly, but were particularly focused in efforts to find patients, which is really I think what you're getting at as well as to continue to build our story of value and preparation for conversations with payers. So.
But we'll certainly have more to share on this in the coming months, obviously as we approach the BLA filing and future commercialization.
Great. Thanks, and then just one more did the FDA and EMA may seen over all pleased with the current efficacy and durability data to date.
And do you think they were just looking for a maintenance of what has been seen previously with a greater number of patients.
I think that's a fair conclusion I mean.
Certainly you wouldn't have gotten ormat and prime designation is as we did if they werent very encouraged by the.
Early data so that was the first step in recognizing that they believe the product has great potential.
And Arctic away from the interactions was was also that they they see the potential there are very engaged responsive.
And.
But in the end absolutely as we've said in this call and.
As you just said I think it's a matter of.
Of getting a bit more data in patients treated at the proposed commercial dose.
And ensuring that we're focused on an endpoint. We all agree is clinically meaningful and gathering those data in as robust a manner as possible and none of that is a surprise and.
And so.
We've put together a good plan that accommodates all that.
And we are confident that it's going to result in a vilifying mid next year as we said so.
I hope that helps.
Yes. Thank you.
Right.
Our next question comes from Matthew Liz Cheney with BMO capital markets. Your line is now open.
Hi, guys, great. Thanks for taking the questions.
A couple from me if I may so first on MTM.
We've obviously heard a lot about the primary analysis for the pivotal expansion cohort and I was just wondering if there had been any addition or changes to any of the secondary endpoints that might be worth.
Noting at this point and then second question would be on pump Hey.
Given that you're going to be filing the R&D this quarter.
Can you talk just a little bit about where you guys are in terms of trial set up whether its site selection.
For Col involve Matt just a little bit of color. There would be helpful. And then last question would be just as a as a point of clarification, Matt since I found a little bit like you're hedging with regards to the DMD and c.
Patients that are treated with the nch.
Construct is the plan to.
Share those data not sure those data are only share.
There's something I guess unexpected or on toward that should come out of them. Thank you.
Sure Hi, Matthew Thanks for the questions.
Yes, glad you asked about the secondary endpoint question on M.T.M. So.
Through our conversations I would say that the both authorities zeroed in on.
Both the.
Ventilator.
Time on time on Ventas as a key clinical endpoint, obviously, we land on that as our primary endpoint, but they're also really enthusiastic about.
Achievement of key motor milestones.
Which is something that we'd heard and seen observed as important also in the SDMA clinical gene therapy clinical trial works it wasn't a surprise to us.
So out of that we chose to include as a secondary endpoint.
The ability to sit on assisted for 30 seconds.
Which is obviously a.
Basic and really important motor milestone for kids is age. So that is in fact, a secondary endpoint, it's something that.
We had a lot of success achieving and the patients. So early in the study. So again, it's something we feel very confident that we can we can meet and we believe it will be strongly supportive. We also certainly believe in the biopsy data as strongly supportive everyone's familiar with the fact that we have.
Hi, evidence of VC and protein expression near or above normal levels and significantly normalized.
As the pathology and so that's all very supportive data to that's key to the pivotal expansion cohort study plan.
So.
As far as pump a yeah very active on trial preparations.
Again on multiple numbers the team here have worked on pump a in different forms and.
And then we know the community and so we've been engaged with the K wells for quite some time actually they've been in the background guiding some of our work in the program.
And so we feel good about that and and.
Forward to sharing more details about our how does the protocol, but also operational details, but I believe we'll be able to get up and running efficiently.
And then finally on Duchenne, yes, I, certainly didnt mean to sound hedging I was just trying to be realistic that I think data from one patient with a one or two patients with a product thats.
Going to be outdated quickly.
I just wasn't sure how much we'd be able to rely on that and talk about that but we certainly if we see something.
Interesting that we feel is important to share with the community you can bet that we will share it but I just want to be straightforward about you know I think how to think about the program more holistically and it's likely that the data from our products are manufactured by our process will be really what we should be evaluating for the future of the program and the safety and efficacy of that product.
Perfect. Thanks, so much for taking the questions.
Sure.
Thanks.
And our next question comes from Difei Yang with Mizuho Securities. Your line is now open.
Hi, good afternoon, and thanks for taking my.
Quick question, so with regards to Q1 30.
Thank you.
Matt do you mind, if we were going to see deals to ventilate.
Utilization, what typically what timeframe are we going to observe that post treatment and then secondarily with regards to onset of action with the higher dose.
Do you expect a.
Acceleration onset of.
All said outflow seem this reduction off ventilator use.
Sure Hi, thanks for the questions.
You know.
When one reviews the.
Data from the study to date, we see evidence of improvement in respiratory function very rapidly.
First and foremost through in a matter of weeks.
Through first patient's ability to control their airway.
On their own to then improvements in the maximum inspiratory pressure test that we've been doing for some time and then that in turn leads investigators to get comfortable.
Reducing time on event so.
There's plenty of evidence from a number of patients that you see improvements and reductions in time on a ventilator over the course of.
Of the first 12 to 24 weeks of the study and so that's why when you look at the data we're very comfortable that at 24 weeks, we're likely to hit this endpoint.
And to truly distinguish a statistically significant difference from the controls.
Who are as we said earlier.
Extremely unlikely to change at all from baseline and the requirement that all patients have a baseline which has to be.
Mechanically supported ventilated for 20 to 24 hours a day so.
So there's reason to be very optimistic that at 24 weeks, we'll hit that endpoint.
As far as the higher dose in a faster onset what we observed in it was a part of the decision making process for choosing 314.
We did not see a meaningful difference in the safety profile. The two doses nor the efficacy profile when measured by the key clinical measures like chop intend or.
Even ventilator reduction.
Where do you started to see differences was in the tissue in the biopsies.
And you certainly saw that higher levels of protein activity, but really in the midst of pathology. What we felt we observed was.
That you've got a little closer even to normal over the lower dose and that seemed to happen a bit faster.
And so.
So that's the only area, where I thought we were able to distinguish a difference between the two doses and that can certainly contributed to our decision to go with the higher dose I'm not sure that one could could ever see a difference a meaningful difference when it comes to ventilator reduction between the two doses I don't know that that's practical with that end point, but.
Anyway, we feel really good about the high dose for all the reasons that I think we've talked about before.
And.
And of course, it also has a little bit of an eye towards long term durability of effect and that's the goal we all have as well so.
I hope that helps.
Okay. Thank you.
At this time Im showing no further questions I would like to turn the call back over to Mr., Matt Paterson for any closing remarks.
Great. Thank you again, everyone for your participation and for the opportunity to share our updates looking forward to a busy remainder of 2019 and to updating you on our progress against soon.
Operator that concludes our call today.
Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program you may now disconnect everyone have a great day.