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Good afternoon, ladies and gentlemen, and welcome to the Audentes Therapeutics’ First Quarter 2019 Earnings Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions] 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 Audentes. Please go ahead.
Thank you, operator, and good afternoon, everyone. Just after market close today, we issued a press release with earnings and operating results for the first quarter 2019. The press release and live webcast access are available on the Investors and Media section of the Audentes website at www.audentestx.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 Holles, President and Chief Operating Officer; and Tom Soloway, Executive Vice President and Chief Financial Officer.
Before we begin with prepared comments from our team, I would 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 Company's SEC filings. The content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 7, 2019. Audentes undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of today's call, except as required by law.
I would now like to turn the call over to Matt Patterson, Chairman and Chief Executive Officer. Matt?
Thank you, Andrew, and good afternoon everyone. 2019 has already been a year of meaningful accomplishment for Audentes and I'm very pleased today to highlight the progress we have made across our pipeline and to share with you the important milestones we anticipate for the remainder of the year. Starting with AT132, our lead products candidate for the treatment of XLMTM, just last week we shared a positive clinical data update at the 22nd Annual Meeting of the American Society of Gene and Cell Therapy in Washington DC.
The latest safety and efficacy data from ASPIRO included 48-weeks of follow-up for all patients in dose Cohort 1 at the 1x1014 vector genomes per kilogram dose and 24-weeks for all treated patients in dose Cohort 2 treated 3x1014 vector genomes per kilo. The data showed progressive and sustained improvements in neuromuscular function in both dose cohorts with continued corresponding achievement of clinically meaningful motor milestones.
Respiratory outcomes are significantly improved in all patients and most notably for patients are completely weaned off of mechanical ventilatory support with all other treated patients demonstrating clinically meaningful reductions and ventilator use. Muscle biopsy data show evidence of robust dose dependent transduction, transcription and protein expression across both of dose cohorts.
All biopsies also show marked improvement in histopathological markers of disease with a trend towards continued improvement in the Cohort 1 patient samples from 24-week to 48-week time points and evidence of more rapid pathological improvement by week 24 in the Cohort 2 biopsy samples. And importantly AT132 continues to be generally well tolerated across both of dose cohorts with no clinically meaningful safety differences between doses to date. All reported serious adverse events were successfully managed and patients have shown no evidence of clinical compromise.
As we announced earlier this year, our plan is to dose an additional three to five patients as part of a Cohort 2 expansion. Enrollment is ongoing and we plan our next clinical update to occur at the World Muscle Society Annual Meeting in early October in Copenhagen, Denmark. As it relates to the next steps for the development of AT132, we plan to provide an updated data package to the FDA including a recommendation on optimal dose in the coming weeks and we are on track to provide an update on license application submission plans for AT132 in the third quarter of 2019.
Turning to the important subject of manufacturing, as many of you know, we invested over four years ago in our own internal large scale cGMP manufacturing operation. Importantly, since the beginning of the AT132 clinical program, we have used the same process and scale of manufacturing that we now propose for commercialization, a first within the neuromuscular gene therapy field. This combined with the significant investments we've made in process and analytical development fill-finish and QC testing means that we are uniquely well situated for our CMC package to be BLA ready on timelines consistent with our clinical progress.
We were also pleased to announce just a few weeks ago the launch of a new state-of-the-art internal cGMP plasmid manufacturing facility to improve control over our supply chain, reduce costs and production timelines for this key starting material and accelerate the rapid advancement of our neuromuscular programs from preclinical development through commercialization. Leveraging our AAV manufacturing leadership for rare neuromuscular diseases continues to be a cornerstone of our strategy for long-term value creation.
And as a final important comment on the AT132 program, I would like to recognize and thank our internal team, medical and scientific collaborators and most importantly the patients and families that have supported and participated in INCEPTUS and ASPIRO for the years of effort that have gone into advancing the program to this point. We are privileged to be working with and alongside of the XLMTM community and remain single mindedly focused on advancing this important therapy to market as rapidly as possible.
Turning now to our Pompe disease program, we are very pleased with our continued progress towards our Q3 IND filing for AT845. Importantly, we have recently successfully completed a non-GLP NHP study in which AT845 demonstrated a clean safety profile. Based on these encouraging results, pathology and mouse dose ranging studies are both underway and IND preparations are on track. We continue to believe that leveraging our deep expertise in systemic administration of AAV8 to drive broad tissue transduction and expression provides us with a highly differentiated approach.
We believe AT845 is the only Pompe gene therapy in development today, which is delivering and expressing GAA directly in the tissues affected by the disease. This potentially best-in-class approach stands in contrast to both enzyme replacement therapies and liver directed gene therapy candidates that rely on an inherently inefficient cellular uptake mechanism of GAA from plasma to deliver the enzyme to its site of action. We are encouraged by the recent progress in our Pompe program and look forward to keeping you apprised of our continued progress in the coming months.
Turning now to our Crigler-Najjar and CASQ2-CPVT programs subsequent to the announcement of our recent pipeline expansion, we have completed a strategic review of our product candidates with the goal of focusing internal efforts and resources on those programs that have the potential to provide the greatest long-term value for patients and shareholders. While we continue to believe that both programs remain excellent targets for gene therapy, we have made the decision to focus future efforts on our expanding pipeline in neuromuscular diseases and plan to explore out-licensing opportunities to advance the important work we have completed to date in Crigler and CPVT.
With that forward view towards our focus on neuromuscular diseases, last month we were pleased to announce the expansion of our AAV technology platform and pipeline and a new collaboration with nationwide children's hospital to develop treatments for Duchenne muscular dystrophy and myotonic dystrophy type 1. This new work advances beyond traditional gene replacement combining the delivery power of AAV with the mechanistic precision of antisense oligonucleotide to develop best-in-class genetic medicines for these devastating diseases. In DMD, we are advancing three vectorized exon skipping product candidates, which together have the potential to advance more than 25% of the DMD patient population.
We anticipate commencing a Phase 1/2 clinical study for the most advanced of these product candidates, AT702, in the fourth quarter of this year and planned to utilize the same vector backbone for the subsequent programs, which we believe will enable accelerated preclinical development timelines for AT751 and AT753 as well as future products. And in myotonic dystrophy, we are evaluating both vectorized RNA knockdown and vectorized exon skipping approaches, each of which have been mechanistically validated to block the accumulation of toxic RNA and affected cells.
We expect an IND for our product candidate AT466 to be filed in 2020. And importantly, we should note that we maintained global commercial rights to these programs as is the case across our entire portfolio of product candidates. Finally, we continue to maintain a strong balance sheet with $375 million of cash, cash equivalents and marketable securities at March 31st, which is expected to fund the operations into 2021 and positions us to make a meaningful progress towards our goal of providing transformative AAV based genetic medicines to patients living with serious rare neuromuscular diseases. We are excited by the multiple upcoming milestones for Audentes and look forward to sharing these updates in the coming months.
That concludes our prepared comments for today's call. Operator, you may now open the line for questions.
[Operator Instructions] Our first question or comment comes from the line of Anupam Rama from J.P. Morgan. Your line is open.
Hey, guys. Thanks for taking the question and congrats on all the progress. I was just wondering on the Crigler-Najjar programs specifically, could you walk us through some of the key levers and the decision to sort of out-license that program? Thanks so much.
I think, Anupam, thanks for the question first of all. And look I think with time, we have grown in confidence and appreciation of the knowledge and experience we've got in the neuromuscular gene therapy space. The experience of the MTM program on clinical execution and now on regulatory issues as we approach license applications is extremely powerful. And when you combine that with the investment we've made in manufacturing, but not just manufacturing, but the entire technical operations required to manufacture products of the highest quality and to do so in particular at – when high quantities necessary for neuromuscular diseases, we just realized that that is the source of greatest potential impact for us to have on patients and for value for our shareholders.
So it wasn't an easy decision because as we said just a minute ago, we still believe strongly that Crigler has great potential, but it simply comes down to focusing the resources of our team and our shareholders and we feel that we can have the maximum impact with a focus on neuromuscular. And that's what we're going to do. In the meantime, we will work to ensure that we get as much financial benefit out of an agreement with other parties on those programs as possible, so that we can recuperate our investment and then some – and ensure that we work with someone who's going to help make those products available to patients because we do believe that they will benefit from those products in the future.
Great, thanks so much for taking my question.
Yeah, thanks.
Thank you. Our next question or comment comes from the line of Chris Raymond from Piper Jaffray. Your line is open.
Hey, thanks. It's Nicole Gabreski on for Chris, so just two quick questions, one on AT466. So here you are evaluating two approaches for DM1. Can you just remind us is there the potential to use both of these modalities into the clinic? And then just second following up on the BLA readiness for XLMTM, maybe just help us to understand where you're at in the – at this point in the manufacturing process? And what gives you confidence that this won't be a rate limiting factor for regulatory filing? Thanks.
Sure. Thanks, Nicole. So I think the vision, right, it's a little early to say definitively, but our current vision is that we will research both approaches and myotonic and end up choosing the approach that we feel of is the greatest potential as the one to advanced into the clinic. I suppose it's theoretically possible that we could be so intrigued by both that we would consider clinical development for both, but I think that's unlikely. So that's our current state of mind on it. And we're looking forward to a continued research to evaluate both and we'll see what looks most promising.
And – but in either case with either approach, we feel very good about the guidance to be at an IND in 2020. As far as AT132 for MTM and BLA readiness, I think our confidence on this is, is simply driven by a few factors. So first and foremost, what I mentioned earlier, which is the fact that we've used the same process, same scale, same facility here internally all along to make our material. And we've invested heavily in all these other aspects of tech ops, including all the analytical methods, for example. And so that gives us great confidence. The fact that we own all the internally and that we can work on it together as a team every single day internally is a huge source of confidence as well.
So, of course, we did have an interaction. We started interacting with the agency late last year after the RMAT designation. And we had our first interaction, which has led to additional interactions, which has included some opportunity to have dialogue around CMC issues, certainly not a complete conversation yet. It's an iterative process with some back and forth just like on the clinical, but we feel quite good about where that stands today both in the context of the United States feedback as well as that of the European authorities. So, hopefully that gives you a little color.
I should also say with optimism towards our clinical progress over the course of this year, we began investing in the process validation and facility validation activities, Q4 of last year. And it was a driver for why we wanted to raise money last fall as it was to be in a position to begin investing in commercial oriented activities like that. So for all those reasons we're comfortable with where we stand today.
Thank you.
Sure.
Thank you. Our next question or comment comes from the line of Ying Huang from Bank of America Merrill Lynch. Your line is open.
Hi, guys. It's Aspen on for Ying. Thanks for taking my questions, just one on MTM and one on DMD. So could you maybe discuss what – the disconnect you may be seeing between the superior biopsy data from Cohort 2 and some of the, I guess, more comparable functional scores that you're seeing compared to Cohort 1 for MTM. And then for DMD, what's the – can you discuss kind of broadly what the strategy is behind for the product given that it's likely not to be the first to market? Thank you.
Sure, thanks for the questions. With regards to AT132, I mean, look we're thrilled with the profile of the product that both doses, safety and efficacy and in the biopsies. The biopsy differences are really interesting. At the higher dose, as you know, we see even higher copy number and higher levels of protein expression and it appears possibly an even faster rate of correction attitude in the histology after six months compared to the first cohort. As far as translating that to the clinical measures, look the clinical measures are outstanding measures, but there’re some inherent variability that as always the factor in those tools. And in particular, when you're pushing into the normal ranges for these kids in both cohorts, it's difficult to detect differences between the doses.
But the good news is that the data produced extremely clinically meaningful changes at both doses according to all those different measures, including the CHOP INTEND, the motor milestones on the neuromuscular side as well as the MIP and ventilator requirement on the respiratory side. So I wouldn't read into that too much. I think it's interesting the biopsy data and for those reasons – of those results we do lean a bit more towards the 3E14 dose today as the dose of choice for the future, but we're still finishing that conversation and want to provide our final recommendation to the agency in the coming weeks, as I said. And so, we'll be able to share that in more final decision form soon probably in the context of sharing our Q3 update on our plans for next steps prior to BLA and MAA filings.
On the DMD side, look we feel strongly that our approach has the potential to be best-in-class and to produce the best safety and efficacy for patients with Duchenne over time. And that’s driven by the fact that – in our approach we are replacing our normal or near normal form of the dystrophin protein. And that can be contrasted with the microdystrophin approaches, which are producing a protein that's about 30% of the size of normal dystrophin. And while the initial data from those programs are interesting, we believe it's also early and that time will tell as more clinical data and safety data are evaluated in a wider range of patients with Duchenne. So, we feel very strongly about our approach and have the potential.
As far as execution, we feel very good about our ability to execute rapidly given our experience in MTM, our manufacturing capability in particular. And the fact that – as I've mentioned a couple times, we do feel we can take a very template approach to Duchenne. As I mentioned in the call, it's really fascinating to think about, but you're really using the same basic construct and each product meaning AAV8 with the same promoter, the same small nuclear RNA sequence, you just simply changing the antisense sequence that you're specifically required to use for whatever exon you're skipping.
And so it's a very modest difference. And so with that template approach, we believe we can very efficiently perform preclinical development activities and thus gets IND and get into the clinic rapidly in each of these programs. So in the end, well, time will tell. We feel the differences in the timelines, potentially getting to market, or maybe not as great as people may think. And we're looking forward to next steps on the program.
Thank you.
Our next question or comment comes from the line of Joseph Schwartz from SVB Leerink. Your line is open.
Hi, good afternoon guys. Thanks for taking our questions. This is Dae Ha diving in for Joe. So belated congrats on the data last week at ASGCT. Now looking forward to the next update. Not, you were just talking about, the data package submission in second quarter meeting with the regulators in third quarter, and then the WMS update in October. So can you set the stage for what investors should expect at a World Muscle Society Conference. And when you meet with the regulators in third quarter, what data will they see given that World Muscle is in fourth quarter, and then I've got a follow-up. Thanks.
Sure. So, let's see – let's try to take them in order. So I don't have a specific answer today, on what exact data we'll have at World Muscle Society. Obviously, it will be longer term data and all the patients treated to date. And by then we may have data from the new patients being enrolled today into that cohort to expansion. But as far as the exact number of weeks, etcetera, we're just going to have to defer and share that later when it's clear, when we'll have the data cuts complete. As far as next steps with FDA in particular, so our vision is to, internally with our experts, choose which of the two doses we feel is optimal, and to submit that information with all the updated data, that was just presented last week to the agency.
As a reminder, the last data update that the agency saw was from the World Muscle Society update in October last year. That was, what we had in the time and you were requesting the meeting. And, of course the way this works is you submit the information with a request for a meeting and that meeting gets scheduled usually within a couple months. And that's how, again you get to the discussion and that's that. And so it's not real time as far as providing data updates to the agency, as much as one might think. So in this case, we will provide the updated data from last week to the agency in the coming weeks, along with that dose recommendation, it's a substantial amount of new data, of course, since last fall. So we're looking forward to sharing that. And we believe that will facilitate – in some further discussion with them, about plans for next steps in the program and specifically, what makes sense for additional work prior to a BLA filing.
And that’s – we had a good first conversation in that regard earlier this year, and we're looking forward to further interactions with them, and we feel good about our guidance that in Q3, we will provide an update to everyone with our plans. And what we feel will be necessary prior to the BLA filing. I do expect for clarity for people that – that's likely to be a press release of its own in a conference call where we can answer questions. So that's our current working hypothesis anyway. Hopefully that helps.
Great. Yes, it's very helpful. And next question is sort of shifting gears to manufacturing. So at ASGCT, I noticed that there was quite a significant interest in the actual manufacturing procedures and the vendors. So you mentioned earlier in the call the strategy and the force that you had to internally invest for AT132 development, but now that you're setting your sights on larger, less rare indications in the neuromuscular space. A two part question. How are you thinking about scaling up, and briefly remind us where you are now and when is it appropriate to implement a scale up and to that effect, Tom, Ultragenyx last night spoke of a CapEx commitment to an in-house manufacturing facility. You already have that obviously, but any near-to-mid term CapEx that you guys are thinking about committing to accommodate these multiple assets. Thanks.
Sure. Good question. Thanks. So for a reminder on manufacturing where we are today, is that we manufacture in a mammalian system with 293 cells, specifically in a serum-free suspension culture, which we believe to be extremely robust, and producing material of outstanding quality, which we believe you see reflected in our clinical data in the biopsies in particular. And we manufacture in two 500 liter bioreactors. And, so that's our current facility and capacity, specifically though that capacity translates to enough to meet the global commercial demands for MTM, as well as the near term clinical needs for the other pipeline programs.
So we're in good shape as to where we stand today, and that's a reminder of our current scale. As far as the future. It's a hot topic around here. We're very optimistic about the new programs. And so, and certainly especially as we go towards commercial with MTM, we're going to be very thoughtful about supply. The good news is that within our current existing facility, we have the ability to add 8,000 liters of additional capacity in our existing lease footprint. And so that is an opportunity that sits right in front of us. But in addition to that, we're bound to be looking at options for future redundancies in manufacturing to ensure appropriate management of commercial success.
And so, but that's a moving subject right now. I don't think we have a real clarity to provide you today, but it's certainly something that's on our mind and we're looking forward to sharing updates over the course of the year. I'm not sure if Tom on the CapEx, I don't think there's anything to say today on CapEx, certainly there would be some CapEx spending when we get to the point of pulling the trigger on either the expansion in our current facility or adding a second site in support of our commercial efforts. But we don't have information to share and immediate plan for that for you today.
Great. Thanks for answering the question and congrats on all the progress.
Yes, thank you.
Thank you. Our next question or comment comes from the line of Ritu Baral from Cowen. Your line is open.
Good afternoon guys. Thanks for taking the question. My first question is on the Pompe program and specifically could you explain to us the difference between, I guess the GLP mouse data that was done with the new construct. I believe it was the non-GLP monkey, and then the upcoming GLP dose ranging study in mouse that still remains to be done, but what are the differences between GLP and non-GLP in that context?
Sure. Thanks for the question, Ritu. And yes, this is an important piece of new information for the Pompe program. So what we did is, an initial study in primates, that involved not as many, animals as in a full GLP toxicology study. And also – the difference between GLP and non-GLP often comes down to paperwork and documentation and quality assurance oversight, but from a data analysis perspective, it's very similar. And so in this case, the importance here, of course for those that know that Pompe story well is that, last year when we ran into a challenge with our previous construct, it was in the primates were we saw a safety signal that gave us concern.
And of course, as we've talked about over course of the year, we made a change to the products and, we were been encouraged over the course of the year by our work in particular in the mouse model, which we did with an eye towards the potential safety signal. But now that we've got primate data. It’s – we're very encouraged to meet that milestone and to be able to basically go into our final toxicology work with an even higher degree of confidence that, that study's going to be clean and supportive, and that therefore we're well on track for the IND. So it's another very encouraging step forward for the program, and our approach specifically to Pompe, so hopefully that helps.
Good guys. So you have GLP mouse [indiscernible]. Do you have any more primate studies, GLP primate study to do before you file the IND?
Sorry, yes. So there are two final studies that are ongoing in parallel. One is the GLP toxicology study in primates, and the other is a final dose ranging in the mouse model. And those have already been initiated and are ongoing. And those will be the final pieces required for the IND. The non-GLP primate study that we referred to as something that we did this spring and completed recently and we thought it was important to share with the community today.
Got it. And will you be presenting on any of this GLP primate data at World Muscle for any meeting going forward?
No current plan to share data from either the primate studies or the mouse studies, that certainly could change. But as of today, no plans to present at World Muscle Society in this fall.
Got it. And then moving to the manufacturing of the Pompe product and I think your answer to Dae Ha’s question, I think, I at least inferred that you don't currently have capacity to manufacture commercial sale products for Pompe at the time that you might start dosing early next year. What are your options as far as bridging studies or scale up for the Pompe commercial product as you look at your current capacity?
Well, yes. So we have the current capacity as I said, meets the global need for MTM in the near term clinical needs for Pompe, Duchenne, myotonic. And, but certainly as we see those programs progress and especially with initial data in hand, it will be very happy to invest in additional capacity. And as I said, that could very well be just adding within the existing lease footprint of our current facility in South San Francisco or a separate location, which also could serve as redundant manufacturing for commercialization for all of our programs. As far as the scale, I don't envision a change in the process.
We're very happy with the process. And as far as scale, we are going to evaluate the potential for going to larger scale from the current 500 liter, but it's certainly also possible that we will stay at the 500, and add 500 liter bioreactors as our first step into adding capacity, which would require no comparability or any other fundamental work to address changes in manufacturing. So we're very well positioned and have optionality there to add that capacity when the time is right and to do so in a manner that doesn't give us a regulatory headache.
Got it. Thanks for the taking the question.
Sure.
Our next question or comment comes from the line of Whitney Ijem from Guggenheim Securities. Your line is open.
Hey guys, thanks for taking the questions. I wanted to go back to the ASGCT, XLMTM update. And see if you – can you provide me in protein expression numbers for the biopsies from Cohort 1 at 24-weeks and 48-weeks? I think median was presented at ASGCT. And then as a follow-up, I’m wondering if you can help us to understand how should – we should be thinking about the variability of protein expression across different muscles maybe and over time? And asking in the context of what looks like a drop maybe in terms of protein expression from about 50% at 24-weeks to maybe 5% or 10% at 48-weeks in a couple of patients. Also just try and get some more color there.
Thanks, Whitney, for the question. Certainly for new numbers that were not in the presentation from last week, I'll have to – we'll have to get back to you on that. I don't have that sort of information at my fingertips here. As far as the variability between different muscles, that's something important for everyone to note is that, biopsy isn't inherently variable assessment, hence you're taking, in this case a sizeable amount of tissue from the patient. And so in little kids, of course you need to do that from different locations. We do a baseline and week 24 and a work week, 48 biopsies. So we're doing that from a different location in each case, which is just the simple practical reality of it.
And so, it's inevitable that there'll be some variability between muscle groups. And we reviewed the data of the vector copy number mRNA and protein expression, in great detail with outside experts including my father who you met last week. But we have an entire team of muscle pathologists to read these things in a blinded fashion, and look at those data with us. And, their interpretation was that – there's no meaningful differences like the ones that you're sort of speculating on there and that protein numbers that doesn't resonate with me, the one, the specific one you mentioned. So we'll have to follow-up and talk about exactly what you're looking at there.
But we received a universally positive feedback from the experts about the data we were seeing and then of course, how it translates to clinical outcomes. So we feel really great about the biopsies and especially learning from those experts in their interpretation of it. So, but we'll be happy to follow-up with you after today's call to try to answer some of the other questions that you mentioned.
Okay, great. Thank you.
Sure.
Our next question or comment comes from the line of Debjit Chattopadhyay from H.C. Wainwright. Your line is open.
Hey, good afternoon and thank you for taking the questions. So on the Pompe program, is the understanding currently that you could overcome, especially in older patients, anti-GAA antibodies, bit of high enough expression off the protein in the liver with a very strong liver specific promoter?
Sorry. Overcome the anti-GAA antibodies in older patients and that's…
Well, I mean…
Say the question one more time, make sure I understood it.
Yes. So antibodies to enzyme replacement therapies are pretty common on Pompe, right. So I'm just wondering if you eventually venture into older patients as opposed to in Infantile-onset Pompe disease. And I believe you have a dual promoter strategy. So I believe then the one promoter is probably very liver specific to drive very high expression on GAA in the liver. Is that the – is the thinking behind is very high expression with a very strong promoter can overcome that antibodies to GAA?
So I just want to caution you. I think you may recall 2018, we talked about a dual promoter approach that included a muscle specific promoter, but one with a liver enhancer element, which at the time we theorized would be a good option to go forward. And it was with that construct that we ran into challenges with a safety signal in the non-human primates. Now we haven't elaborated on exactly what aspect of that product we believe caused that safety signal, but we did change the promoter with the new construct. So I cannot confirm for you that there's any liver directed expression with the new construct. And I would highlight for you what we've said consistently, which is that our focus is to use systemic administration to transduce muscle and neuronal tissue and express the GAA directly in those tissues. We do not believe that a majority of GAA expression from the liver is likely to produce the optimal outcome in patients.
So hopefully that's some clarity or some. I hope that's helpful with regards to the product just to make sure you recall the history. And then otherwise, as far as the patient population, we certainly are very familiar with the state of the union in Pompe disease and patients who've been on ERT. We are not significantly concerned about the ability of our approach to be effective and safe in patients who have some preexisting antibody levels. The exact entry criteria we use for our clinical trial, it's still something that's being finalized with our experts. So that may get factored in that to some degree, but right now we're not overly concerned about that aspect of it.
And also for clarity, I do expect that our initial clinical efforts are more likely to start in older Pompe patients and transition to include the very young Pompe patients who are severely affected over time. So, hopefully, I've done okay answering your questions there.
Got it. Thank you so much.
Sure.
Thank you. Our next question or comment comes from the line of Raju Prasad from William Blair. Your line is open.
Thanks for taking my question. Just a follow up on 845, did you evaluate multiple doses in the non-GLP tox study. And if so, how do those kind of correlates kind of on a general basis with the doses that you use for the previous construct? Thanks.
Yes, thanks for asking the question. We did evaluate multiple doses in the non-GLP safety study. And while we're choosing to not go into what exact doses those were, they certainly were relevant to the expected ranges that we would expect to go into in both our toxicology study and then – and of course the support of our vision for the clinical trial. So – yeah, so I think that was the question. Hopefully that answered it.
Yes, great. Yeah, thanks. And then I apologize, I may have missed it in the prepared remarks, but can you just mention what the strategic review on CASQ2-CPVT that program and your thoughts there moving forward.
Sure. CPVT, we haven't spoken much about it as a group in a while, but for those that know the history of it, it was a very compelling preclinical dataset. The IND was filed and cleared last year, but we chose to not advance rapidly and do a clinical trial because as we researched the indication further, we struggled to identify as many patients living with the disease as we expected, which was very surprising given that usually it's the other way around where you end up finding more patients over time with a rare disease than what was initially speculated on in the limited literature that exists.
So while that was of course very disappointing, it was the reality. And in parallel with that assessment, we were evaluating new and interesting opportunities. And over time they just became a more compelling area of focus for the company. And so in that regard it’s sort of similar to the Crigler decision in that based on the experience and expertise we have in place in the neuromuscular space and the capabilities on manufacturing in particular.
We just feel it's better to focus on those indications. And that's why we're talking about Duchenne and myotonic and Pompe as our next clinical programs instead of Crigler and CPVT. And we think that's going to benefit the broadest number of patients and our shareholders. And so, we're looking forward to that. And like I said, we’ll work hard to find good homes for Crigler and CPVT because we think they have a very good potential as gene therapy products.
Great, thanks. And then just one last one, you’ve always talked about bringing plasmid manufacturing in-house. It might be [indiscernible] first companies that have done that so far. Do you have any kind of general numbers you can put around? How much you might be able to save on – say on a per batch basis or per patient basis based on bringing plasmid GMP manufacturing in-house versus using a CRO or CDMO?
Probably not surprisingly, no. I don't have specific numbers of that regard that I can share with you, but I can assure you and everyone else that we feel this is a very powerful investment and capability for the company, especially working in the neuromuscular diseases. The amount of plasmid required to be successful in these indications is striking. And the cost of that – and the timelines associated with getting that from what has historically been largely a single supplier is just the risk profile that we were no longer willing to accept for the longer term success of the business.
So we're really thrilled to take more control over that aspect of our work and feel that it'll end up resulting in a better chance to hit our timelines, to move the whole pipeline forward, to keep costs down and maintain quality of our products. And so, I think that's going to be a powerful investment over time. And I should say, I think it's going to pay for itself very rapidly, very rapidly. So…
Great, yeah, I agreed on that aspect. Just for my understanding the plasmid was or is the most expensive part of our gene therapy. Is that's fair to say?
Yes, the raw material, there's no question it is the most expensive.
Great, thank you.
Yeah.
Thank you. Our next question or comment comes from the line of Matthew Luchini from BMO. Your line is open.
Hi, this is [indiscernible] on for Matthew. Just two questions. For Crigler-Najjar, have you had any interest in the product? And did that help you push – push towards the out-licensing decision. And the second one is on AT466. I know it's early, but given that there's a wide range of disease severity for DM1. Can you discuss your thoughts on patient selection? Is there like a portion of patients too sick for the therapy or not sick enough? Thanks.
Sure. Thanks for the question. I would say, we believe there are parties interested in the Crigler program, but we've only very recently made that decision official, obviously, sharing it publicly today. So those conversations are a bit early, but I have optimism that there will be multiple interested parties because like I said, I think it has great potential and we've identified patients. And so while it may not be the perfect strategic fit for us as a company, I believe it will be for another party. So we look forward to those discussions. The second question is difficult to answer today. I think we don't yet have a refined clinical vision for our first trial in myotonic.
Your point is well taken about the disease, but we really need some additional data from our preclinical work to first guide our understanding of our approach and where we can have the most impact and then have the right pre-IND discussions with the authorities to confirm that they're supportive of our initial vision. So I don't have an answer for you today, but certainly look forward to that conversation as the year progresses and we get closer to an IND next year.
Okay, thank you.
Sure.
Thank you. [Operator Instructions] Our next question or comment comes from the line of Difei Yang from Mizuho. Your line is open.
Hi, good afternoon guys. This is Alex on for Difei. Thank you for taking the question. I have a question on Pompe. Could you maybe comment on how an AAV approach might be differentiated from a lentiviral approach?
Sure. So, it's an AAV approach. In this case involves a single approximately one hour intravenous infusion, which we believe will result in a transduction of the key tissues affected by the disease, muscle in particular, and the production of the GAA protein in that tissue, where we believe will have maximum impact and these are the tissues affected by Pompe disease. And we've shown with our work in MTM that that's a highly credible approach. And so we're very optimistic about that in Pompe disease. A lentiviral approach as ex vivo gene therapy in this case.
So, we're extracting cells from the patient and with some conditioning ex vivo and the use of the lentiviral vector. You're inserting the GAA gene and then you’re re-implanting those cells in essentially a bone marrow transplant procedure. So, certainly, a lot of interesting and exciting data in ex vivo gene therapy for multiple indications in development and approaching commercialization and we wish our colleague companies well in that regard, but in the case of Pompe disease, we feel that the AAV approach is likely to be the superior approach. And so, that's why we're focused on it.
Okay, thank you. And then, just related to your strategy in DMD, are you aware of any other vectorized exon skipping approaches being developed, not in DMD, but in other gene therapy indications?
Other vectorized exon skipping, I am not aware specifically. There are other vectorized antisense generally using different forms of RNA to produce clinical benefit. And indications where there's research happening in that regard include off the top of my head, Huntington's disease and certain forms of ALS in particular. So, we will watch those programs with interest because there's obviously some scientific similarities, but also meaningful differences between those targets and the specifics of those constructs and what we're proposing. But specific to exon skipping, not to my knowledge, vectorized exon skipping.
Okay, great. Thank you.
Thank you. I'm showing no additional questions in the queue at this time. I would like to turn the conference back over to Mr. Matt Patterson for any closing remarks.
Great, thank you again everyone for your participation. We appreciate the opportunity to share our updates and look forward to talking again soon. Thank you very much, Operator that concludes our call for today.
Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone have a wonderful day.