Ladies and gentlemen, thank you for standing by and welcome to the PTC Therapeutics Fourth Quarter And Year End 2019 Financial Results Conference Call. As a reminder, today's program may be recorded. And now, I'd like to introduce your host for today's program, Alex Kain, Head of Investor Relations. Please go ahead, sir.
Good afternoon and you for joining us to discuss the PTC Therapeutics 2019 fourth quarter year end corporate updates and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz, our Chief Operating Officer, Marcio Souza, and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward looking statements based on current expectations. Please take a moment to review the slides posted on our Investor Relations website in conjunction with the call, which contains our forward looking statements and other details shared during this call. Our actual results could materially differ from these forward looking statements as any and such risks can materially and adversely affect our business and results of operation.
For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10 K filed with the Securities And Exchange Commission, as well as the company's other SEC filings. Will disclose certain non GAAP information during this call, information regarding our use of GAAP and non GAAP financial measures and a reconciliation of GAAP to non GAAP is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz.
Thanks, Alex, and thank you for joining us this afternoon. As we provide our update Significant progress was made across our platforms and programs in Our vision is to continue to grow as a diversified rare disorders company with multiple science platforms, the goal of at least $1,500,000,000 in revenue by 2023. PTC's recent transformation has been remarkable to experience. Over the past 5 years, we have transitioned from a single product company with Translarna to treat nonsense mutation Duchenne muscular dystrophy patients to a company with 2 Duchenne muscular dystrophy products Translana and Emflaza to where we are now. We are now selling 4 products globally and have the capabilities to bring therapies to patients to treat SMA patients and our gene therapy for AADC deficiency, our commercial portfolio is expected to further expand.
Our pipeline is also expanding across multiple scientific platforms which will continue to drive innovation and lead to value creation. Let's start with our splicing platform. We recently presented the full results This trial enrolled the broadest population of Type 2 and 3 SMA patients ever studied and more closely represents the type of patients that physicians typically see in practice. Importantly, The vast majority of type 2 and 3 patients are not currently on disease modifying treatment. The positive and statistically significant results observed in this trial confirmed the potential of Risdiplan to be the most competitive global product for a broad range of SMA patients.
Sunfish Part II studied non ambulant SMA patient, 2 to 25 years of 80s, without any limitation to their motor function capabilities, as evidenced by their baseline Hammersmith scores. We believe that these results further support potential approval and reimbursement for a broad patient population. From the pivotal Firefish study in Type I SMA patients. This trial met its primary endpoint and was statistically significant. Complete results from Firefish Part 2 will be presented at AAN in late April.
With these studies date on May 24. The Nxaro splicing modifier moving towards the clinic is for Huntington's disease. We have selected a development candidate, which is in GLP safety toxicology studies and expect to have an IND filed by the end of the year. As a reminder, there are no currently approved therapies candidate demonstrated uniform Huntington lowering systematically and throughout the whole brain, including in the striatum, cortex, and cerebellum. This is critically important as Huntington's disease affects virtually all parts of the brain.
Similar to our SMA program, where we measured SMN2 MR and protein levels, in healthy volunteers, we will also have the ability to measure Huntington Lowery in blood. In mice, We have shown that the level of Huntington lowering observed in blood reflects the level of Huntington lowering in all tissues in the brain with near one one brain to blood, a Huntington lowering ratio. This is exciting because it will allow us to rapidly demonstrate target engagement and clinically affect early in phase 1 clinical program. Moving on our next scientific form. Late last year, we acquired assets for Bioelectron focused on redox pathways.
Which we now refer to our bioE platform. These compounds are all small molecules, orally bioavailable highly selective and efficiently cross the blood brain barrier, similar to our other small molecule therapies. We're very excited about the progress in our PyOE platform with 2 potentially registrational studies to begin later this year. I want to take a moment to discuss the science behind enter the clinic later this year, target 15 lipoxygenase, a key regulator of oxidative stress, lipid based neural inflammation, eponucleinoxidation and aggregation and cell death. Inhibition of 15 lipoxygenase leads to the reduction of key disease mark such as glial cell activation and glutathione depletion.
These critical modulators underpin pathogenesis across broad range of neurodegenerative and mitochondrial diseases. Marcio will provide additional details on this platform later in the call. By targeting specific tissues, which limits systemic exposure and potentially lessens immunogenicity By administering small doses, we also reduce our manufacturing burden. Furthermore, we are pursuing diseases and tissues with lower cell turnover such as in the CNS and the eye, which may lead to improved durability of response. Being able to control our manufacturing 8 is key to our gene therapy strategy.
In 2019, we entered into a long term lease for a state of the art biologics manufacturing facility. We expect to begin in house gene therapy manufacturing efforts in the facility later this year. Importantly, we were able to retain We are now well positioned to start gene therapy manufacturing on our own with the essential facilities, equipment and talent in place. I want to highlight our most advanced gene therapy program for AADC deficiency, which has shown impressive clinical results in 28 patients. The AADC deficiency marketing authorization has been filed and accepted in the EMA.
We plan to submit the BLA to the FDA in second quarter of this year. Our patient identification efforts are ongoing and we continue to identify patients globally with AADC deficiency. AADC deficiency is a rare and devastating inherited disorder that globally affects roughly 5000 patients with an annual incidence of approximately 300 patients. Well, originally, there was a concept that AADC was confined to a genetically defined population in Southeast Asia, approximately 80 different mutant alleles have been identified globally. This highlights that AADC deficiency is a genetic disorder that impacts patients all across the world.
We anticipate more than 300 addressable patients will be identified Taking all these updates into account, we are now well positioned to drive continuous value creation with a number of exciting upcoming milestones and a deep pipeline to drive sustainable innovation moving forward. We look forward to sharing more detailed information on our platform and pipeline on our Analyst Day on June 16th. With that, let me turn the mic over to Marcio. Marcio?
Hey, thanks. It's 2. Let me start with the commercial side of the business. Our DMD franchise remains the foundation for our growth. For Translarna, is growth potential from multiple ongoing efforts.
We expect increased penetration in existing territories, including Brazil, for which we recently received Avisa approval. Geographic expansion into new territories increased disease awareness and early diagnose, we also contribute to growth moving forward. For Emflaza, we expect continued positive momentum with new patients and those switching from prednisone. With the recent label expansion, we are now able to treat all DMD patients 2 years older and continue to increase treatment with Emflaza in these younger patients. Our PTC care team is actively engaged with physicians and payers to ensure that patients receive access to treatment as quickly as possible.
Emflaza clinical differentiation is further supported with new data recently published in treatments with deflazacore was associated with a more than 2 years delay in loss of formulation relative to treatment with prednisone. In addition, the onset of complications like scoliosis was significantly delayed among patients treated with the Flazacorp. Versus prednisone and further functional benefits were observed in the flatter core patients. The data also demonstrated the positive risk benefits of switching to the plasma core from prednisone. PTC continues to leverage our strong Latin American infrastructure to support ongoing and upcoming launch.
The TEGSEDI launch continues to trend well with 100 of newly diagnosed patients genetically confirmed for PTC supported programs. We are finding and treating new patients and due to the hereditary nature of the disease, the process is likely to accelerate in the future. HATTR silencer treatment for stage 1 and 2 polyneuropathic adult patients by ANVISA. There are an estimated 6000 patients with HATTR in Latin America, the vast majority of them in Brazil. We believe that TEGSED is well differentiated and the best fit for these patients.
TEGSED is a subcutaneous at home injection performed by patients in a region where infusion clinicals are often at or newer capacity and in which travel requirements can be challenging, self administration is the best solution for patients. Healthcare professionals. Through our early access program, patients are able to enter our patient service and obtain and other kinds of support, allowing us to build a strong brand loyalty and lasting relationships. Let me now touch upon We are very excited about these programs and they are fit within our current portfolio and the future with both the platforms and standalone therapies. To reiterate, PTC743and857 are advancing the clinic and they both targets 15 lipoxygenates.
And additional compounds PTC-five eighty nine targets a different set of enzymes and has been partnered with a Japanese company sumitomo dineponepharma and is currently being developed for the treatment of ALS and potentially other neurological disease. Following the recent completion of a positive proof of concept study, Sumitomo is planning to move forward with the developments of PTC-five eighty nine for ALS. Sumitomo has commercialization rights in North America and Japan, while PTC remains commercialization rights in the rest of the world including Latin America and Europe. Moving back to our lead compounds, The first indication is in refractory mitochondrial epilepsy and we'll be initiating a potential registrational trial next quarter. 743 is rather unique in that it has already been used to treat over 400 patients with mitochondrial disease through a series of compassionate use and indication specific studies.
Of notes, PTC743 was studied in an expanded access program from 2009 to 2012 were 94 patients throughout the U. S, Europe and Latin America with inherited mitochondrial disease and within 90 days of end of life care were enrolled. That was the specific criteria. 43 of these 94 patients remain alive and on treatments today, which is remarkable considering the expectations at the beginning of treatment This patient has also experienced a meaningful reduction in seizure frequency. The upcoming 743 trial, Winroa approximately 60 patients globally who have inherited mitochondrial disease and associated refractory epilepsy.
All patients will be followed for 1 month to ensure a baseline seizure frequency and then will be randomized to receive either PGC 743 or placebo for 6 months. The endpoint for the trial is reduction in seizure. We expect that there are 5000 to 6000 addressable mitochondrial plexipay in the Friedreich's Ataxia in the following quarter, 3rd quarter of this year, which will complement our gene therapy approach. In an earlier Phase II trial in 63 FA patients in the U. S, treatments with 743 was associated with an improvement in long term disease severity and neurological functions when related to natural history.
The primary endpoint in that trial was measured at 6 months, which now understands is not sufficient to show separation from Placebo. From a safety perspective, 743 has been dosed in hundreds of patients and has generally been well tolerated in the clinic. Incorporating the understandings from the fields that have emerged since the initial proof of concept trial, the upcoming trial of 743 in FA we enroll approximately 100 patients. We will be focusing on the younger cohort and run a trial for 1 year in a 1 to 1 randomization scheme with Placebo. As a reminder, Finally, PTC 857, which we believe is ideally suitable for larger patient populations.
We will enter into the phase 1 healthy volunteer trial in the 3rd quarter. Based on a very strong preclinical rationale, we are targeting GBA defined Parkinson's as the first indication. Now I wanted to provide some For background, an iridium is a genetic disorder, often caused by a nonsense mutation in the PAC-six gene. Which is associated with awkward effects and typically leads to blindness. This trial was randomized placebo controlled study that followed patients for 48 weeks with an additional 96 weeks open label extension.
39 patients were randomized and the primary endpoint was the change from baseline to week 48 in the maximum reading speeds years of age. While the trial did not meet statistical significance, a trend of Zoom serves in favor of atalorem. For reference, the data has been included in our slide deck posted in conjunction with this call. As a next step, we intend to discuss the results with experts on the following weeks and decide the path forward for the program. Importantly, this safety profile in an Eureka patients was similar to that of previous studies Moving on to DMD.
We expect results from the atlauren U. S. Dystrophin trial in the second quarter of this year. This is a 40 week open label single study into NCNonsense mutations DMD boys H2 to 7. Needle biopsies were taken at baseline in 40 weeks following treatment with Vasyloran.
The primary endpoint is the percent dystrophin change from baseline as measured by ECL. With a positive and statistically significant results as we expect, we intend to submit for accelerated approval in the U. S, which will be in conjunction with the current clinical data for ATLauren. From other studies. Moving now We continue to make No cost blood testing has been deployed globally.
It will have observed increased patient identification through the simple blood test after launching last year particularly for patients with symptoms that mimic cerebral palsy atlapsey, which was across all regions, including Europe and Latin America. As we can see, PTC spoiled for continued growth with upcoming clinical, regulatory and commercial catalysts across all our platforms. I'll now hand the call over to our CFO, Emily Hill so she can review the financial progress. Emily?
Thank you. RC on Stu outlined our several development and commercial products that place us in a strong financial position to have revenues and royalties that fund our ongoing innovation to drive us toward our $1,500,000,000 target in 2023. We made good progress towards that goal in 2019. The press release issued earlier this afternoon summarizes the details of our fourth quarter year end 2019 financial results. And I will take a few minutes now to review key details for the year and our guidance for the full year 2020.
Please refer to the press release for additional details. Starting with our top line results, we reported $307,000,000 in combined net revenue for the full year 2019 compared to 2 $4,700,000 for the full year 2018. This includes the $15,000,000 milestone payment to PTC from Roche triggered by the acceptance of the risdiplam NDA. Translarna net product revenues were $190,000,000 for the year compared to $171,000,000 for the full year 2018. This growth reflects the expanded commercialization of Translarna.
As a reminder, Translarna was the 1st therapy approved in Brazil for DMD last April. With a near term price impact but which should result in long term expanded market access. For Emflaza, we reported net product revenues of approximately $101,000,000 for the full year 2019, which compares to $92,000,000 for the full year 2018. Emflaza sales were impacted by an increase in the utilization of Medicaid, which changed our gross to net assumptions and the transition to a new specialty pharmacy distributor. These factors impacted Emflaza sales in the third quarter of 2019 in particular, and we saw improvements in the 4th quarter that have continued through early 2020.
Total DMD franchise net product revenue was $291,000,000 for 2019 and we anticipate full year 2020 DMD franchise net product revenue to be between $320,000,000 $340,000,000. New products launches, including PEGSEDI revenue and potential risdiplam milestones and royalties are also expected to contribute 18, excluding $20,800,000 in non cash stock based compensation expense compared to $155,900,000 for full year 2018, excluding $16,100,000 in non cash stock based compensation expense. The increase in R and D expense reflects costs associated with advancing the gene therapy platform, increased investment in research programs, advancement of the clinical pipeline, and the upfront $200,000 for the full year 2019, excluding $21,300,000 in non cash stock based compensation expense. Compared to $136,400,000 for the full year 2018, excluding $17,200,000 in non cash stock based compensation expense. The increase in SG and A expense is primarily due to continued investment to support our commercial activities.
We anticipate non GAAP R and D and SG and A expense for the full year 2020 to be between $545,000,000 $575,000,000, excluding approximately 65,000,000 and estimated non cash stock based compensation expense. The anticipated increase in R&D and SG and A expense are based in part on highly leverageable and scalable investments towards the $1,500,000,000 projected revenue target in 2023, including gene therapy manufacturing in increase in was $251,600,000 compared to a net loss of $128,100,000 for the full year 2018. Cash, cash equivalents and marketable securities totaled $686,600,000 as of December 31, 2019, compared to 227.6 $1,000,000 as of December 31, 2018. I will now hand the call over to the operator to start our questions and answer session. Operator?
Our first question comes from the line Alethia Young from Cantor Fitzgerald. Your question please.
Hey guys, thanks for taking my question and congrats throughout all the progress over this last quarter. I guess I just wanted to maybe ask you two questions. 1, just kind of wanted your perspective on how you guys kind of think about the risdiplam data as it relates to maybe the firefish upcoming readout, which some may believe may lead to a more comparable data set of sorts. And then the second one just is, can you talk about the synergies between Frutris ataxia and gene therapy and then with the Redox platform, please? Thanks.
Sure. Hey, thanks, Alethia. Thanks for the question. I think from the perspective, yes, I think you're absolutely right in terms of the the notion of the SUNFISH trial that we recently had data. That was a very broad trial with patients to the twenty five years of age with a very broad inclusion criteria.
So it's much like the patient population that that real that physicians really see day to day in their patients. So, and we did that on purpose because that's what we wanted to see how the the drug would function in that line and would obviously, we saw a 1.5 points difference that was statistically significant that we're pretty happy with that. In terms of the fire push, I think that's probably in some ways a multiple gene, this population, although there are differences. But I think you saw even in part 1, how well was the plan, functions and even the comparisons see that it did quite well and from my perspective was really showed to be the most competitive drug there. We anticipate for part 2, the same event.
We already said that it was statistically significant. And that we expect, as you'll see, coming up into, in AAN, the results of is more clearly. And so we're excited about that. And I think you'll be able to more clearly have a little better comparison when you say how well did we do versus other drugs. So I think that's probably, while nothing's absolutely perfect in terms of apples to apples, that's probably as close as you can get.
And I think you'll assume that Risdipline will do quite well. In terms of the FA, both gene therapy and the drug, one is obviously gene therapy that will be directed into the into the directly into the brain, whereas the other one is that McNellico different mechanism, maybe Marcy wants to go through a little bit of
Thanks to him. Hi, Alicia. Thanks for the question. So what we mentioned before, right, that our interest as a company, our goal the end of the day to treat the entire patient. When you look into disease like pridori contacts, yeah, you have a component that is systemic I specifically for this, amongst many others, the hearts, it's very affected.
And then you had deterioration neurological deterioration that occur with these patients over time, specifically on their teenage years and later. What you're looking into with the 2 modalities really try to address most if not all of the issues these patients go through. By injecting directly into the dense nucleus of the cerebellum, we expect to stop the progression of the disease and hopefully, I will start and function there neurologically. And by giving 743 would have a more systemic measure, including the hearts. So we see both approaches quite complementary.
They are in similar development timeline. Although 743 is more advanced in terms of the stage of the trial. So when we start this trial later this year, fully enrolling that about 100 patients, we expect that after 1 year in the redialysis would be a pivotal trial. So we we should be able to register 743 before our gene therapy candidate.
Great. Thank you.
Thank you.
Thank you. Our next question comes from the line of Joe Thome from Cowen and Company. Your question please.
Hi, there. And thank you for taking my questions. The first one is on the the Anuridia data that were presented today. I guess, did the placebo arm perform as you would have expected with that 3.3% change. And is there anything different about sort of the patients that did respond to Translarna therapy and those that didn't in terms of their current disease severity.
And then one more on a follow-up to the first question in Friedreich's ataxia. In order to use the 2 products in combination, if they are going to be complementary mechanisms, do you have to study those in a formal clinical study or just achieve independent registration? Thank you.
Yes. Hey, thanks Joe for the, the question. Maybe the first one on on Anuridia. Let me just say that your point is that what we expected is sort of in a way we didn't know necessarily what to expect since this was the first trial really ever done in Anarrhea in terms of following it. So the real natural history and understanding of the disease wasn't all that well understood.
And in fact, we initially had the trial since it was sort of a early trial. To be a safety study compared to Placeboza treatment. We just thought that, let me change, to looking at MRAM to to be able that if we saw something that we'd be able to go and talk to regulators. But I think at the end of the day, I think At the end of the day, it was hard to be able to power directly what we thought the trial would be because there wasn't just enough information. But that being said, in a way, we learned a lot about this.
And I think as you go and look at the the data, in the deck, you'll see why, we think that while the drug was effective in these patients. And so when you compare the number of patients that were that saw benefit versus the placebo, why we think that? It's just a change in variability of the assay that I think that would prevent it from being statistically significant. I mean, that's how we look at it. Marshall, when
Yes, just a little detail to complement that. Thanks, Stuart. The patient will not randomize based on this criteria, right? So we had some interest like variability coming from the randomization itself that was not that well balanced. So your question about Placebo the placebo B8 similarly to what we're expecting, there was one patient that we saw there that has a response that was somewhat unexpected.
But in general, there was other issue. It's more the size of the trial and the effect of the organ necessarily, balance at baseline this was not the regional endpoint that is still at SaaS. We are looking for safes and some biomarkers originally. So We learned a lot with you that for this size of the trial when the point estimates moving on the right direction, it does not negate the effect we're expecting to see in very important lessons of Florence in the market in several counties for GMD the safety profile is exactly where we're expecting here.
And then the 2 products, the FA gene therapy versus the small molecule. So we're going to have 2 independent trials that were be going on. So I don't think you initially have to actually do them both together. So I don't think that would be an issue. We're going to be happy in two products that then might with very different met.
1 is the underlying cause of the disease that has the the protein itself, which is lost in the disease. And the second one really affects, affecting inflammation. And so the combination of those 2, we think obviously when you have the information, you have a problem. And in a sense, reducing it is often good, especially with chronic inflammation. The second one in terms of bringing the, the protein that is not made would be important to it.
So they can be worked together, but we don't think right now that we have to do a combination study. Great.
Thank you. Congrats on the progress.
Thank you. Our next question comes from the line of Martin Auster from Credit Suisse.
Thanks for taking the call.
I had a couple of questions for
you as well. From the Anarridya pivotal data, I'm curious if you see any read through to the ongoing TRIFEN study. I don't know if you as you've looked through maybe more of the secondary endpoints, you had any chance to analyze some of those? Is there anything in there that kind of elevates your conviction in the drugs MOA and kind of supports an expectation for demonstration of just different expression about study. And I know you've set some fairly grounded expectations around that one?
And then the second,
you guys have generally sounded,
I would say, incrementally more excited about the BioE forms since that deal was signed and closed. And I'm curious then at the R and D day, is there going to be any new data presented then? Or will we be seeing just detailed presentations
of preclinical and clinical results
you've outlined to us already? Thanks.
Sure. Yes, so And iridium, dystrophin, I don't think are, you know, you could say one from the other. The one is trying to understand the clinical manifestations that would occur with treating which we learned in terms of and which we learned as a consequence of that and the variability of the given endpoints In discipline, we feel pretty comfortable that we've done all we can do in terms of assuring that as best we can that this will be a positive study. We think that the assay that we have is, incredibly sensitive and linear. And so we think we're pretty good shape in terms of getting that.
And we're hopeful that, that we're going to see. And since we had data already from the 2004 study, this is we think is this more sense of that, I think, replicate that. That being said, we'd look at this as a being able to have a positive result and be able to go to the FDA for approval in the United States. In terms of the BioE, platform, yes, we're excited about that. We think it's an important platform and a novel set of compound that work in a different way than other companies have worked on before.
So we're pretty excited about that. And I think you'll see on Analyst Day, We'll talk more about the not only the MEK is in the more detail of some of the things we studied. We alluded to into the talk here today in terms of other work with some would come well in terms of ALS and we'll, we'll talk more about that and show you more in terms of preclinical clinical data and that as well. So I think there'll be a lot, that you'll learn as a sequence of the buyer E platform on the June 16, that
Great. Thanks.
Thank you. Our next question comes from the line of Vincent Chen from Bernstein. Your question please.
Great. Thank you very much for taking the question. Congrats on the progress. I was wondering if you could just following up on Translarna in DMD, I was wondering if you could describe the powering assumptions around the Translarna U. S.
Study. And what gives you confidence that the trial is adequately powered? For example, what are your assumptions around the variability in dystrophin levels in the absence of drug? And in the expected effect size.
Sure. You must have answered your question.
Yes. Hey, Vincent, it's Marc here. So the power we believe that in all the scenarios that we look into has been likely, since we've been looking to just one scenario here with an absolute change. We're powered at more than 90% for to show a difference that is statistically significant on that trial. The way we control the variability here, that's exactly the point that has to be controlled through a series of studies leading to and validation work leading to this where multiple cars were analyzed and different biopsies as well.
And we were able to really come throw that. So we're not, concerns that would be an issue. There are obviously scenarios where few patients show a large increase in the majority of the patients show a very small increase versus another one that I would say more likely that you see an increase throughout, but a smaller magnitudes. In neither of them, we can see the thriving well powered to show benefits and such as cost significance, versus the baseline since this is the measure. Based on our validation work as well, what it seems that the vast majority of the patients are going to be below the lower level of classification.
So if that is to be replicated, we don't have a problem of like the noise that we're seeing from some of the other measures. One of the reasons why we went with this method and the both from the acquisition of the biopsy and the densification of dystrophin as we
Our next question comes from the line of Robyn Karnauskas from SunTrust. Robinson Humphrey. Your question please.
Hi, thanks for taking my question and congrats on the progress. Just a couple. So number 1, big picture. So you're you've guided as you have before to $1,500,000,000 over the next few years. What are your thoughts on making sure that DAC can help you achieve some profitability?
Just so I know you take your guidance, what's your thought on your goals there and how you how you're going to think about business development now versus you have in the past? Second question is on at AAUC. For the patient population that you have identified, can you give us a little bit more clarity as far as more recent split to the United case in ex U. S? And then 3rd, on the anaridia data, if you were to exclude that high patient, high responder patient, is there any difference between placebo and, the treatment arm Thanks.
Hi, Robin. This is Emily. Nice to talk to you. And to answer your question about reaching that $1,500,000,000 revenue target by 2023, what you've seen in the past couple of years is we've really best has been driving innovation to continue to grow our revenue. And we'll plan to do that as we have new launches coming onboard this year with TEGSEDI and Waylivra that AADC and the risk of plan royalties.
We just had to invest in our read offs platform or gene therapy platform and our slicing platform. Obviously, as you get towards that $1,500,000,000 net target, there's likely a threshold of profitability, but I wouldn't say that's our priority. Our priority right now is really invest in accelerating those pipelines to continue to drive innovation. And we've done that in the past, both through internal innovation and as you mentioned through business development. And while we have a lot on our plate on the internal side, we always pass to Ynet and landscape, the business development opportunities, and we'll be selectively opportunistic as they arise.
Yes. And so now the AADC deficiency, I think the big picture is we've been finding patients. In all the areas that we've been looking and we had more of a 50 alleles. So that we're I saw mean, in a sense, one of the questions people had, is it a small population, it's only a founder's effect that turns out clearly not to be, the case. And so I think the split, I think most of your team has been working pretty hard on that.
So I want to give a of what we're looking corn, but very rarely.
Of course. So the space that we've been seeing is pretty even out say between the U. S. And the Tier regions outside of the U. S, just a reminder, we're focusing on 5 counties at this first wave.
So, Brazil, the U. S. And the 3 largest markets in Europe. So France, Italy and Germany. We're secondary looking to a number of other markets that we were seeing as well an increase in the number of patients there, but it's fairly balanced.
In terms of the key results that we expect from each one of the teams, since that's how we're measuring performance and how we're putting resource against. It's a split between the U. S. And outside of the U. S.
So we expect half of the patients still continues to be coming from the Americas region and then other parts from European region, between like Eric and Adrian, and leaderships there. The in terms of the things we're doing as well, we just to start with a number of new programs as we learn more, the things that are happening and that are working or not working very well. We've cycled through them very quickly. And this product includes having more people in the field in the U. S, for example, in some of the points of contact that you're seeing, returning more So as we learn, we're able to again focus the resource or refocus the resource towards growth.
And then in the Anarivya account in terms looking at with a sensitivity analysis of removing. We already have a pretty small patient population, but I don't know if maybe you want to comment on that.
So it's a small patient populations to just that, like, it's obviously, if we remove that one patient with large result with Fortiva effect would be seeing a larger separation here and reaching nominal statistical significance. But I don't think it would be appropriate for us to speculate because we don't know if that patient is an outlier or not. What you're seeing is in the distribution and one of the reasons we put the waterfall in this slide, we see the distribution clearly skewed towards increase with Lauren. So it gave us confidence not only for this study, but also some extent to de risk the overall platform of that Lauren.
Again, when we look at that study, when you look at the waterfall plot, which I think is probably in the small patient population, is a nice way to see. It's pretty apparent the effect of the drug on these patients over Placebo. And so we look at this as so we're going to be talking to physicians in the coming week and the key opinion leaders. And so I think we've learned a lot of this and I think it helps, as Marcio said, really given people confidence in terms of the effectiveness of the drug.
Great. Thank you.
Thank you. Thank you. Our next question comes from the line of Raju Prasad from William Blair. Your question please.
Hi, there. It's Sandy on for Raju. I was wondering if what format you might be presenting the, dystrophin results? What kind of format you'll be presenting whether it'll be a medical conference or a press release. And if you have had any discussions or if you plan on having any discussions with the FDA, ahead of that resubmission.
Okay. Yes, we haven't yet defined whether we'll do it at a meeting or a press release. But our goal is that when we know this to get this out as rapidly as possible, so there's a good chance if, yes, we'll put something out as a press release so people know, and then we could be able to present either that or a call even free. We'll figure that out. And then the second part was, Marcie, what's your
Yes, sure.
So the in terms
of interactions GSTA. So we've been having interactions throughout this planning phase and the execution of this study. We intend to have a pre NGA meeting well. If we come to that, when they said it's positive, it's being discussed already with the agency, it should be in the books. Pretty soon.
And there is many other matters, as you can imagine, other than they study itself, right? There is the update of the Safe database, there is the update of the other studies. The completion of the GZI studies are done between the 2 submissions. So a number of things that will be dealt into the agency and having productive discussions with them.
Great. And then I was wondering if you could just discuss some of the potential outcomes or next steps for the INARIDIA program depending on your conversations with experts. Are you guys kind of thinking if the program might get tabled or running another study and having it power differently? Just what your far.
Well, I think that's a good question. And I think that's why we're going to go and talk to the key opinion leaders and talk among ourselves for that. And then we'll if we come with a plan, I think we can talk about next steps then. Our next
question comes online of Gena Wang from Barclays. Your question please.
Thank you for taking my questions. My first question is also regarding the biomarker data. For Translarna. Just wondering, could you remind us which muscles would the BOLPS be taken? And then would that be taken from the same side of the patients and how many bowel plays taken from each patient each time?
Hey, Jin MR. So we're taking 2 samples, for every patient, 2 biopsies, three course for biopsy. So we'd have a thought of 6, as a base. There's an alternate muscle as well that we haven't price before in case that is already set coming from the 6. So we have enough sample coming there.
And as I mentioned on the answer to since it earlier, we have run some of the tests in terms of the validation when we know, based on the very kind donation of time and systems that we have from different patients that it shouldn't be a problem. We're doing the bisectors and the gastroides for, despite the primary sites and the TA as a secondary site or tertiary site, may I say, here. So the primary is really to read the 6 course that it would have, one of the nice things during the validation as well is that when we compare the cars, we've seen very, very small variability at the So we can use any of them to measure. Did that answer?
Yeah. Yeah. So but will you have individual data or you will pull these baseline data together?
Yes. So that's a very good question. So we will show, so the way that answers it is a difference for the individual patient from their baseline, right? Obviously, we're going to compute that in a fair test later statistically, but each one of those patients are going to be looking versus their baseline. Because while we expect that the baselines are going to be very, very small, even below the level of classification, we cannot guarantee that that's the case.
So a simple, pools analysis and change could skew the results. So each one of them are going to be looked individually and then we're going to compute the difference, the main difference for all the patients.
I was wondering, say each individual patient, they have 6 samples, will these 6 samples put together? All the individual logistics baseline?
No. So just one, so it's the vast sample for baseline and for week 40 for each one of the patients that's going to be used for the analysis.
Okay, great. And then I have questions regarding the mitracunture epilepsy trial. Just wondering, was the primary endpoint Was that based on the FDA discussion feedback? And also how do you measure the seizure? And then do you capture both generalized seizure or partial seizure?
And how do you record a seizure events, especially for those active seizure if you wanted to cover them?
Sure. No, absolutely. I would say the trial design is to some extent, very similar to other drugs that was that were just approved with a genetic flexis in general. Like, I'm sure you know, the ones I'm mentioning, we are developing like virus, specific diary for this trial that's going to account for this patient population. So looking to generalize seizures at this point in time, for these patients and looking for the chains.
Like there were obviously discussions with the different regulatory agencies here the key design of this trial was agreed under a scientific advisory working party protocol review with DMA and we're using the same for the FDA, of course.
Okay. Sorry. Just one more question. Regarding generalized seizure, so in a case that patient, I'm just wondering will caregiver also have a follow indication of a generalized seizure and then the patient actually wasn't aware, he had a seizure because he was passed out. And wake up, how would you record events like that?
Well, that's going to be recorded by the caregiver. Actually, it should have made year, right? So most of these patients we're talking about are infants or toddlers or young kids. We're talking about the caregiver recorded the IRS here.
Thank you. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your question please.
Hey guys, thanks very much for taking my questions. Can you give us a sense of the agency's comfort around the ECL assay, just in terms of validation and quantitative ability for dystrophin measurement relative to other techniques versus Western? Secondly, can you characterize in general how the regulatory interactions have been going for Risdiplam initially and your level of confidence in a timely approval with broad label. And then lastly to maybe ask an earlier question a different way on risdiplam. Now that you guys have had an opportunity to further explore the firefish and sunfish data and looking at potentially comparative subgroups and endpoints, what's your level of confidence that the magnitude of benefit is comparable to SPINRAZA in types 1, 2 and 3 patients?
And are there any subtypes where you think efficacy may be better? Thanks.
Yes, sure. So maybe we'll start with the dystrophin measurement. That was one obviously, when we've had substantial discussions with the FDA on this, and it wasn't one where we said that in essence, we actually saw a member of discussing first saying how I'm sure you would want a Western Blonde. They said no, not really. And they don't like Western blot.
They understand the limitations of those. If you have a better assay, we'd be interested. And so we had been working on and we have been using in our own laboratories, this unique form of an eliza see out. And so, and they like that. So they, we worked with them and, Marcy and the team had worked for quite some time.
And so maybe why don't you talk a little bit about, sort of the, it was sort of a 6 to 8 months interaction, and they were pretty much pleased, I think, very much with the work and the sensitivity. I mean, I think they're very excited about the assay.
Right. It's right. So we worked very closely with the FDA and specific officers there, on the validation of the essay. And they they are completely on the same page as we are as a result of the measure itself, right? Obviously, the results we're going to see after the trial is read the results soon, but the essay itself and the sensitivity and the way it was validated was obviously a concern, I would say in general from us and for the FDA from the beginning because this is full and dystrophin is very different than what others were doing.
We had to have that external standards. Once you were doing the ESL, the external standard has to be hypercure and so on. So we did all this work with them and, to the satisfaction of the agency and obviously ourselves as well. We decided to use a third party lab to do this eliminated the potential bias that an internal app could add to such major non blinded medicines. So that was, how we got, again, think we're all pleased.
It took a very long time to validate and to discuss with the agents, but we're on the same page now.
Yes. In terms of the risk of plan, in terms of broad label. I think we're actually in terms of the heavy firefish and sunfish and the partnering part 1, but Part 2. I think both of them actually help really understand and further of the drug itself and how effective it can be. I think in terms of the SUNFISH trial, really it's hard to compare because concerned that no one else has done a two to twenty five year old, a trial with in such a broad label a broad inclusion criteria that we have patients with scoliosis with Hammersmith, Safelite, Hammerslip, Safelite scores less than 10.
And I should point out that those in the real life patients, even in the two to five year old, 20% of the patient had Hammers withdrawals, less than 10, and there was a scoliosis and contractors. And so, you're really going to have a hard time. So we're pretty excited with the fact that there was a statistically significant improvement in this broad population and we think that gives us a leg up and that no one else has the data when you talk not only to physicians, but to payers that you've actually studied the the types of patients that you're going to, that you're going to be treating. And in fact, no one else has that. I think in terms of, when you think about Firefish, Firefish, I think if there's anything for comparable, think that becomes clearer.
And I think in terms of looking at age is probably the most determinant of thing where you could see. And I think you could look at the Rizacam data and you have a patient called greater than 5 months of age. You still saw increases in shop in 10. And that wasn't seen in other trials as well. So at the end of the day, I think when you're going to compare if you want to do a comparison, those are the closest.
And you could look at the other trials and they have basically far younger patients than what we saw. And yet, we saw very strong data, not only in the early patient, but also in the Type 1 that were even older. And so, we're pretty happy about that. We look forward to actually talking far more about that at the AAN. So I feel pretty pretty strongly that Risdiplam is a highly efficacious drug, that will be used quite broadly in the population?
Thanks so much, Stu. Thanks, Marcio, and congrats on all the progress guys.
Thank you. Our next question comes from the line of Joel Beatty from Citi. Your question please.
Hi guys, this is Sean Egan calling in for Joel. Two questions for me today. First to you on the LATAM franchise with ONPATTRO getting ANVISA approval. Can you talk about what advantage is having an established LatNAM infrastructure gives you guys for marketing TEGSEDI. And then AnweilIVRA following a positive Phase III broadened study in PL.
Why don't you have that data be included when you guys submit in the second half? And then I have one follow-up on the redox agents.
Sure. So, thanks for the questions. Talking a little bit about SelectAM, right? So the approval giving us a lot of advantage here in terms of the overall timing first. A lot of things were done in the swing.
So one of them obviously had took out a price agreed with the government, just to size new that takes some time and we're well on the way here. The second is the genotyping infrastructure, as mentioned on my prepared remarks, but hundreds of patients now with typically confirms HATTR, not only in Brazil, but in Argentina and Colombia and other places. So we are way ahead of the game there. And then the last one that is not less important, I would Day, together with the infrastructure that we have in the country that is very robust since we have substantial sales of Translarna Foundation is is the fact that the health system, like, and look at the situation we're all right now discussing health system capacity in the words in general, don't think he wants to overload hospitals with IV, delivers in general. So the ability to deliver this on people's home the ability to monitor them, as we have the nursing network had been by fundamental and we're seeing a really positive feedback.
So the launch is now underway and we were expecting to see, we should expect to see more and more updates on us in relation to that. Your second question in relation to Waylivra, right? So the first approval we expect for FCS in short to complement that data set with FPL. So it wouldn't be at least our base case right now is not to have the 2 indications, approx.
Got it. Thank you, Marcio. And then on the 743 redox agent in epilepsy, for that pivotal study, can you maybe talk about how plan to enroll? Will it be an all comer study for patients with metabolic mutations or will you be enrolling any kind of particular mutations more or less? And then kind of going one step further, what could if this study is successful, what could the indication look like?
And are there any till for, if there's like a clear benefit in some genetics populations for like a smaller approval?
Yes. No, that's a great question. The so there it's kind of both, right, in this study. As we went through the scientific advice, what we heard very loud and clear, specifically from VMA is that they wanted both a very general populations themselves. Genetically advised mitochondrial epilepsy, with seizures that are not controlled.
So we could potentially treat any patient, any commerce that will after the approval, if the unapproval is to come, but also to have the most common mutations being represented. So we're going to be discussing that a little bit more in detail, but there are 4 major groups, of mutations that are going to have, balance for those patients. One of them, one of the most common is lead syndrome, with Mike, with Amira and Milas, as well amongst others. So on the June 16, we're going to be like well underway on planning this and hopefully executing as well. Going to be discussing exactly what is the expectation of the trial and the market potential and so on.
As I mentioned on the on the prepared remarks as well, we do expect about 5000 to 6000 patients with the geographical population here. So it's very large And these patients, because of the type of stress they have, they do not respond well to any of the common therapies that are available right now. So this would be really like changing for them. And we really expect and we're powering the drivers of that. Great.
Thanks very much. I appreciate it.
Thank you. Thank
you. Our next question comes from the line of Vincent Chen from Bernstein. Your question please.
Great. Thanks for taking a few follow-up questions. Just a few on the DMD trial for Translarna. First one is simply, did I hear correctly you'll be comparing the best sample of baselines as a best sample at the end. How is the best sample determined and why not use the average?
Second is I was wondering, you lose to a very low variability in the validation test. I was wondering if you could quantify the degree of variability you've seen and sort of how were those run. And then well, maybe a third actually, given that the FDA has shown comfort with using Western blot historically, even if it has has its imperfections. What was the rationale for going through the work to sort of move to ECL rather than using Western blot given that regulators seem to be willing to use West 1.
Yes. So maybe I'll start with the last first is that the Well, they've been, I don't think they're actually all that comfortable with the Western Bluff. I think it's the best that they probably had, but they don't think that it's a great assay for a large protein that doesn't block very well. And that and so And so we thought also gives you I think that in the situation, it could give you depending on how it works. Greater variability, more chance for potential missing things that are positive.
So at the end of the day, we think of that, a more reliable asset, gives a better chance for success. And then once you my CFO, please?
Sure. So the decision about using the, best case, right? So one, it obviously is all simulated. And the weight is the most reliable. So one, you can have a situation on one of the cars or one of the thrombals is contributing to credit by tax.
So that's one of the reasons not to average, because it wouldn't be a true average, right? We just got unlucky to some extent. And I think when you look into other studies, our study for example, all the studies came by marine run and to expand some of the other drugs that are in the market, you do see samples that cannot be used or have to be heavily compensated because of that So that's one of the reasons to use. The other, as you asked in terms of the validation itself, the expectation, we didn't know where the sample was coming from, upfront, right? We're asking the question, can I biopsy a patient multiple times?
And see the results that are very similar. And the answer is yes with this method. One more reason not to use all their methods, like if you're looking to both types of biopsies that were used before, number 1, and classification methods that were used before. You see interest sample variability like we are 40% sometimes. And that's obviously not acceptable.
As Stu said, when you block approaching this bid, we're going to have intrinsic variable. Unless you're looking for a super truncated part of the process in the not the case, like we're really looking into full length here.
I see. Thank you very much.
Thank you.
Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Stuart Peltz, the E. O.
Thank you. Joining us today on the call. And I don't know, as you may be aware, the rare disease day was this past Saturday. And I think it's a good time for us take stock of where we are as a company and the importance of the work that we do that ultimately with benefit patients. And so With that in mind, we're quite proud to be a global commercial diversified biopharmaceutical company that's focusing on these therapies to help treat rare genetic disorders.
So with that, let me thank you again and, we look forward to seeing you at our Analyst Day later this year.
Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.