Ladies and gentlemen, thank you for standing by, and welcome to the PTC Therapeutics Fourth Quarter and Year-End 2019 Financial Results Conference Call. At this time, all participants are in listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star one on your telephone. As a reminder, today's program may be recorded. Now I'd like to introduce your host for today's program, Alex Kane, Head of Investor Relations. Please go ahead, sir.
Good afternoon, and thank you for joining us to discuss the PTC Therapeutics 2019 fourth quarter and 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 contain 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. We 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 for the 2019 fourth quarter and end of the year review. Significant progress was made across our platforms and programs in 2019, which has continued in 2020. Our vision is to continue to grow as a diversified rare disorders company with multiple science platforms, with the goal of at least $1.5 billion in revenue by 2023. PTC's recent transformation has been remarkable to experience. Over the past five years, we have transitioned from a single product company with Translarna to treat nonsense mutation Duchenne muscular dystrophy patients to a company with two Duchenne muscular dystrophy products, Translarna and EMFLAZA, to where we are now. We are now selling four products globally and have the capabilities to bring therapies to patients in 50 countries.
With potential approvals for risdiplam 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 from our successful SUNFISH Part two pivotal trial. This trial enrolled the broadest population of type two and three SMA patients ever studied, and more closely represents the type of patients that physicians typically see in practice. Importantly, the vast majority of type two and three patients are not currently on disease-modifying treatment. The positive and statistically significant results observed in this trial confirm the potential of risdiplam to be the most competitive global product for a broad range of SMA patients.
SUNFISH Part Two studied non-ambulant SMA patients two to 25 years of age, 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. We also recently announced successful top-line results from the pivotal FIREFISH study in type one SMA patients. This trial met its primary endpoint and was statistically significant. Complete results from FIREFISH Part Two will be presented at AAN in late April. With these studies now completed, we anticipate a MAA filing with the EMA next quarter and look forward to the upcoming PDUFA date on May 24th. The next oral 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 for the treatment of Huntington's disease. In preclinical studies, our Huntington's disease development candidate demonstrated uniform huntingtin 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 mRNA and protein levels in healthy volunteers, we will also have the ability to measure huntingtin lowering in blood. In mice, we have shown that the level of huntingtin lowering observed in blood reflects the level of huntingtin lowering in all tissues in the brain with near one-to-one brain-to-blood huntingtin lowering ratio. This is exciting because it will allow us to rapidly demonstrate target engagement and clinically affect early in phase I clinical program.
Moving on our next scientific platform, late last year, we acquired assets from BioElectron focused on redox pathways, which we now refer to our Bio-E 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 Bio-E platform, with two potentially registrational studies to begin later this year. I want to take a moment to discuss the science behind this platform. PTC-743 and PTC857 will both enter the clinic later this year. Target 15-lipoxygenase, a key regulator of oxidative stress, lipid-based neural inflammation, alpha-synuclein oxidation and aggregation, and cell death. Inhibition of 15-lipoxygenase leads to the reduction of key disease markers such as glial cell activation and glutathione depletion. These critical modulators underpin pathogenesis across a broad range of neurodegenerative and mitochondrial diseases.
Marcio will provide additional details on this platform later in the call. Turning to our gene therapy platform, our strategy is to replace genes of interest 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 fate 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 the vast majority of biologics manufacturing talent at this facility.
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 the 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 5,000 patients, with an annual incidence of approximately 300 patients. While 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 affects patients all across the world. We anticipate more than 300 addressable patients will be identified by launch across the U.S., Europe, and Latin America. 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, Stu. Let me start with the commercial side of the business. Our DMD franchise remains the foundation for our growth. For Translarna, there is growth potential from multiple ongoing efforts. We expect increased penetration in existing territories, including Brazil, for which we recently received Anvisa approval. Geographic expansion into new territories, increased disease awareness, and early diagnosis will 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 two years and 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 the Journal of Comparative Effectiveness.
In that study, treatment with deflazacort was associated with a more than two-year delay in loss of ambulation relative to treatment with prednisone. In addition, the onset of complications like scoliosis was significantly delayed among patients treated with deflazacort versus prednisone, and further functional benefits were observed in deflazacort patients. The data also demonstrated the positive risk/benefits of switching to deflazacort from prednisone. PTC continues to leverage our strong Latin American infrastructure to support ongoing and upcoming launches. The Tegsedi launch continues to trend well with hundreds of newly diagnosed patients genetically confirmed through 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. As a reminder, Tegsedi was the first approved hATTR silencer treatment for stage one and two polyneuropathic adult patients by Anvisa.
There are an estimated 6,000 patients with hATTR in Latin America, the vast majority of them in Brazil. We believe that Tegsedi is well-differentiated and the best fit for these patients. Tegsedi is a subcutaneous at-home injection performed by patient. In a region where infusion clinics are often at or near capacity and in which travel requirements can be challenging, self-administration is the best solution for patients and healthcare professionals. Through our early access program, patients are able to enter our patient service and obtain access and other kinds of support, allowing us to build a strong brand loyalty and lasting relationships. Let me now touch upon the Bio-e platform that Stu referenced earlier. As mentioned, we are very excited about these products, and they are fit within our current portfolio and the future with both the platforms and standalone therapies.
To reiterate, PTC-743 and PTC857 are advancing the clinic. They both target 15-lipoxygenases. An additional compound, PTC-589, targets a different set of enzymes, and it has been partnered with a Japanese company, Sumitomo Dainippon Pharma, and is currently being developed for the treatment of ALS and potentially other neurological diseases. Following the recent completion of a positive proof-of-concept study, Sumitomo is planning to move forward with the developments of PTC-589 for ALS. Sumitomo has commercialization rights in North America and Japan, while PTC retains commercialization rights in the rest of the world, including Latin America and Europe. Moving back to our lead compounds, PTC-743, 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 note, PTC-743 was studied in an expanded access program from 2009 to 2012, where 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 of survival of only 90 days or less. These patients have also experienced a meaningful reduction in seizure frequency. The upcoming 743 trial will enroll approximately 60 patients globally who have inherited mitochondrial disease and associated refractory epilepsy.
All patients will be followed for one month to ensure a baseline seizure frequency and then will be randomized to receive either PTC-743 or placebo for six months. The endpoint for the trial is reduction in seizure. We expect that there are 5,000-6,000 addressable mitochondrial epilepsy patients in the U.S. and Europe combined. We also plan to initiate another registrational trial with 743 in Friedreich's ataxia in the following quarter, the third 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., treatment with 743 was associated with an improvement in long-term disease severity and neurological function when related to natural history. The primary endpoint in that trial was measured at six months, which now understands is not sufficient to show a 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 will enroll approximately 100 patients. We will be focusing on the younger cohorts and run a trial for one year in a one-to-one randomization scheme with placebo. As a reminder, we expect that there are 25,000 addressable FA patients globally. Finally, PTC-857, which we believe is ideally suitable for larger patient populations, will enter into the phase I healthy volunteer trial in the third 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 perspective on the Translarna aniridia trial.
For background, aniridia is a genetic disorder often caused by a nonsense mutation in the PAX6 gene, which is associated with ocular defects 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 as measured by the MNREAD Acuity Charts, only in patients older than eight years of age. While the trial did not meet statistical significance, a trend was observed in favor of ataluren. 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, the safe profile in aniridia patients was similar to that of previous studies and the ongoing commercial use of ataluren. Moving on to DMD, we expect results from the ataluren U.S. dystrophin trial in the second quarter of this year. This is a 40-week open label single study in 20 nonsense mutations DMD boys aged two to seven. Needle biopsies were taken at baseline and 40 weeks following treatment with ataluren. The primary endpoint is the % dystrophin change from baseline as measured by ECL. With a positive and statistically significant result, 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 ataluren from other studies. Moving now to our AADC deficiency program. We continue to make good progress in patient identification using a multi-pronged approach.
No-cost blood testing has been deployed globally, and we have observed increased patient identification through the simple blood tests after launching last year. Particularly for patients with symptoms that mimic cerebral palsy and epilepsy, which was across all regions, including Europe and Latin America. As we can see, PTC is poised 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. Marcio and 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 $1.5 billion target in 2023. We made good progress toward that goal in 2019. The press release issued earlier this afternoon summarizes the details of our fourth quarter and year-end 2019 financial results. 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 million in combined net revenue for the full year 2019, compared to $264.7 million for the full year 2018. This includes the $15 million milestone payment to PTC from Roche, triggered by the acceptance of the risdiplam NDA.
Translarna net product revenues were $190 million for the year compared to $171 million for the full year 2018. This growth reflects the expanded commercialization of Translarna. As a reminder, Translarna was the first 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 million for the full year 2019, which compares to $92 million for the full year 2018. EMFLAZA sales were impacted by an increase in the utilization of Medicaid, which changed our growth 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 fourth quarter that have continued through early 2020.
Total DMD franchise net product revenue was $291 million for 2019. We anticipate full year 2020 DMD franchise net product revenue to be between $320 and $340 million. New product launches, including Tegsedi revenue and potential risdiplam milestones and royalties, are also expected to contribute in 2020. Non-GAAP R&D expenses were $236.6 million for the full year 2019, excluding $20.8 million in non-cash stock-based compensation expense, compared to $155.9 million for the full year 2018, excluding $16.1 million in non-cash stock-based compensation expense. The increase in R&D expense reflects costs associated with advancing the gene therapy platform, increased investment in research programs, advancement of the clinical pipeline, and the upfront $10 million payment for the acquisition of the BioElectron assets.
Non-GAAP SG&A expenses were $181.2 million for the full year 2019, excluding $21.3 million in non-cash stock-based compensation expense, compared to $136.4 million for the full year 2018, excluding $17.2 million in non-cash stock-based compensation expense. The increase in SG&A expense is primarily due to continued investment to support our commercial activities. We anticipate non-GAAP R&D and SG&A expense for the full year 2020 to be between $545 million and $575 million, excluding approximately $65 million in estimated non-cash stock-based compensation expense. The anticipated increase in R&D and SG&A expense are based in part on highly leverageable and scalable investments towards the $1.5 billion projected revenue target in 2023, including gene therapy manufacturing, an increase in the number of programs advancing into the clinic, and commercial launches. Net loss for the full year 2019 was $251.6 million, compared to a net loss of $128.1 million for the full year 2018.
Cash, cash equivalents, and marketable securities totaled $686.6 million as of December 31st, 2019, compared to $227.6 million as of December 31st, 2018. I will now hand the call over to the operator to start our questions and answer session. Operator?
Certainly. Ladies and gentlemen, if you have a question at this time, please press star then one on your touch tone telephone. If your question has been answered and you'd like to remove yourself from the queue, please press the pound key. Our first question comes from the line of 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. One, just kind of wanted your perspective on how you guys 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. The second one just is, can you talk about the synergies between Friedreich's ataxia and gene therapy and with the Bio-e platform, please? Thanks.
Sure. Hey, thanks, Alethia. Thanks for the question. I think from the perspective, yeah, I think you're absolutely right in terms of the notion of the SUNFISH trial that we recently had data. That was a very broad trial with patients two to 25 years of age with a very broad inclusion criteria. It's much like the patient population that physicians really see day to day in their patients. We did that on purpose because that's what we wanted to see how the drug would function in that line and obviously we saw a one and a half point difference that was statistically significant, we're pretty happy with that. In terms of the FIREFISH, I think that's probably, in some ways, a more homogeneous population, although there are differences. I think you saw, even in part one, how well risdiplam functions.
Even in comparisons, you could see that it did quite well, and from my perspective, really showed to be the most competitive drug there. We anticipate for part two the same event. We already said that it was statistically significant, and that we expect, as you'll see coming up in AAN, the results of that more clearly. We're excited about that. 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. 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 see that risdiplam will do quite well.
In terms of the FA, both gene therapy and the drug, one is obviously gene therapy that will be directly into the brain, whereas the other one is the systemic molecule. Different mechanism. Maybe Marcy wants to go through a little bit of that.
Absolutely. Hi, Alethia. Thanks for the question. We mentioned before, that our interest as a company, our goal at the end of the day is to treat the entire patient. When you look into a disease like Friedreich's ataxia, you have a component that is systemic, specifically for this, amongst many others, the heart is fairly affected. Then you have the deterioration, neurological deterioration that occur with these patients over time, specifically in their teenage years and later. What you're looking into with the two modalities really to try to address most, if not all, of the issues these patients go through. By injecting directly into the dentate nucleus of the cerebellum, we expect to stop the progression of the disease and hopefully restore some function there neurologically. By giving 743, would have a more systemic measure, including the hearts.
We see both approaches quite complementary. They are in similar development timelines, although 743 is more advanced in terms of the stage of the trial. When we start this trial later this year, fully enrolling that about 100 patients, we expect that after one year and the results, this would be a pivotal trial. 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 Zone from Cowen and Company. Your question, please.
Hi there, and thank you for taking my question. The first one is on the aniridia data that were presented today. I guess, did the placebo arm perform as you would have expected with that 3.3% change? 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? Then one more on a follow-up to the first question in Friedreich's ataxia. In order to use the two 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.
Hey, thanks, Joe, for the question. Maybe the first one on aniridia, let me just say that, your point is going to, is it 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 aniridia in terms of following. The real natural history and understanding of the disease wasn't all that well understood. In fact, we initially had the trial, since it was sort of an early trial, to be a safety study compared to placebo as a treatment. We just thought that we changed to looking at mRNA to be able that if we saw something that we'd be able to go and talk to regulators.
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. That being said, in a way, we learned a lot about this, and I think as you go and look at the data in the deck there, you'll see why we think that why the drug was effective in these patients. When you compare the number of patients that saw benefit versus the placebo, why we think that it's just a change in variability of the assay, I think that would prevent it from being statistically significant. I mean, that's how we look at it. Marcio, want to.
Yeah, just a little detail to complement that. The patients were not randomized based on this criteria, right? We had some inherent variability coming from the randomization itself that was not that well balanced. Your question about placebo, the placebo behaved similarly to what we were expecting. There was one patient, as you saw there, that had a response that was somewhat unexpected, but in general, that was not the issue. It's more the size of the trial and the fact that they were not necessarily balanced at baseline since this was not the original endpoint that Stuart said. We were looking for safety and some biomarkers originally. We learned a lot. We feel that for this size of the trial, when the point estimate is moving in the right direction, it does not negate the effect we're expecting to see.
Very importantly, since Translarna in the market in several countries for DMD, the safety profile is exactly what we're expecting here.
Then the two products, the FA gene therapy versus the small molecule. So we're going to have two independent trials that we'll 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 having two products that then might, with very different, one is the underlying cause of the disease that has the protein itself, which is lost in the disease. The second one really affects most likely inflammation. So the combination of those two, we think obviously when you have inflammation, 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 protein that is not made, it would be important.
They can be worked together, but we don't think right now that we have to do a combination study.
Great. Thank you, and congrats on the progress.
Thank you. Our next question comes from the line of Martin Auster from Credit Suisse. Your question, please.
Yeah. Thanks for taking the call. I had a couple questions for you as well. From the aniridia pivotal data, I'm curious if you see any read-through to the ongoing dystrophin study. I don't know if as you've looked through maybe more of the secondary endpoints, you had any chance to analyze some of those. If there's anything in there that kind of elevates your conviction in the drug's MOA and kind of supports an expectation for a demonstration of dystrophin expression in that study. I know you've set some fairly grounded expectations around that one. The second, you guys have generally sounded, I would say, incrementally more excited about the Bio-e platform since that deal was signed and closed.
I'm curious then at the R&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. Yeah, aniridia and dystrophin I don't think are. You could say one from the other. The one who's trying to understand the clinical manifestations that would occur with treating, which we learned as a consequence of that, and the variability of the given endpoints. In dystrophin, we feel pretty comfortable that we've done all we can do in terms of assuring, as best we can, that this will be a positive study. We think that the assay that we have is incredibly sensitive and linear. We think we're in pretty good shape in terms of getting that, and we're hopeful that we're going to see. In a sense, we have data already from the 004 study. This is, we think, is this more sensitive assay that can replicate that.
That being said, we look at this as being able to have a positive result and then be able to go to the FDA for approval in the United States. In terms of the BioE platform, we're excited about that. We think it's an important platform and a novel set of compounds that work in different ways than other companies have worked on before. We're pretty excited about that, and I think you'll see on Analyst Day, we'll talk more about not only the mechanism, but more in detail of some of the things we studied. We alluded to it in the talk here today in terms of the work with some of them in terms of ALS, and we'll talk more about that and show you more in terms of preclinical clinical data in that as well.
I think there'll be a lot that you'll learn as a consequence of the Bio-e platform on the June 16th date.
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. Marcio, why don't you?
Yeah. Hey, Vincent. Marcio here. The power, we believe that in all the scenarios that we looked into as being likely, since we didn't look into just one scenario here with an absolute change, we are powered at more than 90% 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, is through a series of studies and validation work leading to this, where multiple cores were analyzed and different biopsies as well. We were able to really control that, so we're not concerned that would be an issue. There are obviously scenarios where few patients show a large increase and the majority of the patients show a very small increase versus another one that is, I would say, more likely that you see an increase throughout, but at smaller magnitudes.
In either of them, we can see the trial being well powered to show benefit and statistical significance versus the baseline since this is the measure. Based on our validation work as well, what we've seen is that the vast majority of the patients are going to be below the lower level quantification. If that is to be replicated, we wouldn't have a problem in terms of the noise that we've seen from some of the other measures. One of the reasons why we went with this method and both from the acquisition of the biopsy and the quantification of dystrophin as we did.
That answer-
Great. Thank you.
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. Number one, big picture. You've guided, as you have before, to $1.5 billion over the next few years. What are your thoughts on making sure that that can help you achieve some profitability? Just so I know you can't give guidance, but what's your thought on your goals there and how you're going to think about business development now versus you have in the past? Second question is on AADC. For the patient population that you have identified, can you give us a little bit more clarity as far as more recent splits in the U.S. and ex-U.S.? Then third, on the aniridia data, if you were to exclude that high patient, high responder patient, is there any difference between placebo and the treatment arm? Thanks.
Hi, Robyn. This is Emily. Nice to talk to you. In answer to your question about reaching that $1.5 billion revenue target by 2023, what you've seen in the past couple of years is we've really invested in driving innovation to continue to grow our revenue, and we'll plan to do that as we have new launches coming on board this year with Tegsedi and WAYLIVRA, then AADC and the risdiplam royalties. We've decided to invest in our Redox platform, our gene therapy platform, and our splicing platform. Obviously, as we get towards that $1.5 billion target, there's likely a threshold of profitability, but I wouldn't say that's our priority. Our priority right now is to really invest in accelerating those pipelines to continue to drive innovation. We've done that in the past, both through internal innovation and, as you mentioned, through business development.
While we have a lot on our plate on the internal side, we always cast a wide net and landscape the business development opportunities, and we'll be selectively opportunistic as they arise.
Yeah. 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 have more 50 alleles. In a sense, one of the questions people had is that there's a small population, so a founder's effect. That turns out clearly not to be the case. I think the split, Marcio, your team has been working pretty hard on that, so why don't you give what we're looking for in the various areas.
Of course. The split that we've been seeing is pretty even, I would say, between the U.S. and the key regions outside of the U.S. Just to remind you, we're focusing on five countries at this first wave. Brazil, the U.S., and the three largest markets in Europe. France, Italy, and Germany. We're secondarily looking to a number of other markets where we are 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 are measuring performance and how we're putting resource against, it's a split between the U.S. and outside of the U.S.
We expect about half of the patients to continuously be coming from the Americas region and then other parts from the European region, between Eric and Adrian and leaderships there. In terms of the things we're doing as well, we just started a number of new programs. As we learn more of the things that are happening and that are working or not working very well, we cycle through them very quickly. These programs include having more people in the field in the U.S., for example, and some of the points of contact that we are seeing returning more patients. As we learn, we're able to, again, focus the resource or refocus the resource towards growth.
On the aniridia outcome in terms of looking at, in a sense, sensitivity analysis of removing. We already have a pretty small patient population, but, I don't know, maybe you want to comment on that.
Yeah. It is small patient populations too, just as. It's obvious if we remove that one patient with the large result, placebo effect, we'll be seeing a larger separation here and reaching nominal statistical significance. 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 a waterfall in the slides, we see the distribution clearly skews towards increased with Translarna. It gave us confidence not only for this study, but also to some extent, to de-risk the overall platform with Translarna.
Yeah. Again, when you look at that study, when you look at the waterfall plot, which I think probably in a small patient population is a nice way to see, it's pretty apparent the effect of the drug on these patients over placebo. We look at this as we're going to be talking to physicians in the coming week and the key opinion leaders. I think we've learned a lot of this, and I think it helps, as Marcio said, really giving 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 Tammy on for Raju. I was wondering what format you might be presenting the dystrophin results. What kind of format you'll be presenting them in, whether it'll be a medical conference or a press release. If you have had any discussions or if you plan on having any discussions with the FDA ahead of that resubmission.
Okay. Yeah. We haven't yet defined whether we'll do it at a meeting or a press release. Our goal is that when we know this, to get this out as rapidly as possible. There's a good chance that 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. We'll figure that out. The second part was, Marcio?
Yeah, sure. In terms of interactions with the FDA, we've been having interactions throughout the planning phase and the execution of the study. We intend to have a pre-NDA meeting as well, if we come to that, when the study is positive. It's being discussed already with the agency. It should be in the books pretty soon. There is many other matters, as you can imagine, other than the study itself, right? There's the update of the safety database, there's the update of the other studies, the completion of the DDI studies that were done between the two submissions. A number of things there. We've been talking to the agency and having productive discussions with them.
Great. I was wondering if you could just discuss some of the potential outcomes or next steps for the aniridia program, depending on your conversations with experts. Are you guys thinking if the program might get tabled or running another study and having it powered differently? Just what your thoughts are.
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 after that. If we come with a plan, I think we'd talk about next steps then.
Thank you. Our next question comes from the line 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 biopsy be taken? Would that be taken from the same side of the patients? How many biopsies taken from each patient each time?
Sure. Hey, Gena. Marcio here. We're taking two samples for every patient, two biopsies, three cores per biopsy. We'd have a total of six as a base. There's an alternate muscle as well that we haven't described before in case there is only fat coming from the sixth. We have enough sample coming there, and as I mentioned on the answer to Vincent earlier, we have run some of the tests in terms of the validation. We know, based on the very kind donation of time and citizens that we have from different patients, that it shouldn't be a problem. We're doing the biceps and the gastrocs for the sites, the primary sites, and the TA as a secondary site or tertiary site, may I say here. The primary is really to read the six cores that it would have.
One of the nice things is, during the validation as well, is that when we compare the cores, we've seen very, very small variability. We can use any of them to measure. Did that answer?
Yeah. Will you have individual data, or you will pool these baseline data together?
Yeah. That's a very good question. The way the analysis is a difference for the individual patient from their baseline. Right. Obviously, we're going to compute that in a fair test later, statistically. Each one of those patients, we're 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 quantification, we cannot guarantee that that's the case. A simple pooled analysis and change could skew the results. Each one of them are going to be looked individually, and then we're going to compute the mean difference for all the patients.
Sorry, Marcio. I was wondering, say, each individual patient, they have six samples. Will these six samples be pooled together?
Oh, I see.
Will be individual, like a six baseline?
No. It's the best sample for baseline and for week 40 for each one of the patients. That's going to be used for the analysis.
Okay, great. I have questions regarding the mitochondrial epilepsy trial. Just wondering. Was the primary endpoint, was that based on the FDA discussion feedback? Also, how do you measure the seizure? Then do you capture both generalized seizure or partial seizure?
Yeah
record the seizure events, especially for those absent-
Yeah
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 were just approved with genetic epilepsies in general, like I'm sure you know the ones I'm mentioning. We are developing a specific diary for this trial that's going to count for this patient population. We're looking to generalize seizures at this point in time for these patients and looking for the change. There were obviously discussions with the different regulatory agencies here. The key design of this trial was agreed under our Scientific Advice Working Party protocol review with EMA, and we're using the same for the FDA, of course.
Okay. Sorry, just one more question. Regarding generalized seizure, in a case that, just wondering, will caregiver also have a follow?
Right
If a patient has a generalized seizure, and then the patient actually wasn't aware he had a seizure because he was passed out and woke up.
Right.
How would you record events like that?
That's going to be recorded by the caregiver. Actually, I should have made that clear, right? Most of these patients we're talking about are infants or toddlers or young kids. We're talking about the caregiver-recorded diary here.
Okay. Thank you.
Thank you.
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? 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 one, two, and three patients? Are there any subtypes where you think efficacy may be better? Thanks.
Yes, sure. Maybe we'll start with the dystrophin measurement. That was one, obviously, when we had substantial discussions with the FDA on this, and it wasn't one where That, in essence, I remember us discussing first saying how I'm sure you would want a Western blot. They said, "No, not really." Actually, they don't like Western blots. They understand the limitations of those. If you have a better assay, we'd be interested. We had been working on, and we had been using in our own laboratories, this unique form of an ELISA, the ECL. They liked that. We worked with them, and Marcio and the team had worked for quite some time. Maybe why don't you talk a little bit about, it was sort of a six to eight months interaction.
They were pretty much pleased, I think very much with the work and the sensitivity. I think they're very excited about this assay.
That's right, Stu. We worked very closely with the FDA and specific officers there on the validation of the assay. They are completely on the same page as we are in terms of the measure itself. Obviously, the results we're going to see after the trial is read the results soon. The assay itself, the sensitivity and the way it was validated was obviously a concern, I would say, in general, from us and from the FDA from the beginning, because this is full length dystrophin. It's very different than what others were doing. Had to have an external standard. Once you're doing the ECL, the external standard has to be hyper-pure, and so on. 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 to eliminate any potential bias that an internal lab could add to such measure, not unblinded study. That was how we got on it. Again, I 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.
Yeah. In terms of the risdiplam, in terms of the broad label, I think we're actually, in terms of the having FIREFISH and SUNFISH and not only part one, but part two, I think both of them actually help really understand and further the drug itself and how effective it can be. I think in terms of the SUNFISH trial, really, it's hard to compare because no one else has done a two to 25-year-old trial with, in such a broad label, a broad inclusion criteria that we have patients with scoliosis, with Hammersmith Scale scores less than 10. I should point out that those in the real-life patients, even in the two to five-year-olds, 20% of the patients had Hammersmith scores less than 10, and the result was scoliosis and contractures. You're really going to have a hard time.
We're pretty excited 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 this data when you talk not only to physicians, but to payers, that you've actually studied the types of patients that you're going to be treating. In fact, no one else has that. I think in terms of when you think about FIREFISH, I think if there's anything for comparable, I think that becomes clearer, and I think in terms of looking at age is probably the most determinative thing where you could see. I think you could look at the risdiplam data and patients greater than 5 months of age, you still saw increases in CHOP INTEND, and that wasn't seen in other trials as well.
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 patients, but also in the type 1 patients that were even older. We're pretty happy about that. We look forward to actually talking far more about that at the AAN. I feel 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.
Thank you.
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 from me today. First two on the Lat Am franchise. With Pamparao getting an Anvisa approval, can you talk about what advantages having an established Lat Am infrastructure gives you guys for marketing Tegsedi? On WAYLIVRA, following a positive phase III BROADEN study in FPL, will any of that data be included when you guys submit in the second half? I'll have one follow-up on the Redox agent.
Sure. Thanks for the question. Talking a little bit about Lat Am, right? The approval of Tegsedi last year, giving us a lot of advantage here in terms of the overall timing first. A lot of things were done in between. One of them, obviously, we had to get a price agreed with the government just to sign new. That takes some time, and we're well on the way here. The second is the genotype infrastructure. As mentioned on my prepared remarks. Hundreds of patients now with genotypically confirmed hATTR, not only in Brazil but in Argentina and Colombia and other places. We are way ahead of the game there.
The last one that is not less important, I would say, together with the infrastructure that we have in the country that is very robust since we have substantial sales of Translarna from the region, is the fact that the health system, I can look at the situation we're all right now discussing health system capacity in the world in general. I don't think you want to overload hospitals with IV deliveries in general. The ability to deliver this on people's home, the ability to monitor them, as we have the nursing network, has been quite fundamental, and we're seeing really positive feedback. The launch is now underway, and we should expect to see more and more updates from us in relation to that. Your second question in relation to WAYLIVRA.
The first approval we expect for FCS and shortly thereafter to complement that data set with FPL. We wouldn't be, at least our base case right now is not to have the two indications up front.
Got it. Thank you, Marcio. On the 743 redox agent in epilepsy. For that pivotal study, can you maybe talk about how you 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? Going one step further, if this study is successful, what could the indication look like? Is there any potential for, if there's a clear benefit in some genetic subpopulations for a smaller approval?
Yeah. No, that's a great question. It's kind of both in this study. As we went through the scientific advice, what we heard very loud and clear, specifically from the EMA, is that they wanted both a very general population in terms of genetically defined mitochondrial epilepsy with seizures that are not controlled. We could potentially treat any patient, any comers after the approval, if an approval is to come, but also to have the most common mutations being represented. We're going to be discussing that a little bit more in detail, but there are four major groups of mutations that is going to have a balance for those patients. One of them, one of the most common, is Leigh syndrome, might be familiar in MELAS, as well amongst others.
On the June 16th, we're going to be well on the way on planning this and hopefully executing as well. We're going to be discussing exactly what is the expectation of the trial and the market potential and so on. As I mentioned on the prepared remarks as well, we do expect about 5,000-6,000 patients to be the addressable population here, so it's very large. 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. This would be really life-changing for them, and we really expect and we're powering this trial for success.
Great. Thanks, Marcio. I appreciate it.
Oh, 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 that you'll be comparing the best sample at baseline to the best sample at the end? How is the best sample determined, and why not use the average? Second is, I was wondering, you allude to a very low variability in the validation test, and I was wondering if you could quantify the degree of variability you've seen and how were those run. Well, maybe a third actually. Given the FDA has shown comfort with using Western blot historically, even if it 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 Western blot?
Yeah. Maybe I'll start with the last first, is that while I don't think they're actually all that comfortable with Western blot. I think it's the best test they probably had, but they don't think that it's a great assay for a large protein that doesn't blot very well. We thought also it 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. At the end of the day, we think that a more reliable assay gives a better chance for success. Once you've, Marcio.
Sure. The decision about using the FAST cage, one, it's obviously result simulated, and the way it's the most reliable. One, you can have a situation on one of the cores or one of the samples is completely infiltrated by fat. That's one of the reasons not to average, because it wouldn't be a true average. We just got unlucky to some extent. I think when you look into other studies, our study cores, for example, all the studies gave gain by Marine Ron, and to extend 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. That's one of the reasons to use. The other is, as you asked in terms of the validation itself, the expectation, we didn't know where the sample was coming from.
We're asking the question, can I biopsy a patient multiple times and see the results that are very similar? The answer is yes with this method. One more reason not to use other methods, like if you look into both types of biopsies that were used before, number one, and quantification methods that were used before, you see intra-sample variability of 30% or 40% sometimes. That's obviously not acceptable. As Stu said, when you blot a protein this big, you're going to have intrinsic variability unless you're looking for a super truncated part of the protein, but that's 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 CEO.
Thank you. Thanks for joining us today on the call. I don't know, as you may be aware, Rare Disease Day was this past Saturday, and I think it's a good time for us to take stock of where we are as a company and the importance of the work that we do that ultimately would benefit patients. 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. With that, let me thank you again, and we look forward to seeing you at our Analyst Day later this year. Thank you.
Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.