Good afternoon, ladies and gentlemen, and welcome to the PTC Therapeutics third quarter 2018 earnings conference call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Ms. Emily Hill, Head of Investor Relations. Ma'am, you may begin.
Hello. Good afternoon, and thank you for joining us to discuss our 2018 third quarter corporate updates and financial results. Joining me on today's call is our CEO, Stuart Peltz, our Chief Operating Officer, Marcio Souza, and our Principal Financial Officer, Christine Utter. 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 our slide on our simultaneous presentation, which contains our forward-looking statements. 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 quarterly reports on Form 10-Q and annual report on Form 10-K filed with the Securities and Exchange Commission, as well as the company's other SEC filings, including our current report on Form 8-K filed on August 24th, 2018. 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 for joining us this afternoon. Joining me on the call today are Marcio and Christine. Marcio will provide the commercial and clinical development updates. Christine will review our financials. I'd like to ask you to turn now to the slides we have posted on our website to highlight some accomplishments in the third quarter. Let's start on slide three. I'm going to spend time on today's call talking about our path to continue to build a leading fully integrated biotech company that has multiple platforms. Our mission over the last two decades has been to be a scientifically innovative company that discovers, develops, and commercializes new therapeutics for patients suffering from rare disorders with high unmet medical need. From this effort, we developed a strong DMD base business, a potential best-in-class therapy in the development for SMA, and two therapies in clinical development for patients suffering from rare cancers.
At our Analyst Day earlier this year, we went into detail on our orphan oncology pipeline. Our development strategy is to generate early clinical data showing benefit to patients in these programs, and then determine the best path that maximizes shareholder returns. I am happy to report the most advanced programs, PTC299 and PTC596, have recently entered the clinic. These efforts have built a strong commercial and scientific infrastructure with a solid revenue base. Over the next three to five years, our strategy is to continue to build and grow our orphan disease franchise, creating significant value for all of our stakeholders. As you can see on our pipeline chart on slide four, we are excited to be in such a unique position. We have a strong revenue base, strong talent, and a diverse portfolio of small molecules and gene therapy candidates.
This includes therapies in development, as well as products in regulatory review or have been approved. We will maintain our focus on the rare disease space, focusing on monogenetic disorders with high unmet medical needs. Next, on slide five. I am pleased to report that we have already been executing on this strategy. With the acquisition of the gene therapy company, Agilis, we have added three gene therapy programs, including one program with robust clinical results that is expected to be submitted with regulatory authorities next year. In addition, we have in-licensed two products from Akcea, in which we will be commercializing in Latin America. This is the first public call since the closing of the Agilis transaction. I could not be happier with the integration that puts PTC in the position to bring potential life-transforming treatments to patients using our newest innovative platform, the CNS gene therapy platform.
I want to spend time reviewing this with you. Please turn to slide six. When we began our business development process, one of the principles was that as an ultra-orphan rare disorders company, we needed to have gene therapy as one of our platforms to treat monogenetic disorders. We were interested in certain approaches to gene therapy. Specifically, we wanted at first to focus on utilizing gene therapy targeting tissues with low turnover to ensure durability of effect. We also considered that delivering gene therapy to a small, contained region of the body has the advantage of being able to use microdoses to treat patients, allowing manufacturing of lower amounts of the viral therapy.
These considerations led us to the acquisition of Agilis with their CNS gene therapy platform. Our three lead gene therapy programs in CNS are for Aromatic L-amino acid decarboxylase deficiency, or AADC, Friedreich's ataxia, or FA, and Angelman syndrome, or AS. What they all have in common, in addition to being CNS disorders of high medical need, is that targeted delivery of the gene therapy can be employed. Next, on slide seven, the market opportunity for each of these gene therapies is exciting. Our estimate for the combined potential market of these indications is 100,000 patients, including approximately 5,000 AADC deficiency patients, 25,000 FA patients, and 70,000 patients suffering from Angelman syndrome. We believe this is a valuable platform, and we estimate that the combined addressable global market for these programs is in excess of $5 billion.
One of the major benefits of this CNS therapy approach is the small quantity of material required. For instance, the direct injection of the AADC gene therapy into the brain utilizes a microdose of viral vector of only approximately two times 10 to the 11th viral particles. This is the total dose, and is between 1,000 to 10,000-fold smaller compared to the systemic gene therapy dosing. This reduced dose requirement allows for scalable modular manufacturing. Because delivery in the CNS is relatively contained and only small doses are used, there is a lower risk of immunogenicity. In fact, almost no immune response has been observed in the AADC gene therapy program. Lastly, another important point is that of the durability of the response, which is an issue in growing tissues.
The CNS tissue has a lower rate of cell turnover, which is important because it allows the virus to be maintained and adds to the durability of effect of the gene therapy treatment. In sum, the low dose required for targeted gene therapy, combined with targeting slowly dividing cells, is a strong competitive advantage of this platform. Turning to slide eight. These gene therapy programs to treat the orphan neurological disorders fall into our area of expertise. We have over 20 years of experience discovering, developing, and commercializing therapies for rare disorders with high medical need. We understand the rare disorder market and have experience with country-by-country market access and pricing, driving genotyping efforts, and patient finding. This is enabled by our global commercial and medical infrastructure and is the basis for our success in commercializing rare disorder products.
I'd now like to talk more in depth on the two most advanced programs in our gene therapy pipeline. Let's turn to AADC deficiency first, starting with slide nine. AADC deficiency is a devastating disorder which halts infant neurological and motor development, and similar to spinal muscular atrophy, the children are never able to achieve motor milestones such as holding their head up, sitting, or standing. In its most severe form, this disorder results in childhood mortality between four and eight years of age. Following a single direct CNS gene therapy treatment, these patients have shown improvements in functional developmental milestones, including having the ability to hold a head position, to sit, to stand, and even to walk. The results in clinical trials have shown increases in motor functions that were durable in the five-year clinical trial follow-up. Now, let's turn to slide 10.
The AADC treatment is delivered via a single dose through direct delivery into the putamen using an established surgical technique. The AADC gene therapy program has substantial long-term evidence of durable clinical benefit. The first patient was treated eight years ago. Our regulatory package relies on data from 26 patients treated over the past eight years. The data for this regulatory package has the longest term follow-up demonstrating durability of effect in the gene therapy space. The improvements in these patients have been measured using multiple motor scales. Here on slide 11, you can see this. Observed clinical improvements are seen here in two clinical trials. The Peabody Developmental Motor Scale demonstrates clinical improvement in treated patients at the one and five-year follow-up. As you can see, every patient experienced rapid and durable improvements in both fine and gross motor skills, regardless of their age when the treatment was initiated.
This is compelling when set in context of the natural history where none of these motor milestones are achieved. Patients in these studies demonstrated remarkable improvement after gene therapy treatment, including head control, sitting, and standing. What's really remarkable about this gene therapy are the transformative changes that were observed in the treated AADC patients. I would like to share a video demonstrating robust improvements in motor development and cognitive ability in an AADC gene therapy-treated patient. On slide 12, I'd like to share one of the many videos we have of such a patient. What you will see here is a child suffering from AADC deficiency at two years old, before initial treatment. You can see the child has limited motor function and is unable to lift his head or sit. At two years of age, he received a single treatment.
You can see, after one year of follow-up, there is substantial change. You can see the child sitting upright independently and grasping a mirror. After an additional year of follow-up at four years of age, we see continued growth in fine motor function and cognitive improvement. The child is now standing and interacting with a caregiver. We believe these results are impressive, and you can see why we're excited to bring this therapy to patients as rapidly as possible. We are working on the BLA now and expect to submit in 2019. Turning to slide 13, let me transition to Friedreich's ataxia gene therapy program. This is the most advanced program in development for the underlying cause of FA. FA is a triplet repeat disease causing the loss of frataxin protein.
Again, the gene therapy will be directly targeting the appropriate region in the brain that is involved in ataxia and will be utilizing microdosing. You can see on slide 14, we're very encouraged by the preclinical data showing that in two large species, protein levels above the normal have been achieved. The robust animal data allows us to find an appropriate dose range to be used in patients. Let's move to slide 15. We plan to file an IND for the FA gene therapy program in 2019 and start dosing patients. We believe this program will benefit from high patient advocacy group engagement. We already have a good relationship with FARA, the leading FA patient advocacy group. Let's move to slide 16. We are very excited about the path forward for these programs, including the earliest stage program in Angelman syndrome.
We're very proud of our gene therapy pipeline, which we believe will drive both near and long-term value creation for patients and shareholders. I'll now pass the call to Marcio to review our growing DMD franchise and the products for which we in-license in Latin America commercial rights. This important new collaboration with Akcea leverages our strong commercial infrastructure and brings us two new substantial commercial opportunities. I will also ask Marcio to update you on the advances that we've made in our niche oncology programs.
Hey, thanks, Stu. As part of the strategies Stu just outlined, we also looked for in-license opportunities that would leverage our strong existing commercial infrastructure. In the third quarter, we were pleased to announce an important agreement with Akcea, which allowed us to commercialize two rare disease drugs in Latin America, Tegsedi and Waylivra. Tegsedi has been approved for the treatment of patients with hATTR with polyneuropathy in the U.S., Europe, and Canada. The polyneuropathic form of hATTR occurs more frequently in individuals of Portuguese ancestry. Because Latin America, and in particular Brazil, contains a large portion of such patients, the region is of strategic importance for Tegsedi. Based on market research data we conducted, we have learned that Tegsedi is highly regarded by physicians in Latin America for its clinical profile.
In fact, the predicted allocation of market share by the physicians shows a predominant use of Tegsedi over competitive products. We believe an additional contributing factor for this competitive advantage is that the subcutaneous delivery method is preferred in Brazil, which as a country lacks sufficient infrastructure for infusion center across its extensive geography. We estimated about 6,000 eligible patients in Latin America for Tegsedi. Genetic confirmation of hATTR diagnosis and general patient mapping are key next steps to enable successful launch, and we are well underway with such activities. On the regulatory front, we intend to file a market authorization with Anvisa in the first half of next year. Our strong existing business infrastructure positioned us as a partner of choice for Akcea. This infrastructure is based off the success of our growing DMD business with both Translarna outside of the U.S. and EMFLAZA in the U.S.
Our DMD franchise was strengthened in the first half of this year on several fronts. The EMA approved a label expansion for Translarna in nonsense mutation DMD for patients aged two to five. Because DMD is a degenerative disease, treating patients early allows for better preservation of muscle function. Importantly, this label expansion allows patient encounters that recognize DMD approval to gain access to therapy at a younger age. We have recently submitted for a label expansion for non-ambulatory patients. The EMA has validated our application, and we are working now going through the regulatory process. While most clinical programs focus on ambulatory patients, there is an equal and urgent unmet need to treat non-ambulatory patients with DMD. Our DMD franchise also includes EMFLAZA for all U.S. DMD patients over age 5. We are working hard to establish EMFLAZA as the standard of care in the United States.
As we stated last quarter, there are a number of levers to pull to effectively establish EMFLAZA as a standard of care. One such factor we discussed was the bridging program to allow for access to therapy before reimbursement. This was important, too, in our early commercialization efforts to bring patients on board. For a subset of patients, however, the bridge program is low reimbursement timelines. In September, this program was discontinued, and patients from Bridge are now being transitioned to commercial products. We are seeing the early impact of this change since the end of the third quarter. In addition to the termination of the Bridge program, the recent publications regarding EMFLAZA's effects support our efforts to establish its standard of care. We remain focused on maximizing the value of EMFLAZA, and part of the equation is to have the right structure in place.
Based on our experience over the first year, we've been able to adjust and redeploy our field force. We have recently decided to expand the field team, both on the medical and commercial side of the business, to increase our coverage to the accounts, especially the ones outside of the main centers. In the third quarter, our revenues for the DMD franchise totaled approximately $53 million. This includes $22.6 million for EMFLAZA and $30.4 million for Translarna. Since the close of the third quarter, we have received a sizable order of Translarna from Latin America, which is in the process of being finalized. Based on this visibility, we are maintaining our 2018 Translarna guidance of $170 million-$185 million for the full year.
For EMFLAZA, based on our visibility of individual patient use and order dispensing dynamics, we are narrowing the range of our guidance to $90 million-$95 million. Therefore, we are adjusting our DMD franchise guidance for the full year 2018 to $260 million-$280 million. We're also reiterating our guidance of 15% composite growth for Translarna through 2022. I want to express my enthusiasm for our gene therapy platforms. We have started pre-commercial efforts ahead of our BLA filing for AADC next year. These efforts include patient identification, mainly in cerebral palsy and epilepsy centers, where AADC patients are often misdiagnosed. We have preliminarily identified a large group of patients with cerebral palsy with normal MRIs. At this stage, we believe there are in between 100,000-150,000 patients from these centers with normal MRI who should be screened for AADC.
We are in the late stage of establishing partnerships to sponsor the use of a sensitive and low-cost blood test, which can be used to screen those patients for AADC deficiency. Because patient finding and identification have such a strategic value and impact for all current and future indications we are working on, we have decided to create dedicated units within medical affairs to globally coordinate such efforts. We are happy with the progress we've seen so far in patient identification, and we plan to share more details early next year. Our research supports the prevalence previously reported. We estimate 5,000 patients worldwide, with about 1,200 patients in the U.S. living with AADC deficiency. Let me now transition to another important milestone achieved this quarter in our oncology portfolio.
At Analyst Day, we shared our goal to file an IND for PTC299 in AML and have it cleared with the FDA before the end of the year. I am pleased to report that we not only achieved this. We also have the site open and have the first patient screened in this trial. We expect to continue to advance 299 in the AML indication during 2019. Our second oncology candidate, PTC596, has progressed as well. The DIPG trial is open for enrollment. We expect the second trial in sarcomas to be open before the end of the year. We look forward to sharing more on these programs as they progress. I'll now turn the call back to Stuart. Stu?
Thanks, Marcio. Most of you are familiar with our spinal muscular atrophy program, which is in pivotal studies. The SMA program reflects the scientific innovation of which PTC is founded. The idea of a small molecule selectively altering splicing was foreign only a few years ago. This technology has now been used to discover potential new therapies for SMA, a rare genetic neuromuscular disorder that generally manifests early in life and is the leading genetic cause of death in infants and toddlers. We have a robust program in collaboration with Roche and the SMA Foundation around oral SMN2 splicing modifiers. We believe that an oral systemic therapy provides a competitive advantage because of its broad tissue distribution, systemic SMN protein increases, and ease of administration. Earlier clinical data has shown that risdiplam drives SMN2 splicing towards a complete restoration of full-length SMN2 messenger RNA.
This program is currently in pivotal stages with 2 registrational studies, FIREFISH for type 1 infants and SUNFISH for type 2 and 3 patients. Data from the dose-finding arms of FIREFISH and SUNFISH were recently presented in the World Muscle Society Congress. An important aspect of the World Muscle Society Congress presentations was the first clinical data presented from the type 2 and 3 patients. The SUNFISH study reported a median 3-point improvement in motor function measurement at 12 months of treatment. The pivotal portion of SUNFISH is fully enrolled and powered to detect a 3-point difference in motor function measurement at 12 months. There is a potential to file an NDA for this program as early as next year.
The SMA program is not only progressing towards an oral and systemic treatment for SMA patients, it also validates that our splicing platform technology can identify selective compounds that modulate pre-mRNA splicing. We are now applying our expertise to other challenging diseases with high unmet medical need and have internal preclinical programs. These include programs in Huntington's disease and familial dysautonomia. I'd now like to turn the call over to Christine Utter, our Principal Financial Officer. Christine?
Thanks, Stu. Earlier today, we issued a press release summarizing the details of our financial results for the third quarter of 2018, and I refer you to that release for full details. I'll start with a few comments on our financial performance and our guidance for 2018. Starting with our top-line results, we reported $53 million in combined revenue across our DMD franchise for the third quarter of 2018, compared to $41.8 million in the third quarter of 2017. Translarna net product revenues were $30.4 million for the third quarter of 2018. This compares to $32 million in the same period last year. As Marcio mentioned, we recently received a large order from Latin America. This visibility allows us to reiterate our full-year Translarna guidance. Our Translarna guidance of $170 million-$185 million contemplates uneven ordering patterns and reflects the total patient demand for the year.
We are happy to reiterate our 15% CAGR for Translarna through 2022. For EMFLAZA, we reported net product revenues of $22.6 million in the third quarter of 2018, an increase from $9.8 million reported in the third quarter of 2017. We adjusted the range on our EMFLAZA guidance for 2018 to $90 million-$95 million from the prior guidance of $90 million-$110 million. As a result, we are adjusting our 2018 DMD franchise revenue guidance to $260 million-$280 million from $260 million-$295 million. Non-GAAP R&D expenses were $49.9 million for the third quarter of 2018, excluding $4.4 million in non-cash stock-based compensation expense, compared to $26.4 million for the same period in 2017, excluding $3.6 million in non-cash stock-based compensation expense.
This increase in R&D expense reflects increased investment in our research programs and the advancement of our clinical pipeline, as well as the Akcea upfront licensing fee of $12 million paid during the third quarter. Non-GAAP SG&A expenses were $33.9 million for the third quarter of 2018, excluding $4.5 million in non-cash stock-based compensation expense, compared to $27.9 million for the same period in 2017, excluding $3.5 million in non-cash stock-based compensation expense, reflecting continued investment in commercial activities to support our DMD franchise. Net loss for the third quarter of 2018 was $51 million, compared to a net loss of $33.7 million for the same period in 2017. Cash, cash equivalents, and marketable securities totaled approximately $249 million at September 30, 2018, compared to approximately $191 million at December 31, 2017. We are proud of these transactions we announced in the last few months.
As a result of these transactions, I'd like to update our non-GAAP R&D and SG&A expense guidance for the full year 2018 to $280 million-$290 million from the previous guidance of $250 million-$260 million. This increase reflects our investment in the gene therapy programs and also includes the upfront licensing fee to Akcea paid in the third quarter. This non-GAAP guidance excludes estimated non-cash stock-based compensation expense of approximately $35 million. I will now hand the call over to the operator to start our question and answer session. Operator?
Thank you. Our first question comes from the line of Ritu Baral with Cowen. Your line is open.
Hi, guys. Thanks for taking the question. Could you walk us through a little more about the dynamics that you're seeing with EMFLAZA that's leading you to sort of tighten the range? Forgive me if I missed it, but is it connected to the discontinuation of the bridge program in some capacity? Can you talk about what you're seeing? I've got one follow-up.
Sure. Hey, Marcio.
Yeah, of course. Hey, Ritu. It is and it isn't, right? It is in a sense that was one of the drivers I discussed last quarter in terms of accelerating the conversion, that we were looking to this at the beginning of the year. As I mentioned before, we normally expect the conversion between prescription to dispense around 3 to 6 months. We're trending more towards the upper ends of this guidance. Part of this was a large number of patients that we had on this bridge program, where we saw some apathy on the patient and on the physician side to give us information to continue to move forward. One of the decisions we made was to terminate this program so the sense of urgency would be instilled to move things forward then. This is having an impact, and it is moving.
With that, we are being able to model and to look into individual patients. Now, the dynamics of the market in general, when you look into individual patient conversion, the number of prescriptions we have right now, ordering patterns for the specialty pharmacy is what is letting us or getting us to narrow the range, since we are relatively close to the end of the year. That's the main reason why, considering the base of patients we have and the number of scripts we are seeing per day.
Okay. Is it fair to say your time to fill is continuing to improve and that your insurance discussions and coverage is not getting worse?
Oh, no, it's definitely fair to say it's not getting worse. If anything, our team is out there really trying to remove some of the barriers. I mentioned this before as well in previous call. The most common step edits we have is around 6 months on prednisone previous to start EMFLAZA. What we are seeing is a number of plans, and it's still a small number, but we see this improving moving forward, removing that altogether or reducing to a number of weeks or reducing to one or two months. We're seeing improvements on the general condition, and now it's really getting this paperwork through, getting these patients that we have in-house. It's still on the order of hundreds that we have in-house, move to commercial while we build the new prescription. In a sense, the entire team focus is twofold, right?
One, for this year, and to get to the numbers that we just discussed, is continue to execute on the conversion, but keeping an eye on building the number of prescriptions for next year as well. We have a lot of focus and great daily calls and with different accounts and moving. I'm pretty confident as we move forward to have a good end of the year.
I think it's also we're trying to remove the impediments, as Marcio said, and we're helping them by the number of publications that continue to come out demonstrating that EMFLAZA has superiority over prednisone. Now not only the SYNERGY data that came out, that publication, the paper on the ACT DMD trial, and there's others that are coming out as well. I think that's helping as well.
That's definitely helping. Yeah.
Yeah. I was able to follow that. Can you characterize persistence on treatment and how that figures into everything?
Yeah. Persistence, like in the U.S., one of the advantages that we can track, and we do track patients every order. We are seeing a very good persistence on treatments. One of the things that we didn't quite tackle this year to the extent that we would like to is adjustment of dose to a dose that is, in our view, more associated with better therapeutic index on these patients. That's something, moving forward, we're going to put a little bit more focus on. Since we discussed this before, but maybe it was not clear, some of these patients are on half of the therapeutic dose, for example. We're discussing actively with the prescribers if this is a leftover from the previous regimen or if it's really something they want to focus. Persistence being really good.
What we ideally want is persistence at the best dose for that given patient, and we're moving towards that as well.
Got it. Super helpful, guys. Thank you.
Oh, thank you.
Thank you.
As a reminder, ladies and gentlemen, please press star and the number 1 on your touch-tone telephone if you'd like to ask a question. Our next question is from the line of Martin Auster with Credit Suisse. Your line is open.
Hey, all. Thanks for taking the question. Appreciate it. I had a question. Was wondering if you could give us an update on when you expect the enrollment in FIREFISH to complete, and also just with the SUNFISH phase pivotal part of that trial completed, is there anything you can tell us about the baseline characteristics around the age of the patients or the SMN2 status or things like that? Thanks.
Sure. Yeah. Thanks for that question, Martin. Two things. One is the, as we all know, that the SUNFISH trial has completed enrollment and probably at the appropriate meeting, we'll be describing what the baseline characteristics are like. We'll do that at a meeting most likely. In terms of FIREFISH, as we said, that we anticipate that it would be completed by the end of this year, and we fully expect that to be the case, so that it would be completed, enrollment would be completed by the end of this year, and the trial would be finished next year. We fully expect that to occur. We believe that we're well on track to finish enrolling that trial.
Great. Thanks. If I could maybe ask a follow-up, I had a question about the AADC gene therapy program. Thanks for giving us a little bit, sort of deeper look in your gene therapy programs overall. I was curious, what can you tell us about the differences of your approach versus other clinical stage AADC approaches that are directed at Parkinson's? Is there a long-term opportunity for this product to potentially be developed for that market as well? Thanks.
Sure. Maybe I'll start.
Of course. Yeah.
Yeah, so our view of the AADC in terms of it's obviously, in this case, a deficiency of the decarboxylase gene, where we think by injecting into the putamen gives the results that you see here that we showed within the video, and there's many videos that do that. We think that's clearly versus Parkinson's or something else, which is probably this is more for the direct effect of the disease, not for the symptoms of it. It's a difference in that perspective. Maybe you want to-
Yeah. Two, on the biology itself, right? The cells are preserved here that we are injecting on the area. We can go to the general area in the putamen. Maybe this was not clear before. The precision of the procedure obviously has to be precise, but it's not as precise since it's largely preserved. These are normal brains, in terms of neuroanatomy, where you are just trying to get dopamine to be produced. As you've probably seen before, Martin, like in the PET scan images, we're seeing all the way to five years that that's why we have PET scans. We're seeing the production. In Parkinson's, one of the potential issues here is you have degeneration, right? What you're trying to do, is to find the cells that are still able to have an effect.
Underlying cause versus potentially reducing the effects, that those are likely or actually in reality, the models to be quite different, here as well. You might have a little bit different constructs. If you look forwards, it wouldn't be outside of the things we are considering potentially expanding this program. The current focus of the company, I think we've been clear, is on rare disease, and we're going to continue to plow through that and to deliver these treatments. The AADC team is laser focused on getting the BLA filed next year and getting everything ready. We continue to discuss the management and other areas of the company potentially expanding.
Yeah. In that view also, we know that for this, we know it's due specifically for mutations in the DDC gene. In the case of Parkinson, there could be multiple other genes that could be involved in this as well. Even for making for dopamine, it might be one of the other genes. You might have to, when you think about how to do this, you may do it in a way where you have multiple genes being expressed. There's more things to think about in general of how you would do a general gene therapy, perhaps for treating Parkinson's patients.
Thanks for your thoughts on that. Appreciate it.
You bet.
Our next question is from the line of Joel Beatty with Citi. Your line is open.
Hi. Thanks for taking the question. First one is on EMFLAZA. Given the hundreds of patients that have a script but it's waiting to be fully processed, do you anticipate that most of those patients will go on to be started at EMFLAZA at some point in time? Or could there be a sizable number of those patients that may eventually not be able to transition for whatever reason to EMFLAZA?
Yeah, we are committed, Joel. Martin. We are committed to get every patient who is prescribed EMFLAZA to eventually get it, right? The conversion rate is actually very high. In the order, like very, very high, as you would expect. It's just a matter of time, in general. Obviously, some of these patients never qualify, for one reason or another, and we have a PAP program as well, where some of those patients go through. We continue to look into ways for them to be on therapy. Sometimes they never had exposure to prednisone, and they are in a plan that really requires that, and they have to get exposure. At the end of the day, we're seeing like a terminal conversion extremely high, and we're considering talking about these numbers in the next call as we finish the year and so on.
Not as much of a problem in terms of getting them there, eventually, but it's more on the timing of getting them there. When a physician prescribe EMFLAZA right now, what we are seeing, and Stu always highlights the publications and so on, they really believe it. It's more of a question of really the back and forth with insurance that I guess, you're always hearing from other companies as well as we are, right? On how much back and forth has been happening right now, and we are no different than that. The order of magnitudes for EMFLAZA, for our neuromuscular clinic is much higher than for the other products.
It's a lot of their attention and paperwork, and we've seen that's taking a little bit of the slowing down that we mentioned before, and that's why we put extra incentives for people to really pay attention and give the attention this deserves, and we're seeing some good traction there.
Yeah, I think also, as Marcio said, we had a large number of patients who were in the bridge program that transitioned over. This is sort of, there's always some where if you don't put in some sort of an additional pressure, it would stay on until a pressure is being put on. This is our way now of sort of moving those patients through the process. That additional pressure just seems to be working. It's sort of a reminder that it's not here forever, and that you have to move on to commercial drug.
Yeah. That's right.
Got it. That makes sense. If I could ask a question on the AADC program. Could you give us an update on the key steps that still need to take place before filing the BLA in 2019?
Sure. I'll start. Then I'll test. Just a reminder, the AADC program, as we have discussed previously, and I even think I had talked here, is that obviously we think the data is quite good and that it's really now, from the regulatory discussions, that it was a matter of that it's ready to be filed. Really, we're having discussions now in terms of that. Obviously the next step is to make sure the CMC is ready for the filing. Let me pass that to Marcio-
Yeah
to focus on that.
Of course. Thanks, Stu. We have a strategic partnership with MassBiologics to manufacture this. The key step here, I would say the most important step is really to continue to produce material towards the ones to be commercialized. We mentioned previously, and I believe we filed in the Q that we had some interactions with the FDA. We're expecting to have more interactions with the FDA. This is progressing nicely in terms of conversations we had before and parameters and strategy for CMC that we had discussed continue to look positively for what we are doing with MassBiologics and internally here at PTC as well. We affirmed today that we are filing the BLA next year. This is all progressing nicely. On the clinical models of the BLA, on the preclinical models of the BLA, we're all now moving towards finalizing the documentation.
We want to be as ahead as possible in terms of everything that is not rate limiting. I'm very happy with the progress that that's taken. At the moment we have the final CMC package, we can submit it next year. Everything is moving from a regulatory perspective with the U.S. very nicely. The package for Europe is very similar. That's all based on the same. Our team in Europe is working towards that submission as well. That includes few other steps, as you know, like pediatric investigation plan and so on. Everything is progressing. We should be able to file a BLA and an MAA in Europe and potentially other jurisdictions in a very short period of time to each other. We're very happy.
Again, I know it was not in your question, but one last thing here. The patient identification has been going very well as well, as I mentioned on my remarks, because obviously we want to make sure to get the launch and to have a good base of patients who benefit from this launch. They're going hand in hand.
Great. Thank you.
Our next question is from Gena Wang with Barclays. Your line is open.
Hey, this is Sherman Dahlin for Gena. Thank you so much for taking our questions. Maybe just a couple from me. For Translarna, can you give us more color regarding the growth in different geographies? Also if you can exclude the Latin America part. The second part is can you update us regarding the U.S. regulatory status? Like when do you plan to start the dystrophin biomarker study?
Sure. Okay. Maybe I'll start and then we'll go in. From the regulatory status for the dystrophin study, I think as we've said, we plan to start the dystrophin study by the end of this year, so that it'll be completed by the end of next year and would be filed after that. We're on target to do that as well. We feel good about getting that going. Therefore it's anything really above background, in terms of the amount of dystrophin that would actually give us the accelerated approval. We feel good about moving about that. In terms of Translarna's growth and development, I guess what I could say on the high level is that we continue to grow Translarna in all the areas. Maybe I'll let Marcio go into some details in terms of-
Sure
the dynamics of the area.
Sure, Stu. Two major areas for us, right? The European and Middle East area and the Americas, that's how we look. It's a basket of countries in each one of them. We see progression, when you look into the full year, and we always look into full year because inside each one of those regions, there is several countries with very uneven order pattern. It doesn't make sense to look quarter-on-quarter for us.
When I look into my full year latest estimates that we always run periodically here, that is double-digit growth in each one of them, which is exactly where I would like to be, which put us in a position to continue to reinforce and reaffirm the 15% long-term growth to 2022 that we mentioned before. Specifically on Latin America, that we called out in the Collins part of your question, like Brazil, Argentina, Colombia, important business for us. We always monitor there. There are countries that are used to only order periodically through the year in lump sum, I would say, orders for several patients. We receive one of these orders after Q3 ended for Latin America specifically, working through the paperwork right now to get it shipped.
That's something that sometimes get a little bit delay from one quarter to another, and that's why we always message that and talk to all of you about how lump it is. Having that in hand relatively early in Q4 give us confidence to get the guidance where we are for the year. Does that help?
Yeah. That's very helpful. Thank you so much.
Maybe it's also worth, though, just for everyone to know, is we always talk about lumpiness of Latin America, but even country by country over time, maybe it's worth talking a little bit-
Yeah
about that as well.
Sure. That's what I was mentioning in terms of even Europe, right? We are shipping to more than 40 countries now. When you look into the combination of all of them, several of them have orders for more than three months throughout the years, just because of that's how their supply agreements work. It end up being lumpy in general. One of the reasons why we got this question before, why not looking to quarter by quarter, for us, it's really not possible right now. We have a exclusive ex-U.S. business for Translarna, it's fairly unusual. There's not a lot of other products that are like that, it's a very common pattern, to Stu's points. We highlighted more Latin America before, it's really in general, in our business.
We sort of know how many patients there are and how much we get over the year, but the ordering patterns could vary. That's just, I think, important for people to understand over the time within Europe.
Okay. Thank you so much.
Thank you.
Our next question is from Brian Abrahams with RBC Capital Markets. Your line is open.
Hi, this is Bert on for Brian. Thanks for taking our question. I wanted to ask on your new oncology studies, could you just remind us of the pharmacology of 596 and 299, and maybe talk a little bit about the DIPG, like the incidence and prevalence in the clinical course of that disease?
Sure. I think you're referring to what's the mechanism of action.
Yes.
Yeah, sure. Maybe we'll start with PTC299, which is an inhibitor for dihydroorotate dehydrogenase. It's a very potent effective inhibitor of that. That turns out to be important, in particular in leukemic cells, where you need pyrimidines to be made, and if you inhibit that, you can actually cause differentiation of leukemic cells into that, and that's been seen not only over in the diverse array of leukemias, but in particular in AML itself. We think this has a very promising effect, possibility of having effect in these diseases. We also know already just because of our previous clinical studies in this, that we know we do see inhibition in patients of DHODH by seeing increased levels of the dihydroorotate in the bodies when you treat patients with PTC299. We know we're on target.
Now all we need really to go is to prove the next hypothesis, which is that will cause leukemic cells to differentiate. We feel pretty good about that. PTC 596 was identified as an inhibitor of BMI-1, which is a stem cell-regulated protein that is important in many different tumors, in particular in brain tumors. The other thing is that when we selected it as a molecule, in particular, we selected it for being able to go to the brain and actually stay in the brain. We know that it's not inhibited or pumped out by brain pumps. I think that's an important aspect of this being an effective molecule that could get to the brain and stay into the brain. You want to talk a little bit about.
Yeah. Let me talk a little bit about the numbers that you mentioned. DIPG, so the trials, just to remind everyone, 299, we started in AML. It's a dose-escalating trial right now. We're trying to get to the dose that is the most efficient and most efficacious, and at the same time confirm toxicity as we normally do here. I think the AML market is well understood in general. For the DIPG, the DIPG is a pediatric brain cancer, relatively rare, about 1,000 new case per year in the U.S. The age of onset or the age of symptoms is between five and six years of age in this patient. It's absolutely devastating. If you look it up, you're going to see for all the pediatric cancers is the one with the lowest five-year survival. The median survival, once the patient is diagnosed, is nine months.
They virtually all die, unfortunately, before the second year with the disease. It's only 2% survival at two years and 1% at five years. The trial that we are doing right now is with the DIPG Network. We are very happy to work with them. They're well established out there. The game plan right now is really a numbers one. We need to get sites open throughout the U.S., and that's what we are doing. Because these patients die so quickly, we need to be able to get them. In terms of design, the trial's in combination with standard of care, that is radiation, on this patient, so we have to have the courses back to back. One more reason to have a number of sites. We have sites open right now.
We have patients coming through for the network, but we really want to enroll this quickly because, again, it's very unfortunate for the patients, but relatively good for drug developments that the mortality is so high. As we see clinical benefit, as we expect to do so, we'll be able to see this relatively quickly. This is moving forward, and we expect to include the second trial with 596 for leiomyosarcomas to start later this year. It's all lined up. We just need to get the site open to start that trial.
Thanks. That's very helpful.
Oh, you bet.
Our next question is from Eric Joseph with JP Morgan. Your line is open.
Hey, guys. Thanks for taking the questions. I just wanted to follow up on AADC manufacturing. You previously talked about having a CMC meeting with FDA by year your expectation, I'm curious to know how iterative you expect that interaction to be. Also, as it relates to manufacturing, I'm wondering to what extent your current efforts with MassBiologics for AADC commonly apply to the Friedreich's ataxia program. Is the idea to have MassBio reproducing product that you would be taking into clinic when the IND gets underway? Thanks.
Hey, Eric, and thanks for the questions. We have discussed before, right? We're going to have a Type C meeting with the FDA in relation to CMC or before the end of the year. We had the meeting, and we're moving forward with the feedback that we got. Very productive in general. Extremely happy with the interactions with the officers at the FDA and glad for all the feedback they've been giving. It's more a strategy and how we go through finalizing the process with MassBiologics moving forward. Again, we got that milestone that we mentioned before. We normally don't give regulatory updates in general, I hope it's not expected that we're going to give play by play. Since this was important, we thought we would give this update right now. MassBiologics is now fully focused on AADC.
We see the capabilities there to expand to other programs. We obviously talk to them all the time. Part of the strategy here, and we do the same with Translarna, we just don't talk much about it, is have a diversified base for all the products we have. We have other partners we're discussing with right now. At the appropriate time, we're going to be disclosing who they are and which stage they are and looking to other options for manufacturing in general. While it is still a small volume for FA, it's obviously, in general, a bigger incidence and prevalence of the disease, so we're going to need more material. We are considering that as well as we expect to be successful with AADC.
They're going to have demands for MassBiologics in terms of production versus having FA, which we are getting to the point that the product has to be available for the clinical trial for next year, as we mentioned before. I'm reaffirming now we're filing an IND next year. We are considering all the needs on the short and long term for this product and what is the best strategy moving forward. Neil and his team is really focusing on this, and I think we're all very happy to get them out there and talking to different folks and getting the base expanded.
Great. Thanks for taking the question.
Thank you.
Our next question is from Alethia Young with Cantor Fitzgerald. Your line is open.
Hi. This is Irene on for Alethia. Thanks so much for taking the question. Just one on JEWELFISH. Can you characterize what data you're looking for that would really change the prescribing behavior beyond what we might see from the SUNFISH data set with respect to switching or anything that you guys are also thinking about? Then for Tegsedi in Latin America, how many of the 6,000 patients have been identified, or do you estimate are under care right now? Have you gotten any feedback from regulators with respect to the safety or monitoring from a Latin America perspective?
Yeah. I'd say for the JEWELFISH with the switch, it's really for those patients who want to move from one therapy to the next therapy. It's almost an open label trial for that. As you saw, probably what we did at the World Muscle, we did demonstrate, as we've seen for all the other trials, that the levels of the SMN protein went up to near normal levels that we saw in carriers. Again, to me, that's a very important point, because at the end of the day, it's the loss of that protein that leads to disease. You're getting to the right levels for those patients, then we'll be following them over time.
Yeah, I think one additional point here, right? Obviously, as it gets to the launch and Roche obviously thinking a lot about that together with us in the collaboration, it's important to have some safety data that patients can switch from one therapy to another. That's going to give that data. Stu just mentioned, I'm just going to highlight that it's actual increase or change in SMN levels, not cartoonish change, like actual numbers that is being out there. I think some people believe that just showing illustrations is good enough. We don't. We believe that we have to be able to show-
Of course
protein expression increase. I think that's quite important. We look into the numbers of Tegsedi in Latin America, the majority of those patients are identified. Some of them are not genotyped yet, and some of them are not being followed by the centers as we would want them to be. The effort right now is twofold. Obviously, you can diagnose, and especially in areas like Brazil, which is somewhat endemic because of the genotypic population, phenotypic population by the clinic. We believe that for the best interest of these patients, they should have a genotype; they should have a mutation on the gene. We established a very robust program, which is up and running, to genotype these programs. The early feedback from the physicians that they really appreciate what we've been proposing.
It's an exceptional program, in my view, because they can not only diagnose the hATTR patients, but also expands to other disease that might become misdiagnosed. From the physician perspective, they're very happy. We think only about 20%-25% of the patients are currently genotypes. We want to get this number to be much bigger. We're moving towards that before the launch. In terms of the feedback for the monitoring program, we are discussing that as part of our regular interactions with Anvisa and other agencies. We do not expect that to be an issue for two reasons. One, it's only a small % of the patients that might drop the platelets.
The second is we have a very robust program in Brazil and Argentina and Colombia and the rest of Latin America in terms of monitoring the patients right now for Translarna. Obviously, the monitoring is not as extensive as the one that is required for Tegsedi and eventually WAYLIVRA, but it's present. What we did earlier in the year, as we were discussing with Akcea, we locked down the best vendor in the region. Really the only one that can provide this kind of service to work exclusively with us. We have a process by which every patient's going to be visited on their house to get the blood draws and going to be sent to a central lab, and the physician's going to receive the results.
Just like a couple of weeks ago, we had a large advisory board with a number of physicians there. They all deemed this to be more than appropriate. They're all happy, actually, that we're going to be doing that because it's not only the monitoring, it's making sure they're using products correctly. Obviously in healthcare, everyone is interested for proper use. We feel very good about that.
Actually, to put it in perspective, when we think about ultra-orphan rare disorders, Marcio said 25% we already know. That's a huge number when you think about it from a disease that had no real treatment for it before. In a way, in Brazil, many physicians know it more as almost like the Portuguese disease, so that they're highly aware of this. This should really help quite a bit in terms of patient identification.
Thanks so much.
Thank you.
Our next question is from Raju Prasad with William Blair. Your line is open.
Thanks. Just taking the question. One for me on Translarna. Can you just provide some color on the non-ambulatory patient population and how that contributes to the 15% CAGR go through 2022?
Sure. Right now, obviously, as we've said, that we've already submitted in to get a label expansion. As of right now, we don't have anything in as part of the CAGR for that, it's not really counted now. As we've said before, this obviously could be quite extensive as there's 40%-50% of the patients increase. It would be an interesting addition, obviously, to get to these patients.
Great. Then on SMA, obviously Novartis discussed some quality data today. Given the commentary in type 1 SMA, does that change at all your thoughts on where risdiplam may be used, and pricing potential, obviously, does that change at all based on how Zolgensma is priced?
Obviously, that's their consideration. From our point of view, what we think is that the risdiplam has the potential to be best in class. Obviously, we're, I think, the only drug that's really been able to show protein levels to levels of what a carrier would have within patients. That's one of the ways we define what's the appropriate dose to go after. We think that based on the data that we hope to have, both in the type 1s as well as in the type 2, 3 experiments of FIREFISH and SUNFISH, that that's the potential to be best in class. Obviously, that's the way we're thinking about that now. I know there was some discussion in their call today.
We think the fact that you have a drug that distributes not only to the CNS, but also is orally bioavailable, gets to every tissue that's affected, is what we think is a much bigger advantage to be able to get it both to muscle, bone, liver, as well as nerve, and be able to treat the whole patient, we think is an important advantage to treating an SMA patient, both type 1s, 2s, and 3s. In terms of the pricing, actually, what we think of that in terms of the AADC space, where when you look at the results that we currently have for AADC deficiency, where we have a fair number of patients who've been taking it up to eight years that have demonstrated a very durable response.
We think if that's the pricing that's being considered, that really bodes well for the data that we have for AADC, I think that's an important consideration.
Great. Thanks. Appreciate the questions.
Thank you.
Thank you. I'm not showing any further questions. I'll now turn the call back over to Stuart for closing remarks.
Well, thank you all for joining today. I hope that you've seen that our vision is really to continue to build this fully integrated rare disorder biotech company. We're leveraging really our scientific expertise as well as the world-class commercial capabilities that's continuing on our 20-year history of innovative science. I think there's a number of milestones in the coming year that's going to create value both to the patients and shareholders alike. Thank you again for joining the call.
Ladies and gentlemen, this does conclude the program. You may now disconnect. Everyone, have a great day.