Emily Hill - Head of Investor Relations Stuart Peltz - Chief Executive Officer Marcio Souza - Chief Operating Officer Christine Utter - Principal Financial Officer and Treasurer.

Ritu Baral - Cowen Martin Auster - Credit Suisse Joel Beatty - Citi Gena Wang - Barclays Eric Joseph - JPMorgan Raju Prasad - William Blair.

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. [Operator Instructions] As a reminder, this 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 update 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 operations.

For a detailed description of applicable risks and uncertainties we encourage you to review the company's most recently quarterly report 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 24, 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 or joining us this afternoon. Joining me on the call today are Marcio and Christine. Marcio will provide the commercial and clinical development update. Christine will review our financials. I'd like to ask you to turn now to the slide we have posted on our website to highlight some accomplishments in the third quarter. Let's start on Slide 3.

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 our 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 PTC596 and PTC299 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 growth our orphan disease franchise creating significant value for all of our stakeholders.

As you can see on our pipeline chart on Slide 4, 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 need. Next on Slide 5, I'm pleased to report that we have already been executing on this strategy.

With the acquisition of a 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 stories [ph] next year. In addition, we have in-licensed two products from Akcea and which will be commercializing in Latin America.

This is the first public call since the closing of the Agilis transaction. I couldn’t 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 6.

When we began our business development process, one of the principals 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 are interested in such approaches to gene therapy.

Specifically we wanted to first focus on utilizing gene therapy targeting tissues with low turnover to ensure durability of effect. We also consider that delivering gene therapy through a small contained region of the body has the advantage of being able to use micro doses to treat patients allowing manufacturing lower amounts of the biotherapy.

These considerations led us to the acquisition of Agilis with their CNS gene therapy platform. Our three gene therapy programs in CNS are for Aromatic Amino Acid Decarboxylase deficiency or AADC, Friedreich Ataxia or FA and Angelman Syndrome or AS.

What they all have in common in addition to being seen as disorders of high unmet medical need is that targeted delivery of the gene therapy can be employed. 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 AADC gene therapy into the brain utilizes a micro dose of viral vector of only approximately two times tend to be 11 viral [ph] particles.

This was the total dose and it is between 1000 to 10,000 smaller compared to the systemic gene therapy dosing. This reduced dose requirement allows for scalable modular manufacturing. Because delivering 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 with 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 effective 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 8, these key therapy programs to treat the orphan neurological disorders forward to our area of expertise. We have over 20 years of experience discovering, developing and commercializing therapies for rare disorders with high unmet medical need.

We understand the rare disorder market and have experienced both country by country market access and pricing, driving genotyping effort and patient funding. 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 9.

AADC deficiency is a devastating disorder with halts infant neurological and motor development is similar to spinal muscular atrophy the children are never 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 4 and 8 years of age.

Following a single direct CNS gene therapy and treatment, these patients have showed improvements in functional, developmental milestones, including have the ability to hold I 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 followup. Now let's turn to Slide 10. AADC treatment is delivered via a single dose through direct delivery into the [indiscernible] 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 followup 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 Scales demonstrate clinical improvement in treated patients at the one and five-year followup. As you can see every patient experienced rapid and durable important in both fine and gross motor skills regardless of their age when the treatment was initiated. This is compelling.

When seen 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 remarkable about this gene therapy are the transformative changes that were observed in the treated AADC patient.

I would like to share a video demonstrating robust improvement 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 2 years old before initial treatment.

You can see the child has limited motor function and is unable to lift his head or sit. At 2 years of age he received a single treatment. As you can see, after one year of followup there was substantial change. You can see the child sitting upright independently and grasping a mirror.

After an additional year of followup at 4 years of age we see continued growth and fine motor function and cognitive improvement. The child is now standing and interacting with the 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. Now, turning to Slide 13, let me transition to Friedreich Ataxia gene therapy program. This is the most advanced program in development for the underlying cause of FA.

FA is a triple repeat disease causing the loss of frataxin protein, again the gene therapy will be directly targeting the approximately region in the brain that is involved in ataxia and we'll be utilizing micro dosing.

As you can see on Slide 14, we're very encouraged by the preclinical data showing that in large specious proteins 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 19 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 their early stage program in Angelman syndrome. We are very proud of our gene therapy pipeline which we believe will drive both near and long terms value creation for patients and shareholders.

I'll now pass the call to Marcio to review our growing DMD franchise and the product for which we in-licensed in Latin America commercial rights. This support 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 have made in our niche oncology programs..

Hey thanks Stu. As part of the strategies Stu just outlined, we also looked for in-license opportunity that would leverage our strong existing commerce infrastructure. In the third quarter we're 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 in Portugal or Brazil contains a large portion of such patients. The region is of strategic importance for Tegsedi.

Based on one such data we conducted we have learned that Tegsedi is higher regarded by physicians in Latin America for its clinical profile. In fact the projected allocation of market share by the physicians shows a predominant use of Tegsedi over comparative 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 6000 eligible patients in Latin America for Tegsedi.

Genetic confirmation of hATTR diagnosed in general patient mapping are key next steps to enable successful launch and we are well underwent with such activities. On the regulatory front, we intend to file our market authorization with ANVISA in the first half of next year.

Our strong existing business infrastructure positions 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 our label expansion for Translarna in nonsense mutation DMD for patients aged 2 to 5. Because DMD is such a [indiscernible] disease, treating patients early allow for better preservation of muscle function.

Importantly, this label expansion allows patient encounters that recognize EMA approval to gain access to therapy at a younger age. We have recently submitted for 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 problems focus on ambulatory patients there is a niche unmet needs to treat non-ambulatory patients with DMD. Our DMD franchise also includes Emflaza for all U.S. DMD over age 5. We are working hard to establish Emflaza as the standard of care in the united stated.

As we stated last quarter, there are number of levers to pull, to respectively establish Emflaza as the standard of care. One such factor we discussed was the breathing problem to allow for access to therapy before reimbursement. This was an importance too in our early commercialization efforts to bring patients on board.

For such type of patients however the breach program is low reimbursement and timelines. In September this program was discontinued and patients from bridge which are now being transitioned to commercial products. We are seeing the early impact of this change since the ends of the third quarter.

In addition to determination of the bridge program the recent publications regarding Emflaza's effects supports 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 chain 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 to $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 to $95 million and therefore we are adjusting our DMD franchise guidance for the full year 2018 to $260 million to $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 the 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 to 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 and we estimate 5,000 patients worldwide with about 1,200 patients in the United States 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, but we also have this site open and they have the first patients screening 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 and the DIPG trial is open for enrollments and we expect the second trial in sarcomas to be open before the end of the year. We look forward to sharing more of these program 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. We estimate program reflects the scientific innovation of which PTC is founded. The idea of a small molecule selectively altering splicing was found 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 [ph] SMA 2 splicing modifiers.

We believe that an oral systemic therapy provides a competitive advantage because of its broad tissue distribution, Systemic SMA protein increases and ease of administration. Earlier clinical data has showed that risdiplam drives SMA to splicing towards a complete restoration a full length SMN2 to Messenger RNA.

This program is currently in pivotal stages with two 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 power 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 with Huntington's Disease and familial dysautonomia. I'd like now 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 to $185 million contemplates uneven ordering patterns and reflects the total patients demand for the year and we are happy to reiterate our 15% CAGER 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 to $95 million from the prior guidance of $90 million to $110 million.

As a result we are adjusting our 2018 DMD franchise revenue guidance to $260 million to $280 million from $260 million to $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 investments 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 to $290 million from their previous guidance of $250 million to $260 million.

This increase reflects our investment in the gene therapy program and also includes the upfront licensing fee. 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? And I got one followup..

Sure. Hey Marcio..

Yes, of course Ritu.

So it is and it isn’t, right? So it is in a sense that we, that was one of the drivers I discussed last quarter in terms of accelerating the conversion that we were looking to that at the beginning of the year, as I mentioned before we normally expect the conversion between prescription to dispense around three to six months or trending more towards the upper ends of this guidance.

Part of this was a large number of patients that we have on this program and this bridge program where we saw some apathy on the patient and on the physician side to give us information to continue to move forwards. So one of the decisions we made was to terminate this program.

So this sense of urgency with being still on and to move things forward then and this is having an impact. And it is moving, so with that we are being able to model when to look into individual patients.

Now the dynamics of their markets in general when you're looking to individual patients' conversion, the number of prescriptions we have right now are the patterns for the specialty pharmacies what is leading us or getting us to narrow the range, since we are relatively close to the end of the year.

So that's the main reason why considering the base of patients we have and the number of scripts we’re seeing per day..

Okay, so is it fair to say your time to sell is continuing to improve and that your insurance discussions and coverage is not getting worse?.

No, it's definitely fair to say it's not getting worse and if anything our team is out there really trying to remove some of the barriers. I mentioned this before as was in previous call.

The most common step edits we have is around six months on provisions zone previous just to start Emflaza, what do we’re seeing is a number of plans and is still a small number but we see this improving moving forwards, removing that altogether or reducing to like a number of weeks on reducing to one or two months.

So we're seeing improvements on the general condition and now it's really getting this paperwork through getting this patient that we are having ours to see on the order of hundreds that we have in-house like move to commercial, why are we building the new prescriptions. So in a sense like the entire team focus is twofold.

Right so one for this year and to get likes to the numbers that I was just discussing is continue to execute on the conversion, but keeping an eye on building the number of prescriptions for next year as well.

And we have a lot of focus and like great daily calls and with different accounts and moving like I am pre confident as we move forward to have a good end of the year..

And 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 and now they are not onlty another not only the synergy data that came out that publication the paper on the act DMD trial and there are others that are coming out as well.

So I think that's helping that..

That’s really helping. Yes..

Yes, I was able to follow that and then can you characterize persistence on treatment and how that figures into everything?.

Yes, so it's versus it's like we're in the U.S. the one of the advantage that we can track and we do track patients like every order. And 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 it would like to is the adjustment of those that is more in our view more associated with better therapy to [indiscernible] so 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 like half of the therapeutic dose for example.

And we we're discussing actively with the prescribers if it is a leftover from the previous regimen or if it's really something that wants to focus, so persistence being really good. What we ideally want this persistence at the best those for that given patient. And we're moving towards that as well..

Got it. Super helpful guys. Thank you..

Thank you..

[Operator Instructions] our next question is from the line of Martin Auster - 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 then also just with the SUNFISH Phase pivotal part of that trial completed is there any and tell us about the baseline characteristics around the age of the patients or the ESMO 32 status and things like that? Thanks..

Sure. Yes. So thanks for that question Martin.

So two things one is the, as we all know that the SUNFISH trial has completed enrollment had probably be appropriate meeting we'll be describing what the baseline characteristics are like, so we'll be we'll do that at a meeting most likely and then in terms of FIREFISH, you think that if we said that we anticipate that it would be completed by the end of this year.

I mean 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. So we fully expect that to occur, so we believe that we're well on track to finish enrolling that trial..

Great thanks. And if I could maybe ask a followup, I had a question about the AADC again therapy program. Thanks for giving us a little bit sort of deeper look in your genetherapy programs overall.

Just curious what can you tell us about the differences of your approach versus other clinical stage AADC approaches that are directed at Parkinson's or is there a long term opportunity for this product to potentially be developed for that market as well? Thanks..

Sure, maybe I will start and then – so yeah, so our view of AADC in terms of it's obviously in this case a deficiency of at the top of the latest gene when we think by injecting into the butane and gives the results that you see here that we showed within the video and there's many videos that do that.

So we think that's clearly versus Parkinson's or something else, now it's we're just probably this is more for the direct effect of the disease not for the symptoms of it. So it's a difference in that perspective..

Yes, so on to the biology itself right. The cells are preserved here that we are injecting on the area we have, we can go to the general area at the time and maybe this was not clear before. So the precision of the procedure obviously has to be precise, but it's not as precise since it's largely preserved.

So these are normal brings up in terms of neuro anatomy where you are just trying to get the dopamine to be produced and as you've probably seen before Martin's liking the bad scan images we're seeing, all the way to five years and that's why we have that scans we're seeing the production.

Just in Parkinson's one of the potential issues here is that you have the generation right. And what you are trying to do is to find that cells that are still able to have an effects so underlying cause versus potentially reducing the effects that those are likely or are acting in reality the models to be quite difference here as well.

You might hear of a little bit different constructs. But if you look forwards, it wouldn't be outside of the things we're considering potentially expanding this problem.

The current focus off 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 this treatment, the AADC team is later focused on getting the BLA filed next year and getting like everything ready, but we continue to discuss the management and all that adds up the company potentially expanding..

Yes, in that view also we know that just it could be for this we know it’s due specifically from mutations and the in the AADC genes, in the case of Parkinson that going to be a multiple of other genes that could be involved in this as well, so even from dopamine and might be one of the other gene.

So you might have to when you think about how do this you may do it in a way we have multiple genes being expressed. So there is more things to think about in general, how you do in general gene therapy perhaps for treating Parkinson’s patients..

Thanks for your thoughts and I appreciate it..

You bet..

Our next question is from the line of Joel Beatty. Your line is open..

Hi, thanks for taking my question.

First one is on Emflaza, given the hundreds of patients to have scripts but is waiting to be fully processed do you anticipate that most of those patients will go on to be served 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?.

Yes, we are committed, hey Joel it is Marcio. So we are committed to get every patient who is prescribed them Emflaza to eventually get it right. The conversion rate is actually very high and in the order like very very high it's as you would expect is just a matter of time in general.

Obviously some of these patients never qualify for one reason or another and we have a [indiscernible] problem as well where some of those patients go through with. We continue to look into new ways for them to be on therapy.

Sometimes they do have to they never had explicit presence on and they are not planned that really requires that and they have to get that exposure. But at the end of the day we're seeing like a terminal conversion is extremely high and we're considering like talking about these numbers in the next call.

As we finished a year and so on, so not as much of a problem in terms of getting them there, eventually but it's more on the timing of getting them there and when a physician prescribed in Emflaza right now, what we are seeing and Stu always highlights the publications and so one we really believe it.

It's more of a question of really the back and forth with insurance that I guess you're not 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 of our neuromuscular clinic is much higher than for other products.

So it's a lot of the attention and paperwork and we've seen that's taking a little bit of the kind of 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 deserve. And we're seeing some good traction there..

Yes, I think also Marcio said is that there's a well we had a large number of patients who were in the bridge program that transitioned over and this is sort of there's always some where if we don't, if you don't put in some sort of an additional pressure it would stay on until a pressure is being put on.

And so this is our way now of sort of moving those patients through the process and that additional pressure just seems to be working sort of a reminder that it's not just it's not here forever and that you have to move on to commercial track..

Yes, that's right..

Got it. That make sense.

If I could have the question on the AADC program, could you give us an update on the key steps that still need to take place before a filing the BLA in 2019?.

Sure. I'll start and then I'll - so just remind you the AADC program as we have discussed previously. I even think I will talk 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.

And so really we're having discussions since now in terms of that and obviously what to the next step is to make sure the CMC is ready for the filing and so let me pass that to Marcio to focus on that..

Of course, thanks Stu. So we have a strategic partnership with mass biologics to manufacture this. The key step here, I would say the most important steps really to continue to produce material towards the wants to be commercialized.

We mentioned previously and I believe we filed in the queue that we had some interactions with the - I think we're expecting to have more interactions with the FDA.

This is progressing nicely in terms of like conversations we had before and parameters and strategy for CMC that we had discussed continue to look positively for what we are doing those mass biologics and internally here at PTC as well. We reaffirmed today that we are filing the BLA next year.

So this is all progressing nicely on the clinical models of the BLA on the preclinical models of the BLA.

We are all now moving towards finalizing the documentation, so we wants to be as I had as possible in terms of everything that is not rate limiting and I'm very happy with the progress that stake and so at the moment we have the final CMC package we can submit its next year, so everything is moving from a rental perspective with the U.S.

very nicely in the package for Europe is very similar, so that's all based on the same our team in Europe is working towards that submission as well that includes a few other staff as you know like projects can discussion plan and so on so everything is progressing.

We should be able to file a BLA and then MMA in Europe and potentially other jurisdictions in a very short period of time to each other, so we're very happy again I'm just going to put, I know it was not in your question but one last thing here, the patient has instigations been going very well as well as I mentioned on the, on my remarks because obviously we want to make sure to get the launch in to have a good base of patients to benefit from this launch so 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 [indiscernible] for Gena. Thank you so much for taking our questions, maybe just a couple for me, for Translarna, can you give us some more color regarding the growth in different geographies. Also if you can exclude the Latin America and the second part is that can you update us regarding the U.S.

regulatory status like when do you plan to start the dystrophin markers study?.

Sure, okay so maybe I’ll start and then we're growing from the regulatory status or the dystrophin study I think as we said, we plan to start a dystrophin study by the end of this year, so that would be completed by the end of next year and would be filed after that and so we're on target to do that as well, so we feel good about getting that going to then be able to be able and therefore if anything really about background in terms of the month of dystrophin that would actually give us be accelerated approval so we feel good about moving about that in terms of Translarna growth and development I guess, what I could say on the high level is that we continue to grow Translarna in all these areas.

May be I'll let Marcio go into some details in terms of the dynamics of area..

Sure, so this like two major areas for us, right so the European and Middle East, are in the Americas and that's how we look at the basket of [indiscernible] in each one off than, we see the progression like when you look into the full year and we always look into a full year because it can find each one of those regions that is several countries with very uneven order pattern, so it doesn't make sense look to quarter-on-quarter for us, so when I look into my full year latest estimates that we always run periodically here.

That is double-digit growth in each one of that was say exactly where we would like to be which put us in a position to continue to reinforce and we have formed the 15% long term growth to 2022 that we mentioned before.

Specifically on Latin America right that we called all in the, in a call in part of your question like Brazil, Argentina, Colombia are important business for us and we always monitor that their countries that are used to only order periodically through the year in lump sum I would say are theirs for several patients, so we receive one of these order after Q3 ended for Latin America, specifically working through the paperwork right now to get it shipped but that's something that sometimes get a little bit delayed from one quarter to another and that's why we always masters that and talk to all a few about how lumpy it is.

So having that enhanced relatively early on Q4 give us confidence to get the guidance where we are for the year.

Does that help?.

Yes, that's very helpful. Thank you so much..

May be it's also worth to us for everyone to know as we always talk about lumpiness of Latin America but even country by country over time may be if you were talking a little bit above that as well..

Sure is and that's one of us what I was mentioning terms of even year our prices like we are shipping to more than 40 countries now and when you look into the combination of all of them several off than have like orders for more than three months throughout the years, just because of that that's how their supply agreements work, so in that being lumpy general and one of the reasons why I have got this question before why not looking to quarter-by-quarter but for us it’s really not possible right now, we have an exclusive ex-U.S.

business for Translarna and it’s fairly unusual there is not a lot of other products there like that but it's a fairly common pattern to Stu’s point. We highlighted more Latin America before but it's really in general in our business..

So we certainly know how many patients there are and how much we get over the year but the ordering patterns could vary and that's just I think important for people to understand and over the time within Europe..

Okay, thank you very much..

Thank you..

Our next question is from Brian Abrahams with RBC Capital Markets. Your line is open..

Hi this is Bird [Ph] on for Brian. Thanks for taking the 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. You saw that, I think you're referring to what's the mechanism of action. So yes sure, so maybe we'll start with PTC299 which is an inhibitor for dihydroorotate dehydrogenase. So it's a very potent effective inhibitor of that that.

That turns out to be important in particular in leukemic cells where you need poly permittings [ph] 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.

So we think this has a very promising effect of possibility of having effect of these diseases.

We also know already just because of our previous clinical studies in this that we know we can - it is we do see inhibit inhibition in patients of [indiscernible] by seeing increased levels of the dihydroorotate in the bodies when you treat patients with PTC 299.

So we know we’re on target, so look - so now what we need really goes to prove the next hypothesis which is that will cause leukemic cells to differentiate, so we feel pretty good about that.

PTC596 is inhibitor – was identified as an inhibitor of BMI 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 select it as a molecule in particular we selected it for being able to go to the brain and actually stay in the brain, and so we know that it's not inhibited or pumped out by brain pump. So I think that's an important aspect of this being an effective molecule that could get to the brain and stay into the brain.

Do you want to talk a little bit?.

Yes, let me talk a little bit about the numbers that you mentioned right. So the IPG, so the trials just reminds everyone right 299 we started AML, it is a dose escalating trial right now. We're trying to get to the dose that is the most efficient the most efficacious and at the same time counter toxicity as we normally do here.

I think AML market is well understood in general. For DIPG, the DIPG is pediatric brain cancer, it is rare about a 1000 new case per year in the United States. The age of onset or the age of symptoms is between five and six years of age in these patients is 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. So the median survival once the patient is diagnosed is nine months. So they virtually all die unfortunately before the second year with the disease is only 2% survival at two years and 1% at five years.

The trial that we are doing right now is with the DIPG network. I’m very happy to work with them. They're well established out there. The game plan right now is really numbers one, right. So we need to get sites open throughout the United States 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 is in combination with standard of care that is radiation on these patients. So we have to have courses back to back and one more reason to have a number of sites. We have sites open right now.

We have patients like coming through the network, but we really want to enroll this quickly because again, it's very unfortunate for the patients, but relatively good for drug development. The mortality is so high, so as we see clinical benefit as we expect to do so would be able to see this relatively quickly.

So this is moving forward and we expect to include the second trial with 596 for leiomyosarcoma to start later this year. So it’s all lined up. We just need to get sites open to start the trial..

Thanks, that's very helpful..

Oh you bet..

And our next question is from Eric Joseph with JPMorgan. Your line is open..

Hey guys, thanks for taking the questions. I just want to follow-up on AADC Manufacturing.

And you previously talked about having a CMC meeting with FDA by year-end, your expectation and I'm curious to know how iterative you expect those interactions to be? And also as it relates to manufacturing, I'm wondering to what extent your current efforts with mass biologics for AADC commonly apply to the Friedreich Ataxia program and is the idea to have mass bio reproducing product that you'd be taking into clinic when the IND gets underway? Thanks..

Hey Eric, and thanks for the question.

So we have discussed before right, we are going to have biopsy meeting with the FDA in relation to CMC likely before the end of the year and we have the meeting and we are moving forwards with the feedback that we got very productive in general like assuming they have interactions with the officer at the FDA and I'm glad for all the feedback they've been giving.

It's more a strategy and how we go through finalizing the process with mass biologics moving forwards. But again, we've got that milestone that we mentioned before. We normally don't give regulatory updates in general.

So I hope it's not expected that we're going to give play by play but since this was important, we thought would give like these updates right now. Mass biologics is now fully focused on AADC. We see the capability there to expand to other programs.

We obviously talk to them all the time, but part of the strategy here and we do the same with Translarna, we just don't talk much about it, have a diversified base for all the products we have. So we have other partners who are discussing with right now.

At the appropriate time we're are going to be disclosing who they are and which stage they are and looking to other options for manufacturing in general.

While with issues more volume for FA, it's obviously in general a bigger incidence and prevalence of the disease, so going to need more material and we are considering that as well as we expect to be successful if they just see they’re going to have demands for mass biologics in terms of production versus having FA which we are quite getting to the point there.

The product has to be available for the clinical trial for next year as we mentioned before them, we are partnering now, we are filing an IND next year.

So we are considering all the needs on the charts and long-term for this product and what is the best strategy moving forward, but Neo [ph] and his team is really focusing on there 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 questions..

Thank you..

Our next question is from Alethia Young with Cantor Fitzgerald. Your line is open..

Hi this is Irene [ph] on for Alethia. Thanks so much for taking the question.

Just one on JEWELFISH, can you kind of 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? And then for Tegsedi in Latin America, how many of the 6000 patients have been identified or do you estimate are under care right now and if you gotten any feedback from regulators with respect to the safety or monitoring from a Latin America perspective?.

Yes, so 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. So that is really - it is almost an open label trial for that.

It will be - but as you saw probably what we did at the world [indiscernible] we did demonstrate as we've seen for all the other trials that the levels of the FMN protein went up to near normal levels that we saw in carriers.

So again, to me that is a very important point because at the end of the day, it's the loss of that protein that leads to disease. And so you’re getting to the right levels for those patients and then we will be following them over time..

Yes, and I think one additional point here right, so there obviously as it gets to the launch and Roche obviously thinking a lot about that together with collaboration, it’s important to have some safety data that the patients can switch from one therapy to another. So that's going to give that data.

As Stu just mentioned, I’m just going to highlight that its actual increase or change in FMN levels not cartoonistic 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 like protein expression increase, so that's I think that's quite important. As we look into the numbers of Tegsedi in Latin America, the majority of those patients are identified. Some of them are not genotype yet and some of them are not being followed by the centers as we would want them to be.

So the efforts right now is two-fold, right it’s to obviously you can diagnose and especially in areas like Brazil which is somewhat endemic because of the genotypic populations, genotypic population by the clinic, but we believe that for the best interest of these patients they should have a genotype, they should have a mutation on the gene.

So we established a very robust program which is up and running to genotype these programs, that already feedback from the physicians that they really appreciate our proposing, it’s an exceptional problem in my view because they can not only diagnose hATTR patients, but expands to other disease that might be commonly diagnosed.

So from the physician perspective, they're very happy. We think only about like 20% to 25% of the patients are currently genotypes, so we want to get this number to be much bigger and we are moving towards that before the launch.

In terms of the feedback for the monitoring problem, we are discussing that as part of our regular interactions with these and other agencies. We do not expect that to be an issue for two reasons, right.

So one it is obviously - can be it's only a small percent of the patients that might drop the platelets, but this 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 [indiscernible] eventually will lever up 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 is are going to be visited on their house to get the blood drops and going to be sent to a central lab and the physician is going to receive the results.

And just like couple of weeks ago, we had a large advisory board with a number of physicians there and they all deemed just to be more than appropriate and they’re all happy actually that we're going to be doing that, because it's not only the monitoring, it is making sure the products are using products correctly and obviously healthcare everyone is interest for proper use.

So we feel very good about that..

And actually to put it in perspective when we think about ultra orphan root disorders, Marcio said 25% we already know, that is a huge number when you think about it from a disease that had no real treatment for it before and in a way in Brazil many of physicians know more almost like the Portuguese disease, so that they are highly aware of this, so this should really help quite a bit in terms of patient identification..

Thank you, so much..

Thank you..

And our next question is from Raju Prasad with William Blair. Your line is open..

Thanks for taking the question.

One from me on Translarna, can you just kind of provide some color on the non-ambulatory patient population and how that contributes to the 50% CAGR through 2022?.

Sure, so right now obviously as we said that we've already submitted to get a label expansion, as of right now, we don't have anything into it as part of the CAGR for that, so it's not really counted now.

And as we've said before this obviously could be quite extensive of those 40% to 50% of the patients' increase, so it's been interesting addition obviously to get to these patients..

Great and then on the SMA, obviously Novartis kind of discussed some quality data today.

Given the commentary in Type 1 SMA does that kind of change at all their thoughts on where risdiplam may be used and pricing potential obviously did that change all based on how [indiscernible] 101 is priced?.

Obviously that's their consideration. From our point of view, what we think is that 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 the levels of what a carrier would have within patients and we can – we think that's one of the ways we define what's the appropriate dose to go after.

And so we think that based on the data that we hope to have both in the Type 1 as well as in the in the Type 2, 3 [indiscernible] some SUNFISH that that's there is a potential to be best in class. So obviously that's the way we're thinking about that.

Now and I know there were some discussions of there, in their call today, but we think the fact that you have a drug that distributes not only to the CMS but also is orally bio-bailable 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 the SMA patient both Type 1 and 2s and 3s.

In terms of the pricing actually what we think of that in terms of the, I think more of that in terms of AADC space where when you look at the results that we currently have for AADC deficiency where we have a fairly a fair number of patients with who've been taking this up to eight years that have demonstrated a very durable response.

We think if that's the pricing that's been considered that really bodes well for the data that we have for AADC and I think that's an important consideration..

Great, thanks for taking the questions..

Thank you..

Thank you. And I'm not showing any further questions, so 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 and we're leveraging really our scientific expertise as well as the world class commercial capabilities.

I think that 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. So thank you again for joining the call..

Ladies and gentlemen, this does conclude the program. You may now disconnect. Everyone have a great day..