PTC Therapeutics Inc (PTCT) 2020 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the PTC Therapeutics Third Quarter Corporate Update and Financial Results Call. (Operator Instructions) Please be advised that today's conference may be recorded. (Operator Instructions) I would now like to hand the conference over to your speaker, Ms. Lisa Hayes, Vice President of Investor Relations. Please go ahead, ma'am.

Good afternoon. Thank you for joining us to discuss PTC Therapeutics' Third Quarter 2020 Corporate Update and Financial Results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz; our Chief Financial Officer, Emily Hill; our Chief Development Officer, Matthew Klein; and our Chief Business Officer, Eric Pauwels.

Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, 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 report, Form 10-Q and annual report, Form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings.

We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to 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, Stu Peltz.

Thanks, Lisa, and thank you for joining us -- for joining the call today. We have made significant progress this quarter with our R&D pipeline as well as our commercial business showing continued growth. We've built PTC to create value for all stakeholders by discovering and developing novel therapeutics for patients with high unmet medical needs and creating revenue by bringing these products to patients through our global commercial engine. Our strong cash position allows us to continue to deliver on the promise of our pipeline to bring more therapies to patients and to grow further the company.

Let me go through some of the achievements this quarter. Starting with Evrysdi for the treatment of SMA. We are very excited about the strong launch of Evrysdi in the U.S. not only for its efficacy and safety profile but also its convenience as the first at-home, orally administered treatment for SMA patients 2 months and older. The ease of administration and access to a home-delivered therapy is particularly important to patients, especially during the COVID-19 pandemic. Evrysdi showed clinically meaningful improvements in motor function and developmental milestones achievement across a broad range of ages and functional abilities of SMA patients.

The Evrysdi launch has had a very positive response from physicians, payers and the whole SMA community. As a reminder, there is high unmet medical need in the SMA community with patients who are treatment-naive and patients who have concerns with durability or the administration burden of current therapies. Our partner, Roche, has reported that 2/3 of initial patients on Evrysdi were previously treated with SPINRAZA or Zolgensma. We are seeing uptake across all types of SMA patients. To date, 25% of patients treated have been Type 1, with the remaining 75% are Type 2 and 3.

There continues to be excellent progress in bringing Evrysdi to SMA patients globally, with approvals already obtained in Brazil, Ukraine and Chile. In addition, an NDA for Evrysdi was filed in Japan, which triggered a $7.5 million milestone payment to PTC. Evrysdi is also under review with the EMA, with a decision expected [as early as] (added by company after the call) in April 2021. We appreciate the strong effort made by our partner, Roche. Let me comment on our commercial team's progress this quarter.

Across our commercial portfolio, we saw increased patient uptake and associated revenue. Our net revenue increased 66% year-over-year and net product revenue increased 16%. We are very pleased that we've continued to grow globally despite the COVID-19 challenges, including securing a purchase agreement with Brazil's Ministry of Health for Translarna.

You can see we've made considerable progress on our commercial products, but I'm equally excited about the progress we've made in R&D programs and the value they will create. Let's start with our splicing platform. PTC was the pioneer in discovering and developing a selective small molecule for splicing with Evrysdi as the first product approved from this platform. We have a number of exciting wholly-owned splicing programs that are moving forward. Our plan is to create value by internally developing these products and to bring them to patients globally.

After Evrysdi, the next most advanced compound from our splicing platform is PTC518, which is being developed for Huntington's disease. I'm excited to report that PTC518 will enter the clinic this quarter. Analogous to how we discovered Evrysdi, PTC518 was constructed to be an orally bioavailable molecule that distributes to all tissues in the body, is very effective in crossing the blood-brain barrier and is highly selective. We've learned that these elements of selectivity, biodistribution and pharmaceutical properties are critical to successfully developing differentiated splicing molecules.

The Phase I trial will be performed in healthy volunteers, with results expected in the first half of next year. Similar to the SMA program and because there was a direct correlation of blood and brain levels in preclinical studies, the results from the Phase I healthy volunteer study should allow us to demonstrate target engagement and proof-of-concept of the reduction of HTT mRNA. This will allow us to select doses for the subsequent study in HD patients.

Now let me turn the attention to our late-stage clinical programs. From our Bio-e platform, we recently announced that enrollment again in a registration-directed trial called MIT-E with our compound, vatiquinone, to treat mitochondrial epilepsy. As a reminder, about half of all children with inherited mitochondrial disease suffer from refractory seizures. These seizures result from disregulation of the electron transfer process, leading to oxidative stress and inflammation. Vatiquinone targets the enzyme 15-lipoxygenase, which is a key regulator of the neuro-inflammation and oxidative stress response. We estimate that there are approximately 12,000 commercially addressable mitochondrial epilepsy patients globally.

In addition to registration-directed trial with vatiquinone in Friedreich ataxia, called MOVE-FA, is also planned to initiate by year-end. FA disease pathology results from high levels of oxidative stress, inducing neural inflammation, which is known to be an important FA disease pathology and progression. Vatiquinone modulates these pathways to reduce inflammation. Previous Phase II results showed that vatiquinone altered the course of FA disease, and we are excited to initiate the registration-directed study this year.

Our third late-stage program is PTC923 for the treatment of PKU, where we expect to initiate a pivotal Phase III study in mid-2021. With an estimated 20,000 PKU patients in the U.S. alone, there continues to be high unmet medical need as the majority do not initially respond or are not adequately controlled on Kuvan. Results from previous studies demonstrated that approximately 50% more patients responded to PTC923 when compared to Kuvan. Furthermore, in these studies, the results demonstrated that the drug had greater than twice the reduction in phenylalanine levels compared to Kuvan. We are currently conducting nonclinical studies to support the long-term dosing for the planned Phase III trial.

I want to turn now to the Translarna dystrophin study, Study 045. You may recall that this was the outcome of our discussion with the FDA about potentially securing an accelerated approval for Translarna in the U.S. so that these patients would be able to receive the therapy. I'm very happy to report that with a very strong effort by the team, despite the challenges of COVID-19, the final muscle biopsy from the patient in Study 045 has just been completed. Preparation and analysis of the samples according to our protocol is now underway, and we look forward to sharing top line data in the first quarter 2021. We are excited that PTC has the potential to accelerate access to Translarna for U.S. patients.

We are also continuing to make progress with our gene therapy platform. The gene therapy manufacturing facility in Hopewell is occupied and ready for production. As we have discussed previously, our most advanced program is to treat AADC deficiency, where we have observed transformational and durable results in AADC-deficient patients that have been treated for almost a decade. Our MAA has been submitted and under review by the CHMP. Due to COVID-19-related delays, PTC now expects the CHMP final opinion for AADC deficiency application in the first half of 2021. For the BLA, PTC expects submission to the FDA will also be in the first half of 2021.

We also recently initiated a Phase II/III trial for PTC299 for COVID-19 called FITE19. We recognize that PTC299 has a unique dual mechanism that is potentially effective against both stages of the viral infection, including viral replication and enhanced immune response. The combination of the mechanism, the preclinical data, the well-established safety profile and the compound's oral bioavailability gives us great confidence in PTC299's potential as a treatment for COVID-19. We anticipate reporting top line results in the first half of 2021. With that, I'll now turn the call over to Matt Klein for key updates on our clinical program. Matt?

Thank you, Stu. We have had a very productive quarter as we continue to advance innovative therapies from all of our R&D platforms. Our development teams have been working tirelessly throughout this COVID-19 pandemic to minimize impact on ongoing trials and ensure that our next set of trials initiates without delay.

As Stu mentioned, we are very excited to report that we have now completed the final muscle biopsies for Study 045, the Translarna dystrophin study. Analysis of the biopsy samples is now underway, and in accordance with the protocol, we remain blinded to study results until all biopsy analyses are completed. As a reminder, the primary outcome of this study is an increase in dystrophin expression over baseline as assessed by an electrochemiluminescence assay that we developed in collaboration with the FDA. We expect to have top line data from the 045 dystrophin study in Q1 2021.

Turning to our Bio-e platform. We have initiated enrollment in the MIT-E trial, the registration-directed trial of vatiquinone in children with mitochondrial epilepsy. This Phase II/III trial will enroll approximately 60 children with genetically confirmed mitochondrial disease and associated refractory seizures. The study design includes a 1-month front-end period to ensure that all eligible subjects have a minimum number of seizures, followed by a 6-month parallel arm phase in which subjects will receive either vatiquinone or placebo. The primary outcome of the trial is reduction in observed motor seizures, with secondary outcomes related to other aspects of seizure burden as well as disease morbidity. The FDA has granted vatiquinone orphan designation and rare pediatric designation for the treatment of mitochondrial epilepsy.

The Phase III vatiquinone Friedreich ataxia trial, MOVE-FA remains on schedule to initiate enrollment by year end. This trial will enroll approximately 110 children and young adults with Friedreich ataxia. The study design includes an 18-month parallel arm placebo-controlled phase, during which subjects will receive either vatiquinone or placebo. The primary endpoint measurement for the study is the Modified Friedreich Ataxia Rating Scale, or mFARS, with key secondary endpoints assessing ambulation and activities of daily living. This endpoint strategy was developed in collaboration with both the FDA and EMA. There are approximately 25,000 patients worldwide with Friedreich ataxia.

In the second compound from our Bio-e platform, PTC857, we have completed the Phase I single-ascending dose study as planned and expect to complete dosing in the MAD study by year-end 2020.

Turning to our splicing platform. The PTC518 Huntington disease program remains on schedule, with the Phase I trial in healthy volunteers to initiate in this quarter. This Phase I study includes both single- and multiple-ascending dose regimens to inform safety and pharmacologic parameters as well as to guide dose selection for subsequent registration trials. Importantly, we are also planning to measure HTT mRNA levels in healthy volunteers to gain early proof of splicing mechanism, as was done in the risdiplam SMA development program. We expect to have data from the Phase I PTC518 study in the first half of 2021.

Next, I'll provide an update on our PTC923 PKU program. We have initiated the long-term toxicology studies needed to support the initiation of the Phase III PKU trial that is scheduled to begin in mid-2021. This registration-directed trial will be a double-blind placebo-controlled study that will include both children and adults with PKU. PTC923 is an oral formulation of synthetic [sapropterin], a highly bioavailable precursor to BH4, the critical [dose] factor for phenylalanine hydroxylase, the enzyme that is affected in PKU. There are an estimated 50,000 PKU patients globally and 20,000 patients in the U.S., and as Stu mentioned, there remains a significant unmet medical need for PKU patients.

Turning to our gene therapy platform. Due to COVID-19-related delays, PTC expects the final CHMP opinion on the AADC MAA in the first half of 2021. The treatment procedures for the AADC deficiency patients with a commercial cannula to be completed by year-end 2020 and the submission of the BLA to the FDA to be in the first half of 2021.

Finally, I want to provide an update on our FITE19 trial, the study of PTC299, our orally bioavailable DHODH inhibitor being developed for the treatment of COVID-19. Through its actions at DHODH, PTC299 targets both key aspects of COVID-19, viral replication and the cytokine storm leading to lung disease. The trial consists of 2 stages, with a planned interim analysis focused on safety at the completion of stage 1. Enrollment is ongoing and we remain on schedule to complete the first stage of the trial by year-end and the second stage in H1 2021. I'll now pass the call over to Eric to provide a commercial update.

Thanks, Matt. Our customer-facing team at PTC delivered a strong quarter across the franchise with 16% growth year-over-year from our in-line commercial products. We continue to accelerate growth with Emflaza. Product revenues increased 68% year-over-year, and we continue to see newly-prescribed patients and the reductions of time from prescription to commercial reimbursed therapy.

Also, some U.S. payers have lessened access restrictions to Emflaza therapy. And importantly, the current base of DMD patients have maintained high compliance, with few patient discontinuations demonstrating the long-term therapeutic benefits of Emflaza. We continue bringing awareness to this importance of Emflaza as the standard of care for all DMD patients, with compelling real-world evidence demonstrating clinical benefit over prednisone.

Translarna continues to exceed our expectations in all regions outside of Brazil, where we were impacted by the timing of a group purchase order in Brazil in Q3. We are pleased that in October, we entered in a purchase agreement with Brazil's Ministry of Health to supply Translarna for both new and existing patients. The PTC Brazil team, DMD advocacy groups and the key opinion leaders all worked together to bring awareness of this important therapy, and we were ultimately successful in securing the order with Brazil's Minister of Health and ensuring continuity of treatment for DMD patients. This order is important, given the governmental administrative delays in Brazil hit exceptionally hard by the pandemic. The agreement specifies 2 shipments, one of which was received this quarter and the subsequent one is expected in the first half of 2021.

Now switching to Tegsedi. We continue to engage in pricing discussions for Tegsedi in Brazil and expect to finalize the public price by the end of the year. For both Tegsedi and Waylivra, we continue to engage in patient-finding in Latin America and continue to see success in these programs. We also continue to engage in early access programs in Latin America as we await a decision on our Waylivra and (inaudible) filings in Brazil.

Now moving on to AADC. We continue to aggressively pursue patient-finding activities in preparation for potential launches in Europe next year. We expanded our geographical reach in more than 17 countries and have implemented 60 screening programs focused on enriched high-risk populations, particularly in cerebral palsy and epilepsy clinics. New programs, such as PTC Pinpoint, were launched, which is a single source that health care providers can access to screen potential AADC patients via targeted genetic panels at no cost. We are also adapting to local country needs by leveraging the local diagnostic labs in key markets. And lastly, we are partnering with key centers of excellence globally to develop algorithms to execute patient-finding against existing high-risk patient databases. We are also actively working with these key treatment centers to ensure that they are ready to treat AADC patients.

In addition, we accelerated our digital presence with health care professionals through the continued virtual master classes and for patient advocacy by supporting AADC Awareness Day and the great informational content at aadcfamilynetwork.com. These initiatives have proven useful in education and awareness about AADC and supports earlier diagnosis of patients. I will now turn the call over to Emily.

Thanks, Eric. PTC continues to deliver strong growth in our business while maintaining a robust balance sheet. As Stu shared, we are very pleased with the multiple international approvals of Evrysdi and the start of a strong launch. In the third quarter, we received a total of $35 million in milestones with the first commercial sale in the U.S. and the filing of the MAA with the EMA. Additionally, in the fourth quarter, we received $7.5 million from Roche for the SMA Japan submission. On October 15, Roche reported initial Evrysdi sales of approximately CHF 8 million. As a reminder, PTC retains approximately 57% of Evrysdi royalties until Royalty Pharma receives a return of $1.3 billion, after which 100% of the royalties revert to PTC.

I'll now highlight the third quarter 2020 financial results, which are summarized in the press release issued earlier today. Starting with our top line results. We reported $118.4 million in total revenues in the third quarter of 2020, a 66% increase year-over-year. The $118.4 million includes $82.7 million of net product revenue and $35.7 million of collaboration and royalty revenue. Emflaza and Translarna continued to show growth, with the exception of the delay in timing of the Brazil order for Translarna, and we are pleased that we have now secured that order. As Eric mentioned, the first segment of the order was received in the fourth quarter.

Translarna net product revenues were $43.4 million for the quarter compared to $48.3 million in the third quarter of 2019. Again, the delay of the Brazil group purchase order is the primary driver of this year-over-year decrease. Translarna continues to exceed our expectations outside of Brazil and we are seeing continued global growth. For Emflaza, we reported net product revenues of $38.5 million for the third quarter of 2020 compared to $22.9 million reported for the third quarter of 2019. Growth in net product sales were driven by new patient prescriptions and continued operational improvements and efficiencies in our commercial business.

Non-GAAP R&D expenses were $83.8 million for the third quarter of 2020, excluding $9.2 million in noncash stock-based compensation expense compared to $58.1 million for the third quarter of 2019, excluding $5 million in noncash stock-based compensation expense. This year-over-year increase in R&D expenses reflects costs associated with advancing the gene therapy and Bio-e platforms, increased investment in research programs and advancement of the clinical pipeline.

Non-GAAP SG&A expenses were $50.2 million for the third quarter of 2020, excluding $7.6 million in noncash stock-based compensation expense compared to $43.8 million for the third quarter of 2019, excluding $5.5 million in noncash stock-based compensation expense. The increase in SG&A was due to continued investment in our commercial activities and manufacturing operations to expand our portfolio.

Net loss was $69.7 million for the third quarter of 2020 compared to net loss of $60 million for the third quarter of 2019. The cash, cash equivalents and marketable securities totaled approximately $1.14 billion at September 30, 2020, compared to $686.6 million as of December 31, 2019. The cash, cash equivalents and marketable securities balance as of September 30 includes the $650 million in cash received by PTC in July upon the closing of the Royalty Pharma monetization deal. I will now hand the call over to the operator to start the question-and-answer session. Operator?

(Operator Instructions)

Our first question comes from Eric Joseph with JPMorgan.

I just have a couple on PTC518 for Huntington's, if I could. First, could you -- I guess, with plans -- the plan still being on track to start the healthy volunteer study within this quarter, can you confirm -- does that mean that you filed the IND at this point? And I'm just also wondering, based on your dose-ranging finding studies, what sense you have right now sort of the starting -- what the biologically effective dose might be in humans? And do you have a sense of how many dose [quarters] you would anticipate escalating through in the Phase I setting?

Sure. Maybe we'll start with the Huntington, right? So we're actually pretty excited about this. It's the first in humans, in which the Huntington's protein, which is a splicing protein that -- a splicing molecule that reduces the level of both the Huntington messenger and Huntington protein. And we've shown that it's -- again, to remind you, it's an orally bioavailable molecule that passes the blood-brain barrier, stays within the brain and very nicely reduces both the RNA and Huntington protein.

And so we've shown that the levels that we've observed in blood are the levels that we see in brain, so we'll be -- and the levels of reduction in Huntington are what we're seeing in brain in preclinical models. So we feel pretty good that by being able to look at the PK and levels within the healthy volunteers, we'd be able to find the exposures that we want to get to within patients. And so we'll be doing first in human, and I'll let Matt talk a little bit about the Phase I study for PTC518.

Yes. Matt here. So we are going to -- as we said, we'll be starting the Phase I before the end of the year. We are conducting this ex U.S., so there was not an IND filed but there was a CTA obtained, and I can share that all of the regulatory and ethic documents that needed to be approved have been approved. So we're just now getting to the starting blocks to get the study going, having passed all of those regulatory hurdles. This will be, of course, the SAD and MAD study. And as we mentioned, we're excited about having this opportunity as well to get important proof of splicing mechanism in the Phase I study of healthy volunteers, again analogous to what we did with risdiplam in the SMA development program.

Got it. And as far as tracking or collecting samples in the (inaudible) to look at mRNA down-regulation of Huntington, is that something you expect to be tracking as early as SAD, the single-ascending dose portion? Or would that happen more in the multiple-ascending dose portion of the study?

Yes, we'll be -- the nice thing about it is that you have (technical difficulty) [to the changes]. We'll be looking both at the SAD as well as the multi-dose. And so then obviously, what we'll do is we'll share the relevant data as it becomes available.

Our next question comes from Danielle Brill with Raymond James.

So I guess a couple. First, I'd be curious to hear what your thoughts were on the Scholar Rock data in SMA that were announced this week. And do you have any thoughts on how that might ultimately fit into the treatment landscape in the long term? And then a couple of follow-ups on your mitochondrial epilepsy trial.

Sure. So the -- obviously, when you're thinking about Evrysdi or risdiplam really treats the underlying cause, right? It produces the [motor SMN] protein and that's actually quite important. And we've seen obviously that it helps SMA patients both gain development milestones and meaningful functional improvements in SMA Types [1 through 3]. So we think that's important.

Now when you think about other things that could be improved in terms for the patient that is that a combination therapy that can help muscle growth and degeneration in concert with having SMN protein, then combinations like that can be quite useful, but you could see improvements in muscle tone along with the SMN protein. So anything that could help patients, obviously, we are excited about in that we and our partners are obviously thinking and considering what are the next steps in terms of what's the best decision for the patients for this program. And clearly, the notion of building muscle is really quite important. So we're excited about the notion that -- especially the Type 2, 3 patients, that they can more rapidly show improvement and if it would be beneficial, then more power to having combination.

Understood. And then just that the mitochondrial epilepsy trial is up and enrolling. Do you have any rough idea of what time lines might look like for enrollment? And then can you provide a little more color, just remind us as to what you saw in the expanded access program in terms of seizure benefits that gave you confidence in this indication?

Sure. So just to remind everybody, we're doing a mitochondrial epilepsy, refractory epilepsy trial and just that really the electron transfer and oxidative stress are key points within these refractory epilepsy patients. And so we have a unique inhibitor of 15-lipoxygenase, an inhibitor that is actually a key regulator in controlling oxidative stress and neural inflammation. So we're pretty excited about that. And there's certainly data. There's certainly a preponderance of data showing that this is a key regulator.

And so based on that, there's some early data that I'll have Matt talk about in terms of the data that we have with vatiquinone. But the -- and so this is initiating with the mitochondrial epilepsy, notwithstanding any other additional delays that could be a consequence of COVID, could be completed by the end of 2022. So Matt, you want to go through a little bit?

Yes, absolutely. Danielle, thanks for the question. As Stu mentioned, we're expecting -- what we're doing is working closely with the foundations, physicians and family networks throughout the world where we're going to have study sites to try and get the study enrolled obviously as quickly as possible. Also in light of COVID, we've developed a strategy of really having globally distributed test sites so that we can be prepared to deal with what will be sort of the emergence of COVID in different areas over time.

And finally, we've also been able to incorporate a number of different aspects into the protocol that will allow for remote assessments, again so we ensure that there is minimal impact as possible to the conduct of the study from COVID from this wave and any that may arise.

Turning to the historical data. So we've looked at obviously (inaudible) mitochondrial disease patients in a number of different studies over time in the expanded access study as well as some disease specific or indication-specific studies. And what we've seen in a number of these different studies is an impact on seizures themselves and many aspects of seizure-related morbidity. So in the expanded access, as you mentioned, we had reports of decreased seizure frequency, resolution of refractory status epilepticus in trials of other mitochondrial disorders such as Leigh syndrome, where seizures occur. We have reports of decrease in seizure frequency in these patients.

And in a investigator study in a specific mitochondrial disease subtype, known as PCH6 or pontocerebellar hypoplasia type 6, which is a mitochondrial epilepsy, seizures will start in the first [8 weeks] of life. And these kids just basically continue to seize refractory to all medications and typically die from seizure to complications in early childhood. We treated 5 subjects at a single site and that study demonstrated a significant reduction in seizure frequency, in some cases, over 70% or 80% as well as the ability to influence the occurrence of status epilepticus and importantly, a significant reduction in seizure-related hospital days.

So really, when we look over the collection of studies we've done, we see evidence across many different mitochondrial disease subtypes of an impact not only in seizures themselves, but importantly, on seizure-related morbidity.

Our next question comes from Tazeen Ahmad with Bank of America.

Stu, I wanted to get a little bit of color, if I could, about what our expectations should be for the Translarna data? How much dystrophin production do you think is needed? Have you had any preliminary discussions with the agency on this point? And if they do give you the go-ahead, can you talk us through time lines for what would need to happen in order for you to get a formal approval for the drug in the U.S.? And then I have a couple of follow-ups.

Sure. So we're obviously pretty excited that we were able to complete this trial and really get all [20] patients in so that we'll be able to generate the data. And so with the positive dystrophin data, this is what we've talked with the FDA on, that with the positive dystrophin data, coupled with the really extensive clinical and safety data that we've accumulated on Translarna, we'll move forward to submission in the first half of the year.

And you might recall, and we talked about this multiple times over the years, is that the trial -- this trial was discussed with the FDA, the use of the ECL was discussed with them as well. And then it was -- really the result is if we could show a statistically significant increase in dystrophin levels over baseline, we expect that we'd be able to pursue an accelerated approval in the U.S. on that. So we've now completed all the biopsies in accordance with the protocol, which we obviously remain blinded to until everything is finalized and completed.

So again, the time line there would be submission in the first half of the year. So we think that the data takes about a quarter to analyze this with the protocol, and so the analysis is clearly a priority to us. And so we really do look forward to submitting the NDA with positive data and move forward in bringing this drug to patients in the U.S., who I think have been waiting for some time.

Okay. And then a question on AADC. How is the patient identification process going for that indication? And can you give us a little bit of color on what the rate-limiting factors are right now to get the BLA?

Sure. So let's start with -- Eric, why don't you actually go through a little bit on the -- your work that you and your team's been doing on the patient identification?

Yes, sure. Right now, we're really actively working to identify patients. And obviously, there's really -- this is an ultra-rare disease with approximately 5,000 patients worldwide. So we've actually increased the levels of patient education, and we've rolled out a number of things, including the master class program. And actually, the digital presence that we've had has attracted a tremendous amount of interest from health care providers.

And what we've done more so in the last probably 3 or 4 months, we've expanded our geographical reach. Now our -- in more than 17 countries where we know we're going to have access in reimbursement. And we've implemented 60 screening programs that are really focused on the high-risk population and particularly the cerebral palsy clinics. We launched a program called PTC Pinpoint this quarter, this last quarter, and it's really a nice single source where health care providers can go right to and screen patients via this genetic targeted panel and there's really no cost.

I think during the middle of COVID, we did -- we've got a lot of tests out there, but there was some disruption in terms of patients being actually screened and tested and getting results back. This last quarter, I think we've seen a tremendous amount of movement, and we have really upped the numbers in terms of screening. So I think overall, it's going quite well.

Are you able to give us an update on how many have actually been identified? I think you had started to in the early stages.

Yes. We continue -- I mean, our goal is to continue to have 300 or more addressable patients, and addressable obviously means patients that could be treated. And we are looking in those markets globally where we have access to high-cost rare disease medicines. And we want to have those patients ready to go by the time we have our first commercial launch. I think we're on track to get to continuing to screen that sort of high-risk and enriched population. And more than anything else, we're becoming better and better at understanding which screening programs are giving us the best results.

Our next question comes from Vincent Chen with Bernstein.

A couple of them, one on PTC518 and then one on the AADC gene therapy. So starting with PTC518, I was wondering if you could provide us with some additional color on this initial trial in healthy volunteers. Specifically, I'm kind of curious, just what are the endpoints of the study beyond peripheral Huntington knockdown? What level of peripheral Huntington knockdown are you looking for and how do you measure it? And I guess just sort of timing-wise, what's your kind of thinking for when you would have a readout to support moving into patients? Let's start with that 1 and then a follow-up on -- and then the next one on AADC.

Yes, sure. So as you -- so as you know, right, because it's -- we spent a lot of time making sure that it was selective and specific for Huntington and that we can measure the Huntington on a protein knockdown in blood. And so in the volunteer study, obviously, it's safety as well as looking at RNA and protein levels. We're escalating both single and multi-ascending dose. And we're looking for changes probably up to 50% in reduction. You might remember that in the preclinical trials, and this is again a nice aspect to have an orally bioavailable drug that's getting measure.

In preclinical animal studies where we can look at both the blood and the brain, we were able to look at exposures of a small molecule in the blood demonstrate really that there was almost a 1:1 correlation in what we saw in the blood versus what we saw in the brain, looked at the reduction as a consequence of that. And so we were able to see -- determine exposures that reduced pretty substantially the level of the Huntington's protein. So we feel that we can, in a sense, dial it up or down depending on the level of the drug that we're shooting, the exposure that we have that would then reduce the level protein.

And again, the other nice aspect of this is because it's an orally bioavailable molecule that gets into -- passes the blood-brain barrier, gets to all blood tissues -- brain tissues that you see the whole brain getting in so we can measure in all aspects of the brain so that we've gotten to everywhere. And so what we'll be doing here is obviously measuring the exposure levels, looking at safety and the reduction of the Huntington RNA protein so that we can just define an exposure of up to 50% reduction of HDT. That's the -- so really, it's defining what we think is the right dose and looking at the exposure of safety characteristics.

I see. And then maybe a second one on the AADC gene therapy. So I guess you alluded to this delay in the CHMP. I imagine it's related to sort of COVID and just taking a little longer to respond to a letter of questions. I was wondering you could provide a little color on the questions from the EMA and how they compare to what the FDA has asked for. And then just to sort of zero in a little bit on time line, could you confirm that you've submitted the response to the letter of questions? Or is this something that's upcoming later this year or early next year?

Yes. No, I think you're right in terms of the obviously -- obviously, in working with CROs and stuff with -- not only with COVID but also the fact that many of these contract organizations are also working on vaccines but through the significant -- there are delays within all of this. So we've been pushing forward on this. And there was obviously some specific analysis that we need to get done in order to do that. And I'll let sort of Matt go through sort of the time and thoughts of the general questions that are being asked.

Yes. Vince, thanks for the question. So as Stu mentioned, these were fairly standard questions that come up for a regulatory review, asking for some additional details around some of our assays and additional analyses with them and some detailed questions on some of the other aspects of the data. And really, the key time-limiting factor was the fact that the CMOs that we're using to do our bioanalytical assays are also engaged in COVID activities, including labs that do diagnosis as well as help develop therapeutics. And so we've had to take a little bit of a backseat to those COVID-related activities. And that's what's delayed our response to the questions and we're in the process of getting those resolved and hope to have that submitted as soon as possible, and that's why we're saying that we expect to file CHMP in H1.

Our next question comes from Robyn Karnauskas with Truist Securities.

Just first on Huntington. So I think UniCare has announced that they will be doing a controlled blinded study for their initial trial in Huntington's and that came from the FDA suggestion. Maybe comment a little bit about your thoughts on why not do a controlled study, a blinded study so that maybe you have earlier approval. And then second question is on AADC -- or actually on PCU and AADC, PCU. Give us more time lines regarding that program? Like what are your thoughts on the time lines for the trial? And then I'll have a follow-up.

Okay. So you sort of were going in and out a little bit on the Huntington. But basically, where we are within the Huntington trial and why not do a placebo control. Was that what the question was?

Why not blinded? Why not blinded? The FDA sort of suggested to them a blind -- they're saying that FDA suggested a blinded trial so that the read might be to potentially...

Yes. Within our trial, there are also -- it also has -- it's a placebo-controlled trial as well. And it's a Phase I trial, though so -- and predominantly for safety and the fact that I think we're, in a way, in an unusual position that even though that we're dosing in healthy subjects so they're not Huntington patients, we could rapidly do pharmakinetic studies so we can look at the exposures. But because they have Huntington -- we can -- at the same time, we can also utilize this to monitor the reduction of Huntington RNA and protein.

So even in healthy volunteers, it's very analogous to what we did in SMA. And there are placebo patients and it is predominantly to make sure in terms of looking at it safely, so it's blinded through the period of doing it. And then you look at the analysis at the end of that. So right now, we're basically doing healthy volunteer studies. And the advantage there is we'll be able to define what exposure causes a reduction in the Huntington levels. And then from there, we're going to Huntington's patients where we'll engage with the FDA to design the appropriate study that we can then accelerate.

But an advantage again is that we -- even very early on in Phase I studies, we're able to look at precisely define the dose that gives us to -- the greatest reduction that we want to treat patients with. And we think that alone is going to help accelerate and bring the drug to patients. Does that help you?

Yes. So do you get a sense that the FDA would be more willing to do a smaller in Huntington study? Like -- because they're doing a blinded trial, which is very early stage. So it feels like the FDA is more willing to approve on more limited patients on a good quality early study. I was just wondering if you were getting that sense as well, so that from a competitive standpoint...

The reason we go into healthy subjects in the beginning is that you can do these studies more rapidly, right? That's the beauty of going into it, right? Because the first thing you really want to do in these studies is to find a dose. And so this is gene therapy, which probably not doing a healthy volunteer. It's a different path. We have a small molecule. And in using Phase I studies, you sort of wind them up. They're healthy subjects, they're coming in. They get the drug, they're hooked up onto. So you get all the blood at multiple times. You can look at on a protein level. And so you do this very rapidly.

Then from there, you can define what dose gives you the exposure that you want to get that reduces the Huntington level. And that then lets you go into patients right there, but it is the more appropriate dose that you think could be -- will be efficacious. So obviously, there's no question of the significant unmet medical need for Huntington's disease. And we think that what's really unique about PTC518 is that we know it hits directly the reduction of Huntington protein and RNA, it passes the blood-brain barrier. The fact this is that blood gets to every brain cell. So we think there's a lot of major advantages in this and so we think this is the fastest way to get there.

Our next question comes from Alethia Young with Cantor.

It's Li on for Alethia. I just wanted to follow up on AADC. Sort of curious about your perspective on the launch activity, especially in Europe. I mean, you have the screening programs. Do to early trends that you've seen support your confidence in the product? And I have a follow-up.

Sure. So I think in terms of, in a sense, what are we doing to get ready for launch? I think there's a lot of activities going. Eric and the team have been working pretty hard on this. Eric, why don't you go through a little bit on what we're doing?

Yes. Of course. Thanks for the question. We feel very confident about AADC. And as I mentioned, the first and most important thing we've done is to really activate a number of different key sites in Europe. We've launched and we've adapted a lot of the local activities, especially using labs, local labs, because we know, in many cases, each country has their own preferences and connections about how to screen. So we've accelerated a number of those programs. And as I mentioned, we're now at 17 countries with 60 different programs.

We're also using an algorithm based, kind of retrospective approach in Europe, and we're using that to partner with various health care providers. And this really helps them develop algorithms to execute against identified patient bases already, where we can be able to find patients and begin the process of treating them. In addition, one of the key component is ensuring site readiness and that the sites are preparing not only to just receive the vial and treat the patient but also all the work upfront and after the treatment to ensure that there's continuity of care.

We're doing a lot of work with regard to access and reimbursement. We're looking at preparing all the doses for the health technology assessment. One thing I would remind you is that what's unique about our AADC gene therapy treatment is that it will be the first approved product in Europe and will be rolled out as the standard of care. And so it's not replacing other therapies like other gene therapies that have been approved for different indications. So AADC will have its first treatment and only treatment.

In terms of launch sequence, following CHMP positive opinion, we certainly will begin the process of launching and sequencing many of the countries, which would include classical like Germany first and as well as garnering many of the early access programs in Europe where those are available in the southern and northern Europe.

Got it. That's helpful. And then on U.S. dystrophin study, we've sort of seen the regulatory environment is getting a little bit more conservative. So my question is, do you think that dystrophin will be -- still be an approvable endpoint? Or do you think the FDA might want to see function data as well? Just maybe give us a sense of your recent discussion with the agency. That would be helpful.

Yes. So remember, when we talked about this as first, we talked about the discussion with the FDA, which was that they want -- really, the 1 thing that we didn't have was that in their mind, the dystrophin level in the way that they wanted them to do and to do that experiment. But they did have -- they did look at our data. They looked at both the extensive, critical and safety -- safety data that we have as well as the efficacy over the trials that we've done. That's why at the end of the day, what they told us is that the dystrophin levels, that all that it has to be is over -- is the -- it has to be above the background. That's -- and it has to be statistically significant.

And that, along with the clinical data that we have is -- would be sufficient for accelerated approval with [7 41] after completion would be then for full approval. And I think that is appropriate as you think about other companies that they've gotten approved on dystrophin alone without any sort of data of clinical benefit. So I think we have the combination, hopefully, with the results that come out that we'll see dystrophin data that, along with the clinical data that we have, will actually be a nice strong path to get those both clinical benefit as well as the dystrophin data. And then we have the trial that's ongoing, that would be for full approval.

Our next question comes from Joel Beatty with Citi.

The first one is on Translarna in Brazil. For the recent order there, could you characterize how the pricing and volume compares to the previous bulk orders from Brazil?

Yes, sure. Eric, do you want to talk a little bit about that?

Yes, Joel, in Brazil, Brazil's pretty lumpy in terms of their orders. And I can say that we're -- first of all, I'm really proud of the PTC Brazil team that has been managing what I think is a very, very challenging situation right now in Brazil. The country has been hit exceptionally hard by the pandemic. COVID-19 has disrupted not only the administrative aspects of it but just the way health care has been sort of spending has been diverted.

We know many companies haven't received any orders this year. So the team there really has done a terrific job to work with advocacy groups and key opinion leaders and others to really sort of bring about awareness that patients should be off-treatment. I mean, the good news is that we continue to find patients, and we've added substantially more patients to the order and that's important. But due to some of the constraints in budget and everything else, Minister of Health had asked us to split the orders between Q4, which we already received, and we'll be shipping the second order in Q1.

Now we don't necessarily give out specifics but what we're happy about here is that the order was substantial enough to cover not only the existing number of patients but also a substantial number of new patients that have been diagnosed and had gone through the judicialization process. So I'm very pleased that we're able to get patient -- drug to patients this year and that the continuity will be in the first half of next year as well.

Got it. And then 1 other question on AADC. Could you help characterize what needs to be completed between now and the NDA filing? And part of the reason I asked is it seems like recently, there was some hope that the filing could be by the end of this year, and now it seems to be in the first half of next year, which seems to be up to a 6-month delay. So what maybe accounts for the extending of the time line?

Yes. So I'll start and then I'll ask Matt to go into a little bit more detail. But part of -- there's really a lot associated with of the pandemic. And obviously, we talked previously about the surgical procedures as a gate factor to get a few additional patients in and the pandemic has been an issue for us. So we're expected to complete it now in the fourth quarter. Matt, do you want to talk a little bit of what is needed after that?

Yes, sure. So as Stu mentioned and we've talked about before, one of the key gating items for the BLA was fulfilling an FDA request to treat patients with the cannula that we're going to use commercially. And the cannula was the device that delivers the gene therapy into the precise area of the brain. And we had those surgeries scheduled in the third quarter. They've gotten delayed due to COVID and our schedule's on the fourth quarter. So we expect to do those procedures.

Now again, the important thing here is it's a study of the cannula, not the safety of the gene therapy or the efficacy of the gene therapy but basically demonstrating that we can get the gene therapy to the right location without any procedural complications. So the plan will be to gather the data from those procedures and then make sure we're aligned with the FDA and move forward with the submission.

As you mentioned, obviously, we're well aware of the evolving landscape in gene therapies and some of the feedback that the agency has to look to other companies. We're obviously watching it very closely. That's also why we want to make sure after we have these data that we are aligned and move forward, and we expect that we'll be able to do that, move forward with the BLA submission in H1 2021.

I also want to emphasize that we remain incredibly enthusiastic about the program because one of the things we've been able to do during this delay is continue to harvest long-term data from the patients that have been treated already. And this package is a very strong package with long-term follow-up, 5, 6, 7, 8 years following therapy, where we're able to demonstrate durability of dopamine production as well as durability of clinical response. And we know that, that durability of treatment effect is really a crucial aspect to a gene therapy package. So we look forward to being able to have the procedures done, aligning on any other issues with the agency and moving forward with presenting this package to the agency.

Our next question comes from Joseph Thome with Cowen.

On vatiquinone in Friedreich ataxia, can you remind us, is there a reduction in the [FAR] score that physicians highlight as clinically meaningful around that 72-week time frame that you're looking? And are you making any considerations regarding patient enrollment depending on disease severity? And then on a related note, now that Hopewell is online, can you give us any updates as to when you expect to submit the IND for your Friedreich ataxia gene therapy?

Sure. Let's start with Matt, you want to -- go ahead.

Yes, absolutely. So the Phase III FA 743, the MOVE-FA trial, is one that we're building on a body of experience in our own clinical studies as well as those of others. One of the most -- a couple of important points. One is you mentioned the target in MOA of 743 targeting enzyme 15-lipoxygenase and the associated pathway of inflammation and [RNA] oxidative stress is clearly one that it's shown to be incredibly important to FA pathology.

And on top of that, we obviously have the Phase II data, which demonstrated over a prolonged period of treatment. After 24 months, we had a significant reduction in the [FAR] score, which translates to a significant improvement in disease severity. Just to give you an example on that, the overall improvement in those treated was improvement of 1.8 points on the FAR as relative to the natural history match cohort, which is a worsening of 4.8 points. So we believe that is a significant magnitude of effect relative to the understood natural history of disease.

And so we do expect to have a clinically meaningful effect on the mFARS. And in addition, I think, as we're all well aware of, is the FDA's desire to have an endpoint strategy that we not only include the mFARS but also key secondary endpoints that reflect key aspects of feel and function. And those, of course, are going to be -- the activities to [live] and walk test, which we -- is an endpoint strategy that we've aligned with both the FDA and the EMA on because we've realized that's a crucial aspect of the disease.

The selection of the 18-month duration of a parallel placebo controlled phase again is based on our own experience as well as that of countless others where there is a placebo effect that had put in Friedreich ataxia that is present even at 6 months and sometimes longer. And we believe by being able to treat for 18 months, we'll be able to again see what we saw in a Phase II study, which was a long-term effect on disease progression and also a dampening and hopeful elimination of that placebo effect, which, of course, is so incredibly important to be able to then demonstrate a statistically significant effect on the mFARS scale.

Regarding your question about disease severity, obviously, we understand that disease severity is an important aspect of Friedreich ataxia and also can impact the potential response in the therapy and rate of progression for those in the placebo group. And while we not only have a range of mFARS scores to bookend that disease severity, we also plan to stratify our randomization on the mFARS to ensure that we have balance between both the treatment and placebo group on this critical set.

Great. And then the last -- the second part was just on the IND for the Friedreich ataxia gene therapy. Does bringing Hopewell online kind of give a little bit more clarity on when that could be submitted?

Yes. I think we're pretty enthusiastic still about the Friedreich ataxia gene therapy and the needs in the center that we're working on and to support it. And we'll -- I think as we move forward on that, we'll be able to give you a more precise update on the timing.

Our next question comes from Raju Prasad with William Blair.

Just a follow-up on some of the comments you made on the dystrophin study. Stu, would you mind sharing just what the kind of delta is versus is there a significance above background for the study? And then I have a follow-up.

Sure. I'll start and then pass it on to Matt. For us, the important point, there is no real -- and actually, you might remember when Dr. (inaudible) talked about this. Basically, she said, it's particularly in terms of the approval that there was no precise number just above that [background] to that BCL is quite analytical and very sensitive so that we should be able to monitor and see what's above background in terms of the level. Matt, you want to talk a little bit about the ECL and where we are on that?

Yes, absolutely. As Stu said, we recognize that it's not only what we know from our experience that the same that was seen with in Sarepta's studies and NS Pharma, both of whom have recently had approvals based on the dystrophin endpoint alone. We know that there's typically very low levels of dystrophin expression at baseline in patients. And therefore, it was incredibly important for us to develop an assay that was incredibly sensitive, right? We really want to be able to capture those lower levels of dystrophin expression because we want to show that we can have that improvement over baseline statistical significance that we need.

And so what we've done in obviously setting up this study is modeled a number of different scenarios, assuming low levels of baseline dystrophin expression and looking at potential increase in dystrophin baseline, coefficient and variation to ensure that with our 20 subjects that we have more than sufficient power to demonstrate that statistically significant improvement over baseline, which really was the threshold that the agency has not only established for us but obviously had established for others as well.

Great. And on the commercial franchise, obviously, COVID is kind of spiking up again going into the fourth quarter. Is there anything that maybe you guys could give us some color on expectations for Translarna and Emflaza into the fourth quarter, given potential headwinds or any learnings you have from the second quarter?

And then on risdiplam or Evrysdi, looks like a good number. The split between Type 2 and 3 and Type 1, do you think that, that's just a function of the nature of the disease and the prevalence of the disease? Or are you seeing something from early adopter physicians being more willing to prescribe to 2 and 3 patients?

Yes, sure. So from the -- in terms of we've seen for Translarna and Emflaza, really very good performance from the portfolio that we've been doing for both Translarna and Emflaza. And so even in spite of COVID, in some ways, even with COVID, that it's done actually quite well. We -- the insurance company has almost been allowing more things to get through. So the flows for Translarna and Emflaza, we see pretty good production, and Eric can talk more about that as well.

But that's also true of risdiplam, I think the fact that it's orally bioavailable, distributed directly to patient is a really big advantage. And so people have been able to continue with that. Eric, do you want to put a little more color on this?

Yes, sure, Stu. I think, first of all, as Stu mentioned, the DMD franchise is in a really strong position, and we're continuing to see growth quarter-on-quarter and year-on-year, especially strong growth from Emflaza, with over 60% growth from the previous quarter. And we anticipate that growth to continue into -- well into the fourth quarter. Main drivers there have been, again, new prescriptions. We've had a great response so far in the quarter with new prescriptions, and the time from that prescription to the time of reimbursement has been very positive.

We've seen payers that have either eliminated or reduced a lot of the step edits that are involved with prednisone, which is important in terms of timing. And the team that we have -- I'm really proud of the U.S. team. Our PTC Cares team has really focused on the base of patients that we have for Emflaza. These patients here have maintained very high compliance, well over 90%. And that's incredible during the pandemic and we've seen very few dropouts on Emflaza.

As for Translarna, we certainly are seeing growth even in areas that are hit hard by the pandemic in Europe. So we accrued new patients in the quarter in places like Spain and Italy, in France and other places where we say COVID has really hit them very hard. So we continue to see growth in all regions with Translarna. And importantly, that is -- now that we have the quarter in Brazil, I think it's safe to say that we don't see any major headwind in the quarter.

Our next question comes from Brian Abrahams with RBC Capital Markets.

This is [Steve Mallon] on for Brian Abrahams. On 518, you touched on this just a bit but do you anticipate the 1:1 blood-brain depletion ratio will be extended to deep brain structures? And given the progressive nature of Huntington's, how early do you think you'll have to start treating patients to see clinical gains?

Yes. Thanks for that. Yes. So that's the beauty again of an orally bioavailable, small molecule that's across where you have very good exposure within the brain. So we've shown indeed in preclinical studies that the lowering of the Huntington protein in all regions of the brain were observed as a consequence of treatment with PTC518. And that the blood levels correlated very well with that in the brain.

So I think that -- to me, that's always been a major advantage, especially in a disease like Huntington's where -- that you could certainly get -- you certainly get a -- you get cell death. So there's a real advantage of that. So that -- and then in fact, PTC518 is systemic so it reaches all tissues as equally distributed. And it's obviously titratable as well. So yes, so I think we're in a pretty good belief that, that's important and it's a degenerative disease, we obviously believe the benefit of reducing Huntington patients is important.

And then obviously to your question, your sort of question is an interesting one from the point of view of trying to treat patients because Huntington's patients, obviously, they take time. There's no way to predict when you'll be able to do that. So the notion of being able to do [pre-dermo] patients all night is hard to do because you don't know how long the study would be. So I think you need to start with in terms of clinical trial, with manifestation, ultimately, right, because then you know they have -- you have something which you can measure, look at the stage or the course of the disease.

So obviously, we're starting early looking at manifestations. But we're looking obviously to treat all patient types, including not only the manifest patients, but there's the juvenile patients with still rapid onset. And clearly, that's something we should look at as well because that occurs earlier and goes more rapidly. So that could [be a potential route]. And then ultimately, you want to get pre-dermo patients and move into that once you know more of that because, obviously ultimately, you want to get the patient well before they're manifesting that.

But the first step is to show that you can alter the course of the disease, understand the learnings from that and then move as rapid as possible into both JC and pre-dermo . So -- and we're going to be learning over time as we do this. But I think that really, from my perspective, it's really good news from us is that we know and the fact that it's orally when you look at blood to see the reductions. We know we're on target. Now it's about really -- just like we did an SMA to demonstrate clinical effect.

Our next question comes from Gena Wang with Barclays.

This is David on for Gena. So 1 question on AADC program. So since the CHMP opinion will be on first half of next year, what has been reimbursement discussion with payer like? What's the current consideration for pricing? And then are you planning for installment -- you stopped payments as well?

Yes, sure. So obviously, the AADC program and the results that we have are really quite compelling, and we've done a lot of work in terms of looking clearly. It's an easy one to see the effects of this drug. And Eric, maybe you want to talk a little bit about all the work that we've done in terms of getting ready.

Yes. And that all ready, it's quite good. I think it's interesting because we've been getting ready now for a long time, and we're ready to go because we have been studying patients and we have a very strong participant data. And as a reminder, when we go forward with our HTA assessment, by which we have had multiple early payer discussions in Europe, those who have early access mechanisms and those who are going to approve the drug more commercially after approval.

But what we try to emphasize more than anything else is that this is a high unmet need. There is no treatment currently available for children with AADC, and that all children with AADC need to have this treatment. And importantly, that when treatment is given, there is durability. We have data now that goes out, in some cases, for 5 years, 7 years. We have patients that are treated even longer than that.

So from a health technology assessment perspective, we're bringing a new standard of care and we're bringing the only standard of care. So the pricing will reflect a number of different things in Europe, as well as in the United States. And we've been very good at maintaining a very narrow pricing corridor across Europe and across international markets. But it will certainly be based on the population that is addressable, the unmet need, and of course, the willingness to pay and the mechanisms by which each country will have.

As I mentioned earlier, we anticipate to have our first commercial launches in the traditional markets in Europe, such as Germany, where approval and free pricing would have its first benefit. And then we would subsequently go to a number of key markets that have already asked us about early access programs. So many of those countries in southern Europe would be targeted as well. And following the European approval, we will be targeting other markets outside of Europe, like Latin America and potentially Asia Pacific.

So our pricing strategy, where we won't discuss price at this point in time, will certainly not be based on a replacement of a product, which other gene therapies are, but as an established standard of care, new standard of care that will meet a high unmet need is a big burden. And it's a relatively small population, [5,000] patients worldwide.

Got it. That's really helpful. So just a follow-up. Actually, another question on the Bio-e 743 program for mitochondrial epilepsy. So you need to be administering as a TID dosing. So what's the [pure PK] like? I mean, can you just provide some more color on the PK profile of the drug, including the half-life, the T-MAX and also any split effect?

Sure. Matt, do you want to go?

Yes, absolutely. So 743 is a TID dose medication. Obviously, we've been treating patients for a number of years and also understand the pharmacologic progress of the drug quite well. It's given 3 times a day with food. It could be administered. It's administered as a solution for young children, which is particularly helpful, given that many children with mitochondrial disease, including those with mitochondrial disease or refractory seizures are feeding tube dependent.

So being able to administer the drug through a feeding tube is quite -- in solution form is quite convenient and then, of course, it's 3 times a day, breakfast, lunch, dinner given with meals. And 3 times a day dose of regimen is obviously generated, given the half-life of the drug, which is between [4 to 8 hours] (corrected by company after the call) in patients. And so obviously, again, yes, the dosing regimen has been well informed based on previous pharmacologic evaluations as well as obviously the safety and efficacy record of the drug.

Our next question is a follow-up from Vincent Chen with Bernstein.

I have a couple of deep in the weeds follow-ups on Huntington's, if you're amenable. The first is simply -- I'd love to dive a little deeper into what's the minimal amount of knockdown or a range of knockdown you're looking for? I know you've shown 50%-plus all the way to 80% or so in mice. But I imagine, less than this may well be adequate, especially given sort of a uniformity of distribution throughout the brain. And I also wonder, is there some point at which you worry about loss of function, adverse effects from excess knockdown?

And the second question is, I'd be curious to get your thoughts on how you expect the likely dosing range could compare to, I guess, for the sake of an easy comparator, risdiplam. Basically, are preclinical studies of the pharmacokinetics for the Huntington's program comparable to risdiplam? And how high can you go on dose from a safety perspective based on what you've seen preclinically?

Yes. Thanks, Vince. Appreciate that. The -- so the question on what dose, you've seen the preclinical results and the nice aspect of an orally bioavailable drug is that it was titratable, and you can get -- and therefore, you could titrate to the levels that you want to get to. Obviously, I think what the community thinks is somewhere up to 50% would be good. There's a discussion of between 30% and 50% could be associated with therapeutic benefits based on some preclinical results. So we're shooting in that range for benefits as a consequence of that. And we think we'll certainly be able to do that of probably with once-a-day dosing or so, and that's our expectation. But we'll obviously be able to measure the effect in blood and adjust accordingly.

And that will be -- it's hard to actually say until we put it in the humans. But that's our expectation. We think it will be, in some way, similar to what you're saying with risdiplam, that it's a once-a-day dosing. That's somewhat of our expectation, but you'll always wait and see how it does in humans.

Yes, go ahead.

Oh, your question on -- yes. I think a lot of -- we're thinking about the question you had in terms of what -- in terms of -- we think you probably can go substantially down post-development. And that's something we ultimately want to look at if we can. But we think that 30% to 50% in that range would be just fine to be able to do it. But we do sort of think about how high can we go. I mean, obviously, if we can go higher, that's even better but we're just trying to figure some of this out and experiment it.

I see. And then I guess, dose-wise, risdiplam, I guess, was sort of limited at the upper end by some of the preclinical safety effects, and I guess you don't need to go that high so that all works out very well. Preclinically, is there anything that's been seen with [RG518] -- I'm sorry, PTC518, that would lead you to think that -- basically put some sort of an upper limit on how high you could work up to in patients or in healthy volunteers?

Yes. I think so far, in the nonclinical studies that have let us -- I think we have a nice data package that supports us being able to go to the doses that we think will be very much adequate for being able to reduce that. So we feel pretty good that we're in a pretty good spot for this. Obviously, we spent a lot of time on this molecule in terms of identifying selectivity, specificity but also on the pharmaceutical properties. Obviously, for us, some of the key things was not getting passed the blood-brain barrier, that we could get a substantial appropriate levels within that there was no e-flux within the cell, because if you think a lot of drugs that people take, the reason they don't work for issues in the brain is even if they could pass the blood-brain barrier, they get e-flux then they don't maintain within the brain.

And so we've done a lot of work to make sure that this drug has not e-fluxed on top of having all the right properties that it can pass the blood-brain barrier and gets into all tissues is not e-flux. So we feel pretty good about this. And so we're looking forward to the results in the Phase I trial.

And I'm showing no further questions at this time. I'd like to turn the call back over to Stuart Peltz for closing remarks.

Okay. Well, thank you, and thank all of you for calling in today. And I think as you can see that despite the challenges that have been presented by the COVID pandemic, I'm pretty proud of how the PTC team has executed and performed during this time. If you think about it, the approval of Evrysdi was the culmination of many years of discovery development by our teams. And we were also able to complete the biopsy, so that is -- that we've enabled the potential submission of the Translarna NDA, and so we're excited about that as well.

We are -- just started the registrational studies for vatiquinone in mitochondrial epilepsy. We initiated and are performing now the Phase I trial for the PTC857 for GBA Parkinson's. And we're already -- as you've seen, PTC518 for Huntington. So a lot has actually gone on. We're excited about the future potential of this -- really of all the drugs that we have in the portfolio that we've built, where we're discovering and developing and commercializing really the next generation of value-creating therapies for patients with high unmet medical need that we think will be quite valuable to all our stakeholders. So with that, I want to thank you again for taking the time -- for spending some time with us.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.