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PTC Therapeutics Inc
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Ladies and gentlemen, thank you for standing by and welcome to PTC Therapeutics Third Quarter Corporate Update and Financial Results Call. At this time all participants are in listen-only mode. [Operator Instructions]
I would now like to hand the conference over to your speaker Miss Lisa Hayes, Vice President of investor relations. Please go ahead, ma'am.
Good afternoon. Thank you for joining us to discuss the 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, Stuart Peltz.
Thanks, Lisa. And thank you for joining the call today. We have made significant progress this quarter with our R&D pipeline as well as our commercial business so we've continued growth. We've built PTC to create value for all stakeholders by discovering and developing novel therapeutics for patients with medical needs, increasing 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 a 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 a first add home orally administered treatment for SMA patients two 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 improvement 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 physician, 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 two-thirds of the initial patients on Evrysdi were previously treated with spinraza or [indiscernible]. We are seeing uptake across all types of SMA patients. To date, 25% of patients treated have been type one, with the remaining 75% are type two and three. 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 AMA with a decision expected in April 2021. We appreciate the strong effort made by our partner Roche.
Let me comment on our commercial 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're 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 polio splicing programs that are moving forward. Our plan is to create value by eternally developing these products and to bring them to patients globally. After Evrysdi, the next most advanced compound from our splicing platform is PTC 518, which has been developed for Huntington's disease. I'm excited to report that PTC 518 will enter the clinic this quarter.
Analogous to how we discovered Evrysdi PTC 518 was constructed to be an orally bioavailable molecule that distributes to all tissues in the body. It 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 molecule. The Phase 1 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 1 healthy volunteer study should allow us to demonstrate targeted engagement and proof of concept of the reduction of HTT mRNA. This will allow us to select doses for the subsequent study in HT patients.
Now, let me turn the attention to our late-stage clinical programs. From our binary platform, we recently announced that enrollment again in a registration-directed trial called mighty with our compound Vatiquinone the treatment of congeal epilepsy. As a reminder, about half of all children with inherited mitochondrial disease suffer from refractory seizures. These seizures result from dysregulation of the electron transfer process, leading to oxidative stress and inflammation, particularly known targets the enzyme 15 lipoxygenase, which is a key regulator of the neural inflammation and oxidative stress response.
We estimate that there are approximately 12,000 commercially addressable mitochondrial epilepsy patients globally. An additional registration directed trial with Vatiquinone can move he is also planning to initiate by year end. F8 disease pathology results from high levels of oxidative stress inducing neural inflammation, which is known to be an important F8 disease pathology and progression. particularly known modulates these pathways to reduce inflammation. Previous Phase 2 results so that particular non-altered the course of F8 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, we expect to initiate a pivotal Phase 3 study in mid-2021. With an estimated 20,000 PKU patients in the U.S. alone, there continues to be high medical need, as the majority did not initially respond or not adequately controlled on kubek. Results from previous studies demonstrated that approximately 50% more patients responded to PTC923 when compared to kubek. Furthermore, in these studies, the results demonstrated that the drug had greater than twice the reduction in centrality [ph] levels compared to Kobe. We are currently conducting non-clinical studies to support the long term dosing for the planned Phase 3 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 security and accelerated approval for Translarna in the U.S. so that these patients will 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 AGC deficiency, where we have observed transformational and durable results in ADC deficient patients that have been treated for almost a decade. RMA has been submitted and under review by the CHMP. Due to COVID-19 related delays, PTC now expects the CHMP final opinion for ADC deficiency application in the first half of 2021. For the VLA, PTC expects submission to the FDA will also be in the first half of 2021.
We also recently initiated a phase 2/3 trial for PTC299 for COVID-19 called fight-19. 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 compounds oral bioavailability gives us great confidence in PTC299 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 in our clinical program, Matt.
Thank you, Stu. We've 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 profile the transformer district 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 district and expression over baseline, as assessed by an electrochemiluminescence asset that we developed in collaboration with the FDA. We expect to have top-line data from the over five districting study in Q1 2021.
Turning to our bioheat platform, we have initiated enrollment in the mighty trial, the registration directly trial of Vatiquinone in children with mitochondrial epilepsy. This phase 2/3 trial will enroll approximately 60 children with genetically confirmed mitochondrial disease and associated refractory seizures. The study design includes a one to one front end period to ensure that all eligible subjects have a minimum number of seizures, followed by a six-month parallel art phase in which subjects will receive either Vatiquinone or a 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 3 Vatiquinone Friedrich ataxia trial move FA remains on schedule to initiate enrollment by year end. This trial will enroll approximately 110 children and young adults with Friedrich ataxia.
The study design includes an 18 month parallel arm placebo-controlled phase, during which subjects will receive either Vatiquinone or a placebo. Primary pinpoint measures to this study is a modified Friedrich ataxia rating scale for employers with key secondary endpoints assessing ambulation and activity is a daily living. This endpoint strategy was developed in collaboration with both the FDA and EMEA. There are approximately 25,000 patients worldwide with Friedrich ataxia. The second compound from our Biwi platform, PTC857, we have completed the phase 1 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 1 trial and healthy volunteers to initiate in this court. This phase 1 study includes both single and multiple ascending dose regimens to inform safety and pharmacologic parameters, as well as to guide those selection for subsequent registration trials. Importantly, we're also planning to measure htt mRNA levels in healthy volunteers to gain early proof of splicing mechanism, as was done in the risk to plan SMA development program. We expect to have data from the phase 1 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 study of needed to support the initiation of the phase 3 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 highly bioavailable precursor to BH4, the critical cofactor for phenylalanine hydroxyl, the enzyme that is effective in PKU.
There are an estimated 50,000 PKU patients globally and 20,000 patients in the U.S., as Stu mentioned, there remains a significant unmet medical need for PKU patients. Turning to our gene therapy platform through the COVID-19 related delays, PTC expects the final CHMP opinion on the ADC MA in the first half of 2021. The treatment procedures for the AADC deficiency patients with commercial tangler 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 fight 19 trial. The study of PTC299 are orally bioavailable, the DHODH inhibitor being developed in the treatment of COVID-19. Through its actions of DHODH, PTC299 targets both key aspects of COVID-19 viral replication and the cytokine storm leading to lung disease. The trial consists of two stages with a planned interim analysis focused on safety at the completion of stage one. Enrollment is ongoing and remain on schedule to complete 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 inline commercial products. We continue to accelerate growth within 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 implies a 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 the importance of Emflaza as the standard of care for all DMD patients with compelling real-world evidence demonstrating clinical benefit over pragmatism. 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 work 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 two 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 visa filing in Brazil.
Now moving on to agency, 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 ADC patients. These targeted genetic panels at no cost. We're also adapting to local country needs by leveraging the local diagnostic labs in key markets.
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 masterclasses and for patient advocacy by supporting AADC Awareness Day, and the great informational content at ABC Family network.com. These emissions have proven useful in education and awareness about AADC and support 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 CMA Japan submission. On October 15, Roche reported initial overseas sales of approximately 8 million Swiss francs. As a reminder, PTC retains approximately 57% of Evrysdi royalties until royalty farmer receives a return of $1.3 billion, after which 100% of the royalties revert to PTC.
Now highlights 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 products revenue and $35.7 million of collaboration and royalty revenue. Emflaza and Translarna continued to show growth with exception of the delay in timing of the Brazil order for Translarna. 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 orders 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 that product sales are driven by new patient prescriptions and continued operational improvements and efficiencies in our commercial business. Non-GAAP R&D expenses were at $83.8 million for the third quarter of 2020 excluding $9.2 million and non-cash stock-based compensation expense, compared to $58.1 million for the third quarter of 2019, excluding $5 million in non-cash stock-based compensation expense.
This year-over-year increase in R&D expenses reflects costs associated with advancing the gene therapy and bio-e platform, increased investment in research programs and the 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 non-cash stock-based compensation expense, compared to $43.8 million for the third quarter of 2019, excluding $5.5 million and non-cash 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 of $69.7 million for the third quarter of 2020 compared to net loss of $60 million for the third quarter of 2019. Cash, cash equivalents and marketable securities totaled approximately $1.14 billion as 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 section. Operator?
[Operator Instructions] First question comes from Eric Joseph with JP Morgan. Your line is open.
Hi, good evening. You can hear me? Thanks for taking the questions. I just have a couple on PTC518 for Huntington's if I could. First, could you I guess, with plan 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 findings studies what sense do you have right now of sort of the starting? What's the biologically effective dose might be in humans? And do you have a sense of how many dose courts you would anticipate escalating through in the phase 1 setting?
Sure maybe we'll start with the Huntington, right. So we're actually pretty excited about this. It'll be the first in human in which the hundreds of project which is a splicing protein, that splicing molecule that reduces the level of the both the Huntington messenger RNA and Huntington protein. We've shown that it's again, to remind you it's the only available molecule that passes the blood-brain barrier, stays within the brain and very nicely reduces both the RNA and Huntington protein. So to that extent, 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 and what we've seen in brain in preclinical models. So we feel pretty good that by being able to look at the PK levels within the healthy volunteers, we'll 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 1 study for PTC500.
Hi, Matt here. So we are going to as we said, we'll be starting the phase 1 before the end of the year. We are conducting it xUS so there was not 95 but there was a CTA obtained, and I can share that all of the regulatory and ethics documents that needed to be approved had 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 study as we mentioned, we're excited about having this opportunity as well to get important proof of splicing mechanism in the phase 1 study of healthy volunteers again, analogous to what we did with Reza clan and the FMA development program.
Got it. And as far as tracking or collecting samples in the periphery to look at mRNA down regulation of Huntington, is that something you expect to be tracking as early as the single ascending dose portion? Or would that happen more on the multiple ascending dose? Portion of that.
The nice thing about [Technical Difficulty] will look it will be looking both at the FHP as well as the multidose. And so then, obviously, what we'll do is we'll share the relevant data as it becomes available.
Great, thanks for taking the question.
Our next question comes from Danielle Brill with Raymond James. Your line is open.
Hi, guys. Good afternoon. Thanks so much for the question. So I guess a couple first, I'd be curious to hear what your thoughts were on the scholar rock data and 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 up on your mitochondrial epilepsy trial?
Sure, obviously, when you think about the underlying cause of the disease, like in SMA the original plan really treats the underlying cause it produces the amount of protein, and that excellent quite important. And we've seen obviously, that it helps SMA patients, both game developer milestones and meaningful functional improvements and estimate types one [Technical Difficulty] three, so we think that's an important. Now, when you think about other things that could be improved in terms of for the patient that is that combination therapies that can help muscle growth and degeneration, in concert with having SMA protein, then combinations like that can be quite useful but you could see improvements in muscle tone in long with the SMA protein. So anything that can help patients.
So obviously, we decided about 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, you know, especially the type two, three patients that they can more rapidly show improvement and if it would be better to show them more power than having combination.
Understood. Thanks for that. And then, just now that the mitochondrial epilepsy trial is up and enrolling, do you have any rough idea of what timelines 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 competence in this indication? Thanks.
Sure. So just to remind everybody, we're doing a mitochondrial epilepsy refractory epilepsy trial. And does that really be electron transfer and oxidative stress are key points with these refractory epilepsy patients. And so we have a unique inhibitor, p15 [ph] inhibitor, that is actually a key regulator in controlling oxidative stress detox and neural inflammation. So we're pretty excited about that. 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 Matt talk about, in terms of the data that we have with particular known, but the minor. And so this initiating, and we think that the amount of times 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?
Yeah, absolutely. Danielle, thanks for the question. As Stuart mentioned, we're expecting data by end of 2022. And what we're doing is working closely with the foundation's position within family networks throughout the world, we'll have study sites to try and get the study enrolled obviously as quickly as possible. Also in light of COVID we 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's a minimal impact with possible to conduct of the study from COVID from this wave and any that may arise.
Turning to the historical data, so we looked at obviously specifically for mitochondrial disease patients and a number of different studies over time and the expanded access study as well as some of these specific or indications 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 [ph]. In trials of other mitochondrial disorders such as least syndrome where seizures occur, we have reports of decrease the seizure frequency and these patients. And in a investigators study in a specific mitochondrial disease subtype known as PC6 or cross cerebral hyperplasia, type six, which is a mitochondrial epilepsy seizures a start in the first eight weeks of life, these kids just basically continue to see refractory to all medications and typically died procedure related complications early childhood.
We treated five subjects at a single site in 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 you've done, we seeking evidence across many different mitochondrial disease subtypes have an impact not only on seizures themselves, but importantly on seizure related morbidity.
Great, thanks so much, Matt. For all those details, appreciate it.
Our next question comes from [indiscernible] with Bank of America. Your line is open.
Hi, good evening, thanks for taking my questions. Wanted to get a little bit of color if I could about what our expectations should be for the trans learner data? You know, 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 timelines from for what would need to happen in order for you to get a formal approval for the drug in the US? And then I have a couple of follow up. Thanks.
Sure. So we're obviously pretty excited that we were able to complete this trial and really get all 20 patient savings so that we'll be able to generate the data. And so with the positive distance for the data, this is what we've talked with the FDA that with the positive dystrophin data coupled with the really extensive clinical and safety data that we've accumulated on [ph], we'll move forward to a condition in the first half of the year. And you might recall, and we've talked about this multiple times over the years, is that the trial, this trial was discussed with the FDA, the use of the sale was discussed with them as well. And that it was it 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 US on that.
So we now completed all the biopsies in court in accordance with the protocol, which we obviously remind blinded to until everything's finalized and completed. So again, the timeline, 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 and being this drug to patients in the US, who I think have been waiting for some time.
Okay. And then of course on AIBC, 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 BOA?
So let's start with, Eric wants to actually go through a little bit on your work that you and your team's been doing on the patient identification.
Yeah, sure. Hi, Susie. And right now we're really actively working to identify patients. And obviously, there's only this is an ultra rare disease with the proximately 5000 patients worldwide. So we've actually increased the levels of patient education, we 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 three or four months, we've expanded our geographical reach. Now are 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 [indiscernible].
You know, we launched a program called PCC pinpoint this quarter, last quarter and it's really the nicest single source where health care providers can go right to in screening patients via this genetic targeted donor. And there's really no cost. I think, during the middle of COVID, we did 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.
And you're about to give us an update on how many have actually been identified, I think you have started to in the early stages?
We continue, I mean, our goal is to continue to have 300 or more addressable patients. And addressable obviously means patients to 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 a first commercial launch. I think, we're on track to get to continuing to scream that sort of high risk and enrich population and more than anything else. We're becoming better and better understanding which screening programs are giving us the best results.
Our next question comes from Vincent Chin with Bernstein. Your line is open.
Thank you very much for taking my questions and congrats on progress. A couple of them one on PTC 518 and then one on the ADC gene therapy. So, starting with PTC 518, I was wondering if you could provide us with some additional color on the initial trial and healthy volunteers specifically, I'm kind of curious just what are the endpoints of the study beyond peripheral Huntington knockdown? What level peripheral Huntington knockdown you're looking for? And how do you measure it? And I guess, just timing wise, what what's your kind of thinking for when you would have readout to support moving into intubations? Let's go with that one, and then a follow up on, the next one ADC?
Yes, sure. So right, so as you know, right, because we spent a lot of time making sure that we're selective and specific, for Huntington that we can measure the Huntington, protein down in blood and so in the volunteer study, obviously phase 2 as well as looking at RNA and protein levels within the escalating bulk signal 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 you can measure. In preclinical animal studies where we can look in both the blood in the brain, we're able to look at exposures of a small molecule in the blood demonstrate really that it was almost a one to one correlation between what we saw in the blood versus what we say, looked at the reductions as a consequence of that.
And so we were able to see determine exposures. That reduced pretty substantially the lack of the Huntington protein. So we feel that we can get a sense, dial it up or down depending on the level of drug that we're shooting, the exposure of that would better reduce the level of protein. Again, the other nice aspect of this is because it's an orally bio-available molecule, it gets into all passes the blood brain barrier gets the awkward tissues of brain tissues that you see the whole brain getting in so we can measure in all aspects of the brain. So that it got to everywhere.
And so what we'll be doing here is, you know, obviously measuring the exposure levels looking at safety, and the reduction of the Huntington RNA and protein. So that we can, define an exposure of up to 50%, reduction of HDT. That's the so really, this is defining what we think is the right dose, and looking at the exposure and safety characteristics.
I see, and then maybe a second one on the ADC gene therapy. So if you delay in the CH MP measures related to sort of COVID, and just taking a little longer to respond to questions, that's where 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 a little bit on timelines, can you confirm if you've submitted the response to the letter of questions? Or is this something that's upcoming later this year early next year?
Yeah, no, I think you're right, in terms of obviously, working with CIOs and stuff with not only with COVID. But also the fact that many of these contract organizations are also working on vaccines. And so to the significance there are delays within all of this. But we've been pushing forward on this. And, you know, 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.
Yeah, thanks for the question. So, as Steve mentioned, these were fairly standard questions that come up during regulatory review asking for some additional details around some of our acids 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 bilateral 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 response to the questions and we're in the process of getting those resolved and hope to have soon as possible. And that's why we're saying that we expect to follow CHMP in H1.
Very helpful. Thank you very much and Congrats again on all the progress.
Our next question comes from [indiscernible]. You line is open.
Hi, thanks for taking the questions. I'm just for -- 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, you knows, why not do a controlled study blind, a blinded study so that maybe you have earlier approval? And then second question is on ABC correction PQ, a bit more timelines regarding step programs, like what are your thoughts on that timeline for the trial? And then I'll have a follow up thanks.
Okay, so you're sort of going in and out a little bit on the Huntington but basically, where we are within the Huntington trial, and why to not do a placebo controlled trial?
Why not blinded? The FDA sort of suggested to them a blind, they're saying that FDA suggested a blinded trial.
Within our trial there are folks, it’s a placebo controlled trial as well. It's a phase one trial, though. So, predominantly for safety and in 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 station, we could rapidly do some of the pandemic studies, so we could look at exposures, but because they have Huntington, we can, at the same time, we can also utilize this to monitor the reduction of Huntington RNA protein. So even in healthy volunteers, very analogous to what we did in FMA. And when to see both patients and predominate will make sure in terms of looking at it safely. So it's blinding through the period of doing it. And then you look at the analysis at the end of that. So, right, basically healthy volunteers studies, start these months and the advantage there is we'll be able to define what exposure causes a reduction in Huntington's 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 the advantage, again, is that even very early on, in Phase 1 studies, we’re able to look and precisely define the dose that gives us the greatest drug reduction that we want to 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 at the FDA, if you weren't more willing to do a smaller in Huntington’s study? 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 are getting that sense as well from the side of -- standpoint…
The reason we go into healthy subjects in the beginning is that you could do these studies more rapidly. That's the beauty of going first [ph]. Because the first thing you really want to do in these studies is to find an adult. And so this is -- gene therapy was probably not doing unhealthy volunteers. It's a different path, we have a small molecule and in using Phase 1 studies, you sort of line them up. They're healthy subjects, they’re coming in, they get the drug, they're hooked up on to -- so you get all the blood at multiple times, we can look at RNA and protein levels. 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, then lets you go into patients right there, but I guess the more appropriate dose that you think will be efficacious. So obviously, no question of the significant unmet medical need for Huntington's disease and we think that what's really unique about PTC’s [indiscernible] is that we know it hits directly -- the reduction of Huntington, protein and RNA passes the blood brain barrier. The fact 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.
Okay, great. Thank you.
Our next question comes from Alethia Young with Cantor. Your line is now open.
Hi. This is Li on for Alethia. Thanks for taking the call. I just want to follow up on AADC, sort of curious about your perspective on the launch activity, especially in Europe. You have the screening for one. Do the 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 image defense to get ready for launch? I think there's a lot of activities going on. Eric and his team have been working pretty hard on this. Eric wanted to 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 -- book lab. 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 in 17 countries with 16 [ph] programs. We're also using an algorithm-based retrospective approach in Europe and we're using that to partner with various healthcare providers. And this really helps them develop algorithms to execute against the identified [ph] patient cases already, where we can be able to find patients and begin the process of treating them. In addition, a key component is ensuring site readiness and that the sites are preparing not only to just receive the vial and do 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 accessing reimbursement. We're looking at preparing good [ph] health technology. 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 it 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 long sequence, following CHFC, 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 who are available in southern and northern Europe.
Got it, that's helpful. And then on U.S. dystrophin study, we started seeing 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. Thank you.
Yeah. So, remember, when we talked about this first, we talked about the discussion with the VA, which was that they wanted -- really the one thing that we didn’t have was that in their minds that dystrophin levels 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 the -- both the extensive clinical and 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 -- 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, would be sufficient for accelerated approval with study 41, after completion would be bad for full approval. And we you know, I think that, you know, is appropriate if 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 that we'll see dystrophin data that along with the clinical data that we have will actually be a nice strong passage that are both clinical benefit as well as the dystrophin data. And then we have the trial that's ongoing that would be for full approval.
Thank you very much.
Thank you. Our next question comes from Joel Beatty with Citi. Your line is now open.
Hi, thanks for taking the questions. 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, 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 PTT 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 healthcare has been, sort of, spending has been diverted. We know many companies haven't received any orders here. So the team there really has done a terrific job to work with, advocacy groups, and help and few opinion leaders, and others to really sort of bring about awareness that patients shouldn't 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 risk constraints and budget and everything else, Minister of Health and 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 continuity will be in the first half of next year as well.
Thanks for that one. And one other question on AADC. Can you help characterize what needs to be completed between now and the NDA filing? And part of the reason I ask is because it seems like recently, there's some hope that the filing could be by the end of this year, and now that seems to be in the first half of next year, which seems to be up to six months delay. So you know, what maybe accounts for the extending of the timeline?
Yeah, so I've gotten my math to go a little bit more detail. But part of it is -- really a lot is associated with the pandemic. And obviously, we talked previously about the surgical features as a gig factor to get a few additional patients and the pandemic has been -- news report that we're expected to complete it now in the fourth quarter. Matt, you want to talk a little bit of what we did after that?
Yes, sure. So as you mentioned, and we've talked about it 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 got delayed due to COVID, and are now scheduled on the fourth quarter. So we expect to do those procedures. Now again, the important thing here is to study of the cannula, not the safety of the gene therapy or the efficacy of 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 the 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 of 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 on therapy. We're able to demonstrate durability of dopamine production as well as durability and clinical response. And we know 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.
Got it. That's helpful. Thank you.
Our next question comes from Joseph Thome with Cowen. Your line is open.
Hi, there. Thank you for taking my questions. On a vertical note in Friedrich ataxia, is there a reduction in the FAR Score that physicians highlight as clinically meaningful around that 72 week timeframe that you're looking? And are you making any consideration regarding patient enrollment, depending on disease severity? And then on a related note, now that is online? Can you give us any updates as to when you expect to submit the IND for Friedrich ataxia gene therapy? Thank you.
Sure. Start with Matt, you want to join us?
Yes, please. So the phase three FA743, the efficacy [ph] trial is one that we're building on a body of experience in our own clinical studies, as well as those of others. And one of the most -- a couple important points. One is to mention the target in lipoxygenase and the associated pathway of inflammation and iron base 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 two data which demonstrated over a prolonged period of treatment. After 24 months, we had a significant reduction in the FARS score which translates to a significant improvement in disease severity. Just to give you an example of that the overall improvement in those treated was an improvement of 1.8 points on a FARS 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 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 mFARS, but also key secondary endpoints that can reflect key aspects of feel and function. And those, of course, are going to be the activities of daily living and walk tests, which is an endpoint strategy that we've aligned with both FDA and EMA on, because we realized that's a crucial aspect of the disease. The selection of the 18-month duration of the 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 put in Friedrich ataxia that is present even at six months or sometimes longer. And we believe by being able to treat for 18 months, we'll be able to again, see what we saw in phase two 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 statistically significant effects on the endpoint scale.
Regarding your question about disease severity, obviously, we understand that disease severity is a important aspect of Friedrich ataxia. It also can impact the potential response to the therapy and rated progression for those in the placebo group. And while we not only have a range of mFARS scores to book in that disease severity, we'll also plan to stratify a randomization on the mFARS to ensure that we have balance between both the treatment and placebo group on this critical set.
Great, thank you. And then the last -- the second part was just on the I&D for the Friedrich ataxia gene therapy, does bringing Hopewell online kind of give a little bit more clarity on when that can be submitted?
Yeah, I think we're pretty enthusiastic still about the Friedrich -- the gene therapy and the insulin center that we're working on, and to support it. And well, I think, as we move forward on that, we'll be able to give you a more precise update on the timing.
Great, thank you very much.
Our next question comes from Raju Prasad with William Blair. Your like is now open.
Thanks for taking the question. Just a follow up on some of the comments made on the dystrophin study. So would you mind sharing just what the kind of delta is versus background for the study, and then I have a follow up?
Sure. I’ll start. For us -- the important point there is no real and actually, you might remember when Dr. Woodcock talked about this, basically, that she said, it's particularly in terms of the approval, but there was no precise number in addition to [indiscernible] is quite analytical and very sensitive. So that we should be able to monitor and see what's above background, and 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 you said, we recognize that. Finally, we know from our experience that the same that we're seeing with interruptive studies, and as far as most of whom who 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 them that we can have that improvement over based on 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 of variation to ensure that with our 20 subjects that we have more than sufficient power to demonstrate a statistically significant improvement over baseline which really was the threshold that the agency eventually established for us, but obviously established for others as well.
Great. And on the commercial franchise, you know, obviously COVID is kind of spiking up again, going into the fourth quarter, is anything that maybe you guys could give us some color on expectations for Emflaza into the fourth quarter given your potential headwinds or any learnings you have from the second quarter? And then on risdiplam, it looks like a good number. The split between two and three -- 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 two and three patients? Thanks.
Yes, sure. So from the '20 -- you know, in terms of risdiplam/Emflaza really, really very good performance from the portfolio that -- that we've been doing both in Emflaza. And so even in spite of COVID, in some ways, because -- even with COVID, it's done actually quite well; the insurance company has been allowing more thing with to get through. So the transplant of Emflaza was pretty good production, and Eric can talk more about that as well. But the advantage through the 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, Stuart. I think first of all, as Stuart mentioned the DND franchises 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, time -- 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 US team, our PCC Care's 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, very few dropouts on Emflaza.
As for Translarna, we certainly are seeing growth even in areas that are hidden by the pandemic in Europe; so we accrued newer patients in the quarter in places like Spain, in Italy, in France and other places where we think 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 order in Brazil, I think it's safe to say that we don't see any figurehead within the quarter.
I appreciate the color. Thank you.
Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is now open.
Hi, this is Steve [ph], I'm for Brian Abrahams. Thank you for taking my question. On 518, you touched on this just a bit, but do you anticipate the one to one blood-brain diffusion 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 drug really had very good exposure within the brain. So we've shown indeed, in preclinical studies, that the lifting of the honeys protein, in all regions of the brain were observed as a consequence of treatment with PCC 1518, and that the blood levels correlated very well with that in the brain. So, I think that that -- to me, that's always been a major advantage, especially in a disease like Huntington's where -- that you can certainly get -- you certainly get brain you get self-death. So, you know, there's a real advantage of that; so that, and in fact, PCC 1518 is, is the -- is systemic; so it reaches all tissues and equally distributed, and it's obviously titratable as well.
So, yes I think we're in a pretty good belief that that's important and, you know, it's degenerative disease; we obviously believe that benefit of reducing toxic Huntington's patients is important. And, obviously, to your question -- your sort of questions, I'm interested in one from the point of view of trying to treat patients because Huntington's patients, you know, obviously they take time, there is no way to predict when you're when you'll be able to do that. So the notion of being able to do put dermal patients while nice, is hard to do, because you don't know how long the study would be. So I think we need to start with in terms of clinical trial with manifest patient, ultimately, right, because then you have, you have something we can measure. You know, look at the things and of course, disease. So, you know, obviously, we're studying early looking at manifestation. But we're looking obviously treat all patient types, including, not only the manifestations, but, you know, there's the juvenile patients, which so rapid onset, and clearly, that's something we should look at as well, because that occurs earlier in, it goes more rapidly, so that well, and then ultimately, you want to get to the prodromal 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 rapidly as possible, as possible into both JC and Perdomo. So, we're going to be learning over time as we do this, but I think they're really, you know, from my perspective, and the really good news from us is that we know what we're, you know, and the fact that it's our only when you look at blood, to see the reduction, we know we're on target now it's about really just like we did an estimate to demonstrate clinical effect.
Thank you.
Our next question comes from Gina Wang with Barclays. Your line is now open.
I think it's setting our questions. This is David [ph] on for Gina. So one question on a PC program. So as soon as the CH-MP opinion will be on first half of next year, what has been reimbursed the discussion with paralyzed? What's current consideration for pricing, and then I claim for installment payments as well.
Yeah, sure. So, obviously, the ABC programming 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 registered.
Yeah, and that’s ready. It's quite there. I think it's interesting, because we've been getting ready now for a little a long time. And we're ready to go because we have been studying patients. And we have very strong data. As a reminder, when we go forward with our HTA assessment, by which we have had multiple early pair discussions in Europe, those who have early access mechanisms, and those who are going to prove 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 this, for children with ADC, and that all children with ADC need to have this treatment. And importantly, that when treatment is given, there's durability, we have data now that goes out, in some cases for five years, seven years, we have patients that are treated even longer than that. So, from a healthcare 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, Europe, as well as 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 free markets that have already asked us about early access programs. So many of those, those countries in southern Europe would be targeted as well, I think and following the European approval, we will be targeting other markets outside of Europe, particularly Latin America and potentially Asia Pacific. So our pricing strategy where we 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 make a high unmet need big burden, and it's relatively small population 570 patients [ph] worldwide.
Got it, that's really helpful. So just a follow up; actually another question on the ballot, he attended 3 program [indiscernible], so you could be administering a T ID dosing. So, what's the pure burden like and you can just provide some more color on the PK profile of the drug, including the half-life of the T Max and also any foot effect?
Sure, Matt you want to go?
Yeah, absolutely. So 743 is a TID dose medication. Obviously, we've been treating patients for a number of years and also understand the pharmacologic parameters of the drug quite well. It's given three times a day with food, it can 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 within solution form is quite convenient. And then, of course, it's three times a day, breakfast lunch, dinner is given with meals, and three times a day dose, though some renderings obviously, generated given the half-life of the drug, which is between two and four hours in patients. And so obviously, again, yeah, just imagine and that's been well informed based on previous pharmacologic evaluations, as well as obviously this is of the drug.
Thank you so much.
And next question is a follow up from Vincent Chin with Bernstein.
Hey, thank you so much for taking the follow us, I have a couple of deep in the weeds follow ups on Huntington's if you're amenable. The first is simply love to dive a little deeper [ph] into what's the minimal amount of knockdown or range of knockdown you're looking for I know, you shown 50% plus all the way to 80% or so in mice. But imagine lessons is made may well be adequate, especially given sort of a uniformity of distribution throughout the brain. And I still also wonder, Is there some point at which you worry about loss of function adverse effects from excess knockdown? And the second question is, because, again, it's often how you expect a likely dosing range could compare to, I guess, for the sake of an easy competitor, risdiplam, basically, a preclinical studies or the pharmacokinetics, for the Huntington's program comparable to the plan, and how high can you go on dose from a, from a safety perspective, based on what you've seen preclinically?
Yeah, no, thanks for appreciate that. So the question, and what does that Yeah, you've seen the three clinical results in the nice aspect of an orally bioavailable drug is that it was titratable. And therefore, you could titrate it to the level that you want to get to. Obviously, I think what the community thinks that somewhere up to 50% would be good, there's a discussion but between 30% to 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. Probably with, once a day goes bigger, so, and that's our expectation. But well, you know, obviously be able to measure the effect and just accordingly and that will be up, it's hard to actually say until we put in the humans, but that's our expectation. We think it'll be in some way, similar to what you're saying with, we used to plan that it's a once a day dose thing, some of our expectation, but you know, you always wait and see how it does in humans.
Your question on -- yeah, I think a lot of , we're thinking about the question you had in terms of you know, In terms of the we think you probably can go substantially down post development. And that's something we definitely want to look at if we can. But we think that 30% to 50% of that range would be just fine able to do it. But we do sort of, think about how high can you go? Obviously, higher, that's even better. But we're just trying to figure some of this out and experimentally.
I see. And then, I guess, dose wise, risky plan, I guess what sort of limited at the upper end by some of the preclinical stages. Actually I guess you don't need to go that high. So, it all works out very well. Pretty clinically, is there anything that's been seen with sorry, pG 518. That would lead to think that basically put some sort of an upper limit on how high you could work up to invasions or in healthy volunteers.
Yeah, if you want I think so far, in the non-clinical studies that have led us, I think we have a nice data package, that supports us being able to the doses that we think will be very much adequate for being able to reduce that. So we feel pretty good, that was a pretty good spot for this. You know, obviously, we spent a lot of time on this molecule, interval, identifying selectivity is specificity, but also on the pharmaceutical properties. You know, obviously, for us, some of the key things was not to test the blood brain barrier, that we could get as substantial appropriate levels within that there was no D flex within the cell. And because they can pick up if you think a lot of drugs that people take, the reason they don't work for issues in the brain just goes, even if they could pass the blood brain barrier, they get heat flux, and so they don't maintain within the brain. And so, we've done a lot of work to make sure that they that this drug does not eat flux on top of having all the right property, that it couldn’t pass the blood brain, and then it gets into all tissues. Isn't that nice, but so we feel pretty good about this. And so we're looking forward to the results in the phase one trial.
Awesome. Thanks for taking the follow up. Appreciate the discussion.
Thank you, but I appreciate the question.
Thank you. And I'm sure no further questions at this time; I would like to turn the call back over to Stuart Peltz for closing remarks.
Okay, well, thank you. Thanks and thank all of you for calling in today. And I think as you can see that, despite the challenges that you know, have been presented by the COVID pandemic. I'm pretty proud of how the PPC team has access to them performed during the time. We think about it, the approval of it was the culmination of many years of discovery development by our teams, then we were also able to complete the biopsy so that there's a, that we've been able to protect us the mission of the translaminar NDA [ph]. And so we're excited about that as well. We are just starting to registrational studies for particular known and mitochondrial epilepsy, we initiated and performing now the phase one trial for the PTCA57 for DBA practices. And we're ready to as you've seen, PTC 518 for honey. So, a lot has actually gone on with 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 needs that we think are 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. Have a good evening.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.