Ladies and gentlemen, thank you for standing by, and welcome to PTC Therapeutics Third Quarter Corporate Update And Financial Results Call. Please be advised that today's conference may be recorded. 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 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 Powell. Before we start, let 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, Stupel.
Thanks, Lisa, and thank you for joining us for joining the call today. We have made significant progress this quarter with our R and 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 need 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 Let me go through some of the achievements this quarter. Starting with Arista for the treatment of SMA.
We are very excited about the strong launch of a risky in the U. S, not only for its efficacy and safety profile, but also it's convenience as a 1st 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-nineteen pandemic. A risdi showed clinically meaningful improvement in motor function and developmental milestones achievement across a broad range of ages and functional abilities of SMA patients.
The Arista launch has had a very positive response from physicians, payers, and the whole SMA community. As a reminder, there was high unmet medical need in the S And A 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 thirds of initial patients on risdi were previously treated with SPINRAZA or SOGENSIMA. 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 23.
There continues to be Ukraine and Chile. In addition, an NDA for Aristi was filed in Japan, which triggered a 7,500,000 milestone payment to PTC. Of Risty is also under review with the EMA with a decision expected in April 2021. We appreciate the strong effort made by our partner Roche. Let me comment on our commercial teams 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-nineteen challenges, including securing a purchase agreement with Brazil 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 and 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 Avisby 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 risdi, the NexmoS advanced compound from our splicing platform is PTC-five eighteen, which is being developed for Huntington's disease. I'm excited to report that PTC-five eighteen We'll enter the clinic this quarter.
And now, like as to how we discovered the RISTI, PTC-five eighteen was constructed to be an orally of bioavailable molecule that distributes to all tissues in the body is very effective in crossing the blood brain barrier barrier and is highly selected. We've learned that these elements of selectivity, biodistribution and pharmaceutical properties are critical to successfully developing differentiated splicing molecules. 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 target engagement and proof of concept of the reduction of HTT mRNA.
This will allow us to select doses for Rags. From our BioE platform, we recently announced that enrollment again in a registration directed trial of my with our compounds at Ticquanone, to treat mitochondrial epilepsy. As a reminder, about half of all children with inherited my 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 neuroinflammation enoxidata stress response. We estimate that there are approximately 12 1000 commercially addressable mitochondrial epilepsy patients globally.
An additional registration directed study trial with Vaticinone and Frederick ataxia called MOVEY 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. Bethicinone modulates the these pathways to reduce inflammation. Previous phase 2 results, so that particular non altered the course of FA disease, and we are excited to initiate the registration directed study this year. Our 3rd late stage program is PTC-nine twenty three for the treatment of PKU.
We expect to initiate pivotal Phase III study in mid-twenty 21, with an estimated 20,000 PKU patients in the U S alone, There continues to be high in my medical need as the majority did not initially respond or not adequately controlled on Results from previous studies demonstrated that approximately 50% more patients responded to PTC19. 3 when compared to KUVAC. 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 non clinical studies to support the long term dosing for the planned Phase III trial. I want to turn now to Translarna Just Different 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 45 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 manufactured facility in Hopewell is occupied and ready for production. As we have discussed previously, Our most advanced program is to treat AATC 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-nineteen related delays, PTC now expects the CHMP final opinion for AADC deficiency application in the first half of twenty twenty one. For the BLA PTC expects submission to the FDA will also be in the first half of twenty twenty We also recently initiated a phase twothree trial for PTC299. For COVID-nineteen 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 pre clinical data, the well established safety profile and the compound's oral bioavailability, gives us great confidence in PTC 299's potential as a treatment for COVID-nineteen. We anticipate reporting top line results in the first half of twenty twenty one. With that, I'll now turn the call over to Matt Klein for key updates in 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 and D platform. Our development teams have been working tirelessly throughout this COVID-nineteen pandemic to minimize impact on ongoing trials and ensure that our next set of trials initiates without delay. As Steve mentioned, we are very excited to report that we have now completed the final muscle biopsies for Study O45, the Translarna 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 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 OFR5 Distributed Study in Q1, twenty twenty one. Turning to our BioE platform, we have initiated enrollment in the Mighty trial, the Registration Directed Trial Vitikinone in children with mitochondrial epilepsy. This phase twothree 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 patiquinone 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 the Tiguan on orphan designation and rare pediatric designation for the treatment of mitochondrial epilepsy. The phase 3 Vitiquinone Friedreichetaxi trial, MOVE FAG remains on schedule to initiate enrollment by year end. This trial will enroll approximately 110 children and young adults with Friedreichotaxia.
The study design includes an 18 month parallel arm placebo controlled phase, during which subjects will receive either methicinone or placebo. Primary pinpoint measurement for this study is the modified Friedreich's Ataxia Rating Scale or EMCARs 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's ataxia. In the second compound from our Biowee platform, PTC-eight fifty seven, 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 PTC-five eighteen Huntington disease program remains on schedule with the phase 1 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 pharmacological parameters as well as to guide those selection for subsequent registration trials. Importantly, we are also planning to measure MRMA levels and 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 1 PTC-five eighteen study in the first half of twenty twenty one.
Next, I'll provide an update on our PTC 923 PKU program. We have initiated a long term toxicology study needed to support the initiation of the phase 3 PKU trial that is scheduled to begin in mid-twenty 21. This registration directed trial will be a double blind placebo controlled study that will include both children and adults with PKU. PTC-nine to three is an oral formulation of synthetic cepiatera, a highly bioavailable precursor to BH4, the critical cofactor for phenylalanine hydroxylase, the enzyme that is affected in PKU. There are 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-nineteen related delays, PTC expects the final CHMP opinion on the AADC MAA in the first half of twenty twenty one. The treatment procedures for the AADC deficiency patients with the 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 twenty twenty one. Finally, I want to provide an update on our FIGHT 19 trial.
The study of PTC-two ninety nine, our orally bioavailable DHODH inhibitor being developed for the treatment of COVID-nineteen. Through its actions at DHODH, PTC299 targets both key aspects of COVID-nineteen. Viral replication and the cytokine storm leading to lung disease. The trial consists of 2 stages with a planned interim analysis focused on safe at the completion of stage 1. Enrollment is ongoing and we remain on schedule to complete 1st stage of the trial by year end.
And the 2nd 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 within Plaza. 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 important of Implaza as the standard of care for all CMD patients with compelling real world evidence demonstrating clinical benefit expectations in all regions outside of Brazil where we were impacted by the timing of a group purchase order in Brazil in 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 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 2 shipments, one of which was received this quarter, and a 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 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. Assume 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 healthcare 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 AAC patients. In addition, we accelerated our digital presence with and for patient advocacy by supporting AADC Awareness Day and the great informational content ataadcfamilynetwork.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 Eversdi and the start of a strong launch. In the third quarter, we received a total of $35,000,000 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 $7,500,000 from Roche for the SMA Japan submission. On October 15th, Roche reported initial overseas sales of approximately 8,000,000 Swiss francs. As a reminder, PTC retains approximately 57 percent of Ed Frisbee royalties until Royalty Pharma receives a return of 1,300,000,000 after which 100 percent of the royalties revert to PTC. I'll now highlight the third quarter 2020 financial results.
Which are summarized in the press release in the third quarter of 2020, a 66% increase year over year. The $118,400,000 includes $82,700,000 of net products revenue, and $35,700,000 of collaboration and royalty revenue. Sempilaza and Translarna continued to show growth with 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 4th quarter. Translarna net product revenues were $43,400,000 for the quarter compared to $48,300,000 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 seeing continued global growth. For Emflaza, we reported net product revenues of $38,500,000 for the third quarter of 2020. Compared to $22,900,000 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 and D expenses were $83,800,000 for the 3rd quarter 2020, excluding $9,200,000 in non cash stock based compensation expense, compared to $58,100,000 for the third quarter of 2019. Excluding $5,000,000 in noncash stock based compensation expense. This year over year increase in R and D expenses reflects costs associated with advancing the gene therapy and bioe platforms, increased investment in research programs, and advancement of the clinical pipeline. Non GAAP SG and A expenses were $50,200,000 for the third quarter of 2020, excluding $7,600,000 in non cash based compensation expense compared to $43,800,000 for the third quarter of 2019, excluding $5,500,000 in non cash stock based compensation expense. The increase in SG And A was due to continued investment in our commercial activities and manufacturing operations to expand our portfolio.
Net loss was $69,700,000 for the third quarter of 2020 compared to net loss of $60,000,000 for the third quarter of 2019. Cash, cash equivalents and marketable securities totaled approximately $1,140,000,000 as of September 30, 2020. Compared to $686,600,000 as of December 31, 2019. The cash, cash equivalents and marketable securities balance as of September 30th includes the $650,000,000 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
Thank Our first question comes from Eric Joseph with JP Morgan. Your line is open.
Hi, good evening. You can hear me? Yes. Great. Thanks for taking the questions.
Hi, hi. Thanks for taking the questions, Tim. I just have a couple on CTC-five eighteen for Huntington, if I could. First, could you, I guess, with plans, the plan still being on track to, start the OBGY 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 of sort of the starting, what the biologically effective dose might be in humans?
And do you have a sense of how many dose cohorts 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 the first in humans, in which the, the Huntington protein, which is a splicing protein that, a splicing molecule that, reduces the level of the both the Huntington messenger RNA and Huntington protein. And we've shown that it's, again, to remind you, it's an early bioavailable molecule that that passes the blood brain barrier, stays within the brain and very nicely reduces both the RNA and Huntington protein. And what's so is that can we've shown that the levels that we've observed in blood are, are the levels that we see in brain.
And so we'll be in and the levels of reduction in how much is that 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 volunteer group to be able to define the exposures that we want to get to within within patients. And so, we'll be doing first in human, and I'll let, Matt talk a little bit about the, the Phase I study for BTC-five eighteen.
Yes. So, hi, Matt here. So we are going to, as we said, we'll be starting to phase 1, before the end of the year. We are conducting as ex U S. So there was not an IND file, but there was a I obtained, and I can share that all of the regulatory and epic 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 MAT study. And 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 Risdipline on any SMA development program.
Got it. And as far as tracking or collecting samples in the periphery, you look at MR and A down regulation of huntington. Is that something you expect to be tracking as early as the SAD the single ascending dose portion or would that happen more in the multiple ascending dose portion of
the setting? Yes, we'll be the nice thing about it is that you obviously see the opportunities. We'll be looking both at the FAD 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.
Great. Thanks for taking the questions.
Our next question comes from Danielle Brooks, 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 ups on your micro Dreal epilepsy trial?
Sure. So the, obviously, when you're thinking about the underlying cause of the disease like in SMA, you know, Avis, the Arisa plan really treats the underlying cause, right, to produce amount of less than protein. And that's actually quite important. And we've seen obviously that it helps SMA patients, both gain develop milestones and meaningful functional improvements in SMA types 1. So we think that's important.
Now when you think about other things that could be improved in terms of for the patient that is that a combination therapy that can help muscle growth and the generation in concert with having SMN, protein, then combinations like that can't be quite useful, but if you could see improvements in muscle tone along with the F and M purchase. So anything that can help patients, obviously, we are excited 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 indolent muscle is really quite important. So, you know, we're excited about the notion that it's, you know, especially the type 2, 3 patients that they can more rapidly show improvement. And if it would be better to show then, 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 on the expanded access program in terms of seizure benefits that gave you confidence in this indication? Thanks.
Sure. So just to remind everybody, we're doing a mitochondrial epilepsy refractory epilepsy trial. And does that really the electron transfer and oxidational stress are key points within, in these refractory epilepsy patients. And so we have, unique inhibitor 50 lipoxinsinase inhibitor that is actually a key regulator in controlling oxidative stress and neurotoxin neural inflammation. So we're pretty excited about that and there's certainly, data.
There's certainly a, 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 the Ticranode. But the monotoren and so this is initiating and we think that the monotoren or epilepsy to not we're spending any other additional delays that could be
a
consequence on 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 questions. As you mentioned, we're expecting data, by end of 2022. And we what we're doing is working closely with, the foundations and physicians and family networks throughout the world. We'll then have study sites to try and get the study at Enroll, obviously, as quickly as possible.
Also, in line with 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 time. And finally, we've also been able to incorporate a number of different aspects into the protocol that rolled out for remote assessment Again, so we ensure that there's a minimum in minimal impact as possible, to the conduct of the study from from COVID of this wave and any that may arise. Turning to the historical data. So we've we've looked at, obviously, 723 in mitochondrial disease patients in a number of different studies over time in the expanded access study as well as some disease specific or indications specific studies. And what we've seen in a number of these different studies is an impact on seizures themselves and, and, and many aspects of seizure related morbidity.
So in the expanded access, as you mentioned, we had ports of decreased seizure frequency, resolution of refractory status epilepticus, in trials of other mitochondrial disorders such as leaf syndrome where seizures occur, We have reports that decreases seizure frequency in these patients and in a, investigator study in a, in a specific mitochondrial disease subtype illness, PCH6 or intracellular hyperplasia type 6, which is a mitochondrial epilepsy, seizures, and start in the 1st days weeks of life. And these kids just basically continue to see refractory to all medications and typically die from seizure related complications in early childhood. We treated 5 subjects at a single site in 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 we've done, we're seeking evidence across many different mitochondrial disease subtypes of 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 Tazeen Ahmad with Bank of America. Your line is open.
Hi good evening. Thanks for taking my questions. I wanted to get a little bit of color if I could about what our expectations should be for the Translarna 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 what would need to happen in order for you to get a a formal approval, for the drug in the US.
And then I have a couple of follow ups. Thanks.
Sure. So we're obviously pretty excited that we were able to complete this trial and we really get all 20 patients seeing, so that we'll be able to generate the data. And so with the so with the positive disconfirm data, this is what we've talked with the FDA on, that was a positive description data coupled with the, really a sense of clinical and safety data that we've accumulated on Translarna. We'll move forward to a submission in the first half of the year. And you might recall when 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 ACL was discussed with them as well. And then it was if really the result is if we could show 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 now completed all the biopsies in accordance with, the protocol, which we obviously reminded to, until everything is analyzed and completed.
So the, 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 the positive data. And move forward in bringing this drug to patients in the U.
S, who I think they've 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 teams have been doing on the patient identification.
And right now, we're really actively working, to identify patients. And obviously, there's always, we know this is an ultra rare disease with approximately 5000 patients worldwide. So we've actually increased the levels of patient education. We've rolled out a number of things, including the master class program. Actually the digital presence that we 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, are in more than 17 countries where we know we're going to have us in reimbursement. And we implemented 60 screen programs that are really focused on the high risk population, particularly those cerebral palsy clinics. You know, we launched a program called PCC pinpoint this quarter. This last quarter. And it's really a nice single source, where healthcare providers can go right to and screen patients this via this genetic targeted trial and there's really no cost.
I think through 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.
Well, we continue. I mean, our goal is to continue to have 300 or more addressable patients. 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 1st commercial launch.
I think we're on track to get to continuing to screen that high that sort of high risk in the rich population. And More than anything else, we were becoming better and better at understanding which screening programs are giving us the best results.
Okay. Thanks.
Our next question comes from Vincent Chen with Bernstein. Your line is open.
Great, thank you very much for taking my questions and congrats on the progress. A couple of them, one on PTC-five eighteen and then one on the ADC gene therapy. So starting with PTC-five eighteen, I was wondering if you could provide us with some additional color on this initial trauma and healthy volunteers, specifically I'm kind of curious just what are the endpoints of the study beyond peripheral hunting can knockdown? What level of peripheral hunting can knockdown are you looking for? And how do you measure it?
And Well, I guess, just for timing wise, what's your current thinking for when you would have a readout to support moving into patients? Let's start with that one and then a follow-up on the next one on ADC.
Yes, sure. So as you right, Vincent, so as you know, right? Because it's, we spent a lot of time making sure that it was selective and specific. For Huntington that we can measure, the Huntington RNA protein act down in in blood. And so in the volunteer study, obviously, it's a safety as well as looking at RNA protein levels.
In the escalating both single and local sending those. 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 having the oral bioavailable drug that you can measure in preclinical animal studies where we can look in both the blood and the brain, we're able to look at, exposures of the 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 spray looked at the reductions as a consequence of that.
And so we were able to see determined exposures, that reduced, pretty substantially the length 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 have that would then reduce the level of protein. And again, the other nice aspect of this is because it's an orderly 5 day molecule is gets into all, passive of lumbar biliary gets to all blood tissues, brain tissues that you see the whole brain getting. And so we can measure in all aspects of the brain and show that it gotten to everywhere.
And so what we'll be doing here is, obviously measured in 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 HCT. That's the so really it's defining what we think is the right dose and looking at the the exposure and safety characteristics.
I see.
And then maybe the
second one on the ADC gene therapy. So if you lose to this delay in the, the CHMP, I imagine it's related to sort of, COVID and just taking a little longer to respond to the questions.
I was wondering if 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 a 0 and a little bit on timeline, could you confirm if you've submitted the response to the letter of questions or is this something that's sort of upcoming later this year or early early next year?
Yes. No, I think you're right in terms of there's obviously obviously working with you know, CROs and stuff with not only with COVID, but also the fact that many of these contract organizations are also working on vaccines, but for the significant or there are delays within all of this. But 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.
I mean, I'll let sort of, Matt go through sort of the timeline and thoughts the general questions that are being asked.
Yes. Vince, thanks for the question. So as, as Steve mentioned, these were fairly standard questions that come up during regulatory review asking for some additional details around some of our assays and additional analyses with them and some detailed questions on, 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 diagnose as well as helped about therapeutics.
And so we've had to take a little bit of a back seat, to those COVID related activities. And that's what's delayed our response to to the questions and we're in the process of getting those resolved and hope to have their agency as possible. And and that's why we're saying that we expect to follow CHMP opinion in each one.
I see. Very helpful. Thank you very much and congrats again on all the progress.
Our next question comes from Robert Karnauskas with Truist Securities. Your line is open.
Hi, thanks for taking my questions. Just first on Huntington, so I think Unical just announced that they will be doing a controlled blinded study for their initial, trial in Huntington's, and that they came from the FDA suggestions. Maybe comment a little bit about your thoughts on why not do a controlled study a blinded study so that maybe you have Probably your approval? And then, second question is on AADC or actually in PKU and ASB, PKU, give us more timelines regarding that program, like what are your thoughts on the timelines for the trial, then I'll have a follow-up. Thanks.
Okay. So, yes, sir, we're going in and out a little bit on the Huntington, but basically where we are within the Huntington trial and why do not do a placebo control? Well, if some question was,
Why not blinded? Why not blinded? The FDA sort of suggested to them a blinded, they're saying that FDA suggested a blinded trial? So that the, you know, the read might be the potentially?
Yes. Within our trial, there are also, it's a it also has it's a placebo controlled trial as well. And it's a phase 1 trial though. So predominantly for safety and the fact that I think we're in the in a way in an unusual position that even though that we're dosing in healthy subjects. So if they're not Huntington's station, we could rapidly do pharmacokinetic studies, so we could look at the exposures.
But because they have Huntington, we can at the same time, we can also utilize this to monitor the of Huntington RNA protein. So even in healthy volunteers, and this is very analogous to what we did in, SMA. And when they're at placebo patients and then it's 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 that the end of that. So right now, we're basically doing healthy volunteer studies.
And the advantage there is we'll be able to find 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 1 studies, we're able to look and precisely define the dose that gives us the reduction, the greatest reduction that we run 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 if you weren't 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 volunteer, healthy subjects in the beginning is that you can do these studies more rapidly. Right? That's the beauty of going into, right? Because the first thing you really want to do in these studies is define the dose. And so this is, you know, you know, gene therapy, which is probably not doing unhealthy volunteers.
It's a different path. We have a small molecule and using phase 1 studies, you sort of line them up. They're healthy subjects that come in. They get the drug. You, you know, you're they're hooked up on to So you get all the blood at multiple times.
We can look at RNAi and protein levels. 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 is the more appropriate dose that you think could be, would 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 PBC-five eighteen is that we know it's directly the reduction of Huntington protein and RNA passes the blood brain barrier. The fact this is when blood gets to every brain cell, we think there's a lot of major advantages on this. And so, we think this is the fact that we need to get there.
Okay, great. Thank you. Our next question comes from Alicia Young with Cantor. Your line is now open.
Hey, this is Lee on for Lee. Thanks for taking the call. I just wanted to follow-up on AADC, sort of curious about your perspective on the land activity, especially in Europe. I mean, you have these screening for ones, do the early trends that you've seen support your confidence in the product? And I have a, I have a follow-up.
Sure. So I think in terms of image sense, what are we doing 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 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 lost and we've adapted a lot of the local activities especially using, labs, book 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 in 17 countries with 60 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 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 regards to access and reimbursement. We're looking at, preparing all of those for the Health Technology assessment. One thing I would remind you is that, what's unique about at our AADC gene therapy treatment is that it will be the 1st approved product in Europe and we'll, we'll be rolled out as a 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 large 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 1st and as well as garnering many of the early access programs in Europe, where those are available in Southern And Northern Europe.
Got it. That's helpful. And then on U S districtive study, we start seeing the regulatory environment. It's getting a little bit more conservative So my question is, do you think that description 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.
Yes. So we remember when, when we talked about this at first, we We talked about the discussion with the FDA, which was that they want really the one thing that we didn't have was the, in their mind, the dystrophin level in, 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 safe to the both the extensive clinical and safety data safety data that we had as well as the efficacy over the trials that we've done. And 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, 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 741 after completion would be then for full approval. And I think that's 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 we'll see the dystrophin data, then along with the clinical data that we have, will actually be a nice strong path if there was both clinical benefit as well as the discipline date. And then we have the trial that's ongoing.
That would be for full approval.
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,
do you want to talk a little bit about that?
Yeah, Angel, you know, in Brazil, Brazil is pretty lumpy in terms of their orders. And I can say that, you know, 1st of all, I'm really proud of the PTC
Ceryx, do you want to talk a little bit about that?
Yes, Joe. In Brazil, Brazil is pretty lumpy and in terms of their orders. And I can say that, first of all, I'm really proud of the PT
Oh, 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 is pretty lumpy in terms of their orders. And I can say that we're 1st 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. 2019 has disrupted.
Not only the administrative 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, you know, advocacy groups and health and, Terrific job to work with advocacy groups and key 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, to the order. And that's important.
But due to some of the constraints and 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 2nd 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, 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.
Got it. Thanks for that. One 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 ask is it seems like recently there was some hope that the filing could be by theendofthisyear and now it seems to be in the first half of next year, which seems to be up to 6 months delay.
So what may be accounts for the extending of the timeline?
Yes. So I'll start and then I'll ask Matt to go a little bit detail, but, part of this is really a lot associated with the pandemic. And obviously, we talked to previously about the surgical procedures as a gauge factor to get a few additional patients in and the pandemic has been an issue for us. So we expect it to complete it now in the fourth quarter. Matt, do you want to talk a little bit of what's needed after that?
Yes, sure. So as you mentioned, and we've talked about before, one of the key gating items, for the BLA was fulfilling an FDA request to treat, few patients with the cannula that we're going to use commercially. And a cannula the device that delivers the gene therapy into the precise area of the brain. And we had those surgery scheduled in the third quarter. They've gotten delayed due COVID and then our schedules 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 therapy. And and and some of the feedback that the agency has to look to other companies, we're obviously watching that very closely.
That's also why we wanna 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 of 2021. I also want to emphasize that we remain incredibly enthusiastic about the program because one of the things we get due during this delay is continuing 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, we're we're able to demonstrate durability of dopamine production as well as durability 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 age see.
Our next question comes from Joseph Thome with Cowen. Your line is open.
Hi, there. Thank you for taking my questions. On Vaticinone in Fisher Cataxia, Can you remind us, is there a reduction in the FARS score that physicians highlight as clinically meaningful around that 72 week timeframe that you're looking and are you regarding patient enrollment depending on disease severity. And then on a related note, now that Hopewell is online, can you give any updates as to when you expect to submit the IND for your Friedreichotaxi gene therapy? Thank you.
Sure. So 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 important points. One is to mention the target and MOA of 74 III targeting enzyme 15 lipoxygenase and the associated pathway of inflammation, and iron based oxygen of stress is clearly one that it's shown to be incredibly important to FA pathology. And on top of that, we obviously have a Phase 2 data, which demonstrated over a prolonged period of treatment out to 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 about the overall improvement in those treated was improvement at one point points on a 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 effect relative to the understood natural history of disease. And so we do expect to have a clinically, clinically meaningful effect on the m FARS in addition, I think, as we're all well aware. Thereof is the FDA's, desire to have endpoint strategy that we not only include the MRs, but also key secondary endpoints that reflect key aspects of field and function. And those, of course, are are going to be, the activities to be able to living and, and walk tests, which we, is an endpoint strategy that we've aligned with both the FDA and in PMA on because we realized that's a crucial aspect of the disease.
The selection of the 18 month duration of the parallel on placebo controlled phase Again, is based on our own experience as well as that accountants others where there is a placebo effect that put in in Friedreich's 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 2 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 effect on the Empire scale. Regarding your question about disease severity, obviously we understand that disease severity is an important aspect of Friedreich potassium also can impact the potential response to the therapy and and rate of progression for those in the placebo group. And while we not only will have a range of m FARS scores to book in that disease severity, we'll also plan to stratify our randomization on the m FARS to ensure that we have balance between both the treatment and placebo group on this critical path.
Great. Thank you. And then the last, the second part was just on the, the IND for the Friedreichotaxy gene therapy. Does bringing hope well online kind of a little bit more clarity on when that could be submitted?
Yes, I think we're you know, we're pretty enthusiastic still about the Frederick, the G therapy and the agent incentive 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.
Great. Thank you very much.
Our next question comes from Rajeev Prasad with William Blair. Your line is now open.
Thanks for taking the question. 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 the significance above background,
for the study? And then
I have a follow-up.
Sure. I'll start with, I'll pass it on to So, Matt, it seems for us, the important point, there is no real. And actually, you might remember when Doctor. Was talked about this basically, that she said, in particular, in terms of the approval, that there was no precise number in terms of the appreciate to that. ECL is quite, 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 you said, we recognize that it's not only what we, we know from our experience that the same that was seen with InSarepta Studies and NS Pharma both of whom who have recently had approvals based on the dystrophin endpoint alone. We we 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 wanna be able to capture those lower levels of dystrophin expression because we wanna show that, oh, that we can have that improvement over based on statistical significance. That we need. And so what we've done and obviously setting up this study is model the number of different scenarios, assuming low levels of baseline to chip in 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 that statistically significant improvement over baseline, which really was, the threshold that the agency has not only established for us, but obviously it established for others as well.
Great. And on the commercial franchise, obviously COVID spiking up again going into the 4th quarter. Is there anything that maybe you guys could give us some color on on expectations for Translarna and Emflaza into the 4th quarter given potential headwinds or any learnings you have from the 2nd quarter. And then on Rizdiplam or Abrisdi, looks like a good number. The split between 2 and type 23 and type 1.
Do you think that that's just a function of the nature of the the disease and the prevalence of the disease or are you seeing something from early adopter physicians be more willing to prescribe to 23 patients? Thanks.
Yes, sure. So from the 20 in terms of we've seen for Translarna and Flazda really, really very good performance. From the portfolio that we've been doing for both Translarna and Plaza. And so even in spite of COVID, in some ways, even with COVID, that it's done actually quite well with the insurance company almost been allowing more things to get through. So the post purchase line in the plaza, we've seen pretty good production and Eric can talk more about that as well.
But that's also true with the discipline. I think the fact that it's orally by available distributed directly to patient is a really big advantage, and 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 D and D 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 the plaza. With over 60% growth from the previous quarter. And we anticipate that growth to continue into it well into the 4th 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 care 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 hit 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 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 quarter in Brazil, I think, it's safe to say that we don't see any major headwinds in the quarter.
Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is now open. Hi, this
is Steve Malin on for Brian Abrahams. Thank you for taking my question. On 5 18, you touched on this just a bit, but do you anticipate the one to one blood brain depletion ratio will be extended to deep brain structures. And given the progressive nature of hunting pins, 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 of an orally bioavailable small bowel acute drug that's where you have very good exposure, within the brain. So we've shown indeed preclinical studies that dilution of the Heinzet protein, in all regions of the grain were observed as a consequence of treatment with PCC-five eighteen, 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 know, if you certainly get break, you can sell debt. So you know, there's a real real advantage of that. So that and in fact, you know, PBC 1518 is systemic. So it reaches all tissues are equally distributed. And where it gets obviously titratable as well.
So Yes. So I think we're in a pretty good, belief that that's important. And there's It's the degenerative disease. We obviously believe the benefit of reducing toxic huntington, the patient, is is important. And then, obviously, to your question, your sort of question is an interesting one from the the point of view of trying to treat patients because Huntington's patients, you know, obviously they take time and there's no no way to predict when you when you'll be able to do that.
So the notion of being able to do Well, 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 is, with manifest patients, ultimately, right, because then you you know, they have, you have something which you can measure, you know, look at the things in the course of the disease. So obviously, we're starting early looking at manifestation, but we're looking obviously treat all patient types, including, but, you know, not only the manifest patients, but there's the juvenile patients, which show rapid onset unclearly that's something we should look at as well because that occurs earlier and, and goes more rapidly. So that could depend. Well, And then ultimately, you wanna get to, for Drombo 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 to show that you can open the course of the disease, understand the learnings from that, and then move as rapidly as possible. As possible into both JHC and perdermal. So, and we're going to be learning over time as we do this. But I think they're really from my perspective, it's the really good news from us is that we know and the fact that it's oral that when you look blood to see the reductions. We know we're on target.
Now it's about really just like we did in FMA to demonstrate, clinical effect.
Our next question comes from Gena Wang with Barclays. Your line is now open.
I think thanking our questions, this is David Dye on for Gina. So one question on AADC program. So since the CHMP opinion will be on, first half of next year. What has been reimbursement discussion with Paylife? What's current consideration
for pricing?
And then, are you planning for installment, any stop payments as well?
Yes, sure. So, obviously, the ADC 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 ready.
Yes. And that ready, it's fine too. And 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 very strong interest data. And as a reminder, when we go forward with our HTA assessment by which we have had multiple early period discussions in Europe.
Those who have early access mechanisms and those who are going to approve the drug more mercially 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 AADC and that all children with AADC need to be 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 Gibra 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. We as I mentioned earlier, We anticipate to have our 1st 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, 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 to take it to Latin America and potentially Asia Pacific. So our pricing strategy where we will 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, a new standard of care, that will meet, a high unmet need with big burden.
And it's relatively small population population worldwide.
Got it. That's really helpful. So just a follow-up. Actually, another question on the VAL E S-seven forty three program metacontractilectomyopathy. So you could be mishearing as a PID dosing.
So what's the fuel brining like? And if you can just provide some more color on the PK profile of the drug including the half life of the Tmax and also any split effect?
Sure, Matt. You want to go?
Yes, absolutely. So 743 is a TID dose medication. Obviously, we we've been treating patients for a number of years and also understand the pharmacologic parameters of the drug quite well. It's giving three times a day food, it could be administered. It's administered as a solution for young children, which is particularly helpful given that many children monoclonal disease, including those with mitochondrial disease or refractory seizures or feeding tube dependent.
So being able to administer the drug, through a feeding tube slight in solution form is quite convenient. And then, of course, it's 3 times a day. It's breakfast lunch dinner that's given with meals, and that three times a day dose of rent rooms, obviously, generated given the half life of the drug, which is between 2:4 hours, in patients And so, obviously, again, we had a dosing regimen. It's been well informed, based on previous pharmacologic evaluations as well as obviously the safety and efficacy record of the drug.
And next question is a follow-up from Vincent Chen with Bernstein. Your line is now open.
Great. Thank you so much for taking the follow ups. So I have a couple of deep in the weeds follow ups on huntington's if you're amenable. The first is simply, the one the dive a little deeper into what's the minimal amount of knockdown or range of knockdown you're looking for?
I know
you've shown 50% plus all the way to 80% or so in mice, but imagine lessons 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, 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 competitor, a risky plan, basically your preclinical studies are the pharmacokinetics for the Huntington's program comparable to risdiplam? And how high can you go on dose from a a safety perspective based on what you've seen preclinically?
Yes. Thanks, Vincent. Appreciate that. So the question on what goes up here, you've seen the preclinical results in the nice aspect. Of an orally bioavailable drug is that it was titratable, and you can get, and therefore, you could titrate to the level that you want to get to.
Obviously, I think what the community thinks is somewhere, up to 50 set would be good. There's been discussions of between 30% 50% could be associated with therapeutic benefits based on some preclinical results. So we're shooting in that range for benefits of the consequence of that. And we think we'll certainly be able to do that, of, of, you know, 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.
So we and that will be up. It's hard to actually say until we put it in the humans, but that's our expectation. We think it'll be in some way similar to what you're saying with, Ruth, the plan that it's a once a day dosing, that's some of our expectations, but, you know, you always wait and see how it does in humans. Thanks for the question.
Yes, sir. Go ahead.
Oh, your question on. Yes, I think a lot of And we're thinking about the question you had in terms of what are in terms of what 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 would be just fine to be able to do it. But we do sort of think about how high can you go?
I mean, obviously, if you can hire 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, with the plan, I guess, 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 it all works out very well. Pre clinically, is there anything that's been seen with, RG-five eighteen sorry, PTG-five eighteen that would lead to think that, 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 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 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 that it doesn't pass the blood barrier that we could get as substantial appropriate levels within, that there was no efflux within of the salary because if you think of if you think a lot of a lot of drugs that people take, the reason they don't work for for issues in the brain is because even if they could pass the blood brain barrier that get efflux, then so they don't maintain within the brain. And so we've done a lot of work to make sure that this drug is not ecloxed on top of having all the rights. Of properties that, you know, that it could pass the blood pressure and then it gets into all tissues is not in flex.
So we feel pretty good about this. And so we're looking forward to the results in the Phase 1 trial.
Awesome. Thanks for taking the follow ups. I appreciate the discussion.
Thank you, Vince. I appreciate the questions.
Thank you. 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. Thanks for and thank all of you for calling me 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 actually formed during this time. If you think about it, the approval of Aritzdi, was the culmination of many years of discovery development of IR teams.
Then we were also able to complete the biopsy so that there's a that we've enabled the potential submission of the Translarna NDA, and so we're excited about that as well. We all just studied the registrational studies for Cquinone and mitochondrial epilepsy. We initiated, and are performing now the phase 1 trial for the PTC 857 for GBA Partnership. And we're ready as you've seen PTC 508 for Huntington's 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, developing and commercializing really the next generation of value creating therapies for patients, with high net medical needs that we think will collect value to 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.