Good day, and thank you for standing by. Welcome to the PTC second quarter 2022 financial results and corporate update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question, you will need to press star one one on your telephone. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Senior Vice President, Head of Global Commercial and Corporate Strategy. Please go ahead.
Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics second quarter 2022 corporate update and financial results. I am joined today by our Chief Executive Officer, Stuart Peltz, our Chief Operating Officer, Matthew Klein, our Chief Business Officer, Eric Pauwels, and our Chief Financial Officer, Emily Hill. Today's call will include forward-looking statements based on our 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 such statements are subject to risk that 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 annual report on Form 10-K and quarterly report on Form 10-Q 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. Stu?
Thanks, Kylie, and good afternoon, everyone, and thanks for joining us today. I'm excited to share PTC's second quarter results for what I expect to be a transformational year for the company. Our mission at PTC is to discover and develop innovative therapies and bring them to patients with rare disorders, and in doing so to create significant value for all of our stakeholders. We've been very successful in pursuit of this mission. Today, PTC has five marketed products, seven development programs, and several scientific platforms which to generate future products. We continue to build a robust pipeline of potential new therapies that at steady state will deliver a new product every two to three years. We made important progress in the second quarter towards achieving our ambitious goals for 2022. We continue to achieve strong revenue growth and to advance towards multiple clinical milestones.
I'd like to highlight several particularly significant achievements in the quarter. Let me begin with our strong revenue growth in the quarter, in which we achieved $166 million in total revenue, with a 42% increase over the second quarter of 2021. This is quite remarkable and puts us in good position to achieve our full year revenue target of between $700 million and $750 million. The DMD franchise is expected to continue a strong growth trajectory throughout the remainder of 2022. We also reported top-line results of Study 041, which was an important step forward for Translarna. In Study 041, we demonstrated a statistically significant benefit for Translarna in nonsense mutation DMD patients across a number of relevant functional outcomes in the broad intention-to-treat study population.
Based on these results, we plan to request conversion of the E.U. conditional authorization to a standard marketing authorization. In addition to the E.U., we look forward to discussing these results and a potential path forward for approval with the FDA and other international markets. In addition, these results will reinforce our strong value proposition with payers in the E.U. and international markets. Matt will go into these results in more detail shortly. We recently announced the marketing authorization for Upstaza by the European Commission. This approval expands our product portfolio to five commercialized products. Upstaza is the third gene therapy ever marketed and the first marketed gene therapy directly administered into the brain. Our goal at PTC is to bring Upstaza to AADC-deficient patients and their families as quickly as possible.
We are well poised for commercial launch and our planned commercial price is between $3 million and $3.5 million. This reflects the exceptional value of Upstaza and takes into account the ultra-orphan AADC patient population with a small budget impact to payers from this one-time durable treatment. Pricing of Upstaza is based on multiple factors, including that the disease is highly morbid and fatal and the high unmet medical needs of AADC-deficient patients with no standard of care. Lastly, Upstaza brings substantial value to patients with transformative clinical results and durable effects, with up to 10 years of follow-up. We have already treated our first patient on commercial drug through the early access program in France, and Eric will go into this in more detail shortly. Let me switch gears to Evrysdi as we continue to achieve strong updates across all regions.
The FDA recently approved the supplemental NDA of Evrysdi for pre-symptomatic infants with SMA under two months of age. Their approval is based on interim efficacy and safety data from the RAINBOWFISH study in newborns, which showed that pre-symptomatic babies treated with Evrysdi achieved key milestones such as sitting, standing, and walking after 12 months of treatment, similar to that seen in normal babies. Turning now to our oncology program with unesbulin, previously known as PTC596. We recently announced encouraging preliminary safety and efficacy results from our phase I-B study in unesbulin, a tubulin binding agent in advanced leiomyosarcoma patients at a podium presentation at ASCO. Based on these preliminary results, PTC initiated the SUNRISE LMS study, a placebo-controlled registration-directed study of the efficacy and safety of unesbulin and dacarbazine in patients with advanced LMS.
PTC has a broad and deep pipeline across a range of diseases, and we eagerly anticipate important results with several registration-directed studies during the next six to twelve months. We believe the positive results from these trials could be transformational for PTC. PTC is clearly having an exciting year and has executed on all that we set out to achieve in the first half of 2022, which is truly remarkable. With that, let me hand it over to Matt for a development update. Matt?
Thanks, Stu. I'm proud to share that our teams continue to execute on our many 2022 goals. We are working tirelessly to deliver on our mission to bring innovative therapies to patients around the world. Beginning with Translarna, as Stu mentioned, we recently announced the positive results from Study 041 in patients with nonsense mutation DMD. As a reminder, Study 041 was designed as a global trial with a 72-week placebo-controlled phase, followed by a 72-week open label extension phase, which is still ongoing. Topline results from Study 041 demonstrated a statistically significant effect of Translarna on six-minute walk distance in the overall ITT population of 359 boys. This is the first disease-modifying DMD therapy to demonstrate a statistically significant functional benefit in a placebo-controlled trial.
A statistically significant benefit of Translarna was also demonstrated in the North Star Ambulatory Assessment and the 10 m run/walk and four-stair ascend timed function tests in the ITT population. These results are not only statistically significant, but provide evidence of clinically meaningful benefit as they represent a 20%-25% slowing of disease progression in a known unilaterally progressive and fatal disease. In addition, in a pooled analysis of the over 700 boys enrolled in our three placebo-controlled Translarna trials, Study 007, Study 020, and Study 041, there is a highly statistically significant benefit across a range of functional assessments.
While the Study 041 MITT population results did not achieve significance, we believe the significant results in the ITT population, which was the pre-specified population, along with evidence of real-world long-term benefit generated from the STRIDE registry, position us to request conversion from the E.U. conditional marketing authorization of Translarna to standard marketing authorization. In addition, we plan to meet with the FDA to discuss the potential for an NDA in the U.S. Turning now to our gene therapy platform. Following on the approval of Upstaza in the E.U., we are now focusing efforts on submission of a BLA to the FDA, which is planned for the fourth quarter of this year. I would like to now share encouraging results from our FITE19 study of emvododstat for the treatment of COVID-19. The FITE19 study was designed as a double-blind, placebo-controlled, 28-day study of hospitalized COVID-19 patients.
As a reminder, emvododstat is an oral small molecule that targets the cellular enzyme dihydroorotate dehydrogenase, or DHODH. By targeting a cellular enzyme rather than a viral protein, emvododstat is less likely to elicit drug resistance, which is particularly important as the COVID-19 virus continues to mutate. Given the changing nature of the pandemic to the outpatient setting, we concluded enrollment of the FITE19 study early, with 189 subjects enrolled in order to review the data collected to date and make an informed decision on next steps. Across all randomized subjects, there was a trend towards emvododstat benefit across several disease-relevant endpoints, including duration of hospitalization and time to reduction of fever. Notably, when examining the cohort of patients enrolled within five days of infection, there was a clear benefit of emvododstat treatment on time to respiratory improvement, duration of hospitalization, dyspnea resolution, and cough relief.
As an example, median time to respiratory improvement, the study primary endpoint, was 28 days in the placebo group and only 10 days in the emvododstat group, with a P value of less than 0.05. These findings are particularly important as they suggest a clear potential for emvododstat in the early treatment of COVID in the inpatient or outpatient setting, where the majority of cases are now managed. We plan to complete the remaining data analyses and will then formulate a strategy for next steps in advancing emvododstat for the treatment of COVID-19. Over the course of the second quarter, we continued to make progress across our other platforms and expect results from several of our ongoing registration-directed trials in the next six to 12 months.
Starting with our ongoing registration-directed APHENITY phase III trial of PTC923 in patients with PKU, we remain on target to share results by year-end 2022. The APHENITY trial is a six-week placebo-controlled study with a primary endpoint of reduction in blood phenylalanine levels. To enrich the randomized study population for likely responders, the study includes a run-in phase during which potential subjects are treated with 923 for two weeks, and only those demonstrating response to PTC923 treatment are randomized. Following completion of the six-week placebo-controlled study, all subjects will be eligible to enroll in a long-term extension study. Turning to the Bio-e platform, we have three ongoing registration-directed trials, two with vatiquinone in mitochondrial disease-associated seizures and Friedreich ataxia, and one with PTC857 in patients with ALS.
Due to COVID-19 related delays in enrollment, we now expect to have results from the MIT-E trial of vatiquinone in patients with mitochondrial disease-associated seizures in the first quarter of 2023. As we have previously shared, the MOVE-FA global trial of vatiquinone in Friedreich ataxia patients is fully enrolled, and we continue to expect results in the second quarter of 2023. Enrollment is ongoing in the CardinALS global placebo-controlled trial of PTC857 in ALS patients. The CardinALS trial is a six-month placebo-controlled study with a target enrollment of approximately 258 subjects. Subjects will be randomized two to one to receive PTC857 or placebo. The primary endpoint of the study is change in the ALSFRS-R score from baseline to six months, with secondary endpoints capturing other aspects of disease morbidity and mortality risk.
Finally, I want to provide an update on our PTC518 Huntington's disease program from our splicing platform. Enrollment is ongoing in our phase II PIVOT-HD study, a global placebo-controlled study of PTC518 in HD patients. This study will consist of two parts, an initial 12-week placebo-controlled phase focused on PTC518 pharmacology and pharmacodynamic effects, followed by a nine-month placebo-controlled portion during which we will collect blood, CSF, and radiographic biomarker data. The study will initially include two dose levels, 5 mg and 10 mg, with the potential to study a third dose. We anticipate data from the 12-week portion of the study by the end of this year. We are very excited about our continued progress across our development programs and look forward to sharing results from several of our studies in the near future.
I will now hand the call over to Eric to discuss our commercial portfolio. Eric?
Thanks, Matt. This is a very exciting time for PTC and in particular for our global customer-facing teams commercializing a diversified portfolio of products that address high unmet needs for patients with rare diseases. We have achieved another very strong quarter, and we are thrilled to add a fifth commercial product to our portfolio with the recent approval of Upstaza and to bring this much-needed treatment to AADC deficiency patients. Our DMD franchise continues to be a key revenue driver as we continue to expand our global footprint that will also support the future growth from the pipeline. Let me begin with Upstaza and our ongoing launch preparations. We are very excited about the recent approval in Europe, and our team is actively executing on all strategic initiatives supporting the launch.
We are off to a good start and have treated our first commercial patients this quarter under the French Early Access Program. Treatment center readiness is well on track, as well as further preparations for surgeries carried out at key European centers. Patient identification is continuing to accelerate, and we anticipate treating additional commercial patients with the upcoming launch in Germany. We are also focused globally on markets that have early access programs such as France, Italy, and others via cross-border healthcare. The Upstaza price is expected to be in the range of $3 million-$3.5 million, which factors in our projections of future pricing negotiations in key European markets.
We are confident that the durable efficacy and safety data we have obtained from over 10 years of patient experience with Upstaza will support HTA submissions for reimbursement as the first and only treatment approved for AADC deficiency patients 18 months and older. We have guided to $20 million-$40 million in revenue from Upstaza. Turning now to DMD. Our global DMD franchise continues to deliver robust revenue across all regions. Our second quarter revenue for the DMD franchise was $134 million. Our EMFLAZA net product revenue for the second quarter was $57 million, which represents 16% growth over the second quarter last year.
Ongoing execution by our EMFLAZA team drove new patient starts, continued favorable access, high compliance, and appropriate weight-based dosing for DMD patients in the United States. For Translarna, we achieved $77 million in net product revenue for the second quarter, which represents a 46% increase over the second quarter of 2021, driven by growth in all regions. As a reminder, we can have large group purchase orders which can create lumpiness due to uneven government buying patterns. Overall, Translarna revenue continues to be globally diversified and robust in all key markets. We continue to make good progress with regulatory approval and pricing and reimbursement in our newer markets in Eastern Europe, the Middle East, and Latin America. We are also continuing to expand our presence in additional markets in Asia-Pacific as this region continues to be of strategic importance for potential future revenue growth for PTC.
We are in a strong position to achieve the 2022 DMD revenue guidance of $475 million-$495 million. In Latin America, our teams continue to strengthen the Translarna and Waylivra franchise. In Brazil, following the innovative drug classification for Translarna, we received the first group purchase order from the Ministry of Health, which was delivered in the second quarter. This is an important milestone for our nmDMD patients awaiting treatment. Furthermore, patient identification continues to be strong and we anticipate additional group purchase orders over the course of the year. Finally, discussions progressed with CONITEC, the National Commission for the Incorporation of Technology, for inclusion of Translarna in the essential drug list, which simplifies access. For Waylivra, we now have patients on treatment for FCS in Latin America, and patient identification continues to progress well.
As a reminder, last December, we submitted an application to ANVISA in Brazil for approval of Waylivra for the treatment of FPL. If approved, Waylivra will be the first approved treatment for FPL in Brazil, and this will mark the first approval globally for this indication. We anticipate a decision in the second half of 2022. In conclusion, our customer-facing teams globally have had an extremely successful first half of the year, and we will be focused on capitalizing on the momentum built and the launch of Upstaza for the remainder of the year. Now let me turn the call over to Emily for a financial update. Emily?
Thanks, Eric. In the first half of 2022, we saw continued strong revenue growth and progress in advancing our pipeline across multiple platforms. Given current market conditions in the biotech space, we are particularly pleased that the royalty monetization for Evrysdi, combined with our strong continued revenue growth, allows a strong capital structure to fund the further advancement of our pipeline. The press release issued earlier this afternoon summarizes the details of our second quarter 2022 financial results. I will take a few minutes now to review these financial results. Please refer to the press release for additional details. Beginning with top-line results, total revenues were $166 million for the second quarter of 2022, a 42% increase over the second quarter of 2021.
This was driven primarily by net product revenue from DMD franchise of $134 million and Evrysdi royalty revenue of $22 million. Our total revenue from the first half of 2022 is an impressive $314 million. As Stu said, we are on track to achieve our 2022 total revenue guidance of $700 million-$750 million. Apart from our continued net product revenue, we also anticipate a $50 million milestone payment from Roche when annual Evrysdi sales reach $750 million. In addition, we have guided to $20 million-$40 million in revenue from Upstaza. Turning now to our DMD franchise. Translarna net product revenues were $77 million, representing year-over-year growth of 46% compared to the second quarter of 2021. EMFLAZA had net product revenues of $57 million or 16% growth year-over-year.
Moving now to Evrysdi. Our partner, Roche, reported 2022 year-to-date sales of approximately CHF 500 million, which translated into second quarter royalty revenue for PTC of $22 million. As a reminder, PTC retains approximately 57% of Evrysdi royalties, with Royalty Pharma receiving the remaining 43% up to a cumulative total of $1.3 billion. After which PTC receives 100% of Evrysdi royalties. Non-GAAP R&D expenses were $144 million for the second quarter of 2022, excluding $14 million in non-cash stock-based compensation expense, compared to $112 million for the second quarter of 2021, excluding $13 million in non-cash stock-based compensation expense. The year-over-year increase in R&D expenses reflects additional investment in research programs and advancement of the clinical pipeline.
Non-GAAP SG&A expenses were $66 million for the second quarter of 2022, excluding $14 million in non-cash stock-based compensation expense. Compared to $57 million for the second quarter of 2021, excluding $12 million in non-cash stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled approximately $506 million as of June 30th, 2022, compared to $773 million as of December 31st, 2021. I'd now like to turn the call over to the operator for question and answers. Operator?
Thank you. As a reminder, to ask a question, please press star one one. Please stand by while we compile the Q&A roster. Our first question will come from Eric Joseph from JP Morgan. Your line is now open.
Hi, good evening. Congrats on the quarter, and thanks for taking the questions. A couple from us on Translarna. First, wondering if you can just sort of unpack a little bit the geographic mix in demand this quarter and the extent to which you saw some large group purchase orders that may have driven the performance and perhaps that we should be sort of backing out and thinking about the sales trajectory in the second half. Relatedly, is there any material FX impact that we should also be considering?
Secondly, as it relates to requesting the transition to standard marketing authorization in the E.U., can you just sort of provide a little more granularity on the timeline for requesting that change and sort of what that review cycle might look like? Thanks.
Yeah. Hey, Eric, thanks for the question. Yeah, I think this was a great quarter where we saw growth of both Translarna and EMFLAZA, quite good. You know, there was growth throughout all geographies. Maybe, Eric, you wanna talk a little bit about where there could be differences in where we saw growth.
Yes. Eric, thanks for the question. We have certainly seen robust growth across all geographies. As you know, Translarna is a product that has international markets, and we have large group purchase orders that can be sometimes a little untimely. In this quarter, we actually saw large orders across all geographies. In particular, it was very robust in Europe. What we see with revenues this year is we never really guide to quarters. Right now what we're doing is we're really focusing on growth in all key markets, and our guidance continues to be $475 million-$495 million. The growth is actually continuing across different markets, and that's really because of new product, new patients.
We've continued to see a really high compliance. We've added, you know, programs that would also include dose adjustments for patients. We're really doing very well in terms of preserving the base and growing the base, but also through geographic expansion. We have new markets that are also significantly contributing. Essentially, we're seeing that robust growth across the global and diversified markets that we have right now.
Right. I you know, I'll say one thing and then I'll pass it to Kylie. I think what's important is, you know, I think you could see we've continued to grow our business quite well, and I think we're gonna continue to do that. We're reiterating that to $700 million-$750 million. I think, you know, we're very comfortable with that. You wanna talk a little bit about FX, Kylie?
Yeah, absolutely. Eric, with your question around FX, I think obviously, you know, in the perspective that Stu said, we are reiterating our guidance. While we do see an impact across the US dollar to the euro, we continue to see a robust and globally diversified portfolio across a number of different geographies. While we are seeing an impact, we remain confident in our business, and this geographic diversity allows us to remain confident and reiterate guidance.
Your question, I think, the timeline. Matt, you wanna take that one?
Yeah, sure. Thanks for the question, Eric. Just as a reminder, Study 041 was part of our commitment following the conditional marketing authorization from the EMA. Really the idea here was to conduct Study 041 to provide comprehensive evidence in support of the benefit risk of Translarna. It's that generation of comprehensive evidence which really triggers our ability to go from conditional and to convert the conditional to the standard marketing authorization. Obviously we're very excited about the results which were collected in the ITT population of 359 boys. When you think about comprehensive evidence, and you think about 359 boys as the largest d ata package in a single trial for DMD and the statistically significant results on functional endpoints, including walk distance North Star, we clearly believe that we have that comprehensive evidence. This is more to the benefit of Translarna.
Of course, the safety collected in this study and a long-term safety package collected not only through our clinical trials, but also in a long-term registry, again informs the favorable safety aspect of the drug. Finally, we also have generated over the past several years the STRIDE data, which provides long-term real-world evidence of benefit in Translarna in delay of loss of ambulation of roughly 5.4 years, delay in loss of pulmonary function of 1.8 years, which are really important given that those are the two key morbid transitions in the disease.
When you put the Study 041 data together with the STRIDE data, we believe we have the comprehensive data that warrants conversion from the conditional marketing authorization to standard. The way this happens mechanically is, as we said before, we are due to provide the data by the end of Q3 that we will submit a type II variation to the CHMP or EMA, which basically requests that conversion. This will initiate a process in Europe that will unfold over the course of several months, where they'll be back and forth if they have questions about the data. It's hard to say exactly what the time will be from initiation of that process in September till the end. We think it will be several months, but clearly much shorter than one would anticipate in a typical MAA submission.
Okay, great. That's very helpful. Thanks for taking the questions.
Thank you. We'll take our next question from Raju Prasad from William Blair. Your line is now open.
Thanks for taking the question. Congrats on the quarter. Can you give us a sense, just now having a couple more months of looking at the Upstaza commercial markets under your belt on the potential cadence of kind of revenue recognition that you anticipate maybe this year? Even if you give a little more color into, you know, how you anticipate the launch going into next year, that'd be helpful. Thanks.
Yeah. Great. Hey, thanks, Raju. Obviously, you know, our goal is to, you know, bring Upstaza to all the AADC deficient patients. You know, maybe just a little bit of color. You know, while we recently just got the approval, then you have to do a bit of work to be able to go then into other places. That's being worked on right now, and then we're gonna be working on or have been working on also market access in different places as well. We're pretty well positioned for the commercial launch. We'll be using both the commercial launch in terms of bringing drug to patient as well as expanded access program to patients as well. We feel like that, you know, we're in a good position.
Like we said, we already have one expanded access case, paid expanded access patient, that has had the surgery and is a commercial patient. The preparation for launch has a lot of work has gone into it. There's you know, a number of key success factors, which is accelerating disease education, patient identification, and then preparation of the surgical center, and then making sure that the key physicians are engaged, and then working with the patient advocacy groups and payer engagement. We've been working hard on that. The first country, obviously, that we'll be going into in Europe is gonna be Germany, followed by other international markets in particular, where we can do expanded access programs.
If you think about it, patient identification has been a key focus of us for the launch preparation, and this just goes on, you know, really forever, and even post-approval. I think, you know, at the end of the day, I think we've shown a strong track record in launching rare drugs. Team is quite experienced, a broad global commercial footprint to get into, you know, over 50 countries. We're pretty confident that this is a significant opportunity for the Upstaza launch.
Great. Thanks, Stu. Then just on a question on clinical trial enrollments, can you give us a sense of where you are with the APHENITY trial on enrollment as well as it looked like the MIT-E trial's first quarter 2023 readout as well as obviously the phase Huntington's study are?
Did you say, for the PKU trial, right?
The PKU trial, and then I just saw in the press release that I think the MIT-E trial is now a 1Q 2023 readout.
Yeah, sure.
Fourth quarter.
We're pretty excited obviously about the PKU trial. We think that, you know, our drug has substantial benefit over Kuvan. We're, you know, pretty excited about that. Matt, you wanna just talk a little bit about where we are on that?
Yeah, sure, Raju. These three trials are global trials leveraging our global development infrastructure. For PKU, the sites are up, running, and rolling. We are on track for results by the end of 2022. Similarly, as we updated on the PIVOT-HD study, we're getting sites up around the world and enrolling that trial with data by the end of 2022 and results by the end of 2022. It's been more as we updated on the PIVOT-HD study, where we're getting insights of the world and enrolling that trial with the data by the end of 2022 and the 12-week portion. Then on MIT-E, we moved the data from Q4 to Q1 2023.
That's mainly due to the COVID-related delays. These children with mitochondrial disease and seizures are quite ill. In fact, when there's not a pandemic going on, seasonal colds and flus can easily put them in the hospital, and even can be fatal events. There's been a lot of caution on the part of parents and physicians to get the kids into the study sites. That's caused a little bit of delay in getting the trial to the enrollment target. We're now on target to have results, as we said, in the first quarter of 2023.
That's helpful. Thanks.
Thank you. We'll take our next question from Kristen Kluska from Cantor Fitzgerald. Your line is open.
Hi. Good afternoon. Thanks for taking my questions, and congrats on the Upstaza launch. Given that you have three registrational trials where we're expecting data through the second quarter of next year and the Upstaza BLA guided for the fourth quarter, could you talk about some of the commercial readiness steps you're taking towards juggling these potential filings and beyond, should they be successful?
Yes, sure. Let me start a little bit where obviously, just the way the structure of the team is such that each team is moving forward on that. In terms of juggling, we don't really juggle it, as each team has in each of the registration-directed programs, each team is doing their work to get ready for both launch and regulatory track. We don't. It isn't like we have to wait for one versus the other. Every team, every one of those has their own team that is moving forward. I think we have a pretty strong track record in moving those forward. The team's pretty experienced in this. I think we'll be able to, you know, be able to move all of them as things move forward.
I think with the global footprint that we have gives us really the capabilities to be able to, you know, knock on wood, all goes well, that we'll be able to launch all of them, and each one, as you know, as it progresses and gets approved both in Europe as well as in the U.S. Does that help you?
Yes. Thank you. Appreciate that. I know in the past you've made a lot of synergies with your splicing platform as it relates to Evrysdi and then of course the work you're doing in Huntington's disease. Now that there's been a lot of commercial experience here, wondering if your views have at all changed, confidence increased or anything that you could really take away from the commercial experience relative to this platform.
Yeah, I think, you know, from our point of view, we're really pleased with the splicing platform and the commercial prospects of it. Obviously, the nice aspect of these molecules is that they're orally bioavailable, you know, especially for neurodegenerative diseases. The fact is that they get to every part of the brain, and therefore, they could treat every aspect of the disease. We think oral, in these cases, is probably the best way to go. You could titrate it.
You could, you know, you can utilize PD markers in the blood to have a concept of where you are in terms of what dose you give and what's the effect of either increasing or decreasing, like we've done with either Evrysdi or PTC518. You're not driving the bus blindly. You're actually, you know, you have a pretty good look into saying what is, you know, based on this exposure level, you're getting this effect on splicing. We think that's really important.
Then you can measure the level of the drug, and therefore know that, you know, in the CSF as well, to know the exposure level that you're getting within the blood, within the brain as well. You get a lot of information that lets you make good decisions at the same time. Obviously from a commercial perspective, the fact that this is the case is a standard sort of commercial program, where you know that you could show everyone that what the dose is, what the right level is. Therefore, you know, with the clinical data on hand, I think this is a really nice commercial product to move forward with. We've spent a lot of time now perfecting the splicing platform, where it's really honed and efficient.
We think this is gonna be a platform that's gonna add multiple programs that ultimately will get to commercial for multiple drugs. We think it's gonna be an exciting platform. I mean, I think it's really an exciting platform.
Okay. Thank you, Stu.
Thanks for the question, Kristen.
Thank you. Our next question will come from Joseph Thome from Cowen. Your line is now open.
Hi there. Good evening, and thank you for taking my question. Maybe one on the mitochondrial epilepsy patients. What's kind of your updated thinking in terms of how many patients are out there, and is it relatively straightforward to identify them? As you're looking at sort of the presentation, are there any variabilities in the type of seizures that these patients experience? Thank you.
Yeah. Hi, Matt, you wanna take that?
Yeah, absolutely. Joe, thanks for the question. Just when you talk about seizures and mitochondrial disease, it's a highly morbid and common component of these disorders. Roughly 30%-50% of kids with mitochondrial disease have seizures as part of their disease, and the vast majority of these seizures tend to be refractory to typical anti-epileptic therapies. The simple reason that most traditional anti-epileptic therapies increase as part of their benefit, they increase oxidative stress, which is actually the pathology underlying seizures in children with mitochondrial disease. In many ways, traditional therapies make them worse. Obviously, the benefit of vatiquinone is it targets the underlying energetic pathways that underpin the oxidative stress-mediated seizures in these children.
We estimate there are about 20,000 patients worldwide with mitochondrial disease-associated seizures, and as you pointed out, within this group, there is some variability. They have variable number of seizures, and as you alluded to as well, Joe, there's also a variability in the types of seizures. They could be motor, they could be myoclonic, they could be tonic, they could be clonic. Most of these children actually have a composite picture with many different seizure subtypes. Obviously, for the purposes of the clinical trial, we're focusing on observable motor seizures as the primary endpoint because those are obviously, one, observable and then, two, quantifiable, which is obviously an important aspect of being able to measure treatment effect.
In fact this study design of focusing on the observable motor seizures, having the observational run-in phase and overall structure mimics the previous trials done in things like Lennox-Gastaut and Dravet. Just using a very well-established study design for pediatric epilepsy syndromes.
Perfect. Maybe just to follow up on that, is there a separation from placebo in terms of reduction in number of major motor seizures that you're looking for in order to go forward with a submission or conversation with the FDA?
Yes. We've powered the study for a delta of about 40%. We're estimating placebo to have a decrease of about 10%, and that's just based on what's been observed in previous pediatric epilepsy syndromes. We are targeting approximately 50% reduction in seizures in the treatment group. That's a median reduction. The way that the change is calculated is, as I mentioned, there's that 28-day run-in period where we establish a baseline seizure frequency, and then we measure the monthly frequency over the course of the six-month placebo-controlled phase.
I think while we're targeting a delta of 40% in terms of difference between treatment and placebo, I would point out that in these children, given how severe their seizures are, how highly morbid these seizures are, and how they're related to other morbid aspects of the disease like aspiration and pneumonia, and in some cases, status epilepticus and death, even an observed decrease of 20%-25% would be clinically meaningful for these patients.
That is very helpful. Thank you very much.
Thank you. We'll take our next question from Tazeen Ahmad from Bank of America. Your line is now open.
Hey, guys. Good afternoon, and thank you for taking my questions. Stu, I just wanted to get your thoughts on how you're viewing the opportunity for emvododstat, you know, in COVID. Number one, I guess it's a little bit outside of, you know, what we've all become used to expecting from PTC in terms of areas of focus. And then also, I think people kind of view COVID as becoming more endemic now, and there are a number of oral antivirals available. Would love to hear your thoughts on where you think the unmet need is. And then secondly, just going back to your study, can you clarify if you met the primary endpoint? And, what additional analyses would you expect to conduct before you make a decision on what to do with the product next? Thanks.
You know, obviously we started this early on as we were learning about COVID, what are the best ways to look at it. It became relatively clear that you know that it was obviously an evolving scene where while even in hospitals, in order to see effects of things that affected both the viral load, you had to look at it early versus having patients who come in much later. It's much harder to see an effect on something that's gonna affect the viral load. That sort of something that was learned, and actually it turns out to be a relatively difficult to be able to guess where is the best sites in order to move forward to it.
Nonetheless, I think what we decided to do is look at the study early when 189 subjects were enrolled in order to review the data collected and to make an informed decision because it was taking a long time in order to complete the trial. We thought we'd be better off looking now and seeing what would be the best way to do it. Across all subjects, there was a trend towards emvododstat benefit across that in several disease-relevant endpoints, including duration of hospitalization and time to the different events. When examining the patients that were enrolled within five days of infection, there was a statistically significant benefit of emvododstat treatment on time to respiratory improvement, duration of hospitalization, dyspnea resolution, and cough relief.
You know, for example, the median hospitalization length in the placebo group was 28 days, 10 days on emvododstat group. I think it's pretty clear that it was particularly important as they suggest a clear potential for emvododstat to work in early treatment in COVID, which is I think what people expect. Clearly, I think one of the better ways to do this is in an outpatient setting, where I think the majority of the cases are now managed. We're considering what's the best way to do the outpatient and to think about what's the best strategy, whether we work with someone else to get the but with the DHODH compounds that inhibit COVID-19, what's the best way to get that to patient?
Personally, I think there still is a need for additional drugs. I mean, 'cause clearly, I think what we've shown here for DHODH is clearly a proof of principle that this would be good in treating COVID-19. The next question, though, is this and other viruses that come up with it, because let me remind you, it's a cellular target, and therefore, we think it would be good for, you know, in terms of low mutation rate. You could see on some of the other drugs where they're, we are already seeing either resistance or additional flashbacks. I think there's a need for additional drugs out there. We'll just have to consider the best way to move this forward. To your point about it's something that we normally wouldn't do.
I think you're right. This isn't normally a position, an area that we would call in a large indication. You know, there was a real need for treatments for COVID. It was a pandemic, and we thought it was important to. We knew that just because the way it works and the role of DHODH in controlling de novo pyrimidine synthesis, where we learned that you need de novo synthesis for viral replication, and that the salvage pathway was what most cells work on isn't enough, and you need this for viral replication. That this is a potentially good target. We thought that this was important enough of a disease and causing enough problems around the world that we'd like to be part of the solution if possible.
That's why we did that.
Okay. Thank you for the color.
Thank you. We'll take our next question from Nishant Gandhi from Truist Securities. Your line is now open.
Hi, and thanks for taking the question, and congrats on the quarter. This is Alex Tong for Robin. What type of cadence we wanted to know for news flow, should we expect to see around the Translarna filing and the launch prep in the U.S. and what kind of communication can we expect? Then also, can you remind us about your manufacturing capabilities and capacity to support launches in both the E.U. and the U.S.? Thanks.
Manufacturing for what are you referring to? Just in general.
Do you anticipate any sort of supply chain issues, and regarding supplying the gene therapy products for an ultra-orphan therapy in the global markets?
Sure. I think, obviously we're excited about the Translarna. We'll be having an end of phase II meeting and talking with the FDA. I think we'll have news flow as we talk and get more clarity, I mean, end of phase III meeting that will then give clarity on that. Matt, you wanna talk a little bit about next steps?
Yeah, absolutely. In terms of Europe, I think we've talked quite a bit about the timeline. We expect to submit a type II variation by the end of September to request a conversion from conditional to standard. In the U.S., as you asked, the plan will be to meet with the FDA, lay out all of the data from 041, as well as the totality of data, which strongly supports the benefit of Translarna. And being able to share the fact that we have statistically significant data in DMD on functional endpoints, which for a therapy that's targeting the underlying mechanism of disease will be a first. We really look forward to being able to share that along with the totality of data that we've collected in the STRIDE registry demonstrating long-term safety and benefit, as we've previously talked about.
Once we have that meeting with the agency and they get alignment on the path to an NDA, we'll obviously move forward, and we will share updates as appropriate.
And the-
Sure.
For supply chain and manufacturing, you know, we work. There's two prongs. There's the small molecule path and the gene therapy path. The small molecule path is something that we've been doing now for almost 20 years. We have a strong supply chain, you know, manufacturer and supply chain group that's been capable of making sure we can manufacture and supply to either clinical or commercial products, multiple ones at the same time. I think they're very good at it, and it's. We've been able to move forward. It can handle multiple programs, and they've shown to be capable of doing this.
Obviously in gene therapy, we have the Hopewell site, which is, you know, close to 300,000 sq ft facility for gene therapy manufacturing. Plus we have a site in Massachusetts that with MBL that we can manufacture as well, another 15,000 or so square feet for commercial manufacturing as well. I think we're well suited and capable of. We have a team of experienced people who've now, you know, have under their belt an approval in gene therapy, right? Really only the third one that's been for commercially selling. I think we're in a pretty good position there. We're, you know, we clearly have a state-of-the-art facility to be able to do gene therapy manufacturing.
In fact, we've also built out in a sense, a small CRO in working with other companies because we have excess capacity that we can make a business out of making plasmids and manufacturing. I think we're in pretty good shape both in the manufacturing of gene therapy as well as small molecule.
Thanks for taking the question.
Thank you. We'll take our next question from Brian Abrahams from RBC Capital Markets. Your line is open.
Hi, this is Steve on for Brian. Thanks for taking our question. On Translarna, I'm curious whether you see any impact of the recent news that FDA may consider accelerated approval for a DMD gene therapy on the path forward for Translarna. Maybe as a related question, can you share whether any additional subgroup analyses you have performed from Study 101, but maybe didn't present yet, might help that application and maybe how many such subgroup analyses you performed? Thanks.
Sure. So, you know, I think, you know, in terms of a couple points. In terms of the gene therapy, I think, you know, first of all, it's limited to the patient population, possibly that they have. I think that Translarna and Spinraza for that matter are probably key foundational treatments that are standard of care for Duchenne muscular dystrophy, that I think have shown a wide age range and benefit demonstrated in a broad range of patients. I think they're always gonna be used for that.
You know, I have a little bit different view in terms of the gene therapy with the high dose, small patient numbers, with benefit yet not demonstrated, with a drug that you can't withdraw or reverse the therapy once treated, and the patients aren't capable of getting other treatments. That it'd be interesting if the FDA in terms of thinking that, and I think there's a number of key questions and issues that are yet to be addressed. I'm very curious to see how viable the accelerated approval pathway is in the gene therapy where there isn't clinical data, and the notion of using a different biomarker that in this case doesn't necessarily predict functional benefit.
How you can bring that to patients when they can't get other gene therapies as a consequence of that. I personally am skeptical of that pathway right now in gene therapy. In terms of the Study 041, I think, you know, the fact that we in the ITT population, as well as we told you in the three to 400 analysis. You see improvement is statistically significant from the ITT population in the three to 400, that you saw statistically significant with the North Star as well as the timed function test. And also in terms of time to 10% worsening.
We have a broad range of analyses, not to mention also the pooled analysis and the statistical significance overall in when you pool all of that together with a 0.0002 p value, both with six-minute walk test, North Star, and timed function test. I think there's the strong data demonstrating that in Study 041 in combination with the other trial, the Study 007 and ACT DMD, the strong results of that.
You know what's nice about, you know, really when you think about we can show that there's a 20% improvement as a consequence of treating with Translarna, and that when you think about translating that to data to what does it really mean to patients from a functional perspective, when you look at the STRIDE registry and then you and when you see the STRIDE registry and see that you see, you know, greater than five years preservation of ambulation, almost two years in terms of preservation of being able to get off the ground and actually a strong preservation of pulmonary function. It shows you how you could. You know, we're in this very interesting position where we have so much data that shows you the results you get in the clinical trial.
What does that mean from a real clinical perspective with a long-term five years of data, showing those preservations of ambulation, getting off the floor and pulmonary function? You now know what those results mean to a patient. You know, we're pretty excited about that. Then you could also the other interesting analysis we did is like with the North Star. You know, it's a number of different functional functions that you measure to get a North Star score. Not only but so what we also do on top of looking at that data, we say not only what does it do, but what how well did it preserve those functions, right? Because, you know, over time they lose function.
We saw when looking at this that you reduce the risk by more than 30%-40% on several tasks. That's equivalent to perhaps saving one or two functions in these kids as a consequence of that. That's again another great example of preservation of function. I think that's really sort of important. You know, at the end of the day, the most important thing I think we have out of this is that it—we got a positive result in the ITT population. That's the whole population of patients. Really every group and it was a large enough study to be able to see this here.
I think all in all of those results really, I think make this a very strong study demonstrating Translarna's effectiveness. Does that help?
Great. Thanks for that color. Yes, yes, thanks.
Thank you. We'll take our next question from Colin Bristow from UBS. Your line is open.
Hi, this is Yihan Li for Colin . Congrats on the quarter, and thanks for taking our question. We have one question on the PTC Upstaza BLA filing U.S. As you said in the call, the filing will be expected in the fourth quarter. Could you please give us some more color on the details? For example, if there's anything remains to be done beforehand and how would you incorporate the E.U. launch experiences for the FDA filing? And have you had any further discussions with the FDA? Thank you.
Yeah, sure. Matt, you want to take that?
Yeah, absolutely. Thank you, Yihan, for the question. As we said all along, we would work hard to get the MAA across the line. Obviously, we're incredibly excited about the approval in the E.U. As Stu said, this is really trailblazing in a number of ways. Now we're focusing the efforts on the BLA submission. As we said, our plan is to meet with the agency. We have not done that yet to align on the package and make sure that we have all that is needed for the submission of the BLA. Then based on the timing of that meeting, we believe we'll be in position to submit the BLA in the fourth quarter of this year.
We believe that obviously, having gone through the experience in Europe and being able to achieve an approval puts us in a very strong position. Obviously, we have the clinical data, the necessary manufacturing data, non-clinical data, all those key components for approval. Obviously, we've been able to provide in Europe, and we look forward to being able to provide those to the FDA as part of our BLA submission.
Thank you.
Thank you. We'll take our next question from Gena Wang from Barclays. Your line is now open.
Hey, and thank you so much for taking my question. This is Xiang for Gena. I have two questions. I wanna start with the Upstaza for AADC. You mentioned before you have identified 300 patients globally. So how many of them are addressable or can be treated based on the E.U. label? Secondly, can you break down the patient numbers by country or regions, and how many of them have early access?
Thanks for your question. Obviously, maybe talk a little bit about AADC deficiency. It's obviously a very severe disease where patients lacking the motor milestones and lack dopamine production. The vast majority of these patients that we've identified really do fall under the, you know, they're missing major milestones. We have the breadth of the label that's very broad, so we were pleasantly surprised by that. This was an important point that we're able to get that. That's going to probably translate to a higher number of additional patients that will get treated.
As I said, we have 300 patients that we have identified and we'll continue to identify patients and continually to do that. We haven't broken them out from place to place. What we're gonna you know certainly what we do is while we have 300 patients, we certainly have. We haven't broken them out by specific countries as well. We found enough patients that I think we're gonna be pretty busy treating them throughout 2022 and beyond. We already have patients that have been reaching out into German centers to get treated. We also have scheduled paid expanded access patients as well. Things from a move as we do this, I think that's doing really quite well.
We look at this opportunity as a greater than a billion-dollar opportunity overall. What we've said is that the revenues will be this year, we've guided to between $20 million and $40 million, and we think that will continue to grow, as we line up all the patients, continue to train and get all of the surgical centers up on site. I think we're pretty excited over the next couple years in getting all the patients we have to continue to find, and continue to find more and more patients to treat.
Thank you very much. May I ask a second question? I just switch gear a little bit to Huntington's, your PIVOT-HD trial. I just wondering what kind of data we should expect by year-end. Will you share like neurofilament data? Also besides biomarkers, what type of other endpoints you will show by year-end such as, you know, any like imaging data like putamen or ventricle volume?
Yeah. You might remember that the trial is really in two parts. One is the 12-week trial, where we're. You know, the first part of this is really to say what we saw in healthy volunteers, do we see in Huntington's patients, right? PIVOT-HD is a placebo-controlled trial, where the first 12 weeks is focused on the pharmacology and pharmacodynamic effects. Then the second is more on biomarkers and clinical endpoints, right? The first 12 weeks will provide the important relationship between dose exposure and HTT mRNA and protein reduction in the blood, at steady state, right?
That, you know, and we think that's important to say is it the same or different, what the PK looks like in the CSF, and exposure, you know, the ratio between them. You might remember that we saw somewhere between a two- and three-to-one in CSF to blood. We wanna see what it looks like in HTT patients. As patients go on, we also wanna look at HTT levels, neurofilament, as well. The first part of it is gonna be the pharmacology and blood PD.
Just want to confirm. By year-end, we would see only PK/PD data at 12 weeks. Are you going to collect the data for some internal reviewing?
I'm sorry, I missed the last part of your.
Last part is, for the first part, the 12 weeks, even though you focus on PK/PD data, are you going to collect any of the biomarker data for, like, internal reviewing?
Yes, you know, probably as we have everything, we'll be looking and being able to monitor. You know, this is all relatively new. There's never been an orally bioavailable drug. Right now we're trying to get all the parameters correct in terms of knowing what the PK/PD looks like in patients, in terms of what it's doing in the cells for protein and RNA.
Thank you very much.
Thank you. We'll take our next question from Danielle Brill from Raymond James. Your line is open.
Hey, guys. This is Alex Tong on for Danielle Brill. Just wanted to touch back on Translarna in the U.S. and the Sarepta read-through and kind of how you're looking at the agency considering their apparent tolerance for some, let's say, dataset flexibility in Duchenne. Are you reading through to this that your Translarna future, it bodes better, or do you think it stands on its own, or are you not considering that there are different FDA divisions at play here?
You know, I don't know if you heard what I said before, but I think that, you know, I think we're hopeful that. Look, Study 041 was a well-done study that demonstrated functional benefit in a broad population of Duchenne muscular dystrophy patients, with the, you know, broad population in the ITT population, demonstrated statistically significant in the six-minute walk test, but also in the North Star and timed function test.
I think that in itself, I mean, that's, if you think about it, that's I think the first example with a, you know, for, with a drug that actually shows for, you know, for the treating the underlying cause of disease where we're seeing in an ITT population, a statistically significant result in multiple endpoints, and everything favored Translarna versus placebo. I think that data, along with the results from Study 007 and Study 014, that really shows that you're seeing clinical benefit, and you don't have to rely on a biomarker that hasn't shown, in our view, hasn't yet shown is predictive of clinical benefit. I think we're in a pretty good position from a clinical perspective.
The data that goes along with it was Study 007 and Study 020, and ACT DMD, and then the STRIDE registry that translates for people. You know, in a way, when you do clinical endpoints, the goal of clinical endpoints is to predict outcomes for patients, right? In this case, we also have that data to show the regulatory bodies where you see that, in the STRIDE registry we saw greater than five years in preservation of ambulation, so greater two years or so of preservation of being able to get off the ground, and a really strong preservation of pulmonary function. Those are really the hard endpoints. You know, when you're a patient, what do you care about? Can you still ambulate? Can you still get off the ground?
Can you know, what do DMD patients die of? Which is pulmonary and cardiac function. If you're showing improvement in those, that is, I mean, the drug is showing clinical benefit. We think we have a strong case there.
Great. Thanks so much.
Yeah.
Thank you. I am showing no further questions at this time. I'd now like to turn the conference back over to Stuart Peltz for any closing remarks.
Oh, great. Well, look, I wanna thank you all for joining us today. I think what you could see from, we've been having really, you know, a great year of making significant progress this year, and have been delivering on a number of the key milestones. We're proud of the approval of Upstaza, which I think is really groundbreaking science and a milestone not only for PTC, but for the entire field of gene therapy and for the AADC community. I think that the positive results from Study 041 demonstrating the benefits to nonsense mutation DMD patients really adds and demonstrates that Translarna's benefits to the patient and adds to the totality of evidence of Translarna.
The other important point is that, and what we've talked about, particularly in the questions that you've asked, is that we have a number of registration-directed studies that are ongoing that we look forward to sharing those results with you in the near future. We're excited and happy at PTC to continue on this mission of discovering and developing these innovative therapies for rare disorder patients. Thanks for joining today, and we look forward to our next conversation with an update.
Thank you. This concludes today's conference call. Thank you for your participation, and you may now disconnect. Everyone, have a wonderful day.