PTC Therapeutics, Inc.

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 11 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 Powles, 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 risk, 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 Pelt.

Stuart? Thanks, Kylie, and good afternoon, everyone, and thanks for joining us today. I'm excited to share PTC's second quarter results in 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 in 2021. This is quite remarkable and puts us in good position to achieve our full-year revenue target of between $700 and $750 million. The DMV franchise is expected to continue a strong growth trajectory throughout the remainder of 2022. We also reported top-line results of study 41, which was an important step forward for Translarna. In study 041, we demonstrated a statistically significant benefit for Translina and NASF mutation DMD patients across a number of relevant functional outcomes in the broad intent to treat study population. Based on these results, we plan to request conversion of the EU conditional authorization to a standard marketing authorization. In addition to the EU, 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 EU and international markets. Matt will go into these results in more detail shortly. We recently announced the marketing authorization for ABEZA 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 PPC 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 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 Upstazer is based on multiple factors, including that the disease is highly morbid and fatal, and the high medical needs of AADC deficient patients with no standard of care. Lastly, Upstazer 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 drugs through the Early Access Program in France, and Eric will go into this in more detail shortly. Let me switch gears to RISD as we continue to achieve strong updates across all regions. The FDA recently approved the supplemental NDA of Evrizzi for pre-symptomatic infants with SMA under two months of age. Their approval is based on interim efficacy and safety data from the Rainbow Fish Study in Newport, which showed that pre-symptomatic babies treated with Evrizzi 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 Unespalin, previously known as TTC596. We recently announced encouraging preliminary safety and efficacy results from our Phase 1B study in Unespalin, our tubulin binding agent, in advanced leomyelococcoma patients at a podium presentation at ASCO. Based on these preliminary results, TTC initiated the Sunrise LMS study, a placebo-controlled registration-directed study of the efficacy and safety of unescolin 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 12 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 of what 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 non-sense 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. Top-line 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 DMT therapy to demonstrate a statistically significant functional benefit in a placebo-controlled trial. In addition, a statistically significant benefit of Translana was also demonstrated in the NorthStar ambulatory assessment and the 10-meter run-walk and four-stair-send timed function test in the ITT population. These results are not only statistically significant, but provide evidence of clinically meaningful benefit, as they represent a 20 to 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 trans-LARNA trials, Study 7, Study 20, and Study 41, 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 EU 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 EU, we are now focusing efforts on submission of a VLA to the FDA, which is planned for the fourth quarter of this year. I would like to now share encouraging results of our FITE-19 study of Invotastat for the treatment of COVID-19. The FITE-19 study was designed as a double-blind, placebo-controlled, 28-day study of hospitalized COVID-19 patients. As a reminder, embolistat is an oral small molecule that targets the cellular enzyme dihydroauricates dehydrogenase, or DHODH. By targeting a cellular enzyme rather than a viable protein, embolistat 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 FITE-19 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 Invotasap benefit across several disease-relevant endpoints, including duration of hospitalization and time to reduction of fever. When examining the cohort of patients enrolled within five days of infection, there was a clear benefit of embodistat 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 embodistat group with a p-value of less than 0.05. These findings are particularly important as they suggest a clear potential for Embodistat 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 Embodistat for the treatment of COVID-19. Over the course of the second quarter, we continue 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 affinity phase three trial of PTC923 in patients with PKU, we remain on target to share results by year-end 2022. The affinity 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 PCC923 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 BioE platform, we have three ongoing registration-directed trials, two with vaticlidone in mitochondrial disease-associated seizures and creature potaxia, and one with PTC 857 in patients with ALS. Due to COVID-19-related delays in enrollment, we now expect to have results from the MITEI trial of the tiquidone in patients with mitochondrial disease-associated seizures in the first quarter of 2023. As we have previously shared, the MOVE-FA global trial of the tiquidone 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 ALS FRS 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 Cluntington disease program from our slicing platform. Enrollment is ongoing in our Phase 2 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, CSS, and radiographic biomarker data. The study will initially include two dose levels, 5 milligrams and 10 milligrams, 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 DMV 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 patient 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 updated price is expected to be in the range of $3 million to $3.5 million, which factors in our projection 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 Absteza will support HTA-DOCA submissions for reimbursement as the first and only treatment approved for AABC deficiency patients 18 months and older. We have guidance to 20 to 40 million in revenue from Upstaza. Turning now to DMV. Our global DMV franchise continues to deliver robust revenue across all regions. Our second quarter revenue for the DMV franchise was 134 million. Our Nplaza net product revenue for the second quarter was 57 million, which represents 16% growth over the second quarter last year. Ongoing execution by our MWASA team to have new patient starts, continued favorable access, high compliance, and appropriate weight-based dosing for DMV patients in the United States. For Translarna, we achieved 77 million in net product revenue for the second quarter, which represents a 46% increased 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 luckiness due to uneven government buying patterns. Overall, TransLarger 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 V&D revenue guidance of $475 million to $495 million. In Latin America, our teams continue to strengthen the tech study and will leave our franchise. In Brazil, following the innovative drug classification for tech study, 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 HHGTR 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 progress with CONITEC, the National Commission for the Incorporation of Technology, for inclusion of tech studies in the essential drug list, which simplifies access. For Relivra, we now have patients on treatment for STF in Latin America, and patient identification continues to progress well. As a reminder, last December, we submitted an application to Endesa in Brazil for approval of Relivra for the treatment of STF. If approved, Relivra will be the first approved treatment for STF 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 safety 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 Upstasia 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 Eversy 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 VMD franchise of $134 million and at RISD royalty revenue of $22 million. Our total revenue from the first half of 2022 is an impressive $314 million. And as Stu said, we are on track to achieve our 2022 total revenue guidance of $700 to $750 million. Apart from our continued net product revenue, we also anticipate a $50 million milestone payment from Roche when annual RISD sales reach $750 million. In addition, we have guided to $20 to $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. And Plaza had net product revenues of $57 million, or 16% growth year-over-year. Moving now to Evrisdy, our partner Roche reported 2022 year-to-date sales of approximately 500 million Swiss francs, which translated into second quarter royalty revenue for PTC of $22 million. As a reminder, PTC retains approximately 57% of Evrisdy royalties. with Royalty Farmer receiving the remaining 43% up to a cumulative total of $1.3 billion, after which PTC receives 100% of Everestie 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 30, 2022, compared to $773 million as of December 31, 2021. I'd now like to turn the call over to the operator for questions and answers. Operator?

Thank you. And as a reminder, to ask a question, please press star 1-1. Please stand by while we compile the Q&A roster. And 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 could just sort of unpack a little bit the geographic mix in demand this quarter and the extent to which you saw sort of large group purchase orders that we 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? And then secondly, as it relates to requesting the transition to standard marketing authorization in the EU, 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.

Hey, Eric. Thanks for the call. I mean, the question. Yeah, I think we've had a, I think we've, I think this was a great quarter where we saw growth of both Transline and in Plaza. quite good. And, you know, and there was growth throughout all geographies. But maybe, Eric, do you want to talk a little bit about the difference, where there could be differences in where we saw growth? Yes, Eric, thanks for the question.

We have certainly seen robust CLOSE ACROSS ALL GEOGRAPHIES. AND AS YOU KNOW, TRANSLARDA IS A PRODUCT THAT HAS INTERNATIONAL MARKETS AND WE HAVE LARGE GROUP PURCHASE ORDERS THAT CAN BE SOMETIMES A LITTLE UNTIMELY. BUT IN THIS QUARTER WE ACTUALLY SAW LARGE ORDERS ACROSS ALL GEOGRAPHIES AND IN PARTICULAR IT WAS VERY ROBUST IN EUROPE. AND WHAT WE SEE WITH REVENUES THIS YEAR is we never really guide to quarters. And right now what we're doing is we're really focusing on growth in all key markets, and our guidance continues to be 475 to 495. So the growth is actually continuing across different markets, and that's really because of new patients. We continue to see a really high compliance We've added, you know, we've added programs that would also include dose adjustments for patients. So, 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. So, essentially, we're seeing that robust growth across the global and diversified markets that we have right now.

Great. Yeah, so 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 can see we continue to grow our business quite well. And I think we're going to continue to do that. We're reiterating that to 700 to 750 million. So, I think, you know, we're very comfortable with that. You want to talk a little bit about that, Kylie?

Yeah, absolutely. So, Eric, with your question around FX, I think obviously, you know, in the perspective that Stu said, we are reiterating our guidance. And so 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. So while we are seeing an impact, we remain confident in our business. And this geographic diversity allows us to remain confident and reiterate guidance.

And then your question to the timeline. Matt, do you want to take that one?

Yeah, sure. Thanks for the question, Eric. So, just as a reminder, study 041 was part of our commitment following the Conditional Marketing Authorization from the EMA. And really, the idea here was to conduct Study 41 to provide comprehensive evidence in support of the benefit-risk of Translarna. And it's that generation of comprehensive evidence which really triggers our ability to go from a conversion – to convert the conditional to the standard marketing authorization. So, obviously, we're very excited about the results, which we're Collected in the ITT population of 359 boys. And when you think about comprehensive evidence, you think about 359 boys is the largest. Data package in a single trial for. 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 at the benefit of transline. And then, 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. And then finally, we also have generated over the past several years, the stride data. Which provides long term, real world evidence of benefit and transline in the way of loss of ventilation of roughly 5.4 years. delayed loss of pulmonary function of 1.8 years, which are really important given that those are the two key morbid transitions in the disease. So when you put the study O4-1 data together with the STRIDE data, we believe we have the comprehensive data that warrants conversion from the conditioning marks and 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 2 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. They may have questions about the data. So, it's hard to say exactly what the time will be from initiation of that process in September until 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. And 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 upstairs commercial markets under your belt on the potential cadence of kind of revenue recognition that you anticipate maybe this year? And even if you give a little more color into how you anticipate the launch going into next year, that'd be helpful. Thanks.

Yeah, great. Hey, thanks for asking. Obviously, you know, our goal is to, you know, bring up things to all the AADC deficient patients. And, you know, maybe just a little bit of color. You know, while we recently just got the approval, you then have to do a bit of work to be able to go back into other places. So that's being worked on right now. And then we're going to be working on or have been working on also market access in different places as well. So 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 extended access programs to the patients as well. And so we feel like that, you know, we're in a good position, but like we said, we already have one extended access patient, paid extended 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 and there's, you know, a number of key success factors, which is accelerating disease education, patient identification, and then preparation of the surgical centers. And then making sure that the key positions 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 going to be Germany, followed by other international markets. In particular, where we can do expanded access programs. And so, if you think about it, patient identification has been a key focus of us for the launch preparation. And this goes on, you know, really forever, even post-approval. So, I think, you know, at the end of the day, I think we've shown a strong track record in launching rare drugs. The team is quite experienced, a broad global commercial footprint to get into, you know, over 50 countries. So, we're pretty confident that this is a significant opportunity for the updates to launch.

Great. Thanks, Stu. And then, just on a question on clinical trial enrollment, can you give us a sense of where you are with the affinity trial on enrollment, as well as it looked like the MIGHT-E trial, the first quarter 23 readout, as well as, obviously, the Phase 2 Huntington study are, yeah. Did you say for the PKU trial, right? The PKU trial, and then I just saw on the press release that I think the MIT trial is now a 1Q23 readout.

Yeah, sure. Yeah, so we're pretty excited, obviously, about the PKU trial. We think that, you know, our drug has substantial benefit over KuVans. And so, you know, we're pretty excited about that. Matt, you wanted to talk a little bit about where we are on that? Yes, Raj.

All three of these trials are global trials leveraging our global development infrastructure. And for PKU, the sites are up running and rolling, and we are on track for results by the end of 2022. Similarly, as we updated on the PIVOT-HT study, we're scanning sites up around the world and enrolling that trial with data by end of 2022 and results by the end of 2022. Similarly, as we updated on the PIVOT-HT study, we're scanning sites up around the world and enrolling that trial with data by end of 2022 on the 12-week portion. And then on MiD, we moved the data front to one quarter to first quarter 2023. That's mainly due to the COVID related delays. These children with mitochondrial disease and seizures are quite ill. 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. And so there's been a lot of caution on the part of parents and physicians to get the kids into the study site, so that's caused a little bit of delay in getting the trial to the enrollment target, but we're now on target to have results, as we said, in the first quarter of 2023. That's helpful.

Thanks. Thank you. And we'll take our next question from Kristin Kluska from Cancer Fitzgerald. Your line is open.

Hi, good afternoon. Thanks for taking my questions and congrats on the Upstazer launch. So given that you have three registrational trials where we're expecting data through the second quarter of next year and the Upstazer 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, it's such that each team is moving forward on that. So, in terms of juggling, we don't really juggle. Each team has, in each of the registration directed programs, each team is doing their work to get ready for both launch and regulatory. So 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. And I think we have a pretty strong track record in moving those forward. And the team's pretty experienced in this. So I think we'll be able to, you know, be able to move all of them as things move forward. And 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, 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. And I know in the past you've made a lot of synergies with your splicing platform as it relates to RISD and then, of course, the work you're doing in Huntington's disease. But 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, that, you know, especially for neurodegenerative diseases, the fact is that they get to every part of the brain, and therefore they can treat every aspect of the disease, we think oral. In these cases, oral is probably the best way to go. You could titrate it. 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 the amount of a protein. like we've done with either a RISD or PTC518. So you could, you actually, so you're not driving the bus blindly. You 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. And we think that's really important. And then you can measure the level of the drug and therefore know that you know in the css as well to know the exposure level that you're getting within the blood within the brain as well so you get a lot of information that lets you make good decisions at the same time um and then obviously from a commercial perspective when you you know um the fact that this is the case is the standard sort of commercial program uh where you have 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 slicing platform where it's really honed and efficient. So we think this is going to be a platform that's going to add multiple products multiple programs that ultimately will get the commercial for multiple drugs. We think it's going to be an exciting, 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 Joe Thome from Cowan. 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? And then as you're looking at sort of the presentation, are there any variabilities in the type of seizures that these patients experience? Thank you.

Yes. Hi, Matt. You want to take that?

Yeah, absolutely. Joe, thanks for the question. So just when you talk about seizures and mitochondrial disease, it's a highly morbid and common component of these disorders. So roughly 30 to 50 percent 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 benefits, they increase oxidative stress, which is actually the pathology underlying seizures in children with mitochondrial disease. So in many ways, traditional therapies make them worse. Obviously, the benefit of vaticanol 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 variability in the number of seizures, and as you alluded to as well, Joe, there's actually a lot of variability in the types of seizures. They could be motor. They could be myoclonic. They could be tonic. They could be chronic. And then 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 effects and, in fact, the study design of focusing on the observable motor seizures, having the observation run in phase, and the overall structure mimics the previous trials and the things like Lennox-Castell and Gervais. We're just using a very well-established study designed for pediatric epilepsy syndromes.

Perfect. And 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?

Yeah, so we've powered the study for adults 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, and then we are targeting an approximately 50% reduction in seizures in the treatment group. That's a median reduction. And the way that the change is calculated is, as I mentioned, there's that 28-day London 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 disease like aspiration and pneumonia, and in some cases, status epilepticus and death, even an observed decrease of 20% to 25% would be clinically meaningful for these patients.

That is very helpful. Thank you very much.

Thank you. And we'll take our next question from Tahzeen 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 Invotostat, 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. Let me hear your thoughts on where you think the undermet 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.

Yeah. So, you know, obviously we started this early on as we were learning about COVID and the way to, what are the best ways to look at it. It became relatively clear that, you know, that it was obviously an evolving scene where, well, 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 going to affect the viral load. So that's sort of something that was learned. And actually, it turns out to be a relatively difficult to be able to guess where's 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 and we thought we'd be better off looking now and seeing what would be the best way to do it. So across all subjects, there was a trend towards some bonus benefit across that in several disease relevant endpoints, including duration of hospitalization and time to defer the vaccine. But when examining the patients that were enrolled five days of infection, there was a statistically significant benefit of Invotastat 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 Invotastat group. So, I think it's pretty clear that it was particularly important as they suggest a clear potential for Invotastat to work in early treatment in COVID, which is, I think, what people expect. And 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. So 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 DH or DH compounds that inhibit COVID-19, what's the best way to get that to patients? Personally, I think there still is a need for additional drugs. I mean, because clearly I think what we've shown here for DH or DH is clearly a proof principle that this would be good in treating COVID-19. The next question, though, is then 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, you know, in terms of low mutation rate. And you could see some of the other drugs, whether they are either resistant or additional. So, I think there's a need for additional drugs out there. So we'll just have to consider the best way to move this forward. And 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 go in a large indication. But, you know, there was a real need for treatment for COVID. It was a pandemic. And we thought it was important to, and we knew that, just because the way it works and the role of the HODH in controlling the novel remining synthesis, where we learned that you need the novel synthesis for viral replication, and that the salvage pathway, it was what most cells work on, isn't enough and you need this for viral replication, but this is a potentially good target. And so, we thought, that this is important enough of a disease and causing enough problems around the world that we'd like to be part of the solution as possible. So that's why we did that.

Okay. Thank you for the call.

Thank you. And we'll take our next question from Nishant Gandhi from Truist Securities. Your line is now open.

Hi, thanks for taking the question and congrats on the quarter. This is Alexander for Robin. What type of cadence we wanted to know for news flow? Should we expect to see around the trans on a filing and the launch prep in the US and what kind of communication can we expect? And then also, can you remind us about your manufacturing capabilities and capacity to support launches in both the EU and the US? Thanks.

Manufacturing. For what are you referring to? Just in general?

Do you anticipate any sort of supply chain issues regarding supplying the gene therapy products for an ultra-orphan therapy in the global market?

Sure. So I think obviously we're excited about the Translarna. We'll be having an interface to meeting and talking with the FDA. I think we'll have news flow as we talk and get more clarity in the Phase III meeting that will then give clarity on that. Matt, you want to talk a little bit about next steps?

Yeah, absolutely. So, 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 standard. And 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. So 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 previously talked about. So once we have that meeting with the agency and again alignment on the path to it, NDA will obviously move forward and obviously we will share updates as appropriate.

And then for supply chain, for supply chain and manufacturing, you know, we work, there's two prongs. small molecule path and then 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, you know, manufacturer 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 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 close to 300,000 square foot facility for gene therapy manufacturing. And 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. So, I think we're well-suited and capable of, and we have a team of experienced people who now, you know, have under their belt approval, an approval in gene therapy, right, really only the third one. that's been commercially selling. So I think we're in a pretty good position there. And so we've been, so we're, you know, we clearly have a state-of-the-art facility to be able to do gene therapy manufacturing. And in fact, we've also built out, in the sense of small CRO and working with Other companies that we have excess capacity. That we can make a business out of making plasma and. Manufacturing, so I think we're in pretty good shape. Both in the manufacturing of in gene therapy as well as small molecule. Thank you for taking the question.

Thank you. And we'll take our next question from Brian Abrams from RBC Capital Markets. Your line is open.

Hi, this is Steve on for Brian. Thanks for taking our question. On Translarna, 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?

Sure. So, you know, I think, you know, for 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 there has. And I think that TransLyna and Asplaza, for that matter, are probably key foundational treatments that are standard for care for Duchenne muscular dystrophy. that I think have shown a wide age range and benefit demonstrated in a broad range of patients. And I think they're always going to be used for that. You know, I have a little bit different view in terms of the gene therapy with, you know, the gene therapy with the high dose small patient numbers with, you know, 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 is the interesting that 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. So, 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. So I personally am skeptical of that pathway right now in gene therapy. In terms of the Study 41, I think, you know, the fact that in the ITT population, as well as we've told you in the 3 to 400 analysis. So, you see improvement in statistically significance in the ITT population in the 3 to 400 that you saw statistically significant with the North Star, as well as the time function test. And also, in terms of time to 10% worsening, So, we have a broad range of analyses, not to mention also the pooled analysis and the statistical significance overall in the, when you pull all of that together with a .002 p-value both with 6-minute walk test, North Star, and time function test. So, I think there's strong, data demonstrating um then study 41 in the combination with um with the other trials the o7 and acting d uh the strong results of that and then you can you know what's next about and 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 what does it really mean to patients from a functional perspective, when you look at the stride registry, and when you see the stride registry and see that you see 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 aculation hitting off the floor and pulmonary function? You now know what those results mean to a patient. So, you know, we're pretty excited about that. And then you could also, the other interesting analysis we did is like with the North Stars, you know, it's a number of different functional functions that you measure to get a North Star score. But not only, so what we also do on top of looking at that data, we say not only what does it do, But how well did it preserve those functions, right? Because, you know, over time they lose function. And so we saw when looking at this that you reduce the risk by more than 30 to 40% on several tasks. So that's equivalent to perhaps saving one or two functions in these kids as a consequence of that. So that's, again, another great example of preservation of function. So I think that's really, really sort of important. So, you know, at the end of the day, the most important thing I think we have out of this is that we got a positive result in the IGT population. That's the whole population. of patients. So, really, every group, and it was a large enough study to be able to see this here. So, I think all in all, all of those results really, I think, makes this a very strong study demonstrating transliners' effectiveness. Does that help?

Great. Thanks for that, Culler. Yes, yes, thanks.

Thank you. And we'll take our next question from Collin Bristow from UBS. Your line is open.

Hi, this is Yihan. I'm for Collin. Congrats on the quarter and thanks for taking our question. So we have one question on the PTC AADC BLA filing US. So as you said in the call, the filing will be expected in the fourth quarter. So could you please give us some more color on the details? For example, if there's anything limited to be done beforehand, and how would you incorporate the new launch experiences for the FDA funding? And have you had any further discussions with FDA? Thank you.

Yeah, sure.

Matt, you want to take that? Yeah, absolutely. Thank you, Ehan, 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 EU. As Stu said, this is really trailblazing in a number of ways, and 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 a package and make sure that we have all that is needed for the submission of the BLA, and we 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 be able to provide those to the FDA as part of our BLA submission.

Thank you.

Thank you. And we'll take our next question from Gina Wang from Barclays. Your line is now open.

Hey, thank you so much for taking my question. This is for Gina. I have two questions. I want to start with the 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 EU label? Secondly, can you break down the patient numbers by country or region, and how many of them have early access?

Yeah, 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. So, the vast majority of these patients that we've identified really do fall under the, you know, they're missing major milestones. And so, our label is really have, we have the breadth of the label that's very broad, so we were pleasantly surprised by that. And so, and this was an important point that we're able to get that. So that's going to probably translate to a higher number of additional patients that will get treated. And as I said, we have 300 patients that we have identified and will continue to um to identify patients uh and continually to do that we haven't broken them out uh from uh place place to place um but what we're gonna you know certainly what we do is while we have 300 patients we certainly have um um and we haven't broken one out by specific countries as well we found enough patients that i think we're going to be pretty busy feeding 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. So 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. Overall, what we've said is that the revenues will be this year, we've guided to between 20 and $40 million. And we think that will continue to grow as A, we line up all the patients, continue to train and get all of the surgical centers on site. So I think we're pretty excited over the next couple of years in getting all the patients we have to continue to find more and more patients to treat.

Thank you very much. May I ask a second question? Do you want to switch gears a little bit to Huntington? people to HD trial. I'm just wondering what kind of data we should expect by year end. Will you share neurofilament data? Also, besides biomarkers, what type of other endpoints you will show by year end, such as any imaging data, like putamen or ventricle volume?

Yeah, so you might remember that the trial is really in two parts. One is the 12-week trial where we're looking, 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? So, you know, so PIV and AC is a placebo-controlled trial. where the first 12 weeks is focused on the pharmacology and pharmacodynamic effects. And then the second is more on biomarkers and clinical endpoints, right? So the first 12 weeks will provide the important results between relationship of dose exposes your HDT, mRNA, and protein reduction in the blood at steady state, right? So then that, you know, when we think that's important, to say is it the same or different, what the PK looks like in the CSS, and exposure, you know, the ratio between them. You might remember that we saw somewhere between a two and three to one in CSS to blood. So we wanted to see what it looks like in HCT patients. And then as patients go on, we also want to look at, HTT levels neurofilament as well. But the first part of it is going to be the pharmacology and blood PD.

Just want to confirm. So by year end, we would see only PK PD data at 12 weeks. But are you going to collect the data for some internal reviewing?

I'm sorry, I missed the last part of yours.

The last part is for the first part, the 12 weeks, even though you focused on PKPD data, are you going to collect any of the biomarker data for internal reviewing?

Yes, probably as we have everything, we'll be looking and being able to monitor And, you know, this is all relatively new. There's never been an oily bioavailable drug. So right now we're trying to get to all the parameters correct in terms of knowing what the PKPD, what it looks like in terms of in patients, in terms of what it's doing in the cells for protein and RNA.

Thank you very much.

Thank you. And we'll take our next question from Danielle Brill from Raymond James. Your line is open.

Hey, guys. This is Alex on for Danielle. I 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, data set flexibility in Duchenne. Do you think that, are you reading through to this that you're the translarna future has, 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 think I, I don't know if you heard what I said before, but I think that, you know, I think we're hopeful that, look, we did study 41 was a well-done study. that demonstrated functional benefit in the broad population of Duchenne muscular dystrophy patients with the, you know, the broad population and the ICT population demonstrated statistically significant in the six-minute walk test, but also in the North Star and time function test. So, 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, with a drug that actually shows, you know, for 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. That data, along with the results from study 07 and 014, that really shows that you're seeing clinical benefit. 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. So I think we're in a pretty good position from a clinical perspective. And then the data that goes along with it was 007 and 0 and Act DMD. And then the Strive Registry that translates for people what is, you know, in a way when you do clinical endpoints, the goal of clinical endpoints is to predict outcomes for patients, right? And 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 angulation, two years or so of preservation of being able to get off the ground, and really strong preservation of pulmonary function. Those are really the hard, you know, when you're a patient, what do you care about? Can you still ambulate? Can you still get off the ground? And can you, you know, what do DMV patients die of, which is pulmonary and cardiac function? And if you're showing improvement in those, I mean, the drug is showing clinical benefit. So we think we have a strong case there.

Great. Thanks so much.

Thank you. And I am showing no further questions at this time. And I'd like to turn the conference back over to Stuart Peltz for any closing remarks.

Great. Well, look, I want to thank you all for joining us today. I think what you can see from we've been having really, you know, a great year of significant progress this year and have been delivering on a number of the key milestones. And we're proud of the approval of the data, which I think is really groundbreaking science and the milestones, not only for PTC, but for the entire field of gene therapy and for the ADC community. And I think that the positive results from study 041 demonstrating the benefits to non-submutation DMD patients really adds and demonstrates that transliners benefits of the patient and answer the totality of evidence of transliners. And so 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. So we're excited and happy at PGC to continue on this mission. of discovering and developing these innovative therapies for rare disorder patients. So thanks for joining today, and we look forward to our next conversation and update.

Thank you. This concludes today's conference call. Thank you for your participation, and you may now disconnect. Everyone, have a wonderful day.