Good day, thank you for standing by, and welcome to the PTC second quarter 2023 financial results conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You'll then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Senior Director of Investor Relations, Ron Aldridge. You may begin. Good afternoon, thank you for joining us today to discuss PTC Therapeutics second quarter 2023 corporate update and financial results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein; our Chief Business Officer, Eric Pauwels; our Chief Commercial Officer, Kylie O'Keefe; and our Chief Financial Officer, Pierre Gravier. Today's call will include forward-looking statements based on our current expectations. Please take a moment to review the slides 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 risks that can materially and adversely affect our business and results of operations. 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, 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 are available in today's earnings release. With that, let me pass the call over to our CEO, Matthew Klein. Matt? Thank you, Ron. Good afternoon, and thank you for joining the call. I'm pleased to share PTC's second quarter results and our expectations for continued strong performance in 2023. First, I would like to extend a warm welcome to our new CFO, Pierre Gravier. I've had the pleasure of working with Pierre over several years, and I am confident his extensive experience in finance strategy and healthcare advisory will be incredibly helpful as we continue to build the PTC of tomorrow. Now let me begin with our second quarter revenue. We achieved another quarter of strong revenue growth, with total revenue of $214 million. This represents 29% growth over the second quarter of 2022. Our DMD franchise revenue in the quarter totaled $162 million, a 21% increase over the second quarter of 2022. This robust second quarter performance puts us in a strong position to achieve our 2023 total revenue guidance of $940 million-$1 billion, which would represent 34%-42% year-over-year growth. To our team's continued strong commercial performance, Evrysdi is now approved in 100 countries, with more than 8,500 patients treated globally. Continued growth is expected as access is achieved in countries where Evrysdi is approved. Based on the recent positive opinion from the CHMP, the Evrysdi EU marketing authorization will now include pre-symptomatic infants, providing another important source of potential revenue growth. As we shared in May, we initiated a strategic portfolio review and associated OpEx reduction. With our previously announced decision to discontinue our preclinical gene therapy programs and other prioritization decisions, we now anticipate non-GAAP, R&D, and SG&A expense for the full year 2023 of between $810 million and $860 million, versus our previous guidance of between $890 million and $940 million. In addition to the expected impact of our May portfolio decisions on 2023 OpEx, we anticipate annualized savings of approximately $150 million in 2024. Moving to our pipeline, Q2 was very busy as we reported results from several clinical studies, including strong data sets from our AFFINITY and PIVOT-HD studies. Let me start with our AFFINITY trial of sepiaterin in PKU patients. In May, we announced that we met the study primary endpoint of blood phenylalanine reduction, with highly statistically significant and clinically meaningful results. Sepiaterin demonstrated substantial fee reduction from baseline of 63% in the overall primary analysis population and 69% in the subset of classical PKU patients. In addition, the vast majority of patients were able to reach target fee levels in line with U.S. guidelines of less than 360 micromole per liter. With these strong data in hand, we requested a pre-NDA meeting with FDA, which has been granted and is scheduled for the third quarter. Pending FDA feedback, we expect to submit an NDA in the fourth quarter of this year. Given the strength of the AFFINITY data, we remain incredibly enthusiastic about the potential billion-dollar-plus global commercial opportunity for sepiaterin. In addition, as Professor Anja Muntau emphasized in our recent PKU commercial deep dive presentation, the physician community is excited about the potential for sepiaterin to fill the persistent, large, unmet medical need for PKU patients worldwide. Moving to PTC-518 for Huntington's disease patients, in June, we reported interim 12-week data from the PIVOT-HD trial. To summarize, all key objectives of this interim data analysis were met. PTC-518 treatment resulted in dose-dependent lowering of blood cell huntingtin protein, with mean lowering of huntingtin protein levels of 30% in the 10 milligram dose cohort. Treatment resulted in the targeted levels of CNS exposure, with a ratio of CSF to plasma exposure of 1.5 to 1 at the 10 milligram dose level. This suggests that greater lowering of HTT protein, possibly up to 45%, could be occurring in brain cells. Importantly, PTC-518 is well-tolerated, with no treatment-related SAEs, no reports of peripheral neuropathy, and no treatment-related CSF NfL spikes, with an overall trend towards lower NfL levels in PTC-518 treatment groups. With these encouraging interim data, we will continue to enroll stage two and early stage three patients into the PIVOT-HD study. Of course, we look forward to the 12-month results of the initial treated subjects, at which time we can learn more about the longer-term effects of PTC-518 treatment on key disease biomarkers. These HD data, along with the continued global success of Erysi, further support the power of our splicing platform. Moving to vatiquinone, we reported results from the MOVE-FA trial in pediatric and adult Friedreich ataxia patients in May. While the trial did not meet its primary endpoint, the results of the MOVE-FA trial did demonstrate evidence of meaningful clinical benefit on key aspects of Friedreich ataxia, including in pediatric patients for whom there remains a large unmet medical need. In particular, the data demonstrating vatiquinone's treatment benefit on the upright stability section of the mFARS scale support a potential long-term benefit in slowing time to loss of ambulation. Given these results, the well-established safety profile of betiquanone in pediatric patients and the remaining unmet medical need for pediatric FA patients, we plan to share these results with the FDA to determine if there is a potential path to approval. We requested and were granted a Type C meeting with the FDA, which is scheduled for the fourth quarter of 2023. We expect a number of additional regulatory activities in the second half of 2023. Beginning with Translarna, we expect the CHMP opinion for the type two variation to convert the European conditional marketing authorization to standard authorization in the third quarter. In the U.S., we plan to submit a Type C meeting request this month to the FDA to discuss the totality of data collected to date that could support an NDA resubmission for Translarna. For Upstaza, as we previously shared, we are awaiting feedback from the FDA on additional bioanalytical data we submitted in support of comparability analyses between the clinical and commercial drug product. Based on the timing of this feedback, we expect to submit the Upstaza BLA in the third quarter. Overall, I am incredibly proud of our continued successful execution across both our commercial and R&D teams. Our commercial performance in the first half of 2023 positions us well to meet our revenue guidance of $940 million-$1 billion. The strong data sets from AFFINITY and PIVOT-HD position us well for continued future growth. I will now hand the call over to Eric and Kylie to provide an update on our commercial accomplishments. Eric? Thanks, Matt. It is exciting to see the progress of our pipeline and the future opportunities of new product launches, and our customer-facing team is eager to bring these much-needed treatments to patients around the world. We are extremely proud of the accomplishments of our global customer-facing team, which has delivered another strong quarter in revenue. The team continues to accelerate the significant momentum built in the first quarter and is focused on executing on the growth strategy of our commercial portfolio of products. Our global DMD franchise continues to be robust, and our strategy of geographic expansion continues to progress in Latin America, Middle East and Northern Africa, and CIS regions, while we continue to build out the future foundation and growth of markets in Asia Pacific. Now, let me turn to the DMD franchise. Translarna and Emflaza continue to be an important growth drivers, delivering an impressive $162 million in net revenue for the second quarter, which is up 21% compared to the second quarter of 2022. With a strong first half for our DMD franchise, we are updating our 2023 DMD franchise revenue guidance from $545 million-$565 million to $545 million-$575 million. For Translarna, we achieved $96 million in revenue this quarter, which is a remarkable 25% growth over the same quarter in 2022. Growth occurred across all major regions, we continue to see growth from new patient starts being added in new growth markets. As mentioned previously, due to the unpredictability of large government orders in some of our regional markets, particularly in Latin America, Central and Eastern Europe, the Middle East, and CIS regions, we expect to see ongoing lumpiness in quarterly revenue throughout the year. Turning to Emflaza. The fundamentals of the Emflaza business continue to be solid. Quarterly net revenue was $66 million, which is 16% growth over the same quarter in 2022. We continue to see strong trends in the number of new patient start forms in the second quarter, which will provide important momentum as we progress through the year, along with continued high compliance, appropriate weight-based dosing, and a continued focus on broad access. ... I'll ask Kylie to update the progress on our current and future new product launches. Kylie? Thanks, Eric. Let me begin with Upstasa, the first and only approved gene therapy infused directly into the brain. We continue our steady rollout across Europe, including treating our first patient in Italy in the second quarter. We continue to see transformative results for the patients that we have treated thus far, which we shared at the recent European Pediatric Neurology Society, the EPNS Conference in Prague. New treatment centers of excellence are being opened internationally to support the treatment of patients as we continue the European rollout. We also continue to leverage early access programs and cross-border treatment opportunities, and expect to treat more patients both in Europe and other international markets throughout the second half of 2023. Moving to Tegsedi and Waylivra in Latin America, we continue to establish Tegsedi as the treatment of choice based on its strong clinical profile and improved quality of life for hereditary ATTR polyneuropathy patients. In Brazil, we completed delivery of the remainder of our second group purchase order from the Ministry of Health. We continue to see robust growth in patient identification, as well as positive patient responses on treatment across the Latin American region. We are extremely excited about the sepiapterin opportunity, as discussed recently at the PKU deep dive presentation. With a substantial unmet need and strong differentiation from both the mechanism of action and the affinity results, the customer-facing teams are looking forward to bringing this differentiated therapy to physicians and PKU patients upon approval. As we discussed at the call, we were able to leverage our strong global commercial infrastructure, and we have now established our internal global launch team. This team is actively working to prioritize the global launch beacons and key pre-launch activities, with the first step of bringing sepiapterin to the U.S. market, followed closely by Europe, Japan, and other key international markets. With physician excitement, as outlined by Dr. Muntau, and PTC's proven track record in commercializing rare diseases, the team is poised to achieve the market opportunity of over $1 billion. In conclusion, our second quarter rounds out an excellent first half of 2023 for the commercial team. With significant progress across all our commercial products and across all geographies, we are well set to achieve our ambitious 2023 revenue guidance. Let me turn the call over to Pierre for a financial update. Pierre? Thanks, Kylie. I want to begin by saying how thrilled I am to join the PTC team as CFO. I have known the PTC team as an advisor for several years, and it's a privilege to be working with such a patient-focused company and bring my skills to continue to build the PTC of tomorrow. It is my pleasure to provide you with the financial highlights of our second quarter 2023. Please refer to the second quarter earnings press release issued this afternoon for additional details. Beginning with top-line results, total revenue for the second quarter was $214 million. This consisted of DMD franchise revenue of $162 million and other revenue of $52 million. Starting with the DMD franchise, Translana net product revenue in the quarter was $96 million, reflecting growth of 25% over the second quarter of 2022, driven by strong performance across all geographies. Emflaza, a net product revenue of $66 million, representing 16% growth in the quarter compared to the second quarter of 2022. Moving to EverySD. Second quarter global revenue of 342 million Swiss francs, which equates to about $380 million, was achieved, earning royalty revenue of $37 million for PTC. As Matt mentioned, the second quarter performance puts us in a strong position to achieve 2023 total revenue guidance of $940 million-$1 billion, including an expected $100 million milestone when EverySD surpasses $1.5 billion in annual revenue. Non-GAAP R&D expenses were $117 million for the second quarter of 2023, excluding $16 million in non-cash stock-based compensation expense, compared to $143 million for the second quarter of 2022, excluding $14 million in non-cash stock-based comp expense. The year-over-year increase in R&D expenses reflects additional investments in advancement of the clinical pipeline. Non-GAAP SG&A expenses were $75 million for the second quarter of 2023, excluding $14 million in non-cash stock-based compensation expense, compared to $66 million for the second quarter of 2022, excluding $14 million in non-cash stock-based compensation expense. As Matt noted earlier, we now anticipate non-GAAP R&D and SG&A expense for the full year 2023 of between $810 million and $860 million. Cash, cash equivalents and marketable securities total approximately $338 million as of June 30, 2023, compared to $411 million as of December 31st, 2022. Cash increased by $52 million from the end of the first quarter, mainly due to the addition of $50 million from restricted cash as a result of the positive sepiapterin data readout based on the Blackstone agreement. I will now turn the call over to the operator for Q&A. Operator? Thank you. One moment, please. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. One moment for our first question. Our first question comes from Kelly Shi from Jefferies. Your line is now open. Thank you for taking my questions and congrats on the great quarter. My first question is, regarding the Translarna sales in Q1, you mentioned the sales benefited from large government order in Europe. Can you comment? How did government order impact Q2, and how should we anticipate for the future Q3, Q4 sales? Thank you. Kelly, thank you very much for the question. Obviously, it was another strong quarter of Translarna revenue. I'll let Eric provide me some more details on the differences between Q1 and Q2. Yeah, thanks for the question, Kelly. First of all, we're really pleased with the quarter. I mean, we've generated $162 million of DMD franchise. That's 21% growth year-over-year compared to last year. I think as, as you've seen in the past years, we've actually invested in geographic expansion. It's been very consistent that we know that lumpiness will occur quarter-to-quarter, and it's really nothing new at this point in time. Since we've expanded in many of these regions, large government orders, particularly in Latin America, Central and Eastern Europe, in the Middle East and our CIS regions, as we've seen consistently, those orders and the size of the orders and the timing is relatively unpredictable. However, unlike Western Europe, and the U.S., which tend to be more predictable from week to week and month to month, I would say that the fundamentals are still the same, and we've received large orders, and the timing of those orders will continue. Our base business in even those markets continue to grow. New patient starts, high levels of compliance, dose adjustments, and very low discontinuation rates have occurred. The fundamentals for both the new markets as well as our mature markets are really solid and in place. We anticipate orders in the second half of the year, and we've raised, if you will, the upper end of the guidance at this point in time to reflect that. The timing and the size of those orders will likely be more defined in the third quarter. As we get closer and closer to the third quarter, we'll be able to, if you will, adjust and confidently achieve that level of guidance. Just stay tuned, Kelly, for an update around the Q3 as we provide a little bit more color and we'll have more visibility on the timing of, of group purchase orders in the second half. Right now, we feel very confident, and we have very good tailwinds in the DMD franchise remaining throughout the year. Thank you very much. I also have two quick follow-ups. First, can you guide out any trigger for PTC to start reporting Upstaza's quarterly revenue? It's for Kylie. Do you wanna talk that? See if you can. Absolutely. Thanks, Kelly. As we've spoken about, while we did provide guidance, last year, I think the intent with providing that guidance was to ensure that we clearly indicated that we expected to treat patients very rapidly into the launch. We weren't expecting a delay from launch to treatment of those patients. As we've said previously, it's very difficult to understand the true forecast in the first 12 months of launch. As we move through that period and we garner a much clearer understanding on how we're seeing patient throughput, pricing and reimbursement, particularly in Europe, being a country-by-country process, getting more clarity into that and a number of registrations ex-US, we'll be able to provide more, more granularity and more clarity. Hopefully that answers the question. Yes, thank you. One last one, if I may. Regarding the Type C meeting with FDA and, and vatiquinone's filing, just curious, what kind of a strategy you could share, like whether you have done some group analysis and also and a focus on, like, improved efficacy, maybe on some genetic marker and also certain group of patients? Thank you. Yes. Kelly, thanks for the question. Can you clarify the Type C meeting for for which indication? FA, yes. As we said, we requested that Type C meeting from the FDA, and it was granted, and that'll take place in the fourth quarter. As we talked about, while we didn't hit the primary endpoint, we had very strong data on a number of important aspects of the disease, in particular, the upright stability subscale. When you think about Friedreich ataxia as a disease and drug development in Friedreich ataxia, one of the main goals of any therapy would be to slow the time for patients to lose ambulation. That is one of the key, if not the key, morbid transition point of the disease, and every drug that targets altering or aggressing the disease seeks to try to slow that time of loss of ambulation. The upright stability subscale of the mFARS has been shown to be a key predictor of time to loss of ambulation. The fact that, 1, we had pre-specified that particular subscale and as an endpoint, and 2, the fact that it is a component of the primary endpoint, and we showed strong signal of effect with a difference of about 1.3 points between treatment and placebo. We've done some work to show that that should translate to a delay in loss of ambulation of at least 8 months, and perhaps more with some other analyses that we've been able to do. We're able to come to FDA and be able to talk about the potential path to an accelerated approval, where we've been able to demonstrate on an intermediate clinical endpoint, upright stability, that we're able to delay, likely delay, a longer-term, significant morbid transition point of the disease, loss of ambulation. The fact that we showed statistical significance and a strong magnitude of effect, we, we can demonstrate that we are able to likely provide a long-term clinical benefit with regard to really the key goal of that phase therapy, which is delaying loss of ambulation. We look forward to having that discussion with the agency. Obviously, with the Skyclarys' approval that's directed towards adult patients. We have a, a study that was included primarily pediatric patients, a very strong safety record of particularly on the pediatric patients. Again, now a data set that has many positive aspects, but in particular, very strong data with regard to ability to slow the loss of ambulation, which is really the key goal of that phase then. Very helpful. Thank you. Anne, thank you. One moment for our next question. Our next question comes from Sami Corwin from William Blair. Your line is now open. Hi, guys. Thanks for taking my questions. I guess first, do you have any clarity as to why the CHMP opinion for Translarna got pushed? I thought that was originally supposed to happen in May. Is there any contingency plan there if it doesn't get approved? I have a follow-up question. Hi, Sami. Thanks for the question. Actually, the initial timing was end of H1. That timeline was put together based on how we thought that the typical back and forth at 1 sees during the CHMP process, such as a type 2 variation. Obviously, there was 1 more term of questions back and forth, and that pushed the H1 into the 3rd quarter. We remain highly confident of our ability to achieve the conversion from traditional marketing authorization to standard marketing authorization, knowing that really the bar here is being able to, as the European statutes state, confirm the benefit that existed at the time of registration, which of course, was in 2014, based on our 1st placebo-controlled study, study 7. Now we have a data set in over 700 boys that not only confirms that benefit but actually expands it with our ability to have shown study 41, a statistically significant benefit on the all-comer ITP population, which is the indicated population, as well as showing significance on a number of different endpoints, including North Star, ambulatory assessment and a time function test. This is really a body of data that not only confirms the evidence, which is the charge, but builds on it. Great, thanks. Then, given you have about $330 million in cash, how are you guys kind of thinking about capital deployment in terms of, either focusing on your commercial franchises and products and, that will be going through regulatory submissions in the near term versus your earlier stage research pipeline? Yeah, I think as we've talked about, Sammy, we are well capitalized to take us to the next, take us through this year and get us to the PKU launch. We've talked a lot about having the infrastructure in place to launch, PKU and other products. We also have a robust discovery and development infrastructure, all the pieces are there, and so we're well-positioned and well-capitalized to move forward the programs and prepare for the launches that we expect to occur in the next 1 to 2 years. Great. Thank you. Anne, thank you. One moment for our next question. Our next question comes from Kristen Kluska from Cantor Fitzgerald. Your line is now open. Hi, everyone. Thanks for taking my questions and welcome, Pierre. First, just wanted to ask what the main questions will be at PKU pre-NDA meeting and essentially what feedback you're looking for here? Sure, Kristen, thanks for the question. Obviously, pre-NDA meeting is often focused around the structure of the NDA, how the components are put together, how we do integrated safety analyses, integrated efficacy analyses, and then going through the checklist of are we in line with in terms of what's needed from a clinical standpoint, efficacy standpoint, safety database, non-tax package, CMC package. It's a fairly standard approach to the pre-NDA meeting. Obviously, we are quite gratified to have the meeting granted, and our expectation is that we'll be able to align with the agency and move forward with the submission in the fourth quarter. Okay, thanks for that. You know, we've often talked to you about the synergies with the splicing platform, especially now that you're progressing along with Huntington's disease. Maybe just kind of wanted to ask the question from the sense of how much overlap you think there is with the neurologist community, and in particular, the adult community, with the experience with Evrysdi, given the launch has been pretty substantial here. Then if you have any initial feedback that you've heard from some leaders in this space based off your early data? ... Yeah, absolutely. I can, I can give a little bit of color, and then I'll turn it over to Kylie for a bit more detail on this. Obviously, SMA, just in general, is, is both pediatric and adult, but, and Huntington is obviously going to be mostly adult till we're able to initiate and complete our work in juveniles. I would say there is broad recognition in the scientific physician as well as the patient communities, importantly, about the power of the splicing platform. Obviously, we've talked a lot about Evrysdi being able to provide us with a blueprint of how to successfully discover, optimize, develop an oral compound for oral splicing compound for a whole brain disease such as SMA and now with Huntington's disease. I would say in many ways, the Evrysdi experience has also, you know, set a path for us as well as we think about getting this out and doing clinical trials in both the patient and physician communities because of their recognition of the power of the splicing platform, the ability to deliver an effective oral small molecule that is not only safe, but be able to deliver meaningful results. Kylie, I don't know if you want to provide any more color on how we're thinking about and working with the, the physicians? Yeah, absolutely. I think what I would add, Kristen, in addition to what Matt said, I think one of the things that we do as a commercial team, which we take very seriously, is making sure we take learnings across all aspects of our business, as well as making sure where there are overlaps between physician specialties and physician target call points, that we're sharing that amongst our different teams. If we look at Huntington's disease, specifically, as Matt said, obviously, it's more adult. One of the things that is consistent is the movement disorder subspecialty within neurology has overlaps between Upstaza and other parts of our business. We're making sure it's not a entirely overlap, but there are some components of overlap. In that case, we're making sure that where we're having consistent touch points, that we're sharing that across the different teams. Great. Thanks again. Thank you. One moment for our next question. Our next question comes from David Lebowitz from Citi. Your line is now open. Thank you very much for taking my question. When you think of the guidance, for Duchenne in for full year, the implication is that at the high end of the guidance, the revenues would actually decline by 27% in the second half. Are we to assume that guidance is just making the most conservative possible assumptions here, and that, the things could very well work out differently as the year progresses, or, or should we expect a decline in the second half? Yeah, thank you, David, very much for the question. Obviously, I had talked a bit about how, how much growth we've been able to achieve and the reasons for that growth in the Translarna franchise. I'll, I'll, talk a little bit about the dynamics in the second half and how we're thinking about, totaling the guidance. Yeah, I think, first of all, I think we continue to see growth. David, I think what we're trying to do is to, is to really modulate a lot of these group purchase orders in countries where we have established ordering patterns that are relatively inconsistent. While we're being a bit conservative in certain areas, the unpredictability of the timing and the size of the orders can certainly play. What we've seen fundamentally in all of these markets, particularly in the Latin American markets, where we continue to see orders and orders from new countries, as well as the Central and Eastern European markets and Middle Eastern markets, which in the last few years have started to sort of, you know, stabilize much in terms of their ordering patterns. There are still some unpredictabilities. Because the number of patients that we have, the large amount of patients in, in certain markets, such as Brazil, and Russia, and a number of other key areas, the, the, the timing and the size of these orders can have fluctuations between one quarter or the next. The fundamentals are still very strong, and I think we're very positive given the fact that we have seen quarter-on-quarter growth. I think we, as I mentioned, I think we have some very nice tailwinds. I think we're going to continue to, to see good growth, and we're very confident that we're going to be able to achieve, you know, the guidance that we've set out, or at least, exceed it. Got it. Thank you very much for that. Just jumping over to PKU, given the trial, the pivotal portion of the trial utilized a diet as, as a part of the protocol, and I know the OLE that you are adding fee into the diet. From a labeling perspective, can the OLE serve as a component to allow diet to not be a requirement for a patient, or will the labeling ultimately include on top of a diet? Hey, David, it's a good question. Obviously, we've talked a lot about all the different aspects of your question. Obviously, the importance of having a stable diet in the trial so that we don't confound the trial results. It's incredibly important that we have an understanding of the effects of sepiapterin relative to placebo in the context of stable diet. We also know, as you refer to, that being able to liberalize diet is really the holy grail for PKU patients. Their diet is highly restrictive and obviously takes an enormous impact on, on the patients and their families in many, many ways. Obviously, one of the key differentiating factors is the ability of sepiapterin to maintain... phenylalanine levels within control and still allow for the liberalization of the diet. We saw in the early Phe data, Phe tolerance data that we have presented thus far, both in this first set of readouts as well as in the PKU commercial deep dive a few weeks back, that we're seeing that signal of Phe tolerance in the face of Phe intake that exceeds RDA levels in many patients. As we're looking at the data that are continuing to come in through the open label extension, we're seeing that to continue to be the case as more and more patients are going through that protocol. We look forward to sharing those data at the SSIEM and at forums in the future. As to what the label will say, we're not sure. It is likely, since the protocol talked about stable diet, that that will be in there. Nonetheless, in all reality, in everyday life, patients will have possibly some component of diet control. Obviously, what they do in daily life and ability to liberalize their diet is going to be much more impactful and not in how it's not how the drug is necessarily prescribed, but just in what the perceived value is, the increased physician uptake and broad patient interest in finally being able to have an oral tolerable therapy that not only provides them control, but finally allows them to liberalize their diet, which is so very important to patients. Got it. Thank you so much for taking my questions. Thank you. One moment for our next question. Our next question comes from Eric Joseph from JP Morgan. Your line is now open. Hi, good afternoon. This is Hannah on for Eric. Thanks for taking the question. Just wondering when we might be able to see maybe a fuller update or presentation of data from the phase three MOVE-FA study. As you guys are considering and conducting additional analyses to take to the FDA, just wondering if there's a plan to present these to the street? Yeah, Hannah, thank you very much for the question. Obviously, we shared the key top-line data from the study, including the positive results in a number of the primary... a number of the secondary endpoints and the two important components of the mFARS, the Bulbar subscale, as well as the upright stability subscale. Obviously, we have done additional analyses, particularly around being able to quantify the likely long-term benefit expected with regards to loss of ambulation, based on the difference we were able to achieve in slowing progression on the upright stability scale. We're gonna continue to do some more work in that area, and we will look forward to showing those, sharing those, analyses, in the future, either as part of a publication or, or a presentation that would be available to the investor community. This may be a little bit more of a niche question, for the diet liberalization study for PKU, just wondering, from your conversations with physicians and patients, is there a specific amount or just% of increased Phe tolerance that patients might achieve that would be considered clinically meaningful to both physicians and patients? I think I would say, as we highlighted and Professor Muntau highlighted very nicely, in our deep dive a few weeks back, how burdensome the restricted Phe diet is for patients. Even slight increases in intake would be an incredible benefit, both, kind of gratifying for physicians, but obviously important for patients in their quality of life. Of course, in looking at our data, we're seeing that patients are able to get beyond the recommended daily allowance of protein that an unaffected individual would be able to have as part of their standard diet and still maintain control. I think that those are incredibly powerful data because that would far exceed what anyone would even hope for in a therapy. For us to be able to observe that, has been very encouraging to us, obviously something that the patients have gotten very excited about. As Dr. Muntau said herself, she and other physicians are very excited about what they've seen so far in those data. Okay, great. Thanks for taking the questions. Thank you. One moment for our next question. Our next question comes from Jeffrey Hung from Morgan Stanley. Your line is now open. Hi, this is Michael Ryskin on for Jeff Hung. Thank you for taking our questions and congrats on the quarter and the progress. If you have favorable U.S. regulatory outcomes in all your late-stage programs, presumably we'd see them launch in a close timeframe. How is the company thinking about preparations for multiple simultaneous launches, especially in the context of the annualized $150 million in OpEx savings in 2024? Would you launch them immediately if that was an option? Thanks so much. Yes, Michael, thanks so much for the, for the question. We would look forward to that opportunity. We have been building for that. We're well, set up for that. We're well-funded for that. I'll let Kylie provide a little bit more color, but let me just say the short answer is, we would welcome that activity and work as quickly as possible, as we always do, to get these important therapies to patients. Kylie, do you want to provide more, a little more color on this infrastructure? Yeah, absolutely. Thanks, Matt, and thanks, Michael, for the question. As Matt said, I think we'd definitely welcome that, that problem to have. As we've talked a lot about, we have a really strong commercial infrastructure in place globally, and this includes both capabilities and capacity to focus on neurology and metabolic. Obviously, the team is gearing up very quickly for a potential PKU launch. In addition to that, obviously, we don't start on day one of launch. The team has done a lot of work while trials are ongoing, to build relationships with KOLs, to build relationships with patient advocacy groups, to ensure that we understand the needs of the payers, to ensure that we understand what's necessary to be successful at launch. All of that takes place, you know, sometimes often up to two years prior to launch. We're in a good position to be ready upon successful regulatory discussions and, and positive movement towards NDA submissions, and it wouldn't require additional resources or infrastructure to be successful there. We have the footprint in more than 50 countries around the world, and we are definitely ready to go. I know I speak for many of, of the colleagues that we are excited for the opportunity to be able to bring a lot of these differentiated therapies to patients with high medical need in neurology and metabolic spaces. All right. Super. Thank you. That's really helpful. Maybe, last one, more of a housekeeping question. Could you comment a little bit on the royalty rate for Visme from Roche? It seems like it's been trending a little bit down in the last few quarters. Any comments here on what we should expect? Thanks so much. Sure, Kylie, do you want to fill that in? Absolutely. Yes. The royalty rates from Roche for Everisi are tiered between 8%-16%. That is on an annualized basis. Every year, they start at the beginning, which is the 8%, and they're tiered up to 16%. From that perspective, throughout the year, they progress through the different tiers, where up towards, as we've seen with CHF 701 million of sales in the first half of the year, we're, we're tiering up towards the second and almost near the third tier of royalty rates. I wouldn't say that they're going down. If anything, they go up, but that's on an annualized basis. Thank you. Thanks for the clarification. Thanks so much. Thank you. One moment for our next question. For our next question, we have Brian Abrahams from RBC Capital Markets. Your line is now open. Hi, this is Gena for Brian. Thank you for taking our question. Just going back to Translarna, can you talk about some of the potential outcomes of this CHMP opinion? Is there a possibility that Translarna can remain on the market with conditional authorization with the annual renewal? And I have a follow-up. Yeah, Gena, thanks for the question. Obviously, the Type 2 variation that we're submitting is to convert the conditional authorization to standard authorization. As we've talked about, we're confident in the ability to do that, given the strength of the data and our ability to meet the requirement of confirming and as I answered earlier, building on the data that already existed at the time of registration. Obviously, if the CHMP were to decide that they want us to continue to collect data, whether that's as part of the longer-term open label section of study 41, which was included the 72-week placebo control portion and the 72-week open label portion. Obviously, the analyses we presented and the analyses that form the basis of the conversion request are on the placebo control portion. That's a possibility. Could the CHMP say, you know, STRIDE's really great, and for the first time provides direct measurements of the long-term benefits of a therapy for DMD, and also is able to capture the fact that we're having an impact on the two key morbid transition points of the disease, loss of ambulation, loss of pulmonary function. They say we want more real-world data to convert. That's totally possible. There absolutely is that possibility that they say continue with the conditional authorization for now, which of course would mean business as usual for Translarna. Got it. Thank you. That was very helpful. Also to touch on the U.S. pathway. I guess if I'm not mistaken, Type C meeting has been requested this month. Is there a typical response time from the FDA to get back to you once the meeting has been requested? And also, how much additional back and forth can you expect to have before the meeting is scheduled? Thank you. Yeah, thanks, Joe. We had said that so that, that meeting request came based on a recent discussion with the division, with the neuro division, where we talked about the potential pathways to a NDA resubmission in the U.S., particularly now, given the volume of data we have, not only from the 3 placebo-controlled studies, Study 7, Study 20, Study 41, but importantly, those slide data that I recently mentioned, which provide very strong evidence that the benefits that we're recording over the course of the time of the clinical trials are translating to long-term, meaningful benefit in the most significant ways possible, by slowing time, the loss of ambulation, loss of pulmonary function. The agency said, "Well, why don't we get all of our data together, including some of the mechanistic data that we generated over the years, any analysis we want, request a Type C meeting, and we'll have a discussion about how we can put together an NDA package that would be suitable for resubmission." As mentioned, we have not yet submitted that request. We will be submitting that request in August. They typically respond within a couple of weeks to let us know if the meeting is granted or not, and typically the timeline for Type C meetings following meeting requests to meeting date is roughly 75 days. Got it. Thank you for the, the clarity. Thank you. One moment for our next question. Our next question comes from Colin Bristow, from UBS. Your line is now open. Hi, this is Yihan Li calling. Congrats on the quarter, and thanks for taking our question. I guess our question is on the PTC 518 HD program. In terms of the U.S. partial clinical hold, just wondering if you have already submitted the Part A data as well as the additional safety data to FDA yet, if there's any feedback or further requirement from FDA to potentially lift the hold? Also the second part on the same program. For the dose escalation, based on your data, it seems like the 10 milligram will be very likely to reach your targeted, you know, HTT reduction goal of like 30%-50% in brain. You previously noted you need some more data at low doses to put to further determine for the dosing escalation. Just wondering, could you please let us know what kind of data set you might need to see to make this decision? Will this potential dosing escalation be included in your conversation with FDA for the clinical hold lifting? When will we expect to see the data, like, the next data update? Thank you so much. Thank you very much for the questions, yeah. I'll start with the first question regarding FDA and the partial clinical hold in the US. Obviously, we were very pleased to see that the data that we presented at in June on the first cohort of patients coming through the first part of PIVOT-HD, demonstrated the drug was safe and very well tolerated. No serious adverse events, no evidence of peripheral neuropathy, no NFL spikes that have been observed in other therapies. Overall, as strong as a safety record as we could have hoped for. Obviously, we're continuing to monitor safety. We also mentioned that we have an independent DSMB that continues to meet and continues to support continuation of the study as it is, and also indicated, based on looking at the 5 milligram and 10 milligram data as part of that interim cut, that they would support, if we would decide to do so, escalating to a 20 milligram dose. We have submitted to the agency the safety data, and our argumentation and support, of reopening, the study in the U.S. That process is still ongoing and obviously we'll provide an update, at the appropriate time. Regarding your second question, on the dosing. You're correct. We were, as we shared, we believe the 10 milligram dose, both based on what we observed in terms of blood reduction in mutant huntingtin protein of approximately 30%, as well as again, seeing higher exposures in the CNS to the blood with the ratio of CSF to plasma of 1.5 to 1, gives us every reason to believe that we're within that targeted range of 30%-50% lowering within brain cells. So what we said we would do, since we believe we are in the range, is continue to collect data on the 5 milligram and 10 milligram dose cohort. Importantly, some of those biomarker data over the second part of PIVOT-HD that we will present with the 12-month data cut, later, once available. That will confirm if we are at the dose level we want. Then we'll probably use that time point to inform any additional decisions regarding going to that higher dose level of 20 milligrams. Of course, it's important to note that we're in incredibly favorable position with an oral molecule that we can titrate, and to be able to have peripheral biomarkers, such as blood huntingtin protein, that can provide important information regarding target engagement and pharmacodynamic effect, is an incredibly important factor in being able to steer this clinical development program forward and taking us to a right dose level that's not only safe, but could provide important benefit potentially to patients. As for now, we're continuing with the 5 and 10. We will expect to have that next data update, the biomarker 12-month data update, approximately nine months from when we had the, the three-month data update. Again, in terms of that decision, it'll be based on what the data look like. As I mentioned, the DSMB has already provided us their okay and support to go to that higher dose if and when we decide we need to. That's very helpful. just... Sorry, just one quick clarification. will, like, will you provide, for example, additional topline data from stage 2 or early stage 3 patients in terms of the program? Or the next update will just be the 9-month data. Thank you. Yeah. Good question. We have a few more data, data updates to go, right? Obviously, those first patients that we presented, the Part A, data on, or that first 3, 3-month data on in June, we'll expect in approximately 9 months from then to have the 12-month data, right? Then obviously, we'll be able to provide the 3-month data update on the additional stage 2 and the early stage 3 patients when those are available. We haven't given that time yet, and we'll provide the timing for that once we have more clarity on the, on the precise date. Got it. Very helpful. Thank you so much. Thank you. One moment for our next question. Our next question comes from Joseph Thome from TD Cowen. Your line is now open. Hi there. Good afternoon. Thank you for taking my questions. Maybe one on Upstaza. Seems like companies are having various ability to treat patients after the approval of the gene therapy in the U.S. and various levels of success here. I guess, is there anything that you can do during the hopeful FDA review process to kind of prime payers to be ready to reimburse Upstaza upon a potential U.S. approval, which I expect will come, you know, sometimes in the back half of next year? Maybe second, we are gonna know what the pipeline looks like by the end of this year, based on the regulatory feedback you get the next couple of months. Like, I believe in your previous deal with Blackstone, there was, like, $500 million earmarked for BD, I guess. Are you ever contemplating using that at all, depending on what comes over the next few months? Thank you. Yeah, sure. Joe, thank you very much for the questions. The first question on Upstaza, I'll let Kyle give some detail on how we're setting the, the U.S. market in terms of payers. I, I will add that we're obviously incredibly gratified to see as we continue treatments in Europe, as well as the treatments that we did as part of the Calyma study that included sites in the U.S., we're, we're continuing to see, you know, very strong data, again, substantiating the fact that this is a, a transformative therapy. It's one of those therapies where we give it and we see the effects that what we hope for with the gene therapy, taking kids who have virtually no dopamine production, no motor function, and then providing an ability to make dopamine and seeing them be able to sit, crawl and walk, is incredibly gratifying. Of course, that in of itself does so much to preset the market and increase both patient and physician desire, desire to get that therapy. Kylie, do you want to talk a little about our preparations for U.S.? Yeah, absolutely, Joe. We are engaging with U.S. payers, and we do this well ahead of launch to understand what are the types of queries that they have and what are some of the roadblocks that might be put in front of us. We obviously, especially with AADC, need to do education around what is the disease, the high morbidity and mortality rates, the lack of standard of care or any disease-modifying therapies out there available, and obviously budget impact. All of that work happens ahead of ahead of approval, and the U.S. team has been actively engaged in that process to date. As Matt said, with a strong data package and transformative data, not just in the short term, but also endurability, which is one of the questions that a lot of payers have put in front of other companies with gene therapies. How well does your treatment perform, not only in the short term, but also in the long term? We feel very, very confident around the data package that we have for Upstaza, and the value proposition in totality has been very well received by U.S. payers, and there has been a high willingness to pay. Joe, on your second question regarding, you know, we'll learn a lot more about, about the portfolio in the coming months. Obviously, we've done a lot of work in our own strategic prioritization. Obviously, the decisions to discontinue the preclinical gene therapy programs as we move more, more towards a coherent strategy and focus, and obviously BD can be an important part of that. Pierre, do you want to add some more color on funding and BD opportunities? Absolutely. As Matt said, the team and the company is well aligned about our capital and our strategy to leverage our expertise and being opportunistic on BD. As it comes to Blackstone, we're very proud to have partnered with such a strong group with life science expertise, and we will always evaluate our funding options as it comes to be on our capital structure. Great. Thank you very much. Thank you. One moment for our next question. For our next question, we have Gena Wang from Barclays. Your line is now open. Hi, it's Tony on for Gena. Going back to the Huntington's program, could you just add some more color potentially on what kind of threshold you might be looking for in terms of CSF protein? I know you talked about 30%-50% range, but is there kind of a specific cutoff you would be specifically looking for? Yeah, Tony, thank you very much for the question. Obviously, there's been a lot of discussion about CSF Huntington protein, what it means, and how do we measure it and many things like that. Look, we're in a position where there's many important biomarkers of disease that we're measuring in the study. We're measuring CSF protein. We're also measuring NfL, which obviously has been shown in neurodegenerative disease to be a very important marker, obviously of safety, in terms of potential nerve injury, which I mentioned we've not seen any signs of thus far in the PIVOT-HD trial, but also efficacy. We can look to the first and accelerated approval as, as an indicator that there is broad interest, including from the regulatory authorities, to look at NfL as an important marker of efficacy in neurodegenerative disorders that are characterized by neuronal injury and neuronal loss. CSF huntingtin protein has, has been a bit less well characterized. What we do know is that in early stages of Huntington's disease, there's no detectable mutant huntingtin protein in the CSF. It's at levels that are so low that it's not detectable by the assays that, that anyone would use. However, over the course of time, as neurodegeneration progresses, there's a gradual increase in the levels of, of mutant huntingtin protein in the CSF. That tells us that it is, in a way, a marker of neurodegeneration. If that is true, and we believe it is, and that that CSF protein is likely coming from spilling from nerve cells, as they become injured and die during the course of the process, the ability to lower, CSF Huntington protein is an important marker that we are having a favorable effect on the brain cells, such that they're less injured and are spilling less Huntington protein into the CSF. All that is to say that that's what we understand about it. Quantifying what change is meaningful is a bit challenging. I don't think anyone has an exact number other than to say, obviously, if you have a marker of disease that is increasing over time as the disease worsens, if you could stabilize and ultimately lower that marker, that's obviously very good. I think the way we think about it is not in terms of any specific threshold, being able to look at our effects on the trajectory of CSF protein with a goal towards lowering. We did share on the 12 recall that we are observing lowering in the dose cohorts at very early points in time before we know that we're reaching a steady state in terms of what we'll ultimately be able to achieve in CSF protein lowering. We're also going to look at that alongside other important markers such as NFL, as well as the volumetric MRI, and that together, those will paint an important picture of the benefit that PTC518 will be able to provide for Huntington's disease patients. Got it. Very helpful. Thank you. Thank you. One moment for our next question. Our next question comes from Tazeen Ahmad from Bank of America. Your line is now open. Hi, what would a shift to a standard approval from, from the status that you're at now for EU practically change in terms of either commercial opportunity, reimbursement, or does that kind of not really matter in the grand scheme of things? As far as the cost savings that you mentioned, about an annualized number of about $115 million or so, to clarify upon what you might have said before, could there be room for additional cost savings beyond what you've just described, as we get closer to 2024 and you take a closer look at your portfolio? Thanks. Great. Thank you very much for the question, Tazeen. On the first question regarding the conversion from a regulatory standpoint, I think the impact is perhaps you don't have to go through a process every year of getting a renewal. More importantly, to the point of your question, the commercial impact, I'll let Kylie talk about that. Tazeen, in a, in answer to your question around the benefit, I think what the team has done is a remarkable job of securing very favorable pricing and market access with conditional approval, and not only being able to secure it, but maintain a really favorable pricing corridor over the years of maturation of the product, which is not easy to do. I think from a benefit perspective, we don't see a huge upside when it comes to the countries that we're already launched in with pricing and market access. There are some smaller countries that would open the door to a discussion post, conversion, but, I think where the true upside is, is the countries that we don't have registration in yet. Great. Then, Tazeen, regarding your second question in terms of potential further cost savings. Look, as, as we talked about at the time of the CEO transition, one of the things that we really wanted to focus on, particularly as we were reading out studies and with the positive PKU data that we ultimately had, we were in a position to start really focusing down and looking at opportunities to reducing our OpEx and reducing our costs. The team spent a lot of time in the spring looking into this. We obviously shared the reductions that we planned associated with the discontinuation of the preclinical gene therapy programs. Obviously, that involved reduction in headcount, and we made these decisions in late May, which obviously gave a bit of a limited time in 2023 to realize an impact in cost savings, which is why we shared that we expect those changes in 2023 to have a greater impact than an impact of approximately $150 million in cost savings in 2024. Of course, we also are going to be in a position where we're going to continually looking at the portfolio. We're looking at opportunities to ensure that we're advancing programs that have a reasonable return on investment, as well as seeking opportunities to save when that's not the case. Let's look at cost savings. We're, you know, we're looking at $940 million-$1 billion of revenue this year. We're incredibly excited about that. We expect as we move our other programs forward and looking forward to the potential launch of the PKU program, which we believe can be an over a $1 billion-dollar market opportunity. We're really in a position where we should be thinking about moving towards a breakeven point and ultimately one day in the future, of being profitable. To do that, we have to continue to be very thoughtful and strategic about our utilization of capital and how we think about OpEx, and we think about program spend. You're correct. This is going to be something that we continue to do over time as we build the company forward. Okay, thank you. Thank you. One moment for our next question. Our next question comes from Paul Choi from Goldman Sachs. Your line is now open. Thank you. Good afternoon, and congratulations on the quarter. My first question is on the commercial side with regard to Evrysdi, your, your partner, Roche, reported the first sequential decline in, you know, basically since the early days of the launch. I'm just wondering if you could maybe comment on, on market trends there, given that your, your, your guidance embeds a milestone for 2023. My second question is also on Huntington's, just with regard to enrollment progress, pending the discussion with the FDA and just how, you know, how you're factoring in the pace of enrollment, contingent upon clarifying the clinical hold there. Thank you. ... Thank you very much for your question, Paul. Let me, let me take the second one, first. In terms of enrollment, look, we've said all along that we were in a position to enroll this study outside the U.S. That's the, the benefit of having a, a global development organization that can run, get trials started and conduct trials in countries around the world. We're have the study up and running in a number of countries, in Europe as well as in Australia, as well as working to do so in Canada. There is a great deal of enthusiasm in all of these countries amongst the physicians and the patient groups to participate in this trial. Obviously, the interim data readout showing that the drug, to date, is shown to be safe, well tolerated, and is having the desired pharmacodynamic effect, has only heightened the interest in enrollment. We're obviously very aware of the desire of patients in the U.S. to participate in the study and physicians in the U.S. to participate in the study. I will say that we're gonna continue to enroll that study without doing anything to slow it down, knowing that if we're in the position to reopen the sites in the U.S., there will be opportunities for patients to participate. Regarding your second question, on Evrysdi, Kylie, did you want to take that? Yeah, absolutely. Thanks. I think one of the things, Paul, that we're seeing with Evrysdi is we're continuing to see the growth in total patients treated, and this is being driven by a number of different factors across the board. It's being driven by continued switches coming from both, Zolgensma and Spinraza, as well as continued therapy-naive patients being treated. In the U.S., you've also heard Roche talk about the infants starting to be an increasing patient segment that we're seeing for Evrysdi-treated patients, and with the recent CHMP opinion, we also expect this trend to continue ex-U.S. They've also talked about the fact that they are global market leaders, or sorry, they are market leaders in most major markets around the world, and expect to be global market leader by the end of 2023. I think one of the things that you do see with Evrysdi, which is consistent to what we see with Translarna and what Eric's touched on throughout this call, is lumpiness to the business, and that's directly related to the international business. Like us, they have large government-based purchase orders that fluctuate throughout the different quarters, and so it is expected that you will see that quarter-over-quarter lumpiness. I think we've seen growth from 2022 into Q1 of 2023, with a little bit of lumpiness in Q2, but we expect the growth to continue throughout the rest of the year. I think we're in a good position for the $100 million milestone that you touched on. If you look at sales through the first half of the year, we're past halfway, so that's a really positive sign. From that perspective, that's why we remain confident with the full revenue guidance for 2023, including that $100 million milestone. Just lumpiness that we see across our Translarna business as well. Okay, great. Thank you for the color. Thank you. I am showing no further questions. I would now like to turn the call back over to Dr. Matthew Klein for closing remarks. Thank you again for joining us on the call today. I'm extremely proud of our many achievements in the second quarter. We look forward to a busy and productive second half of 2023. Thank you all again for joining the call, and have a good evening. This concludes today's conference call. Thank you for participating. You may now disconnect.