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spk09: Today's conference is scheduled to begin shortly. Please continue to standby. Thank you for your patience. Thank you. Thank you. Thank you. Thank you. Thank you. Good day, and thank you for standing by. Welcome to the PTC Fourth Quarter and Full Year 2021 Financial Results 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 during the session, you'll need to press star, then 1 on your telephone keypad. Please be advised today's conference may be recorded. If you require operator assistance during the call, please press star, then 0. I'd now like to hand the conference over to your host today, Kylie O'Keefe, Senior Vice President of Global Commercial and Corporate Strategy. Please go ahead.
spk01: Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics fourth quarter and full year 2021 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 Powers, and our Chief Financial Officer, Emily Hill. Today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our investor 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 is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz. Stuart?
spk06: Thanks, Kylie. I'm excited to share with you today the significant progress in 2021. Over the last few decades, we have advanced innovative therapies from ideas and discovery to commercializing and distributing them to patients around the globe. These efforts have positioned us to continue to grow to an enduring, innovative biopharmaceutical company with substantial revenues. Our vision is to build our pipeline, such that at steady state, we can commercialize a new product every two to three years. This will allow us to continue to create value for all of our stakeholders. Executing on our strategy over the last few years has led us to having a robust pipeline with five registration-directed studies ongoing, and we anticipate results for many of them this year. Along with the growth of our pipeline, I'm pleased to report that the commercial engine has performed exceedingly well. We have reached $539 million in total revenue in 2021. The Duchenne muscular dystrophy franchise continued to grow, contributing $423 million in net product revenue. These products demonstrate robust growth years after approval, and we expect this growth to continue based on the treatment benefit, maintaining treatment compliance, and continuing with geographic expansion. Our goal is to bring TransLiner to nonsense mutation to shed muscular dystrophy boys globally, and we seek continued geographic opportunity in regions like Asia Pacific, Central and Eastern Europe, Middle East and North Africa, and Latin America. In addition, with the potential of successful results, of study 041 mid-year, we look forward to pursuing the registration path to bring Translarna to patients in the United States. We anticipate that the commercial team will execute flawlessly and will have a stellar year. Based on this, we're confident that we'll continue to have a strong and growing revenue base. And our revenue guidance for 2022 is between $700 and $750 million. with $475 to $495 million from the Duchenne muscular dystrophy franchise. In addition to the DMD franchise, Avrizny has shown remarkable growth in 2021, just over a year after launch. Avrizny is now approved in 72 countries, capturing over 20% of the SMA market in the United States and is now the number one prescribed disease-modifying drug therapy in SMA. We also see continued growth in ex-United States markets with approximately 30% market share in Germany. This rapid and sustained update demonstrates the appeal of an effective, orally bioavailable therapy. Tecseti and Ray Libra are now well positioned for successful commercial launches in 2022. Both therapies received Category 1 pricing in Brazil, and this Category 1 designation allows pricing in line with international markets. Eric will go into more detail on this later in the call. In addition to PTC's commercial success, we're excited about the progress across our robust pipeline. By the end of 2022, we expect to have initiated three additional registration-directed studies, and a potential approval in Europe for PTC-AAGC, our first gene therapy. As alluded to previously, we have a number of results expected in 2022, and we believe this will be a transformative year for PTC. Let me share a few highlights. From our BioE platform, results from our registration-directed MITEI-E trial are expected in the fourth quarter for vertiquinone and mitochondrial disease-associated seizures. From our metabolic platform, the registration-directed PTC923 affinity trial for PKU is expected to be completed by the end of this year. As a reminder, there is substantial alumni medical need remaining in PKU, and with newborn screening, well-defined centers of excellence, and a clear path to registration, We're extremely excited about this program. We're moving forward with the next compound from our splicing platform, PTC518, for the treatment of Huntington's disease. As a reminder, the Phase I Healthy Volunteer Study demonstrated that PTC518 reduced HTT, mRNA, and protein levels to the target level of 50% reduction. PTC518 was also measured in the CSF. demonstrated that it crosses the blood brain barrier and has no efflux. The phase two study of the PTC518 in Huntington's disease patients is initiating this quarter. We know that the Huntington's disease community is eager for progress. We made significant achievements in 2021, despite the ongoing COVID-19 pandemic. I'm proud of the continued hard work of our people who have shown true dedication to our goal of bringing therapies to patients. PTC has consistently delivered results across research, development, and commercial business, and we're well-positioned to continue to deliver both short and long-term value to our stakeholders. I'll now turn it over to Matt for more on our development program. Matt?
spk04: Thanks, Stu. We made tremendous progress across our broad development pipeline in 2021. and I'm happy to provide some key updates on the team's progress. I'll start with our BioE platform. Our first compound from the BioE platform is vatiquinone, which targets the enzyme 15-lipoxygenase, a key regulator of the inflammation and oxidative stress underpinning a number of CNS diseases. As Stu highlighted, we have two ongoing registration-directed trials with vatiquinone, the MITEI trial and the MOVE-FA trial. The MITEI trial is a placebo-controlled study of vitiquinone in patients with mitochondrial disease-associated seizures. This study will enroll approximately 60 patients from study sites in North America, Europe, Australia, and Asia. The study includes a 28-day observational phase to ensure subjects are having a minimum number of observable motor seizures, followed by a 24-week placebo-controlled phase during which subjects are randomized to receive either vitiquinone or or placebo. The primary endpoint of the trial is a reduction in observable motor seizures with secondary endpoints assessing different aspects of seizure pathology as well as overall disease morbidity. We expect results from this study in the fourth quarter of 2022. The second registration-directed trial of the tiquinone, MOVE-FA, is being conducted in patients with fadric ataxia. MOVE-FA is a randomized placebo-controlled 72-week trial, with the primary endpoint being change in the modified FARs disease rating scale, with the key secondary endpoint being improvement in activities of daily living, as assessed by the Friedreich Ataxia ABL scale. The trial is fully enrolled, and we expect results in the second quarter of 2023. The second compound from the BioWeek platform, PTC-857, also targets 15-lipoxygenase and is a potent inhibitor of ferreptosis, a recently described cell death pathway demonstrated to be key to neurodegenerative disease pathology. The first indication for PTC-857 is ALS. With the successful completion of the Phase 1 Healthy Volunteer Study, we are planning to initiate the Cardinals Phase 2 trial in the second quarter of this year. This global registration-directed trial is a 24-week placebo-controlled study with change in ALS-FRS scale as the primary endpoint. We will provide more details on the trial as we move closer to initiation. Turning now to our metabolic platform, we initiated the Affinity Phase III clinical trial for PTC923 in PKU patients in 2021 and are expecting trial results by the end of 2022. As a reminder, Affinity is a double-blind, placebo-controlled trial that includes a run-in phase to identify PTC923 responders who will then be randomized to receive either PTC923 or placebo for six weeks. The ability to identify and enroll only responders to PTC923 significantly enriches our primary analysis population. As with previous approved therapies for PKU, The primary endpoint of the affinity trial is a reduction of blood phenylalanine levels. Turning now to PTC518 from our splicing platform, we remain on schedule to initiate the Phase II PIVOT-HD study in patients with Huntington's disease this quarter. The PIVOT-HD study will consist of two parts, an initial 12-week placebo-controlled phase focused on PTC518 pharmacology and pharmacodynamic effect, followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect. The study will initially include two dose levels of PTC518, 5 milligrams and 10 milligrams. A third dosing group may be added based on initial pharmacology and biomarker data leveraging the titratability of PTC518. The primary objectives of the Phase II study are to demonstrate safety, pharmacology, and evidence of HTT mRNA and protein lowering in HD patients. In addition, we will collect CSF, plasma, and CNS radiographic biomarker data, which could provide meaningful evidence of PTC518 treatment effect. As we have previously discussed, we have carefully selected the study population based on extensive review of the existing HD natural history data to ensure that we have a population that is neither too early nor too advanced in terms of disease progression to allow for the best opportunity to demonstrate treatment effect. I am proud of our development team's efforts and accomplishments in 2021 and look forward to providing updates on the numerous milestones that we anticipate this year. I will now turn the call over to Eric for an update on our commercial progress. Eric? Thanks, Matt.
spk03: It is exciting to see the great progress of our late-stage clinical pipeline, and our global customer-facing team is well-poised to leverage our expertise and footprint to bring these treatments to patients. Our team has delivered another excellent quarter worldwide, building on the significant momentum created during the year and closing out what has been the strongest year for PTC commercial success. Our global DMV franchise continues to grow across existing main markets and via new geographic expansion. We delivered on key milestones for our products in Latin America, where we are actively commercializing a portfolio of three innovative rare disease products. And importantly, we are well positioned to execute on our potential launch of the PTC-AADC gene therapy in Europe and other international markets this year. Turning to our DMV franchise, our 2021 revenue for the franchise was $423 million. which is an impressive 28% growth over 2020. The foundation of the Implaza business continues to be solid. Our 2021 Implaza franchise sales was 187 million, an impressive 35% growth over 2020. Operational excellence drove new patient starts, more favorable access, continued high compliance, appropriate weight-based dosing, and lower treatment discontinuation. Now, turning to TransLarda, we achieved $236 million in 2021 net revenue, a remarkable 23% growth over 2020. The growth was due to ongoing expansion of the patient base, high compliance, as well as continued geographic expansion. While Russia was the key driver of the growth, We also continue to see growth in our main markets in Europe. In Brazil, we successfully secured a group purchase order for Tranquilana for both new and existing non-set mutation B and D patients, with the first part of that order delivered in December. Now, turning to Teixeira and White Libra. The Latin American team has delivered on significant milestones for both franchises throughout 2021. Following the reliever approval in the third quarter, we were excited to announce that we successfully received category one innovation classification from CMED, the Drug Market Regulation Chamber in Brazil. CMED price categorization is the first critical step in getting pricing and reimbursement in Brazil. Category one classification is given to innovative treatments that provide greater efficacy than current standards of care, and allows for pricing in line with international markets. Peg Steady also received Category 1 pricing in Q4 2021. Categorization of both products as innovative treatment are key milestones towards optimizing the long-term value in Latin America. Additionally, in December, we submitted an application to Anvisa for approval of WayLever in the treatment of FPL. If approved, Remebra will be the first approved treatment for FPL in Brazil, and this will mark the first globally approved product for this indication. This application has been submitted under the Rare Disease Pathway, and we anticipate a decision in the second half of 2022. I will now touch on the preparation for PCC's first gene therapy launch for PCC-AADC. I am very confident that our team is well prepared to execute on the potential launch of PTC-AADC, which we anticipate will occur in Europe shortly after final approval. PTC's efforts to accelerate patient screening and identification activities in enriched high-risk populations continues to progress well. Significant advancement has been made with the identification and preparation of expert pediatric neurological centers of excellence and advancing medical education throughout the European Union and other key markets to ensure treatment center readiness at the time of launch. We remain focused on identifying patients globally in markets where gene therapies are accessible and reimbursed. Now, let me turn the call over to Emily for a financial update. Emily?
spk10: Thanks, Eric. In 2021, we continue to see strong commercial growth and achievements across our pipeline. We have worked to position PTC to deliver on a number of planned value creating milestones in 2022. The press release issued earlier this afternoon summarizes the details of our fourth quarter and year end 2021 financial results. I will take a few minutes now to review those financial results and our 2022 guidance. Please refer to the press released for any additional details. Let me begin with our top line results. We reported $538.6 million in total revenue for the full year 2021 compared to $380.8 million for the full year 2020. Revenue growth was primarily driven by our global DMD franchise with total franchise revenue of $423 million as compared to $331 million in 2020. Translarna net product revenues were $236 million for the year, compared with $191.9 million for the full year 2020, for a year-over-year growth of 23%. For MFLASA, net product revenues were $187 million for 2021, compared to $139 million for the full year 2020. We recorded $109.7 million in collaboration and royalty revenue for the full year 2021, as compared to $47.4 million in the full year 2020. This increase was due to an increase in Evrizdy royalty revenue and three milestone payments. In 2021, we recognized royalty revenue of $54.6 million, compared to $4.8 million in 2020. We achieved milestones in 2021 of 20 million for the first commercial sale in the EU, 10 million for the first commercial sale in Japan, and a 25 million sales-based milestone for reaching 500 million in sales. Turning now to 2022, our total revenue guidance is 700 to 750 million, which includes expected revenue contributions from all of our approved commercial products and projected revenue sales of PTC-AAGC. Also included in our guidance is an anticipated sales-based milestone from Roche of $50 million, which would be reached upon $750 million in annualized sales of Evrisdy. There is the possibility of an additional $100 million milestone payment if sales of Evrisdy exceed $1.5 billion in 2022. However, this potential milestone is not included in our 2022 guidance and remains potential upside. As a reminder, PTC retains 100% of all milestone payments and 57% of royalties under our agreement with Royalty Pharma. 100% of the royalties from Everisdy will be retained by PTC once we reach the cap of $1.3 billion. Non-GAAP R&D expenses were $487.1 million for the full year 2021, excluding $53.6 million in non-cash stock-based compensation expense. compared to $438.9 million for the full year 2020, excluding $38.7 million in non-cash stock-based compensation expense. Non-GAAP SG&A expenses were $235.9 million for the full year 2021, excluding $49.9 million in non-cash stock-based compensation expense, compared to $213.6 million for the full year 2020, excluding $31.6 million in non-cash stock-based compensation expense. We anticipate non-GAAP R&D and SG&A expense for the full year 2020 to be between $800 and $850 million, excluding approximately $115 million in estimated non-cash stock-based compensation expense. Cash, cash equivalents, and marketable securities total $773.4 million as of December 31, 2021, compared to $1.1 billion as of December 31, 2020. I will now hand the call over to the operator to start our question and answer session. Operator?
spk09: As a reminder, if you'd like to ask a question at this time, please press the star, then the number one key on your touchtone telephone. To withdraw your question, press the pound key. Our first question comes from Alethea Young with Cantor.
spk13: Hey guys, thanks for taking my question and congrats on all the progress that you've made so far. It's exciting. Next 12 months. Maybe just like one and then maybe a little quick one throw in there. Can you just maybe frame for us? I know, you know, Germany may be the first market for ADC. Is there any more color you can give about like how many patients you kind of think might be there, how we should think about kind of contribution of Europe? And then the second part of that question is just in the United States, can you just give us a refresher on where you are exactly with, you know, kind of getting to the finish line and, have any kind of new other matters or concerns, you know, kind of popped up. Thank you.
spk06: Yeah, sure. Yeah, thanks, Alicia. Thanks for the questions. I think, yeah, so we've been working hard to identify patients, develop sites, centers of excellence, so that on approval we're ready to be moving forward. And I think, you know, as you've probably seen in some of the clips that we have, this is clearly a transformational drug. Maybe, Eric, why don't you talk a little bit about where we are in terms of getting ready for the launch, and then Matt could talk a little bit about the trial questions.
spk03: Yeah, absolutely, Alicia. We have been very excited with the progress that we've been making in terms of patient finding. We've expanded a lot of our activity screening programs in many of those countries in Europe. We do anticipate the first country to launch will be Germany. And of course, we'll have free pricing for a period of time, and we hope to treat as many ADC patients. But we will also be exploring early access programs that are currently available to these treatments. So clearly, there are a number of European countries and international markets that following the European approval, we will be able to begin to access and begin to discuss the value proposition. Our focus has really been to prepare sites of centers of excellence and patient identification, and the majority of our efforts have really paid off. We've been seeing new patients coming in quarter on quarter. The disease and educational programs that we have and the testing that we've been doing has been giving us much higher yields, particularly in those enriched populations. So the sequence will be a typical kind of European sequence with Germany, a number of key early access markets, and then international markets that follow following the first launch in Germany.
spk13: And then the U.S.?
spk04: Yeah, so I can take that question. So first just As you pointed out, we expect to be moving forward in Europe and expect an opinion now in April of 2022. There was some additional manufacturing biological data that the CHMP had asked for. We're in the process of collecting that data. We'll have that in by the end of this quarter and put us in a position for the opinion in April. We're in the process of getting ready to meet with the FDA to align on the submission package, and obviously we're going to avail ourselves of the new bioanalytical data we're generating in support of the MAA. And so we'll be including that along with the data we have from the cannula treatment cases. And with that, we plan to submit the BLA in the second quarter of this year.
spk13: Awesome. Thank you.
spk09: Our next question comes from Joseph Thome with Cowan.
spk15: Hi there. Thank you very much for taking our questions and congrats on the progress. Maybe just a couple more on AADC. In terms of the label itself, do you anticipate any sort of guidance on age group or patient size, either in the U.S. or a European label? And then when you talk about reimbursement, I know for what this may cost, others have used kind of pay-for-performance models. Are you debating various ways to get this reimbursed? Thanks. Great. Yeah.
spk06: So, Matt, you want to take the first one?
spk04: Yeah, absolutely. I think what's really impressive, Joe, about the package for ADC is the consistent demonstration of treatment effect across patients of all pediatric age groups, even into early adulthood. So what we really have is a body of data demonstrating not only an important biomarker response in the early months following treatment, but then significant improvement in motor function, achievement of motor milestones. We have children who are unable to move at all and can now walk. So it's really an impressive clinical package that has been demonstrated in patients of all different age groups. And part of that is because AEDC is not a neurodegenerative disorder. Rather, all of the networks and programs coordination that would be needed for motor function remain in place, what's missing is dopamine. And so with the provision of the gene therapy, the dopamine can now be produced and all of those coordinated movements and such can happen. And I bring that up because that's the reason why we wouldn't expect there to necessarily be a treatment effect difference based on age. While younger patients certainly do well, we're seeing impressive results in all different age groups. So at this point, really, the package includes that breadth of age And, you know, we can't comment whether there'd be any restrictions in age at this point. Again, we're putting forward a data package that's really strong in terms of treatment effect across all the ages that we treat.
spk06: And in terms of reimbursement, let me just say that, first of all, I think, you know, from a payer perspective, I'd say we have a really strong package where we have really five years of clinical data, five years of follow-up after that. We show all the patients actually responding. It's transformative where you see younger children being able to go from being floppy babies to walking. And then there's biomarker data demonstrating that dopamine is made continuously for long periods of time. So from a payer's perspective, I think The package is actually quite strong. It's obviously also an ultra-rare patient population. And so we expect that it will have really small budget impact with it. And if you look at another ultra-orphan product, such as the Orchard Gene Therapy for MLG, that was priced at $3.5 million, and that's about twice as big. as AADC. So I think, you know, we think the package is an incredibly strong, highly valuable product. So I think we're excited about this. And so, you know, on approval, we'll talk more about the pricing, but we think it's a highly valuable product.
spk15: Great. Thank you very much.
spk09: Our next question comes from Eric Joseph with J.P. Morgan.
spk16: Hi, good afternoon. Thanks for taking the questions. A few on Translarna from us. First, maybe Eric, can you kind of speak to the brand exposure to Russia and whether you see any impact in being able to access that market from sort of the rising geopolitical tensions with Ukraine? Is your top line guidance at risk at all on the lower end without Russia or sales in Russia? And then looking longer term, I guess, given all the experience and commercial exposure in D&D, what, if any, are the avenues to extend the market exclusivities in TransLana and in PlazaBio on their current terms? How should investors be thinking of any additional R&D or BD activity within D&D to backfill the franchise?
spk06: Thanks. Yeah, sure. So in terms of Obviously, it's unfortunate what's occurring in Europe between Russia and Ukraine. It's obviously a highly volatile situation, and we'll be closely watching the geopolitical tensions. As the situation unfolds, we'll plan accordingly on how to adjust the business, but We've always had puts and takes within our guidance, so as such, we're not changing the guidance as a consequence of that. We'll need to learn more, obviously, about what the sanctions and if they'll affect things like medical. So that's time only to tell someone about that. Then the second question was commercial exposure and how in terms of what we're doing with TechCity and Whaley World, the long run. Eric, do you want to?
spk16: No, it was more about, sorry, Steve, it was more about D&D IP runway, any strategies to extend it, and whether you're doing any additional investment. Okay.
spk03: Eric, do you want to talk a little bit about that? Yeah, sure. You know, And Eric, I would just say, just on the Russia situation, we're watching that closely, but we have a very important and dedicated team in Russia on the ground that will ensure the continuity of product. We have patients on Translarna, and as you know, they received Translarna already. So we're watching that very, very closely, and we don't think there's going to be an overall impact to the overall revenue guidance that Emily and Stuart provided. On the IP situation, We know that the IP, lots of exclusivity for Implaza will be in 2024, but we have a number of different programs that we're actually working on at this stage that look at various ways to capture the patient, hold the patient, because we've been providing exceptional service around Implaza. And we don't know at this point in time that there's going to be the kind of rapid erosion. We have a feeling that we're going to be able to maintain a number of these patients. And we have a number of key programs both in terms of model to distribution and patient capturing and retainment for EMPLASA. For TransLarna, we obviously have extended patent protection that goes beyond, well, into 2029 and potentially beyond. You know, our goal is to continue to innovate. And, of course, with the upcoming results, hopefully, of 041, we could also have a nice runway in the U.S., with Translarna potential approval and the FDA. And that would give us an additional amount of runway. So we have dedicated teams that are working on all aspects around the IP for both products. And I have to say that we're really doing a lot at the patient level to ensure that we're capturing and making that the best experience. I hope that answers your question.
spk16: It does, thanks. If I could sneak in one more. related to Evrizzi. As we're looking toward the potential label expansion for the pre-symptomatic population based on the Rainbow Fish Study, can you just maybe describe how you and Rose are thinking about the incremental market opportunity there and its competitive positioning? Are there any particular geographies that might be more receptive to Evrizzi over the Zolgensma or Spinraza in the pre-symptomatic patient population.
spk06: Yeah, I think, you know, as you alluded to, we recently announced some results from the Rainbow Fish study where we evaluated both the safety and efficacy of RISD in pre-symptomatic SMA babies from birth to six weeks of age. And we saw that overwhelming number, about 80% of the pre-symptomatic infants that were treated for at least 12 months achieved the motor milestones such as sitting, rolling, crawling, standing, and walking independently in the sense similarly to what normal healthy babies do. So it's really quite exciting. And that we put an SNDA in for that. so that these kids could get that. And I think, first of all, I think, you know, obviously in places in particular where they're doing, and Europe does a fair amount more of this in terms of identification of newborn screening and filing. You know, we think in those countries that would make it available. And so the trick here is, you know, really to be the first to be able to do that, and you'll be able to do I think one major advantage is that you can do in-home treatment for pre-symptomatic babies who have SMA. So I think we think that's a real major advantage, and that will be all over the world. We think this is something that people will want to take and could take not only during the early stage but throughout the life and its efficacy over the long term. as a major advantage as such.
spk16: Okay, great. Thanks for taking the questions.
spk09: Our next question comes from Raju Prasad with William Blair.
spk05: Thanks for taking the question. I just want to get your thoughts on some of the clinical holes that we've seen in some of the PKU programs and maybe, you know, how that impacts how you are looking at the commercial market, you know, kind of in the long term for 923 given kind of the gene therapy holdups?
spk06: Yeah, so I think that's, you know, obviously that's an interesting point you've seen where we've seen it in two different trials with two different viral vectors having issues as a consequence of in terms of the viral vectors that they both have been put on hold. And so that's, you know, with the gene therapy. And, you know, the exact consequences of that, you know, could be for large quantities of the enzyme that were produced. It's unknown, really. But, again, the advantage that we have is that it's an orally bioavailable molecule and that, you know, I think that's a real major advantage for us that you could take, that rather than taking orally, we know that you can do this without this sort of issue. So we think obviously, you know, that's a real advantage to us. If you think of it compared to what we're trying to do in terms of our gene therapy, so we think there's a real advantage in terms of our molecule, which we think, you know, has a real advantage there. But also when you think about it in terms of targeted gene therapy and the strategy that we've taken, which is it really goes directly to the tissue that we need to get the gene therapy to add and to do relatively low levels, I think is a major advantage for what we're doing in terms of gene therapy. And that's one of the reasons why we took this approach. We didn't want to have a systemic impact. use concentrations at the very beginning and be able to spend more time understanding and to be able really to go into low levels at first, move into gene therapy that way. So I think it's, you know, clearly in the PKU there's been no really proof of concept in PKU yet. So I think there's obviously a need for an oral therapy.
spk05: Great. And then on AADC, I know in previous quarters you've kind of talked about number of patients that have been identified. You know, at this point, do you have a sense of number of patients that have been identified in EMA territories versus the U.S. and kind of how you're looking at, I think someone else asked about kind of country by country, but how you're looking at the launch just given where you've identified patients so far. Thanks.
spk06: Yeah, no, I think, you know, I understand, you know, we've been obviously really been working hard in terms of identification. We said we've identified about 300 patients worldwide. We haven't broken it out. But I think we're in a pretty good position to be able to, on approval, be able to, you know, rapidly bring patients, you know, be able to perform this, get center of excellences up in terms of being able to do things So we think we're in a good position to keep going. And I think at the end of the day, we're making very good progress in terms of finding patients. And I think we'll continue to find patients in particular on approval and the fact, and even now we're seeing just a quicker uptake in terms of patient numbers as a consequence of people beginning to understand that there'll be a treatment for it. And we've seen this time and time again with ultra-orphan diseases, that as treatments begin to come on board, you find more and more patients, and there's more and more patients than you thought there would be as a consequence of that because there's now a treatment for these patients, and physicians begin to look at them carefully. So we think we're well-positioned to be able to do, you know, to be able to not only have identified a number of patients but get them treated for next year's of this year based on the approval. Thank you.
spk09: Our next question comes from Brian Abrahams with RBC Capital Markets.
spk12: Hey there. Thanks very much for taking my questions and congrats on all the progress. A couple of quick ones on PKU. For 923, I'm curious what the key parameters that you're going to be looking for in the affinity study, particularly the lead-in portion, to guide who's going to optimally respond to 923 and how it's going to be used in the real world. I'm curious if you envision this being used primarily in classical patients or some CUVA non-responders or perhaps more broadly in order to get more patients to be able to normalize their diet. And then my second question is also on 923. Can you remind us where you are on the chronic tox studies and maybe any similarities or differences to what preclinical signals have been observed with Kuvin at comparable doses? Thanks.
spk06: Sure. Matt, do you want to take that?
spk04: Yeah, sure. Hi, Brian. So your first question regarding the trial, you know, And just as a reminder, there was a Phase II trial done with PTC923 comparing it head-to-head with KUVAN, where we demonstrated it was a crossover study. So all subjects got treated with both 923 and KUVAN, and we were able to demonstrate that 50% more patients responded to PTC923 than to KUVAN. And when you looked at the subjects who had a response to both 923 and KUVAN, there was actually an over 200% greater micromole per liter reduction in phenylalanine in the 923 patients relative to CUVAN. So we're seeing that 923 is able to deliver benefit to more patients, including the classical PKU patients, and those with baseline levels of phenylalanine greater than or equal to 1,200 micromole per liter. And when there was a signal effect with CUVAN, 923 had a much stronger response. So that's what gives us a great deal of confidence that we can address the still need for an effective therapy in the PKB marketplace. As we move forward to the Phase 3 trial, we believe this 923 will be able to provide benefit for all patients of all ages. So this study includes pediatric and adult populations and has this run-in phase where basically all potential subjects who pass screening will receive therapy with 923 for two weeks. And we'll ask a simple question. Is there a marked reduction in phenylalanine levels following treatment with 93? If the answer is yes, those subjects will then get randomized to receive 93 or placebo for the six-week placebo control phase. And the primary endpoint of that placebo control phase is reduction in phenylalanine levels in 93 relative placebo. So, again, based on the mechanism, based on the data we have to date, we expect to be able to provide benefit in all populations and all genotypes and degrees of severity, even those classical BKU patients where we've already been able to record a benefit in the Phase II study. In terms of the chronic tox, we have completed all the necessary tox work needed to allow for not only, obviously, a leak, six-week placebo control phase, which is the primary efficacy study on the basis for the efficacy component of an NDA pending the data, but also for the long-term open-label safety portion of the study to which all patients will roll over once they complete the placebo control phase. So those studies have been completed and we're able to now move forward with the full trial, the six-week placebo control phase and the open-label extension.
spk12: Thanks so much, Matt.
spk09: Our next question comes from Gina Wang with Barclays.
spk11: Thank you for taking my questions. I just have one regarding Translana confirmatory study 041 data in mid-2022. Could you provide different scenarios of the outcome and its impact to Translana launch in Europe markets?
spk06: Yeah, sure. So just to remind everybody, what we've done is there's study 041 that will be done in the middle of this year. We're pretty excited about 041 because I think that we were able to utilize all the learnings that we had from the clinical trials that were performed to really be able to define What's the, you know, run of the right endpoints? What's the right patient population that we can study? And so I think we're in a really good position to be able to define, to show that Transline is working and to use the right patient population and to use the right endpoints. And so, Matt, you want to talk a little bit about the details of how we're moving forward?
spk04: Yeah, sure. So, As you mentioned, we really were in a position, Gina, to leverage all of our learnings from the previous study. I think there's always, previous studies, there's always the case, the key is really understanding the right patient population, the appropriate inclusion criteria, the appropriate endpoint, and the appropriate duration. And I think we have all of those coming to bear in this study. The primary analysis group is a population of seven to 16-year-olds, with a baseline six-minute walk distance greater than or equal to 300 meters and a standard supine time of greater than or equal to five seconds. Of note, when we look at the previous studies, when we look at our previous two studies, study 07 and 020, and we look at this group in those studies, we saw that we had a remarkably significant effect. For example, in study 07, there was a difference of 46 meters 46 meters greater walk distance and treated relative to placebo. In 020, it was 43 meters greater walk, greater distance relative to placebo. And those, again, both were marked as statistically significant. So now to be able to design this study with that exact Goldilocks population as the primary analysis population is what gives us confidence in the design of the study. And as you mentioned, we expect to have results of this study in mid-year. Uh, we believe, uh, obviously that with a positive study, we'll be in a position to, uh, go, uh, to the FDA and be able to submit an NDA and, and make sure it's on to the kids in the U S uh, in Europe, where obviously this is a component of the conditional marketing authorization. You know, we, we feel that one of the more important considerations is, is the stride registry that we have, where we've been able to, over the course of years, consistently demonstrate. a significant benefit of TransLana relative to loss of ambulation and loss of pulmonary function, which when you think about it, the clinical trials are really designed to give a picture of what you might be able to do for those significant events in the life of the DMD boys. We really use the six-minute walk test in a shorter period of time to try to say what we might be able to do in terms of preventing loss of ambulation. So to be able to continue to provide those data to CHMP, which we've been able to do and which has formed the basis of our annual renewal of the conditioning marketing authorization, I've been showing in the most recent data cut an extension of a five-year difference in terms of loss of angulation as well as the prevention of loss of pulmonary function, we believe is really a compelling part of the picture and I think will be an important component, remaining component of how the CHMP views Translana.
spk11: So, sorry, just follow up. So if, you know, play devil's advocate, you know, if trial fail, what additional data you will need to provide to maintain Translana on the market in Europe?
spk06: Yeah, so I think that's what Matt was saying, that we have described registry, which has demonstrated years longer in terms of preventing loss of emulation, pulmonary function, being able to get off the ground. The data is really quite compelling. I think you've probably seen this as well in the publications that we've shared with you. And we know that the European regulatory agents are very interested in that as well. So that would be a big piece of data that we think really demonstrates to prevent people of what really matters to DMV patients, which is maintaining motor function. So we think a lot of the renewals, as we've talked about in the past, had been focused on the real-world evidence and the stride data. So if, like you said, you want to play devil's advocate, if that were to happen, we believe that the stride data itself is strong enough that would keep it on the EU marketplace for patients to get.
spk09: Okay, thank you. Our next question comes from Danielle Brill with Raymond James.
spk02: Hi, guys. This is Alex. I'm for Danielle. Thanks for taking our question. Could you remind us where the angioline is? gene therapy program stands. Based on my notes, I'm looking at, I think you were originally targeting 2021 for the IND filing. So we're just curious what needs to be done there to get that IND filed. Thanks.
spk06: Yeah, sure. Matt, you want to go through this a little bit?
spk04: Yeah, absolutely. Hi, Alex. We previously shared that we were in the process of completing the gating tox work to move the program into the clinic. We did have a number of delays related to COVID in terms of both its impact on our CDMOs and manufacturing CMOs, as well as the global shortage of non-human primates. I have a report that we are moving forward now and are continuing our work towards having the IND or CTA ready to get their program into the clinic in the near future.
spk02: Great. Thanks so much.
spk09: Our next question comes from Robin Karnaskis with Truist Securities. Hi.
spk14: Thanks for taking my question. And, again, congrats on all the progress. And you've got a lot reading out this year. I actually had a question on MDS and the BioEat platform. It's going to be coming into focus. Can you just talk a little bit more about the MyEat trial a little bit? I know you're enrolling patients that have to have a lot of seizures, you know, within 14 days of the running period within the last month. Like, what percentage of the population with MDS that you talk about kind of would fit that bucket? And can you help us understand, like, what are any of the risks of the placebo-controlled portion with the range of patients that you're enrolling in age? How variable is it that these patients have, like, a group of seizures and they stop and then they go on again? Just help us understand how to think about that study. And then my second question is just on, you know, the terrible, a lot of mid-caps and platforms are on sale and thoughts on like, you know, your interest in doing M&A in this tape.
spk13: Thanks.
spk06: So Matt, you want to take the mitochondrial disease associated seizures?
spk03: Yeah, sure.
spk04: Hi, Robin. So the mitochondrial disease associated seizures, let me just talk a little bit about them for a second. So about 40 to 50% of all patients with mitochondrial disease have seizures as an important part of their pathology. And these seizures in mitochondrial disease patients tend to be refractory to traditional anti-epileptics. That's because the energetic pathways that are disturbed in mitochondrial disease that cause these seizures are not addressed by the existing anti-epileptic therapies. In fact, many anti-epileptic therapies exacerbate the energetic defects that are causative of seizures in these patients. So whatever potential benefit they would have from the pure anti-epileptic mechanisms of these drugs are offset by the exacerbation of the pathology causing seizures. So that's a long way of saying these kids who have seizures have a lot of them. They're severe. They're a source of a high degree of morbidity, recurrent infections, and are typically a cause of early mortality in these patients. Over the course of the development of vitiquinone, we've studied vitiquinone in a number of different mitochondrial disease subtypes, and these subtypes are the result of different mutations in the mitochondrial and nuclear genome responsible for mitochondrial structure and function. And what we've seen across many different subtypes we've treated is that there's a consistent treatment effect with regards to seizure pathology, including the reduction of seizure frequency, the disruption of refractory status epilepticus, reduction in disease-related morbidity, as well in some cases where there's robust enough natural history data, we've been able to demonstrate a protective effect with regard to mortality. And so coming into the MITEI study, we really based this study on what we've seen to date in terms of effects on seizure, seizure-related morbidity and quality of life in mitochondrial disease patients of all different subtypes and all different ages. And so we developed this protocol as really a basket trial where we focused not on specific genotype or mutation, but on rather the common morbid symptom of drug-resistant seizures, which is quite common in these patients. And so the study is set up with the run-in phase, as you mentioned, where we ensure that there's enough observable motor seizures so we have room to demonstrate benefit. Now, it turns out many of these patients do have those frequent seizures, again, because they're typically poorly controlled by the existing therapies that are available. Then if they have that requisite number of seizures, observable motor seizures over 28 days, which is the number is actually six, they'll then get randomized to receive the tiquinone or placebo for six months, and the primary endpoint is the change in observable motor seizures on either the tiquinone or placebo relative to the number of seizures in that 28-day-one phase. It's a study design that's been well-instantiated and has been used for the approval in other pediatric seizure syndromes. We will importantly, though, include other secondary endpoints assessing other aspects of seizure pathology as well as disease morbidity because, again, metiquidone is not an anti-epileptic. It's rather targeting a core mechanism of disease pathology. We're simply using the seizure measurement as a way of capturing and quantifying treatment effect in these patients. just to make sure I covered all your points here, including many different disease subtypes. We are doing stratification in order to balance enrollment of some of the more common subtypes of disease, again, so we can balance out any particular mutation across both the treatment and placebo arms. And again, there's no particular age limit between zero and including all pediatric patients 18 years and younger. Again, we're focusing just on them having that requisite number of observant seizures.
spk06: And then I think you – so, Ron, I think was your question on what, you know, in this space there's a fair amount of M&A and you wanted us to comment on it? Is that what you – was that the question?
spk14: I think everyone asked this question because of the low valuations for a lot of SNCCAPs, you know, what people are interested in or if they're interested in acquiring – certain platforms. It's sort of like gauging your interest given the tape and whether or not you think there's a high likelihood that we'll see more M&A in the back after the year. I think that's the key question we're all asking.
spk06: I think, well, you know, I guess my view on that a little bit is, you know, M&A is always a complicated question on people's capabilities, on what their pipeline is like, what their commercial capabilities are. Could someone do it better? Do people want to, are they building or are they looking to, or is their goal to become acquired? So it's sort of hard to say. I mean, obviously there's a lot of interest in treating these diseases. But, you know, it's hard for me to say there's going to be more or less. I just think, you know, obviously there's a lot of interest in these types of drugs.
spk09: Okay, thank you. Our next question comes from Judah Frommer with Credit Suisse.
spk00: Hi, thanks for taking the question. Just a couple on 518 as you kind of head toward beginning enrollment there. Just maybe any feedback from the sites as you get them set up on kind of receptivity to route of administration maybe versus other Huntington's programs that are in the clinic, you know, how important that is to patients and doctors and also titratability given, you know, lack of specificity toward mutant Huntington. And then also you do have a functional endpoint in there as a secondary kind of how are you thinking about, you know, potential to show anything there given the length of the study.
spk06: Sure. I think from the first part, I think, well, you know, obviously with the hourly bioavailable small molecule, the right administration, the ease of giving it. It's just a huge advantage, right? I mean, the fact is that it's easy to take. You can do it at home. But I think beyond that, the real advantage comes from that you know that it gets distributed. You know, it passes the blood-brain barrier. It gets into the brain. It gets all over every tissue. You can measure the pharmacokinetics so you know the precise concentration of free drug that's both in the plasma, that's also in the CSF. So you know, there's so much you know, and that when you know that when you get it into the CSF, you know the level that's within the whole brain. Then you can measure not only the level of reduction that occurs in the plasma, so you know there's a very good response as a consequence of that, And then you know obviously as a consequence of that you can see the effect on biomarkers like the HTT protein directly. So there's so much you could learn and you're confident of it's getting to the right place and that when you see it's in the right place it's all over the brain so you know that it has an effect all over. So everyone's really happy about that. I think both sites, patients, physicians, incredibly enthusiastic, you know, on learning that. And then from our point of view, we put the package together to look at not only the reduction of HTT levels, but also to be able to look at biomarkers like NFL, HTT, MRI, volume within the brain, and changes that occur like that. And then see if, well, it's not long enough that you have outcome measures, but then to be able, based on what's been said by Novartis and others, that we're at least in a position for if it is possible to get accelerated approval to be able to do it on that, and then be able to do long-term trials as a consequence for outcome measures for clinical benefit. So I think we're in a real good position to look at reduction of protein levels, reduction of CSF, of HCT in the CSF, the neurofilament, preservation of blood, brain volume. I think that's a pretty good package. Great. Thanks.
spk09: That concludes today's question and answer session. I'd like to turn the call back to Dr. Stuart Peltz for closing remarks.
spk06: Okay. So first of all, let me thank you all for joining us today so that we can discuss the progress that we've made really up to date to 2021. I'm really proud of the team that really continued to execute on the goals. as we continue to grow, and I think we've made significant progress across our research and development pipeline with many upcoming milestones in 2022. And, you know, we're driven to bring these medicines to patients around the globe, and I anticipate that 2022 is going to be a real transformative year for us, and we look forward to the progress and updates that we'll give you. So thank you for joining.
spk09: This concludes today's conference call. Thank you for participating. You may now disconnect.
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