Good day, and welcome to the PTC Therapeutics Fourth Quarter 2022 Corporate Update and Financial Results Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. Instructions will be given at that time. As a reminder, this call is being recorded. I would now like to turn the call over to Kylie O'Keefe, Chief Commercial Officer. You may begin.

Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' fourth quarter 2022 corporate update and financial results. I'm joined today by our Chief Executive Officer, Stuart Peltz; our Chief Operating Officer, Matthew Klein; our Chief Business Officer, Eric Pauwels; and our Chief Financial Officer, Emily Hill. Today's call will include forward-looking statements based on our current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements. Our actual results could materially differ from these forward-looking statements, as such statements are subject to 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, Stuart Peltz. Stu?

Thanks, Kylie. Good afternoon, and thank you for joining the call. I'm proud to share PTC's fourth quarter and full year results and our expectations for continued strong performance in 2023. PTC treats rare diseases by modulating gene and protein expression. Our strategy is to discover, develop and commercialize products to build a robust pipeline of potential new therapy. Our goal is to deliver one new therapy every two to three years. I'm honored to report that PTC has been named the winner of the 2023 EURORDIS Black Pearl Company Award for Innovation. This award recognizes and celebrates companies who have undertaken groundbreaking science to advance rare disease research and development and is a testament to the mission and strategy of PTC. We are planning a very exciting year in 2023, including the celebration of our 25th anniversary. And we're proud of what we've achieved to date. Our commercial portfolio has five marketed products, plus a sixth product for which we collect collaboration and royalty revenue. In 2022, we achieved $699 million in total revenue, which is a remarkable 30% growth over total revenue in 2021. This revenue achievement was despite substantial FX headwind. And when calculated at constant exchange rate, it was $740 million, representing a 37% year-over-year growth. In the fourth quarter of 2022, we achieved $167 million in total revenue. We expect our growth to continue to accelerate in 2023. As announced in January, we expect our total revenue guidance in 2023 to be between $940 million to $1 billion, which would represent more than 30% year-over-year growth. We are continuing to advance the broad and deep pipeline of new therapies that we expect to provide substantial growth to our commercial portfolio in the coming years. I'm proud that these efforts have led to seven promising development programs focused on treating rare disease with high unmet medical need, from which we'll have four important readouts in the first half of 2023, three of which are registration-directed studies. We expect results from the APHENITY study for sepiapterin for PKU, for vatiquinone in both mitochondrial disease associated seizures and Friedreich ataxia and the 12-week data for PTC518 in Huntington's disease. Matt will go into this in more detail shortly. We're very excited about Part 1 data for APHENITY study with sepiapterin and look forward to the results from Part 2 shortly. In addition to these studies, we continue to progress enrollment in our SunriseLMS trial for unesbulin in leiomyosarcoma patients and our CardinALS trial for utreloxastat for ALS patients. With solid growth across our commercial portfolio and many new therapies advancing in our pipeline, we continue to generate strong momentum for many years to come. I'll now hand over to Matt for an update on our development programs. Matt?

Thanks, Stu. Our teams continue to make progress in advancing important new therapies from our pipeline to patients in need. As Stu noted, in the first half of 2023, we will have results from four of our ongoing clinical trials, three of which are registration-directed studies. Let me begin with an update on APHENITY, our global Phase 3 trial of sepiapterin in patients with PKU. As a reminder, APHENITY is a double-blind placebo-controlled study in which subjects are randomized to receive sepiapterin or placebo for six weeks with the primary endpoints being reduction in blood phenylalanine level. To enrich the randomized population for sepiapterin responders, there is a run-in phase during which all screen subjects receive sepiapterin for two weeks. Only those subjects who demonstrate a reduction in phenylalanine levels of 15% or more from baseline will be randomized, with the primary analysis population consisting of those who have greater than 30% reduction. Importantly, all subjects entering the placebo-controlled phase will undergo a washout period of at least 14 days. In January, we shared data from the Part 1 run-in phase for the initial cohort of subjects with greater than 30% reduction in phenylalanine levels. I will now provide an update on Part 1 preliminary data for all subjects. Overall, 156 subjects passed screening and completed the Part 1 run-in phase. Of these 156 subjects, 102 or 65% had greater than 30% reduction in phenylalanine levels from baseline. This is a very high responder rate, over three times the responder rate recorded in the Kuvan responder study. When looking at the magnitude of Phe reduction in the 30% sepiapterin responder group, there was a mean reduction of 66%, which is more than twice that recorded in the Kuvan placebo-controlled phase. Also, I want to point out that the 30% responder group includes 15 classical PKU patients, who had a mean phenylalanine reduction of 61.5%, which is a very impressive result. I'll add that there are additional five classical PKU subjects who had a 15% to 30% reduction in Phe levels during the run-in phase. These Part 1 results including the high responder rate and the mean phenylalanine reductions in non-classical and classical patients continue to support the premise that sepiapterin can potentially meet the persistent unmet medical need of PKU patients. With the high proportion of subjects achieving an over 30% phenylalanine reduction in Part 1, the primary analysis population for Part 2 will be over-enrolled by approximately 25%, beyond the initial target of 80 subjects. Given the time required for these additional subjects to undergo washout and complete the placebo-controlled portion of the study, last patient last visit is planned to occur in March and we expect results of Part 2 in May. Let me now move to the two registration-directed trials of vatiquinone, MIT-E and MOVE-FA. The MIT-E and MOVE-FA studies are based on both the strong scientific rationale as well as data from several previous studies in which we have recorded evidence of treatment benefit across key disease endpoints. The MIT-E study is a global registration-directed trial of vatiquinone in patients with mitochondrial disease associated with seizures. The study includes a 24-week placebo-controlled phase with a primary endpoint of change in observable motor seizures from baseline. The placebo-controlled phase will be completed in March, and we now expect results in the second quarter to allow for data cleaning and database lock. The MOVE-FA trial is a global registration-directed study of vatiquinone in patients with Friedreich ataxia. The study includes a 72-week placebo-controlled phase and the primary endpoint is the change in the validated mFARS rating scale from baseline. Last patient last visit for the placebo-controlled phase will also be in March, and we continue to expect results of the MOVE-FA study in the second quarter. Moving to our PTC518 Huntington's disease program. Enrollment is ongoing at our global sites for the Phase 2 PIVOT-HD trial. As a reminder, PIVOT-HD is a 12-month placebo-controlled trial in two parts. Part 1 is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effects, as well as biodistribution. Part 2 nine months in duration and focuses on blood-based, CSF-based and radiographic biomarkers of disease. The study initially includes two dose levels, 5 milligrams and 10 milligrams, with the ability to include a third dose level of up to 20 milligrams leveraging the titratability of the molecule. As we shared at the J.P. Morgan conference in January, we have initiated additional 5 milligram and 10 milligram dosing cohorts in early Stage 3 patients. We expect results from the 12-week portion of the trial in the second quarter of 2023. Turning now to Translarna. We recently had an informal meeting with the FDA during which we discussed the potential path to an NDA resubmission. Based on the meeting discussion, we plan to request another Type C meeting to review the totality of data collected to-date including dystrophin and other mechanistic data as well as additional analyses that could support the benefit of Translarna. We plan to prepare a request for this meeting in the near future. Lastly, for Upstaza, as we previously shared, the FDA requested additional bioanalytical data in support of comparability analyses between the drug product using the clinical studies and the commercial drug product. We have completed these analyses and have provided the results to the FDA for review ahead of a BLA submission, which we continue to expect to occur in the first half of 2023. I will now hand the call over to Eric to provide an update on our commercial portfolio.

Thanks, Matt. It is exciting to see the great progress of our late-stage clinical pipeline and the global commercial team is certainly ready to leverage our expertise and broad geographic footprint to bring these important treatments to patients. Our global customer-facing team has delivered yet another strong quarter, continuing the significant momentum built throughout the year and closing out what has been a very remarkable year for PTC. Our launch of Upstaza in Europe is building momentum. The global DMD franchise continues to strengthen, and we see our global commercial expansion delivering significant growth. With the fifth product added to our commercial portfolio, we delivered $128 million of revenue in the fourth quarter and an impressive $535 million for 2022, which represents 25% year-over-year growth for our marketed products. Let me start with Upstaza. We are pleased with the initial launch of Upstaza following the approval in the EU. Last year, we treated commercial patients in Germany and patients in France through the early access program. Importantly, we are pleased with the initial interactions with health technology bodies in France and Germany, which will further support pricing and reimbursement in the future. We anticipate continued growth in 2023 by treating patients in other European countries, also enabling cross-border treatment options. Lastly, to continue the growth, we will further focus on geographies outside of Europe with additional registration submissions and named patient programs in Latin America, the Middle East and Asia Pacific. Our DMD franchise continues to deliver robust results with $114 million in revenue in the fourth quarter, which brings our 2022 DMD franchise to $507 million, an impressive 20% year-over-year growth over 2021. This remarkable achievement is despite strong FX headwinds and, when calculated in constant exchange rate, it is $539 million and 27% growth. The fundamentals of the Emflaza business continued to be solid. Revenue in the fourth quarter of 2022 for Emflaza was $58 million. This brings total annual Emflaza revenue to $218 million, which is a remarkable 17% growth over 2021. Operational excellence drove continued new patient starts, broad access and continued focus on high compliance and lower treatment discontinuations. Turning to Translarna. We achieved $56 million in revenue this quarter, which brings our 2022 revenue to $289 million, which is an outstanding 22% growth over the previous year. Again, despite significant foreign exchange headwinds, we continue to see growth in our main markets now that Translarna is in its eighth year of commercialization. Additionally, we continue to push forward with our geographic expansion into new markets in Latin America, Middle East, Northern Africa and Asia Pacific. Now turning to Tegsedi and Waylivra in Latin America. The focus we have had on building the foundation of these therapies is delivering results. We have strengthened our position in Latin America as the pioneers in rare diseases with our recent approval in Brazil for the second indication for Waylivra in familial partial lipodystrophy, or FPL. This is the first treatment for FPL in Brazil and the first approval globally for Waylivra for the FPL indication. As a reminder, Waylivra was previously approved for familial chylomicronemia syndrome and received Category 1 innovative drug pricing in Brazil. For Tegsedi, we have received our second group purchase order from the Brazilian Ministry of Health, which we expect to fulfill in the first half of this year. And our discussions with CONITEC continues to progress. Across the region, we also continue with our geographical expansion with MAA filings for both Tegsedi and Waylivra, and we continue to support and grow our patient base through early access programs. 2022 was a fantastic year for our global customer-facing team and has set us on a solid trajectory for 2023. This has been a transformational year as we continue our launch efforts for Upstaza, large FPL in Brazil and continue to grow our DMD franchise ahead of our near-term pipeline readouts. Now, let me turn the call over to Emily for a financial update.

Thank you, Eric. I will take a few minutes to review our fourth quarter and full year financial results. Please refer to the earnings press release issued this afternoon for additional detail. Beginning with top-line results. Total revenues for the fourth quarter were $167 million. This consisted of net product revenue across the commercial portfolio of $128 million and Evrysdi royalty revenue of $40 million. Translarna net product revenues in the quarter were $56 million, reflecting strong growth in most geographies, despite significant foreign exchange headwinds. Emflaza had net product revenues of $58 million, representing 22% growth year-over-year. Non-GAAP R&D expenses were $175 million for the fourth quarter of 2022, excluding $14 million in non-cash stock-based compensation expense compared to $136 million for the fourth quarter of 2021, excluding $13 million in non-cash stock-based compensation expense. This year-over-year increase in R&D expenses reflects additional investment in research programs and advancement of the clinical pipeline. Non-GAAP SG&A expenses were $79 million for the fourth quarter of 2022, excluding $13 million in non-cash stock-based compensation expense compared to $74 million for the fourth quarter of 2021, excluding $13 million in non-cash stock-based compensation expense. Our total revenue for the full year 2022 was $699 million for year-over-year growth of 30%. This was impacted by significant FX headwinds, which were calculated at CER was $740 million and 37% year-over-year growth. This included DMD revenue of $507 million, which represented 20% year-over-year growth or 27% growth at CER. Evrysdi royalties for the year grew 108% to $114 million year-over-year. Cash, cash equivalents and marketable securities totaled approximately $411 million as of December 31, 2022, compared to $773 million as of December 31, 2021. I will now turn the call over to the operator for Q&A.

Our first question comes from Eric Joseph with J.P. Morgan. Your line is open. There were significant foreign exchange headwinds. Revenue at constant exchange rates was $740 million, representing 37% year-over-year growth. This included DMD revenue of $507 million, which represented 20% year-over-year growth, or 27% growth at constant exchange rates. Evrysdi royalties for the year grew 108% to $114 million year-over-year. Cash, cash equivalents, and marketable securities totaled approximately $411 million as of December 31, 2022, compared to $773 million as of December 31, 2021. I will now turn the call over to the operator for Q&A.

Hi, good afternoon. This is Hannah on for Eric. Thanks for taking the questions. Just a few from us. So, first, can you break down just some of the revenue components in your full year 2023 revenue guidance outside of your DMD franchise? Just wondering how you're thinking about the balance between Evrysdi and Upstaza? And I have a follow-up after that.

Yes. Thanks, Hannah, for the question. Emily, do you want to take that?

Yes, sure, I'm happy to take the question. Thanks. We're looking forward to our guidance for 2023 of $940 million to $1 billion. That obviously reflects continued growth expected in the DMD franchise. As you alluded to also growth in Upstaza, Evrysdi, both royalty and milestone. There's a $100 million milestone expected for crossing a sales threshold for Evrysdi. And then, continued contribution of Tegsedi and Waylivra. We haven't broken out specifically the contributions of Upstaza and Evrysdi, but obviously, you can see now that Roche has Evrysdi approved in over 90 countries, quickly becoming the standard of care in SMA, and we expect significant growth going into next year.

Okay. That's helpful. And then, just moving on to APHENITY. Thanks for providing updated data from the run-in portion. Just wondering if you're able to speak to the variance of blood phenylalanine lowering that you're seeing in that run-in study? And then, should we expect any stratification mechanisms or criteria in place based on magnitude of Phe reduction as part of the Phase 2 patient randomization?

Yes. I think that's a good point. And I mean, one of the things that we always say is that the nice thing about this endpoint is the biochemical marker, so we measure the amount of phenylalanine, and it's a relatively stable measurement. Matt, you want to talk a little bit about the stratification and the measurement?

Yes, absolutely. Hannah, thanks for the question. So, first just obviously, we're really excited about the updated Part 1 data. I think, from what we reported in January, we are seeing the overall response rate up from 61% to 65% and magnitude of Phe reduction for both the non-classical and classical PKU patients is also higher, which continues to give us a lot of confidence going into Part 2. In terms of your question about genetic variance, I believe that was your question, the enrollment includes really the full spectrum of genetic variance, non-classical and classical. We didn't do any specific stratification or exclusion based on any specific genetic subtypes. In terms of the stratification for Part 2, we did stratify the randomization for above and below 600 micromolar per liter, so that was the one strata, as well as stratifying for greater than 30% response in the run-in phase and 15% to 30% response to run-in phase with, of course, the greater than 30% population being the primary analysis population for the study.

And within the greater than 30% patients that are moving on to the primary analysis population, should we assume that there's no further stratification based on what was seen in the run-in portion?

Correct. We predefined the strata as greater than 600 at baseline or below 600 at baseline, as they enter the placebo-controlled phase.

Great. And maybe just one more if I could. Just wondering about the need or the interest in over-enrolling the study relative to your initial study design. Wanted to know if that was borne out of feedback from any regulatory agencies.

Yes. No, we were. Go ahead, Matt.

Yes. That had nothing to do with regulatory interaction. The protocols were agreed upon with the FDA and EMA prior to the start of the study. This really reflected significant interest on the part of patients and physicians. As we've talked about, there is a clear unmet medical need and a desire for safe and effective therapies, and what we saw was significant interest from centers throughout the world. The over-enrollment and the delays in getting to data came from the fact that many investigators and key opinion leaders had patients and really wanted to get them into the study. Of course, we believe that a greater number of patients always strengthens and increases the probability of success in the trial.

Okay. Very helpful. Thanks for taking the question.

Thank you. Our next question comes from Kristen Kluska with Cantor Fitzgerald. Your line is open.

Hi, everyone. Thanks for taking my questions, and congrats on the 25-year milestone. First question I had was, for PKU, can you give us your sense or preliminary thoughts on what the payer's response might be? Whether there might be a generic Kuvan step edit or perhaps how it could differ across different populations such as those with classical?

I think this is a good point. Remember that while Kuvan was the first drug, it was ineffective for a large portion of the patient population. If you look at Palynziq and Kuvan together, they still cover roughly, but not exactly, 10% of the overall population. That means there is a very large group of patients not satisfied with current treatment. There are 58,000 PKU patients globally, so this is a significant opportunity for a new, highly effective therapy. You can see responses of 60% to over 65% in the overall patient population and about 61.5% in the classical population; those numbers are nearly the same, which shows how effective it is. By contrast, Kuvan did not work for classical patients, so this is clearly a superior product. Given how many patients found Kuvan ineffective, we believe we are in a strong position. We do not expect any step edit for classical PKU because it is well known that Kuvan did not work for classical patients. Even if there are step edits that require patients to try Kuvan, many patients have already tried and failed on Kuvan and that is well documented. And for those who have not, the period required to show whether Kuvan is functional is very short, so it should not be cumbersome or difficult to manage. Kylie, do you have anything to add? You have done a fair bit of work with payers.

Yes. Thanks, Kristen, for the question. I think it's a really important one. And as Stu said, we really do believe in this substantial unmet need that exists in the PKU marketplace. And as Stu was talking to, we started to begin a number of different payer engagements to ensure we understand sort of how they're looking at a data package. And from that perspective, as Stu was saying, if you look at the classical PKU patients, Kristen, there has been no effective therapies in that space. And so, from that perspective, we don't foresee any types of step edits or requirements to be able to put these patients on treatment. And as Stu was also saying in the space where they've previously tried Kuvan, even if they were step edits to generic first plans in the case of Kuvan being generic, again, we don't see this as a major hurdle, because in many cases, they've tried and failed Kuvan and therefore the documentation has been established. And even if it needed to be re-established, it is a quick and efficient step in the sense that it is a blood-based biomarker. So, you're able to put the patients on treatment, establish that the treatment isn't working, and move them on to a more effective therapy. And so, from that perspective, we're very confident going into the commercial landscape, that we have the right data set and the right data package assuming success with APHENITY to hit the ground running.

And we don't look at this like as we're competing with the generic. We're competing with a drug that had a very small window of patients to treat of — most of which are the patients weren't successful. And so, we plan on bringing in a sense a new therapy that these patients we anticipate will have — will be more successful on this therapy. But it's very different than fighting with us. You just have a generic and you're trying to fight to get a piece of that pie. We're actually — we actually believe that we'll be able to treat patients that weren't able to be treated before.

Okay. Thank you, Stu and Kylie. And then, I think of your late-stage candidates MDAS perhaps gets less attention compared to especially like PKU and Huntington's disease. So, maybe can you reiterate for us why you remain excited about the program potential here? And how you think about the commercial opportunity and ease of finding some of these patients should it be successful and ultimately approved? Thank you.

Yes, we think vatiquinone is a very important new therapy, in part, because it really does tackle a new area in terms of treating medicine, and that is really sort of mitochondrial dysfunction and the consequences of that. When you think about mitochondrial dysfunction, when you think about the amount of ATP that's produced in order to be functional, it's almost like 15 trillion ATP molecules a second. And if things go into dysregulation and enhanced free electrons that obviously cause all sorts of stress on the cell that causes both — that can cause havoc, and obviously, neuroinflammation and things like that. And the consequence of that is big. When you think about especially like in the brain, where it's only a 3-pound organ, but it uses about 20% of the overall ATP within the body, it could be both dramatic effects, and you could see that with mitochondrial disease with associated seizure. So, I think having a drug that could modulate this and through novel and new mechanism is quite important. And we're excited about that because it can be used really quite broadly. Matt, do you want to talk a little bit about MIT-E and why we're so excited about this?

Yes, Kristen, thank you again for the question. Look, well, maybe it's not getting as much attention, this is a population that's known. There's over 20,000 patients worldwide with mitochondrial disease associated seizures. And as Stu mentioned, this is just the beginning of populations that could benefit from a drug that targets these fundamental access pathways, stress and inflammation pathways that causes that disease. Now we have confidence in the study. It's built on a number of previous studies showing that we can have an important effect on seizure activity, both in terms of seizure frequency and other seizure-related morbidity. And we believe that this can be a very important therapy not only for mitochondrial disease patients, patients with Friedreich ataxia, but many others.

Thank you.

Thank you. And our next question comes from Brian Abrahams with RBC. Your line is open.

Hey, guys. Thanks for taking my question. And Stu, my congratulations as well on 25 years.

Thank you.

I was wondering if you guys could expand a little bit more on the nature of your discussion with the agency on Translarna. I'm curious to learn a little bit more about I guess what their initial reactions were to the full 041 data plus the STRIDE registry. What seems to be the sticking point? And I guess what gives you confidence that dystrophin and some of the other analyses would support approval? And is this something that would be a potential accelerated approval perhaps? Thanks.

Yes. So, we recently had a formal discussion that will allow us to lead to having setting up a meeting with them. And it really was the notion of us talking about the overall package and the mechanism of action as well as why we think we have clinical benefit as a consequence of that. Matt, you want to go through this a little bit?

Yes, sure. Brian, thanks for the question. So, just to take a step backwards, as I think most of you recall, after we had the 041 data, we had requested a Type C meeting with the FDA to discuss 041 as well as STRIDE and the pooled analyses from including Study 7 and Study 20. And the agency informed us that we would have a meeting with written response only. We had asked to be able to have a live meeting given the volume of data and they said that they would provide written response-only comments, but we would have the ability to talk to them afterwards if we still had questions. And obviously, we did have questions after the initial feedback, which seemed to focus mostly on Study 041, itself not meeting the bar of substantial evidence of effectiveness. But clearly, there's evidence of benefit in that study. And when combined with Study 7 and Study 20, you see highly statistically significant and consistent improvement on the key functional endpoints of disease, and then as you mentioned also the STRIDE registry. This meeting was a live meeting offered as a clarification of the comments that were made in the Type C written comments. And again, a lot of that discussion was about why study 041 wasn't believed to have substantial evidence of effectiveness. We talked about totality of data, and it was suggested that we could request a separate Type C meeting to discuss totality of data, including the mechanistic dystrophin data, because the comment in our meeting was made that we had shared those data, which as you all know, we had those data, but actually focused on the functional benefit that was in 041 that came afterwards. So, we see this as an opportunity to again highlight not only 041, but 041 alongside the other placebo-controlled studies, and the STRIDE registry, how the benefits we've demonstrated in the course of a clinical trial are translating into long-term meaningful benefit as far as delaying the key morbid transitions phase of the disease, loss of ambulation, loss of pulmonary function and then bringing all the mechanistic data. We have Study 045 in progress as well, which really confirms that we have a novel mechanism of action in terms of nonsense suppression and that's yielding dystrophin production, which is also associated with the clinical benefits recorded in all of these studies.

That's really helpful. Thanks so much. And if I could just squeeze in a quick follow-up on the PKU program. I think the way to measure phenylalanine levels in modern studies are more reliable. But I was wondering if you could maybe just clarify the way Phe is being measured in the Phase 3 relative to the Kuvan studies and your confidence that the assessment of Phe is repeated or robust enough such that you wouldn't have pseudo responders whose reductions might drop off between the open label run-in and the randomized portion as has had happened with some of the old Kuvan studies? Thanks.

Go ahead, Matt.

Yes. Brian, we're using a blood spot analysis that's done at home. This has been very well validated as a robust measure. I think we have confidence that obviously we're using the same methodology in both the run-in phase and the placebo-controlled phase. And also, it's important to note the way we measure these Phe responses, which in the run-in phase are treated for 14 days, but we're averaging three different time points five, 10 and 14 days, which gives us the value of reduction. So, it's averaged over three points, which is another effort to ensure we're getting an accurate and precise assessment of the Phe reduction. So, this is a method that's been well designed and well validated. We have a GLP laboratory consistent measurement in both the run-in and the placebo-controlled phase. I can't comment on specific differences in the methodology that was used with Kuvan, but I can provide the confidence that we have developed a very well validating method that can provide both accurate and precise assessment of the Phe changes over time.

No, that's super helpful. Thanks, Matt.

Thank you. Our next question comes from Joseph Thome with Cowen. Your line is open.

Hi, there. Thank you for taking my question. Maybe just one. We're going to see some registrational data sets here in the first half, which is great, hopefully some of these are or all of them are successful. But as you did bring these in, is there anything else that you would need outside of the registrational data before a regulatory submission? So, essentially, can you just comment on your comfort with the CMC as it stands right now? And the size of the safety database for sort of the next three that are coming up here? That would be great. Thank you.

Yes. Matt, do you want to take that?

Yes, sure. Thanks for the question, Joe. So, obviously, all both compounds, sepiapterin for PKU as well as vatiquinone, have been in development for a number of years, which has really given the opportunity for the other components of the package when you think about CMC and you think about non-clinical data for those portions of the package to get filled out. Obviously, we're conducting a fairly large study in PKU now with sepiapterin to that — and we believe based on this trial and the other data that have been collected in other sepiapterin studies that we'll have this sufficient database to support the mission with a positive trial. And with vatiquinone, I think one of the real foundations of that therapy is the extensive safety records that's been recorded in kids over the past decade, including patients who have been on drug continuously for over a decade with very strong safety profile. Taken together for both therapies, we believe we have all the components of the package. Obviously, with positive data, we'll meet with the agency to align on the details of the submission and then move forward as quickly as possible.

Great. And then maybe just a quick follow-up on the financial side. In terms of the financial spend guidance for 2023, is there any additional build in the US marketing force anticipated this year? Or would that be more of a 2024 spend item? Thank you.

Yes, sure, I'll take that one on the spend side and then commercial, and anything on the infrastructure. We're pretty well sized on the commercial force. So, there's no significant change in the spend on the US sales force.

Okay. Thank you very much.

Thank you. Our next question comes from David Lebowitz with Citi. Your line is open. David Lebowitz with Citi, your line is open.

Sorry, I — the name fell out for a moment. I guess question number one, on the 923 data, how should we benchmark response rate compared to Kuvan given that patients were on a Phe restricted diet, which would be expected to deepen the overall response?

Yes. So, I think what we're asking for is for people, whatever diet's on, that they keep consistent diet of what they're on. And I think what — I think overall, what you're seeing within the results are pretty dramatic results of greater than 60%, both in the classical as well as the other forms of PKU. So, I think you've seen consistent activity of the molecule. So, I feel we're in — and if it's deeper in the other way, at least here, I think you're still seeing pretty high response rate. Matt, do you have...

Thank you for the question. In general, these patients all tend to be on Phe restricted diet and the key in both studies, obviously, to have them on consistent diets, so that's not a confounding variable. But I think what we're seeing in terms of differences in magnitude of effect is quite impressive. If you look at the Phase 1, which was the Kuvan responder study, they recorded a greater than 30% change in 20% of the patients. And obviously, now we're looking at 65% in this study. So, I think this is clearly a much higher response rate. And again, what we've talked about is really what you'd expect for a more bioavailable and potent cofactor, and obviously, in the phases you said, of a continuous diet.

Thank you for that. And would you be — do you expect to specifically report a response rate for classical PKU patients?

Yes, I mean, overall, we'll be — at the end of the day, we'll break that out as well.

Helpful. Thanks for taking my question.

Thank you. Our next question comes from Kelly Shi with Jefferies. Your line is open.

Thank you. So, for MIT-E data now in Q2, could you help to set an expectation on what kind of reduction of stage of frequency would be considered clinically meaningful? And what other merits we should also focus on to evaluate the clinical benefit of vatiquinone? And then lastly, given that the mitochondrial disease is a very heterogeneous disease, would you expect some groups of patients with certain like genotypes to see a greater benefit based on the mechanism of action of vatiquinone? Thank you.

Thank you again for the question. So, when we talk about benefit in these patients, first, we have to think about the disease itself. So, obviously, mitochondrial disease associated seizures are highly morbid and common aspect of the disease. So, about half the patients with mitochondria have seizures and these seizures don't tend to respond to typical antiepileptics, because the typical antiepileptics don't target the energetic pathways that cause seizures in these patients. In fact, many of the traditional antiepileptics are mitochondrial toxins, so they actually make the disease worse. These kids have seizures that are refractory to typical meds, they can have ten, hundred, even up to thousand a month. So, high seizure volume. It's a highly morbid aspect of disease which frequently leads to aspiration, pneumonia and other infections, and often can be the cause of death for these patients. So, when we think about meaningful reduction, most of the physicians we speak to think that even a 20% to 25% reduction in seizure frequency in these patients can be important. We've powered the study for a 40% differential reduction between the treatment group and placebo group with a hypothesized reduction of 50% in seizure frequency in the active population and 10% in the placebo population. In terms of differences between genotype and response, given the fact that vatiquinone is targeting 15-lipoxygenase, which is a common response pathway outside of the mitochondria, the treatment effect should be agnostic to underlying genotype, and might there be other patient characteristics such as age and stage of disease that could contribute to differential therapeutic response. That's possible. But one of the things we've observed in previous studies is there's no specific relationship between genotype or disease subtype and response, again, because we're targeting element common or response method common to all different causative genotype defect.

Thank you. Super helpful.

Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.

Hi. Good evening. Thanks for taking my questions. Maybe one point of clarification for Translarna. I think Stu and Matt, you've talked about the totality of data as being the premise for a lot of your discussions recently with the agency. But I guess as it relates specifically to dystrophin, if the agency looks for dystrophin as part of the package, can you just remind us when the last time dystrophin was measured in any of your trials to date? And how many patients' worth of data you might have on that?

Yes, sure. So, the way — obviously, the way the — you got to remember also the dystrophin was when we measured it, we measured it in Study 004, which was the first study that we did, to take a look to see its proof-of-concept studies where we showed — and that's a published paper, where we showed that you saw increased levels of dystrophin. And it was a small study, I think, I don't know, 15, 16 patients somewhere around there. And then, we redid Study 045. We did it again in Study 045. That was — we had 20 overall, and there were 18 in analysis population. So, we have those sets of patients. And then, we have, obviously, from a clinical point of view, studies from 007, 020 and Study 041 with a large number of patients where in the ITT population, especially in 041, we saw clinically significant results. And then, not only was it — as Matt had said before, that not only was that — not only was it positive there, but it was also positive in the North Star, the timed-function test. And that was true also in Study 020 as well as multiple endpoints in 007. So, there's a large body of data that demonstrates Translarna's activity in terms of treating patients. And that's then consistent with the STRIDE registry that we've done where we've looked at hard endpoints such as loss of ambulation, loss of getting off of — standing from the ground and loss of pulmonary activity. And then all those results demonstrating that you preserve both the ability to walk, to preserve the ability to get off from the ground and — by year, and preserve the ability to preserve pulmonary function. So, you put all that together — frankly, I have not seen a better clinical package than the one we have. And we believe it's pretty clear that patients benefit from it. And you can see that patients have been on it for now quite a long time. So, we believe — and we have patients from — obviously from around the globe, getting Translarna. And we always think it's appropriate and fair that we should work towards getting patients in the United States this drug. And what we're really asking for is, look, we'd like to — we think that we have a strong package. Let's review it. Let's have an advisory committee, and at least give us — and not just us the patients and their families a fair hearing, so that the folks who have been — and in fact, many of them have been on it for over a decade now, that to give them their due on what we think is a highly active drug.

Okay. Thanks for all that color. I mean, at this point, what do you think needs to happen to get the agency over the finish line for them to say that you should apply for approval? Have they looked at all this data already as part of your written interaction?

Yes. So, we're — look, what we think is we've had years now of working with the agency and not talking to them. And it's not just us. It's been the whole community has only had written discussions, and uncomplicated results with a large body of data, and they have plenty of new people there who may not understand the whole picture and have all the discussions. And not to actually — I simply don't understand that, not to have interaction where you have communication and you talk through it, and just like everything else that we do in life, you need to be able to go back and forth to give points of view that, and how you change people's minds or at least have a shot at it. One doesn't have an easy shot at it if it's every three months, you get the write a response back to questions. So, we think that at least what we need to do is to have a conversation and see where that goes.

Okay. And do you think that that will be sooner rather than later? Or do you have to wait that extra three months just to schedule it?

It takes time. This is the nature of regulatory discussions, you put it in, and there's time for them to get — fit you in.

All right. Okay. Got it. Thanks for that. Appreciate it.

Thank you. Our next question comes from Gena Wang with Barclays. Your line is open.

Thank you for taking my question. I have two questions regarding APHENITY study. First is just clarification. Regarding the 156 patients, these patients actually passed 15% Phe reduction screening test? Or was that 156 patients is a total patient that you screened? If it's 156 patients is a passed 15% Phe reduction, what is the total patient number you screened?

Hi, Gena. So, the 156 refers to all those who went through screening and then completed the run-in phase. So that's 156 subjects who received two weeks of sepiapterin. Of those 156, 102 or 65% had over 30% and 13 had between 15% and 30%. So, in total, that would be 115 or about 74% to 75% had 15% reduction and above. But obviously, far and away, the majority of those, 102 of those were greater than 30% reduction.

So, out of 156, how many of these achieved 15% Phe reduction?

So, of the 156 — so we said 102 had over 30% and 13 had between 15% and 30%. So, in total, that would be 115 or about 74% to 75% had 15% reduction and above.

Okay. Very good. Very helpful. And then, my second question is, can you remind us the rationale of dose escalation with two weeks each of the 20-milligram, 40-milligram 60-milligram for the Part 2 study?

Yes, sure. So, one of the things we're studying, obviously, that the agency always likes to understand is exposure response relationships, so by doing the two weeks at 20 milligrams per kilogram, two weeks at 40 milligrams per kilogram, two weeks at 60 milligrams per kilogram, we can have a very nice curve and understand the relationship between exposure and response, which is important for regulatory purposes. We believe the dose will be 60 milligrams per kilogram, and we're also very confident that two weeks is sufficient to understand what the effect at each dose level will be.

Thank you very much.

Thank you. Our next question comes from Jeff Hung with Morgan Stanley. Your line is open.

Hi. This is Mike Riad on for Jeff Hung. Thank you for taking our questions. First one, once the upcoming APHENITY data readout in May, can you remind us how you're thinking about the cadence and timing of regulatory events? And we have a follow-up after that.

Sure. Our goal is we'll get the result. And then, based on that, we'll obviously report out the results, so publicly and then as rapidly as possible have a set of meetings and get ready to an NDA for the product and get ready for regulatory guys as fast as possible. Obviously, we'll do a pre-NDA meeting. And while we're doing that, we'll be getting all the documents ready to go.

Awesome. Thank you so much. And my second question for the vatiquinone Phase 2/3 MIT-E data, they were expected this quarter, but they're now in the second quarter. Can you talk about any factors that led to the adjustment in timing? Thanks so much.

Yes, I think it's finishing up the last patient out. Matt, do you have any thoughts on this?

It's really a question of having now know exactly when that last patient last visit is going to be, which is going to be in March, and then having sufficient time to do all the database cleaning, the database lock and then getting to data. So, it's really a refinement of the timeline now that we know the definitive last patient last visit date.

Awesome. Thank you.

Thank you. Our next question comes from Paul Choi with Goldman Sachs. Your line is open.

Hi. Thank you. Good afternoon and thank you for taking our questions. I have two pipeline questions. First is on APHENITY. Can you just maybe elaborate on the updated timing from May of this year versus your prior guidance? And can you maybe speak to any geographical differences with regard to practice and clinical treatment of PKU patients in the US versus OUS that we might look for as you top line your results later this year?

Sure. So, I'll just take the first one. I think we've talked about this is the timing really had to do with the large the refinement of the timing of when we would complete the trial had a lot to do with just — there were a lot of patients at the end of the — when we were nearing ready to close the trial. And what we decided to do is — and it was a number of people that we wanted to make sure that some of their patients got in some of the KOLs would be able to do that and as such. We actually brought in more than we thought we would, and that extended the timeline that led to us getting the results, which we think now by everyone's in the trial now, and so we were able to give a pretty refined time on when we would be able to complete the trial. So, we feel pretty good about now that we know exactly where we're at when we complete the trial. In terms of the geographical differences, Matt, do you want to — any comments you want to make on that?

Paul, we really don't expect geographical differences while there may be different guidelines in terms of target Phe reduction in the region to region. The practice is fairly consistent worldwide. And obviously, this is a disease where the cornerstone of management is for now diet modification that starts at birth. Newborn screening is in place in many places around the world. So, we can certainly look at whether there's differential response based on geography, but it's not one that we would expect a priori.

Okay. Thank you for that. And as a follow-up on 518 for Huntington's, can you maybe comment or update us on what feedback or data you've provided to the FDA? And just what your current expectation is for getting the clinical hold lifted there?

Yes, sure. I think as we've discussed in the past, our goal is to share with them some data that we're getting with current patients and go back to them on that — which what we will be doing. And we think that — so, it's having enough clinical data on the set of patients that we can then go back and talk to them on. And so that's what we're doing in terms of that. But we've opened up obviously a fair number of sites around the globe. And so, patients are coming in. We even expanded to take an additional cohort of patients. So, we feel pretty good about bringing them in. And then, we'll bring in, at some point, when we have a set of data that we'll go talk to the FDA about and show them that we're in a pretty good ship. Just to remind everyone, we're doing the 5- and 10-milligram data that would then will be able to go to the 20-milligram data and we'll be able to bring our data to the FDA at some point so we opened it up in the US. That's our game plan.

Okay. Thank you, and congratulations on 25 years.

Thank you, Paul.

Thank you. Our next question comes from Danielle Brill with Raymond James. Your line is open.

Hi, guys. Good evening. Thanks so much for the questions. Just a couple of clarifying ones for me. I think last month at J.P. Morgan, unaudited 4Q revenues for Upstaza were $13 million. Is that number still accurate? And should we be expecting the spillover from the $20 million to $40 million you previously guided for in 4Q to be reflected in 1Q? And then, just a clarification on Translarna as well. The Type C meeting that you plan to request, will this one be in person, or are you expecting just written meeting as well? Thank you.

Yes, thanks for the question. And so, let me take Translarna. We anticipate this to be means where we — it will have conversation, so it's not going to be written. And I believe it's going to be a Zoom call, isn't that right, Matt?

We will request a live interaction obviously, and I know the agency has now started having in-person meetings again. So, the exact details, Danielle, whether this is Zoom, whether it's phone, whether it's live, whether they want to do it another way, obviously, it will be up to them and we'll know better once we submit the request and get their response. Obviously, we would be targeting in-person, but we believe that's the most effective form of discussion, but obviously, this is going to be up to the agency.

And then in terms of, obviously, the patient finding, in terms of Q1, obviously, we most of what we do is focused on identifying patients. And certainly, we remain confident that we want to move those in. In terms of the numbers, I don't think there were any changes in the 2022 numbers. And we'll probably provide more color about how we're doing. We're very early within the launch, right? So, I think we'll be able to provide more color on each of the quarterly calls and certainly at the Q1 earnings call, we'll provide more color on that. Kylie, do you have anything else to add to that one?

Thanks, Stu. As said, Danielle, there is no changes to the number for Upstaza from unaudited to audited. And as Stu said, we're continuing to focus on patient identification and continuing to focus on securing pricing and reimbursement in a number of different countries across Europe, as well as we talked about in January, focusing on looking at new patient programs outside of Europe. And so that's continuing according to plan. As Eric mentioned earlier, we're seeing strong engagement with payers across a number of different HTA bodies, and we look forward to being able to continue that pricing and reimbursement step to treat more patients in this, and we plan to provide more updates at upcoming quarter earnings.

That's helpful. Thank you.

Thank you. Our next question comes from Robyn Karnauskas with Truist. Your line is open.

Hi, this is Alex on for Robyn. We had a question on if there had been any updates into the patient finding or patients identified for AADC for Upstaza, but it sounds like we're going to wait until the first quarter to get some more results on that. Correct me if I'm wrong, we also wanted to now turn towards the US. Can you remind us of the prelaunch initiatives that are ongoing for Upstaza and what additional initiatives may still be needed as we approach BLA submission and anticipated future launch? Thanks.

Yes, sure. Thanks, Alex, for the question. We currently are seeing the dynamics in Europe, but we're also preparing for the launch of Upstaza in the US in a similar way, and we have a dedicated team that's actually doing that. We have focused on a number of key areas, including accelerated disease awareness. We have a number of key programs, including advisory board symposium and publications, key publications and peer review that have been in English, it's also US-based journals. We're talking to payers as well in the US and preparing for this launch. We're talking to a number of key payers about the design because we know that there are gene therapies currently approved in the U.S. but many of them are replacing standard of care. So, Upstaza will be the standard of care. So, we're taking an approach to really understand how the payer view will be on this. We have accelerated a number of patient finding activities, particularly in the high enriched population. And looking at — and also ethnic type groups. We have already where our target is to compare somewhere between 7 and 10 surgical centers to be ready at the time of launch. And importantly, this will be timed and these centers will be timed with the time of launch, we'll be able to work very closely to bring these patients in. So overall, I think we're very pleased with the progress we're making outside of Europe, but we're also sharing a lot of the knowledge from the launch itself in Europe, and we're sharing that continuous learning and execution that we have with the US market, following the BLA approval, we'll be ready to launch the product in the US.

Okay. That sounds great. And also on the same note, now that there have been patients treated in the real-world setting, do you find that the clinical results — this early, still early clinical results that you're seeing and details along with the procedure, match that of the what you saw in the clinical trials, or are there any key differences to note? Thanks.

No, we're — look, it's a nice aspect of AADC deficiency and the gene therapy that we have as we see it is truly a transformational therapy where — and as you've seen that all of the patients perform better in their patients that obviously, while they were growth arrested and weren't able to hold their head up, turn over, sit up, stand or talk have changed. And clearly, you can see some patients where we have one patient that speaks three languages. So that's been exciting, and we continue to see substantial improvement in these patients. So, there's — as we always say, there's nothing more ratifying than being part of a drug therapy and bringing it to patients and having such transformational facts on it. I think that's — it's great for the family to see what it does for the family, the patients and for our own community for just being part of bringing it to them. So, we're excited about it, and it continues to be a transformational product.

Yes. That sounds fantastic. Well, congrats, and thanks for taking my question.

Thank you. Our next question comes from Colin Bristow with UBS. Your line is open.

Hi, I'm calling on behalf of Colin. Thanks for taking our questions. We have two clarification questions. First, on the PKU data — congratulations on the Part 1 results. Could you provide more detail on the primary reason for the top-line delay to May? Enrollment for Part 1 was as planned and had a fixed timing endpoint, so we're trying to understand the rationale behind the delay. Second, on the PTC518 Huntington's disease program: have you heard any updates on more specific FDA requirements, and how long will it take to get the data? Also, regarding U.S. enrollment, has the high-dose portion already started enrolling? Please clarify.

Yes. I think if I — it was a little muffled. I think you're asking why is it in May? Was that the question? So, I think the — so I think maybe — so just so we're clear, the reason is it was the end of the study really occurs when it's the last patient last visit, you've completed that aspect of the study, and that's when all the patients are completed, you can then go and clean the data and ultimately get it analyzed. And really what happened is at the end of there was a large number of patients at the end of the study that were going in. And that's always in a way, a little bit of an air traffic control challenge to be able to get — bring in as many patients as you can and close it as rapidly as possible. And so that makes it — and we're balancing, wanting to close the trial, but also wanting to make sure that patients got in and that patients from multiple physicians get into the trial. And so that we don't anger anybody that they weren't part of it of the trial. And so that's always — it's always a little difficult sometimes to precisely land the plane at the time you think you're going to do it. And this one was in particular, much more at the end, had lots of patients. And that's why the timeline moved from where we thought it would be to May. It's nothing — it's a little bit longer, but we've gotten a lot of — we have a lot of the patients from people from all the key opinion leaders and investigators. So, at the end of the day, it was the small change, so well worth it because we have everybody in the study, and we feel good about it. So, I think that's — at the end of the day, that's what we're comfortable with. I don't think — and well worth the small amount of time change to get everyone in. So that — and in terms of 518, we're now collecting data. We haven't said yet when we're going to clean the data and go back to the FDA. But we plan to do this, and when we do, we'll let everyone know what our plans are, but we haven't done that yet. And we — I don't think we've set it up to say when we're going to complete that. Matt, anything else I have to say on that?

I would just add a couple of things on the PIVOT-HD. This was feedback that came from the non-clinical data that we had committed to the agency that was reviewed at the other agencies. And as we said, all the other countries have allowed us to start the study at 5 and 10 milligrams for a year and even start at 20 milligrams up to a year, and the FDA simply asked for some additional data to support the dosing and duration. As Stu said, we're in the process of collecting what we think will be robust clinical data that will provide comfort for the dosing and duration in the US. In terms of your question regarding the initiation of the higher dose, the 20-milligram cohort, that hasn't started yet. As we said, we want to look at the data from 5 milligrams to 10 milligrams to really make a data-driven decision based on what we're seeing in terms of pharmacodynamic effect, that is reduction in peripheral mRNA Huntington and protein reductions and biodistribution in terms of CSF exposure. Once we have an understanding of what that looks like at 5 and 10 milligrams, we'll then be in a position to make a decision regarding initiation of the 20-milligram cohort. And so, we look forward to having those initial 5 and 10 milligram data to help inform that decision in the near future.

Got it. Very helpful. Thank you.

Thank you. There are no further questions. I'd like to turn the call back over to Stuart Peltz for any closing remarks.

Okay. Thank you, operator. In closing, I'd like to thank all of you for joining the call today and your well wish for our 25 years. We're always excited about that. Especially excited about where we stand today at PTC, where we have, as you can see, strong and accelerating revenues from our product portfolio. We have four data readouts in the first half of 2023, including three registrational studies. So, clearly, we're firing on all cylinders, and we look forward to more updates for you over the coming months. And with that, thank you for staying on and good evening.

Thank you for your participation. You may now disconnect. Everyone, enjoy the rest of your day.