Ladies and gentlemen, thank you for standing by. Welcome to the PTC Therapeutics Fourth Quarter and Full Year 2024 Earnings Conference Call. All participants are in listen-only mode. After the presentation, there will be a question-and-answer session. Today's conference is being recorded. I would now like to turn the conference over to Ellen Cavaleri, Head of Investor Relations. Please go ahead.

Good afternoon. And thank you for joining us to discuss PTC Therapeutics' fourth quarter and year end 2024 corporate update and financial results. I am joined today by our Chief Executive Officer, Dr. Matthew Klein; our Chief Business Officer, Eric Pauwels; and our Chief Financial Officer, Pierre Gravier. Today's call will include forward looking statements based on our current expectations. These statements are subject to certain risks and uncertainties and actual results may differ materially. Please review the slide posted on our Investor Relations Web site in conjunction with the call, which contains information about our forward looking statements and our most recent annual report on Form 10-K filed with the SEC as well as our other SEC filings for a detailed description of applicable risks and uncertainties that could cause our actual performance and results to differ materially from those expressed or implied in these forward looking statements. Additionally, 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. I will now pass the call over to our CEO, Dr. Matthew Klein. Matt?

Thank you all for joining the call today. 2024 was a year of outstanding execution across every part of the company. With our many 2024 accomplishments, we are well positioned for success in 2025 and beyond. I will now review some of our 2024 highlights and discuss some of our plans for 2025. In 2024, our customer facing teams delivered another year of strong commercial performance. Fourth quarter revenue totaled $213 million and full year 2024 revenue was $807 million exceeding guidance. These results are a testament to our commercial team's ability to effectively execute around the globe even in genericized and competitive markets. With this strong commercial performance, effective OpEx management and the rapid monetization for $150 million of the PRV received with the KEBILIDI approval, we ended 2024 with over $1.1 billion in cash. And following the closing of the Novartis PTC-518 transaction, we received an additional $1 billion in January. This strong financial position enables several important things. It allows us to support our planned 2025 commercial launches, continue to invest in our innovative R&D platforms and engage in business development activities to complement our existing commercial and R&D portfolios. In addition, in this time of uncertainty on a macro level, our cash position provides the potential to reach cash flow breakeven without the need to raise additional capital. In 2024, we also achieved all clinical and regulatory milestones on schedule. We submitted four approval applications to the FDA, all of which were accepted for review. KEBILIDI for AADC deficiency, which was approved in November, Sepiapterin for PKU, which has a regulatory action date of July 29, 2025, Translarna for nonsense mutation DMD and Vatiquinone for Friedreich's ataxia, which was accepted with priority review and has a regulatory action date of August 19, 2025. These submissions create the potential to have four commercial launches in the US within 12 months. In addition, outside the US, we submitted a number of marketing authorization applications for Sepiapterin to support the planned global launch. In December, we announced a global development and commercialization collaboration with Novartis for the PTC518 Huntington's disease program. As part of the agreement, which closed in January, PTC received $1 billion upfront and is eligible to receive up to $1.9 billion in development and sales milestones. In addition, PTC will receive a 40% profit share in the US and double digit tiered royalties for ex-US sales. Novartis will assume all development, manufacturing and commercialization costs of PTC518 following completion of the placebo controlled portion of the PIVOT-HD trial. Strong economics of this deal are commensurate with the promise of PTC518 as potentially being the first disease modifying therapy for HD. As we look forward to 2025, we anticipate several value creating milestones, including the global launch of Sepiapterin, 12 month results from the PIVOT-HD study at PTC518 and a number of regulatory decisions in the US and around the globe. Starting with the global launch of Sepiapterin, there's a great deal of excitement in patient and physician communities for Sepiapterin given the significant unmet need and the strong data package generated to date. We continue to collect data that support the potential for Sepiapterin to address all key patient segments, including therapy naive patients, patients not well served by existing therapies and patients who have failed existing therapies. Eric will provide more details on our global launch planning shortly. Also in 2025, we look forward to the potential launch of Vatiquinone in the United States. If approved, Vatiquinone would be the first therapy for pediatric Friedreich's ataxia patients and could provide an effective and well tolerated treatment option for adults with FA. Turning to our PTC518 Huntington's disease program. In the second quarter, we plan to share 12 month results from all patients in the PIVOT-HD trial, approximately 140 in total, which includes Phase 2 two and Phase 3 patients. These results will include safety and tolerability data, biomarker data, including Huntington protein levels, as well as data on clinical scales, including the total motor score and cUHDRS. Based on our discussions with FDA in December, the results of this study could support Huntington lowering as a surrogate endpoint for accelerated approval of PTC518. In summary, with our strong performance in 2024 and demonstrated ability to effectively execute across every part of the business, we look forward to an exciting and successful 2025. I'll now turn the call over to Eric to discuss our commercial performance. Eric?

Thanks, Matt. Our commercial team continued its strong performance in the fourth quarter with revenue results driven by our in line products, including our DMD franchise despite significant challenges for both Translarna and Emflaza. I want to note that Translarna remains on the market in the EU and we continue to generate revenue in the first quarter consistent with 2024 levels and have even had new patient starts and we will continue to provide the only therapy to treat the underlying disease for nonsense mutation DMD patients as long as it remains authorized. As Matt mentioned, Translarna is currently under review by FDA and our experienced US team is well positioned to bring Translarna rapidly to patients pending potential approval. Our Emflaza performance was solid as we see continued brand loyalty from physicians, patients and caregivers. While there may be brand erosion for future generic entries, we continue to successfully defend Emflaza as we prepare to expand our neurology portfolio in the US this year with two potential new product launches. Moving to Sepiapterin for PKU, we are actively preparing for the potential upcoming global launches in the US, Germany, Japan and other key countries. We are focusing on key markets with approximately 58,000 addressable PKU patients where reimbursement of medical therapies is available. We will coordinate a specific strategic launch sequence targeting Sepiapterin access for a majority of these patients in the first 12 months of launch. The US represents the largest opportunity for Sepiapterin with approximately 17,000 PKU patients, of whom a vast majority are not on medical treatments. Of those, most patients have already tried existing therapies and were poorly controlled or failed and are currently without any treatment options other than a highly restrictive diet. The clinical efficacy of Sepiapterin supports its potential to address all PKU patient segments, including patients who have failed current therapies, patients who are not well controlled or tolerating current therapies and therapy naive patients including those with classical PKU. Our customer facing teams are actively profiling main centers of excellence and meeting with key stakeholders in preparation of the upcoming launch this summer. These stakeholders include healthcare professionals, nurse practitioners and metabolic dietitians who are instrumental to medical treatment decisions and are often the first line of contact with children and parents when diagnosed early. In addition, they also provide long term continuity of care well into their adulthood. Our key pillars of successful commercial launch are in place for Sepiapterin. First, along with the newborn screening, there is a well diagnosed prevalent patient population and these patients are closely tied to centers of excellence to manage their disease, even if many are not currently on medical treatment. Second, with the vast majority of PKU patients who have poorly controlled C-levels in need of effective therapy, Sepiapterin's well differentiated dual mechanism of action and clinically meaningful efficacy across a broad population of PKU patients positions its potential to become the future standard of care. Sepiapterin rapidly improves feed lowering, allowing many more patients to overcome the challenges of dietary restrictions and neurocognitive consequences of the disease. Third, the clinical profile of sepiapterin has been presented to many payers who clearly understand the value proposition of more effective feed control that can be measured rapidly via lab testing, potentially reducing the time for patients to receive therapy. With these pillars in place and leveraging PTC's experienced global commercial infrastructure for rare disease, we believe Sepiapterin has the potential to exceed $1 billion in revenue opportunity. Now turning to Vatiquinone program for FA where there is a significant unmet need for all patients. Our US commercial team is preparing to expand our neurology portfolio with an upcoming launch following a potential FDA approval this summer. The current approved therapy for FA is only indicated for patients 16 and older. In the United States, there is an estimated prevalence of 6,000 patients, about one third of them are pediatric and for whom there is no approved therapy. PTC has many years of experience in neurology, especially in raising disease awareness, which can increase earlier diagnosis, benefiting all FA patients. With the potential opportunity to introduce Vatiquinone as the first and only therapy for children with FA, we believe disease awareness and education will move diagnosis to occur sooner and at an earlier age, providing an opportunity to slow disease progression in more FA patients. There are also many adult with FA who are currently not on or cannot tolerate current therapy. And we believe Vatiquinone's well differentiated mechanism of action with long term safety and efficacy can provide an important treatment option for these patients suffering from this devastating rare neurological disease. This is a very exciting time for our global commercial team as we prepare for multiple new product launches throughout the year. With that, I will now turn the call over to Pierre for a financial update. Pierre?

Thanks, Eric. I will now share the financial highlights of our fourth quarter and full year 2024. Beginning with top line results. Total revenue for the fourth quarter was $213 million including $144 million from the DMD franchise. Translarna net product revenue in the quarter was $94 million while Emflaza had net product revenue of $50 million. Roche's fourth quarter global net revenue of approximately $415 million resulted in royalty revenue of $58 million for PTC. Our full year 2024 total revenue was $807 million exceeding guidance. This included DMD franchise revenue of $547 million and Evrysdi royalty revenue of $204 million. For the fourth quarter of 2024, non-GAAP R&D expense was $116 million excluding $9 million in non-cash stock based compensation expense compared to $113 million for the fourth quarter of 2023, excluding $8 million in non-cash stock based compensation expense. Non-GAAP SG&A expense was $76 million for the fourth quarter of 2024, excluding $8 million in non-cash stock based compensation expense compared to $68 million for the fourth quarter of 2023, excluding $8 million in non-cash stock based compensation expense. We have provided a wide initial total revenue guidance for 2025 of $600 million to $800 million, including in line products, potential new product launches and royalty revenue from Evrysdi. We plan to update our guidance as we gain greater clarity on several factors that could impact revenues, including regulatory decisions. We anticipate non-GAAP R&D and SG&A expense for the full year 2025 to be between $730 million and $760 million, excluding estimated non-cash stock based compensation expense of $75 million. Cash, cash equivalents and marketable securities totaled approximately $1.1 billion as of December 31, 2024 compared to $877 million as of December 31, 2023. In addition, in January 2025, we received the $1 billion upfront payment as part of the PTC518 Novartis collaboration. This strong financial position provides us with the resources to execute on our strategy and to achieve all our anticipated milestones as well as advance and expand our R&D efforts and explore business development opportunities to augment our commercial portfolio and pipeline. And I will now turn the call over to the operator for Q&A. Operator?

Thank you. At this time, we will conduct the question-and-answer session. The operator provided instructions for participants. Our first question comes from Kristen with Cantor Fitzgerald.

I have two, the first one is on PKU. So ultimately, the understanding out there is that diet liberalization is something that could impact patient treatment, both for naive patients as well as those on current other therapies. Do you have a sense of what the bar or the minimum that these patients would want to see in terms of liberalizing their diet to at least try Sepiapterin?

You've highlighted one of the most important factors for individuals with PKU: the ability to have a therapy that lets them liberalize their diet and simply take more protein. One of the most compelling parts of the evolving sepiapterin data package is evidence that the vast majority of patients can liberalize their diet. We will give an update on the feed tolerance protocol at the ACMG meeting next month, but as a preview we can show that over 97% of patients in the feed protocol are able to liberalize their diet and about two thirds reach the recommended daily allowance of protein and beyond, including a number of patients who reach twice the RDA. That means we are enabling virtually all patients in the protocol to take more protein, which is incredibly important; any amount of diet liberalization is meaningful. With sepiapterin treatment, many or most individuals can exceed the recommended protein level, which is not a small change but potentially life altering. Social media anecdotes reflect this too, with patients saying they are eating pizza and hamburgers and significantly changing their lives as a result of sepiapterin therapy. The trial data and these patient reports continue to support our conviction that we can deliver a meaningful therapy for the full spectrum of patients, including those not well served by current therapies and those with classical PKU who are therapy naive. We will keep collecting these data, and the story keeps getting stronger.

We'll definitely be interested in that presentation next month. And then on Friedreich's ataxia, I think a lot of people aren't necessarily giving this credit yet. So I'm hoping can you give us a sense of how you're thinking about the market opportunity? You laid out specifically the patient populations that you could target. But how should we be thinking about peak sales, anything around cadence of launch or anything that would be helpful for us as we think about modeling that?

I'll make a jump statement and let Eric comment on how we're thinking about preparations for the launch. Look, we're excited about this opportunity to be able to bring a therapy that's demonstrated to be safe and effective for the full spectrum of Friedreich's ataxia patients, including pediatric patients for whom there's no available therapies. The data package from MOVE-FA, the long term data from MOVE-FA study and the earlier placebo controlled study demonstrate that treatment has been associated with both short and long term modification of disease progression. We also have demonstrated strong safety in the full age spectrum of patients and really look forward to the potential of being able to provide therapy for all FA patients. Eric, do you want to talk a little bit how we're thinking about launch preparation and market dynamics?

First of all, to Matt's point, we're really thrilled that the FDA has accepted the file and given it priority review. It means there is a high unmet need for all FA patients. In particular, we are focusing on three areas immediately. The first is the pediatric population. We have well over eight to nine years of experience with pediatric neurologists, and we know the key children's hospitals where more than one third of these patients receive care. This is an incredibly important segment that currently has nothing. The dynamics in pediatrics are different from adults: healthcare providers and centers are organized around these children, and parents and caregivers are highly engaged in treatment and in ensuring early diagnosis. They view upright stability as an extremely valuable endpoint that is meaningful for their children and important for maintaining ambulation long term. These parents are also focused on high compliance, working closely with their children to ensure adherence and follow-up, and they are strong advocates for access to treatment. What is unique about this segment is that they are seeking a safe and effective treatment with limited or no monitoring requirements. The next segment for us is the adult population. As neurology experts, we understand there is a high unmet need among adults. It has been two years since the currently approved therapy was launched, and still about 80% of diagnosed patients have not received any therapy. There are also adults who are poorly controlled or cannot tolerate the current therapy.

Our next question will come from Eric Joseph with JPMorgan.

Three questions, I'll try to work in quickly. First, what kind of visibility do you have on the Translarna review time process in the US? Do you anticipate a formal PDUFA date in place ahead of the decision? Second, just as it relates to your top line guidance consistent where it was in January. I guess, how does that accommodate or factor in Translarna maintaining authorization in the EU? To some extent, do you think you should be thinking raising or trending kind of off the lower end of guidance? And then thirdly, as it relates to Vatiquinone and the PIVOT-HD update coming next quarter. I guess, how should investors be kind of framing their expectations when looking at measures of functional benefit given the slightly different mix in patients, including stage 3 disease versus the initial 12 month readout last year?

Let me start: I'll take questions one and three, and then I'll pass number two to Pierre. On number one, we know the review of Translarna is ongoing at the FDA. Clinical site inspections are moving along, so it's clear that a review process is occurring. We don't expect it will be an official PDUFA date given the circumstances of the resubmission and the fact that the review and inspections are ongoing, but we remain of the belief that we should have more information and an outcome in the first half of this year. Regarding Vatiquinone, we're planning in the second quarter to provide an update on the complete 12-month data from all subjects enrolled; that will include both stage 2 and stage 3 subjects. The key thing we'll look at here again is the biomarker data. As you asked about clinical outcome scales, we know different scales have different relevance at different disease stages: for example, the total motor score is particularly relevant for stage 2 patients, while in stage 3 patients the cUHDRS remains important as does the TFC. We will look at the whole population on each of those measures—TMS, cUHDRS and TFC—much as we did in the interim readout last June, and we will also look on a stage basis, at stage 2 and early stage 3, to see if there is a different clinical signature. The important point is we have the endpoints in place to capture a differential impact of treatment if one exists; if it doesn't, we could see the same pattern we observed with the interim readout last June. On top-line guidance, I'll let Pierre talk about the inputs to that and the potential for continued Translarna sales in Europe.

As it relates to our guidance for 2025, there's very limited assumed European sales in there. So as you pointed out, Eric, there's definitely room for upside there. And we will update our guidance as we gain greater clarity on several factors that could impact revenues.

One quick follow-up, if I could, on PIVOT-HD. I wonder whether there is the potential for a longer follow-up from the set of interim instead of patients reported in the interim last June, that is to say upwards of 24 months follow-up, particularly when it comes to Huntington decline in the CSF in those patients?

The short answer is, yes, it's possible. But the timing of that readout will be driven by having all of the data available for the 12 month time point. So it's just going to be a question of how much longer term data we have available. But clearly, we understand that there's a strong interest and understanding the effects on the biomarkers over time.

Our next question comes from Kelly with Jefferies.

I also have a couple for the PIVOT-HD trial. Firstly, from the 12 months to 24 months, what kind of improvement do you expect on total motor score and UHDRS and maybe also the TFC, the Total Functional Capacity? And also, can you help us on the info regarding the stage 2 and the stage 3 split for this pivotal trial. Is this relatively similar to the last interim update made for last year?

On your first question, as we move from 12 to 24 months, we expect to see continued benefit and a continued slowing of progression on the total motor score, the cUHDRS, and total functional capacity over time. We have the placebo group out to 12 months, but we fully expect to see continued slowing of progression relative to placebo and relative to the natural history of the disease. Regarding the patient split, overall the study is about half stage 2 and half stage 3. Keep in mind the data readout last June included only stage 2 patients because the initial inclusion criteria were stage 2 and stage 3 patients were added later. In the readout in the second quarter this year there will be more stage 3 patients with new data, and the overall 12-month dataset that includes the initial subjects from last June and this new readout will be a balance of stage 2 and stage 3.

Our next question will come from Tiago with Wells Fargo.

I just have a follow-up on PKU. Kind of one of the pushbacks that we generally get from investors is the low treatment rate for those patients. So I'm curious if you were to break down the $1 billion potential that you see in the US, part of that is an assumption on premium pricing, which you've kind of made clear. But how much of that is also the assumption on potential conversion of existing patients on therapy versus bringing patients back to medical treatment? I'm curious how much is conversion, how much is expansion and how to think about that $1 billion opportunity?

I think one of the important things to understand goes back to an earlier question about what matters for patients with PKU. Desire to be on therapy is often tied to whether the therapy allows diet liberalization. Without a therapy, people with PKU rely on a highly restricted, unpleasant diet, so if a therapy cannot provide diet liberalization there is little motivation to start it. That is why we've emphasized accessing all the segments you mentioned. We know from patients currently on therapy who see some benefit, and from our clinical studies and mechanism, that if you respond to BH4, whether branded or generic, you will likely have a much greater benefit from Sepiapterin, not only in terms of phenylalanine lowering but also in diet liberalization. Our data support that and also show benefit for patients with classical PKU as well as mutations thought to be non-BH4 responsive. We previously shared in vitro data showing significant effects on mutations considered non-BH4 responsive, and we see those mutations in patients in the APHENITY trial, where we can provide significant phenylalanine lowering. Taken together, our data clearly support the ability to access all of those patients. For patients on therapy, we can deliver a more significant effect if they are already benefiting from BH4. If you fail BH4, are therapy-naive, or have classical PKU and are not currently in clinic, we have shown we can address those patients and motivate them to return to clinic because we can offer the potential benefit of diet liberalization, which is what an individual with PKU really wants.

Our next question comes from Brian with RBC.

This is Joe on for Brian. On PKU, what is your sense on how the payers will potentially think about utilization management for those who are currently taking treatments and are looking to switch? And what about for those who are not on any treatments with prior experience in other therapies?

I'll let Eric talk about the work we've done with payers thus far.

So we have had extensive discussions with payers. We've also done significant research with both US and international payers. They absolutely see the profile of diet liberalization. They see benefits of additional feed control. They also see important aspects in terms of quality of life and neurocognitive protection. So these are many of the things that we see with payers. So essentially, what we're seeing right now is a willingness to pay the premium to Palynziq. But more importantly, with a large segment of the population right now, the segment that is actually uncontrolled, payers do not see any issue with going first line and those patients who are poorly controlled, failed therapies or even those who may be on the cusp of reaching potentially the goal but ultimately, physicians would like to have normalization and diet liberalization. So we have not had any pushback at this point in time with regards to our profile and the payers actually see very similar things physicians do and indicate a willingness to pay a premium to Palynziq.

Our next question is from Eli with UBS.

Another couple on the PKU launch. I guess, how should we think about the size of the target prescriber base and is it centralized or dispersed? And in terms of the population, I know you mentioned this a little bit in terms of Tiago's question, like, the longer term. But in the near term, as you approach a commercial launch, who's the population that you think could be the most rapid adopters and I guess how often do these patients see their physicians? And then just last one quickly just on the pricing, did I hear correctly you're talking about a potential premium pricing to Palynziq? Just want to clarify if I heard that correctly and your latest commentary on pricing potentially in PKU.

Let me start. I think I'll tackle the second one, then I'll pass the other to Eric. Eric will explain a little bit. We've clearly mapped these centers of excellence, and one important thing to bear in mind with PKU is that we're entering an established commercial infrastructure. There are centers of excellence, a well-coordinated patient community, and that makes the mapping exercise quite straightforward. We've not only made contact with physicians but, as Eric mentioned in his prepared remarks, with nurse practitioners and dietitians who are incredibly important members of the care team and often make care and prescribing decisions. So when we talk about contact with centers, there is physician contact, but even more importantly there is longer-term connection with the dietitians who manage patients' diets and who are not currently on therapy. When we think about the different segments and where the low-hanging fruit is or where we would go first, we have the ability to address each of these large segments. Unsurprisingly, the initial segments vary from center to center. The important message is that we can access all of them. There is enthusiasm at the centers to treat patients in each segment, and who gets treated first may vary by center. We do know there are centers with long lists of patients they want to put on the drug, and those lists can come from any of these segments. I'll let Eric provide a little more color on that and discuss pricing.

We have received tremendous feedback from these centers. We have profiled about 103 of these centers, which account for 90% of cases. Care is very centralized at diagnosis in infancy and remains very centralized as patients transition into adulthood. To Matt's point, it's very, very centralized. Our medical affairs and patient advocacy teams have been engaged at multiple levels. Physicians, dietitians, and metabolic geneticists want to use this as a first-line option for patients who are poorly controlled or who have failed prior therapies. Showing data in non-BH4 patients has been a real game changer; clinicians believe responders can gain important benefits, including the ability for more patients to relax dietary restrictions, which in turn improves quality of life. We have taken a number of preparatory steps. We expect many centers will have patients in the process of switching, along with patients who have the highest unmet needs and have not responded to other therapies. We also have a disease awareness program called PTC Reimagines PKU that physicians and healthcare providers can opt into, and enrollment is increasing each week and month. We are aligning staff and resources to manage what could be a significant influx of patients at launch following FDA approval. There is a high degree of awareness and strong interest in using this therapy across a broad population.

Our next question comes from Gena with Barclays.

I have two questions. One is regarding ventricle in Friedreich's ataxia. Did the FDA confirm that there will be no AdCom? My second question is regarding the PIVOT-HD data in the second quarter. Based on your FDA feedback, this will be an important data set to show the correlation between Huntington lowering and the clinical measurement. How would you define a correlation? For example, you have three cohorts: placebo, 5 milligram, and 10 milligram. Do you need to see a dose response across all three cohorts in terms of protein knockdown and its correlation to the functional measurement? You mentioned two different important measurements based on stage 2 and stage 3. How would you evaluate the different measurements, and which will be the most important for the FDA based on your feedback?

For your first question, the FDA, in the acceptance of priority review, said they had not yet reached a decision on whether they'll convene an AdCom or not. We expect we'll learn more as the review continues either at the day 74 letter or mid cycle meeting. So we'll, of course, update, as needed. Regarding the PIVOT-HD data readout, as you mentioned, FDA has supported scientifically the concept of HTT lowering, being likely to predict clinical benefit and then asked for us to show in the PIVOT dataset associations between changes in HTT protein levels and clinical measures. They were not prescriptive in terms of one correlation and R squared value, which endpoints. But simply said they wanted to understand from the data whether we can see some associations between changes in HTT protein and changes in the clinical measures that can support that over the longer term. The observed HTT lowering would, in fact, lead to clinical benefit, which is the essence of accelerated approval. And of course, I think it's going to depend a little bit on the data what we're able to show. I think one of the important take home points as you mentioned from the interim readout last June was the fact that we were seeing dose dependent changes on the clinical measures on TMS and on cUHDRS, that's really important because what it says is that if you're having twice as much lowering of Huntington protein, you're having a greater clinical effect. So even something as simple as that certainly supports the idea that the extent of Huntington lowering can influence your clinical course. So we believe we can have similar type of data that would be very supportive. Certainly, if we have outliers or those that have significantly more lowering and have significantly greater clinical changes, data points like that could also be helpful. So it's going to be a little bit of what the data look like. But I think there's a lot of different sources of association between the HTT changes and clinical effect.

If I can may just ask a quick question regarding the protein lowering. Did the FDA care more about the CSF Huntington protein lowering or blood Huntington protein lowering?

So we discussed Huntington lowering as a general concept. Clearly, looking at both the blood and the brain is important. Of course, it's with the understanding that the CSF changes are not a direct reflection of what's going on in the cells. And we've talked a lot about how the CSF is not a cellular compartment but in fact the blood cells are a better reflection of what's going on within the brain cells, because the drug activity is occurring on the neurons. Nonetheless, it is important to see what's going on in the CSF because it does give us a read on what's going on in the central nervous system with regard to Huntington protein. So I would say it's the whole package gene. It's looking both at the blood, the brain and what that's telling us about Huntington lowering and then of course then looking at the associations with the clinical scores.

Our next question comes from Joel with Baird.

This is a follow-up to a question a couple of questions ago. For PKU, you mentioned there's a long list of patients at centers with a bolus of patients waiting. Could you help us think through the cadence of when those patients could start on therapy of Sepiapterin and maybe what the rate limiting factors are for that?

What we were alluding to is the fact that, in general, we're seeing a significant amount of market pull now, a lot of enthusiastic patients, a lot of enthusiastic physicians, as well as other members of the care team and a desire to get on the therapy as soon as possible. Eric, do you want to speak a little bit of how we're thinking about cadence and ramp?

Cadence is really going to be based on how our teams are going to be prepared to handle the physician start forms. We know that those centers we're going to be preparing for already have a significant amount of experience with PKU medical treatments. So this is not going to be something new. We will be working with them very closely before and then after the launch to ensure that all the proper documentation will be assigned for those who actually have failed on previous therapies who are poorly controlled. That way we can minimize step edits and move directly into therapy. Our goal will be obviously to ensure that the time from the start form to the time to prescription is very, very short. And obviously, part of our goal is to align our staffing and ensure that our case management will be able to handle that bolus. And we're very confident with our previous experience in handling that with Emflaza and others that we'll be able to pull a number of these patients through and triage, if you will, the demand at the time of launch.

Our next question comes from Sami Corwin with William Blair.

I was pleasantly surprised to hear that you still have new patient starts on Translarna in Europe. I was curious if you expect that trend to continue into Q2, or what the current status of Translarna is in Europe. Also, how are you thinking about the timing of additional meetings with the FDA regarding Huntington's, and when do you expect to have alignment on a registrational path going forward?

In Translarna in Europe, we are in a bit of a unique situation. We talked about expecting a European Commission action, typically within 60 to 70 days of the CHMP opinion; I think on last count we are at day 133. What we do know is that the European Commission has voiced a desire to find a way to ensure that current patients remain on therapy. Until there is any action from the European Commission, the drug remains fully authorized in Europe. Not surprisingly, there is interest in continuing to put patients on therapy and keep patients on therapy. During this long procedure with Translarna, what was very clear was a strong physician conviction and patient conviction of the benefit of the therapy, the safety of the therapy, and a clear lack of alternative genetically targeted therapies for nonsense mutation patients. So we fully expect there to be interest in starting new patients while authorization remains intact and in continuing patients on therapy. That is what we have heard from physicians and patients, and it may also be the desire of the Commission as they try to find a way to keep patients on therapy. In terms of cadence of meetings regarding PTC518, after the data readout it will take time for us to absorb the package. We will obviously work with our partner Novartis; the partnership is underway and we are quite excited about how well the teams are working. One of the things we considered in selecting a partner for PTC518 was having a team that can bring a lot of resources to the effort and treat this as a priority program, and that is certainly what the partnership is demonstrating. There will clearly be a desire to understand the PIVOT-HD data readout and then move as quickly as possible to discuss with the FDA the potential for accelerated approval. In parallel, all hands are on deck and all efforts are moving forward with efficacy trial planning as we speak. Based on the data we have already seen from PIVOT-HD, there is clear evidence that the drug is working the way it needs to in terms of target engagement, dose-dependent Huntington lowering in the blood, what we are seeing in the CSF, and the early signals of clinical effect. We have exposure data confirming the necessary biodistribution to achieve the efficacy effect over the long term that we fully expect. So regardless of the outcome of the PIVOT-HD interim data readout in the second quarter, it is full speed ahead now in planning for that efficacy trial, whether that will be a Phase 3 trial under a standard pathway or a confirmatory trial under an accelerated approval scenario.

And will Novartis be taking the lead on those regulatory interactions now or will it be a joint effort?

I think as we said, the partnership is about a joint development committee that's going to work together on these key elements.

Our next question comes from Peyton with TD Cowen.

This is Peyton filling in for Joe, and congratulations on all the progress in 2024. You mentioned you are exploring business development opportunities in your prepared remarks. How likely is that to occur in 2025, and does it apply to all three therapies approved this year? Building on that, how do you plan to balance such opportunities with the internal pipeline, and do you plan to bring anything else from the internal pipeline into the clinics this year?

I'll make a few comments, then pass it over to Pierre. We're incredibly excited to be in a very strong position: we built a strong balance sheet with over $2 billion in cash, have a steady stream of ongoing revenue, and several promising prospects for future revenue, including the PKU program, which we view as a foundation for significant future revenue. We also have two valuable, highly differentiated scientific platforms that we are focusing on so we can fully leverage their potential. The PTC518-Novartis deal again demonstrates the promise of small-molecule splicing as a transformative therapy. Many have seen the recent New England Journal of Medicine article about Evrysdi showing that when a pregnant mother was given Evrysdi and the child was prenatally diagnosed with SMA, the child was born without any signs of SMA and after two years there are still no clinical signs. All of these factors continue to confirm the promise and potential of oral small-molecule splicing for genetic disorders. We will continue to apply our experience and the important learnings we've made. As PTC has always done, we'll populate our pipeline and commercial portfolio with a mix of our own innovative products and in-licensed assets. For business development, we will also look to leverage splicing as a source of early-stage strategic partnerships, because while there are many indications where splicing is relevant that PTC could develop and commercialize, there are other potential non-core indications, such as larger degenerative diseases and oncology, with splicing targets that could be valuable partnership opportunities. I'll let Pierre talk about how we're thinking about business development priorities, the commercial portfolio, and additional milestones for this year.

And as Matt mentioned, so BD has always been part of PTC's growth strategy. We'll continue to do so. I think we still have a few cards to turn, obviously. You mentioned it based on your question, is it dependent on those three products approval? We will utilize BD. The question is, are we going to go in near term commercial opportunities or is it going to be intermediate term? And obviously, if we are success across the board, I think our team will be extremely busy launching three products and we welcome that challenge. But obviously, we'll look at more intermediate term, I think that's the way we think about BD's multipronged approach. And let's turn a few cards to really see in which direction we go.

Our next question comes from Paul with Goldman Sachs.

This is Cleo calling for Paul. Thank you so much for taking our question. I guess I'll ask about, I guess, your capital position. So I see that you guys have a very strong cash position right now. And if you take out the asset impairment, it looks like you guys are close to breakeven. I guess the Translarna where is now standing, I'm curious to hear like what your capital deployment plans are for the remainder of the year?

One important aspect of our strong cash position is that it was built on the expectation that we would not receive any Translarna revenue from Europe in 2024 or 2025. The Translarna revenue we have been able to generate in Europe in 2024 and that we continue to see in 2025 is therefore upside on top of the very strong capital base we established. Given where we are today with a solid cash position and a strong foundation of revenue, the near-term prospects for the PKU program, the potential for Friedreich’s ataxia, and the potential for Translarna in the U.S. all represent meaningful future growth opportunities. As Pierre noted in response to the last question, this capital not only enables us to reach cash-flow breakeven and move beyond it without raising additional funds, it also gives us the flexibility to pursue strategic business development in a thoughtful, measured way to augment near-term, intermediate, and long-term commercial revenue.

Our next question comes from Tazeen of Bank of America Securities.

When we talk about splicing modulators in HD, can you maybe talk a little bit how your program could be differentiated from others that are also trying? In HD, for example, Skyhawk has a early stage program, I think it's 0515. And then I have a few questions on Translarna. So how should we be thinking about the cadence of the launch if approved in the US. Would the launches of the PMOs from Sarepta be good markers of examples on how to think about the pace of uptake among patients? How easy will it be for you to find the patients, the nonsense mutation patients here in the US? And then lastly, on Translarna, how are you thinking about the competitive landscape with the introduction of gene therapy, which does seem to be having a good initial update?

So, starting with the question around splicing modulation and competition: I think we've talked a lot about the essential elements needed for a successful splicing molecule. First, having a high degree of selectivity and specificity for the target; second, having full brain biodistribution, which is incredibly important because while Huntington's disease is thought at certain stages to primarily affect the basal ganglia, it is a full brain disease. If you're going to effectively leverage the benefits of huntingtin lowering, you need full brain biodistribution. When we look at some of the more advanced therapies now, PTC518 is the only oral therapy that is highly selective and specific for the huntingtin target and achieves full brain biodistribution. There are, of course, other therapies in much earlier stages that have a long way to go, but right now we're quite confident in our leading position in the field in terms of HTT lowering and the significant differentiating factors that make PTC518 unique and so promising. That is why to date we're seeing important evidence of huntingtin-lowering effect as well as safety and tolerability. On the Translarna launch question, PTC has been commercializing DMD therapies for a long time; we were among the first in the space, so our roots are deep and we're very well connected with patient and physician communities. In terms of capturing the market, I'll let Eric speak to the details, but one important point is that Translarna would be the only genetically directed therapy specifically for nonsense mutation DMD patients. A number of nonsense mutations fall into exons that may be relatively contraindicated or contraindicated for gene therapy, so we believe there is definitely room for a nonsense mutation–specific therapy. Eric, do you want to discuss the resources we have and how we would approach a launch?

We're very excited about the opportunity. I can only say it's really plug and play, to Matt's point. We believe we already have a very strong connection with the DMD community. We've treated thousands of patients over the last eight years and we have a database right now of all these patients who have been treated with Emflaza that we can go back into and provide genotyping and allow them to have access to it if they test for a nonsense mutation. We also have close to 150 patients in our clinical studies and many of them have been on treatment for almost 10 years, so they've been getting benefit from that. We would expect to convert them as well. So between accessing the existing database we have, our experience within DMD, and understanding that approximately 10 to 15 percent of the prevalent population could have nonsense mutations, we're already set to be able to provide the therapy to these patients in a very rapid manner. Having that experience over the last eight years is really, for us, a plug and play situation.

Our next question will come from David with Citi.

In terms of your meeting with the FDA on Huntington's in December, did they provide a framework for which clinical endpoints they want to see and what they want to see from them in an analysis?

They were not prescriptive. The FDA was not prescriptive. What they said is they certainly appreciate the scientific rationale supporting HTT lowering as potentially or likely to provide clinical benefit given the fact that it's a monogenetic disease, the disease is caused by the mutant Huntington protein and the wealth of preclinical and some clinical evidence showing that lowering Huntington has in fact been associated with clinical benefit. So with all of that as background their ask to us was to look at the data that we're collecting and be able to show some associations between changes in HTT levels and clinical effect. And so they were not prescriptive in terms of specific P-value, specific endpoints, specific correlations or analytical methods. But simply said as we look at the data, can we provide some evidence that there's associations. And so we've talked about the dose dependent effects we observed at the interim cutout. And of course, that's one example that supports that the more Huntington lowering you get, the more differentiated clinical effect you could have. So those are the kinds of things we're thinking about heading into the full data readout in Q2.

And then towards that end, did they want to see some of that data with respect to the prior update or they just want to wait until after 2Q?

So to be clear, when we went into the meeting in December, of course, we provided them all the data that we had to date to provide them confidence that we were in fact achieving the magnitude of Huntington lowering between 20% and 50%. That in fact has been associated with clinical benefits. So that was an important part of the story as well as the dose dependent changes. Of course, they were aware that we're going to be having data on additional 100 patients in a few months and not surprisingly, they're interested to see if these trends continue as we turn the card over on the next 100 patients.

Our next question comes from Joseph with Leerink Partners.

A quick question on how you're thinking about the placebo arm versus published natural history, particularly on total motor score. Is that shaping how you're thinking about the larger cohort of patients and your ability to show associations with Huntington lowering that the FDA is looking for? Also other competitors in this space have switched to natural history comparisons after one year of placebo control. Is that something you're also doing? In other words, should we expect to see two year data in that smaller set of patients versus placebo or an external natural history control?

I think the reason we do placebo-controlled studies is that they provide the best benchmark for the patients who enroll and are exposed to therapy. The whole concept behind the gold standard of a clinical trial is that patients are identical except for receipt of the intervention, in this case PTC518. While the placebo group might look a bit different than natural history, that reflects the fact that Huntington’s disease is heterogeneous. Even within stage 2 there are specific factors that could be driving progression, which highlights the importance of a placebo group. In PIVOT-HD we stratified patients by the PIN score, which is a prognostic score that predicts how rapidly patients will progress. We did that because even within stage 2 a number of factors can affect a patient’s baseline status, such as baseline TMS or other scores, and how quickly they progress. We are not concerned by how the placebo group looked; in fact we view it as very important because it provides a good benchmark of how similar patients would have done without PTC518. To our knowledge we are currently the only group in development with 12 months of placebo-controlled data, which we think is very important. Over longer terms we could consider using natural history to augment what we observed in the first 12 months, and that is something we can do over time.

Thank you. This concludes the question and answer session. I would now like to turn it back to CEO, Dr. Matthew Klein, for closing remarks.

Thank you all again for joining the call today. We are incredibly excited about the successes of 2024 and the incredible strong position the company is in for continued success in 2025 and beyond. We look forward to a number of catalysts coming this year and sharing them with you and continuing our growth and success. So again, thank you all for joining the call and have a good evening.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.