PTCT - NASDAQ

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. [indiscernible] fourth quarter global net revenue of approximately $415 million was achieved by Roche, resulting 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 [Operator Instructions]. 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 and that is the ability to have a therapy that enables them to liberalize their diet, quite simply taking more protein. As we've talked about, one of the compelling parts of the Sepiapterin data package that's continuing to evolve is the evidence that the vast majority of patients are able to liberalize their diet. We're going to be giving an update on the feed tolerance protocol at the upcoming ACMG meeting next month in March. But I'll give you a sneak preview and say that we're going to be able to show that over 97% of patients in the feed protocol are able to liberalize their diet and about two thirds of patients are able to get to the RDA, the recommended daily allowance of protein and beyond, including a number of patients who are able to get to 2 times the RDA. What that means is not only are we enabling virtually all the patients in the protocol to take more protein, which is incredibly important for patients, any amount of diet liberalization is incredibly meaningful. But we're able to, with sepiapterin treatment, to enable many or the majority of the individuals to get beyond the recommended level of protein for you or me. So that's not only a little protein, that's really could be life altering. And I think what we've seen on social media, in fact, what you called out in your note in the research that you did on social media posts related to Sepiapterin is that we're hearing anecdotes from patients saying they're having pizza and hamburgers and really changing their life significantly as a result of Sepiapterin therapy. And that's what continue -- that evidence that we're seeing in trials that we're hearing from social media posts continue to support our conviction of our ability to deliver a meaningful therapy for the full spectrum of patients, including those not well served by current therapies and those with classical PKU that are therapy naive. So again, we continue to collect these data and the story keeps getting stronger and 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 for us. It means that there is a high unmet need for all FA patients. In particular, I think we're looking at three areas in terms of our immediate focus. The first is obviously the pediatric population. We have a significant amount of experience well over eight, nine years of experience right now with pediatric neurologists. We know the key hospitals, the children's hospitals where over one third of these patients exist. We know that this is an incredibly important segment that has nothing. The dynamics in the pediatric sector are incredibly important and quite different sometimes than the adult. Healthcare providers and centers are really organized around these kids and these children. The parents and the caregivers are very engaged in treatment and they really want to ensure these patients get diagnosed early. They look at the upright stability as being an incredibly value -- a valuable endpoint that is meaningful for their children and ensuring that they can maintain ambulation long term. Additionally, these parents are really focused on high compliance. So they're really working very closely with these children to ensure high compliance and treatment follow-up and are really advocates for access to treatment. What we know about this whole segment that's very different is they're really seeking for a safe and effective treatment that has limited or no monitoring requirements. The next segment really for us is in the adult population and I would say that we, as a neurology expert as well, understand that there is high unmet need in the adult population. It's been two years since [indiscernible] has been actually launched and there's still 80% of the patients who are diagnosed that have not had any treatment or have therapy. In addition to that there are adults who are poorly controlled and can't tolerate the [Technical Difficulty]…

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 -- I'll take one and three and then I'll pass number two to Pierre. So on number one, we know the review of Translarna is ongoing at FDA. We know that clinical site inspections are moving along and so it's clear that there is in fact a review process occurring. We don't expect it will be an official PDUFA date given the circumstances of the resubmission and why we can't guide to an official date given the fact that the review is ongoing and clinical inspections are well underway, we remain of the belief that we should have more information and outcome in the first half of this year. Regarding Vatiquinone, we're planning in the second quarter to provide that update on the complete 12 month data from all subjects enrolled. As you pointed out, that'll include both stage 2 and stage 3 subjects. The key -- we'll look at -- here again is the biomarker data. And then as you asked on the clinical outcome scales, we know that different outcome scales have different relevances at different stages of disease. So for example, the total motor score is something particularly relevant for stage 2 patients. In stage 3 patients, the cUHDRS remains important as does the TFC. So I think what we'll be doing there is looking for the whole population at each of those measures, at TMS, at cUHDRS, at TFC, much as we did in the interim readout last June. And then of course, we'll be looking on a stage basis, stage 2 and early stage 3 to see if we see a different clinical signature. But the important point is we have the endpoints in place to capture differential impact of treatment if one in fact exists. If it doesn't exist then we could very much 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 [28.33] [Indiscernible] 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, what we would expect to see is continued benefit and continued slowing of progression on the TMS as well as the cUHDRS and TFC as with time. And this is the -- of course, we have the placebo group out to 12 months but what we fully expect to see is a continued slowing of progression relative to the placebo and relative to what would be understood as a natural history of progression. Regarding the split of patients, overall in the study, it was about half stage 2 and stage 3. Now keep in mind, the data readout last June included only stage 2 patients since the initial inclusion criteria of the study was for stage 2 and then we added the stage 3 patients later. So what you should expect in the readout in the second quarter this year is there'll be more patients from stage 3 that have new data. But the overall 12 month data set that includes the initial subjects from last June and this new readout will be a balance of 2 and 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 is it goes back to one of the earlier questions about what's important for patients with PKU and the desire to be on therapy is often related to the ability to have a therapy that allows for diet liberalization. In the absence of a therapy, individuals with PKU rely on highly restricted, highly unpleasant diet. And so if a therapy is not able to provide the ability to liberalize that diet, there's really no motivation to initiate a therapy. And that's why we've talked about being able to access all of the segments that you mentioned, right? We know from patients who are currently on therapy and maybe having some benefit, we've demonstrated in our clinical studies and also just based simply on mechanism, we fully expect if you have a response to BH4 whether branded or generic, you're going to have a much greater benefit from Sepiapterin, not only in terms of phenylalanine lowering but also in terms of diet liberalization. And again, that's something our data substantiate. Our data also show that we're able to provide benefit to patients with classical PKU as well as mutations thought to be non-BH4 responsive. We previously shared some very nice in vitro data showing that we can have a significant effect on mutations of the enzyme considered to be non-BH4 responsive. And then, again, we see those mutations in patients in the APHENITY trial and we see that those are patients, again, who we can provide significant benefit in terms of phenylalanine lowering. So when you take that as a whole, we have a data package that clearly supports the ability to access all of those patients, patients who may be on therapies, we know we can actually give a more significant effect if you're currently having some benefit of BH4. If you fail BH4, you're therapy naive or have classical PKU and not currently at the clinic, we've shown that we can address those patients as well and motivate them to come back to the clinic because we can offer the benefit of being able to potentially liberalize their diet, which is what a subject -- which is what an individual PKU really would want to have.

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 basea 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 -- 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 of that exists and one of the important things to bear in mind with PKU is that we're coming into an established commercial infrastructure, right? There are centers of excellence, there's well coordinated patient community and such, which makes the mapping exercise quite easy. The other thing we've done is not only we made contact with physicians but also importantly, as Eric mentioned in his prepared remarks, nurse practitioners and dieticians who are incredibly important members of the care team and often make care and prescribing decisions. And so when we talk about contact with centers, there's physician contact, yes, but there's also more importantly longer term connection with the dietitians who manage patients diets who are not on a current therapy. Now when we think about those different segments in terms of what are the low hanging fruit or where would we go first, given that we have the ability to address each of these segments and these are each large segments, we've heard not surprisingly that the initial segments vary from center to center. So the important message is we are able to access all of them. There's enthusiasm, enthusiasm at the centers to treat patients in each segment and who will get treated first may vary center to center. But we do know that there's centers where there's already lists of, very long lists of patients that they want to put on the drug that can come from any number of these segments. So I'll let Eric provide a little more color on that as well as talking about the pricing.

And we actually have a tremendous feedback from these centers. We have profiled all 100 -- actually about 103 of these centers that account for 90%. So it's very centralized at the time of when they're diagnosed at birth. And then as the continuity -- as they get into adulthood, so that to Matt's point, it's very, very centralized. Our medical affairs teams, our patient advocacy teams have been engaged at a number of different levels. And what we're hearing is that physicians, the dietitians, the metabolic geneticists, they immediately want to use this as first line for all the patients who are poorly controlled, who have failed. And what has been a really big game changer is actually showing the data in non-BH4. They believe that these patients who are responding can get really key benefits, including getting more patients to go and the diet liberalization component that that in turn leads to quality of life. So we've had a number of different things that we've done to prepare. We believe that many of these centers will have a number of patients in operating [Technical Difficulty] switch patients. And in addition to that, there'll be patients that have the highest unmet needs, the ones that haven't responded to therapy. In addition to that, what we're doing is we have a disease awareness center and program right now where physicians and healthcare providers can actually opt in. So it's called PTC reimagines PKU and we are seeing increased enrollment every single week and month for people who opt in into these programs. And what we're doing is aligning staff and everything else to handle what is potentially a very strong bolus of patients at the time of launch following FDA approval. So there is a high degree of awareness but also a high degree of interest in utilizing this 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 FDA confirm that there will be no AdCom? And then my second question is regarding the PIVOT-HD data in second quarter. Since this -- based on your FDA feedback, this will be important data set to show the correlation between the Huntington lowering and the clinical measurement. So how would you define there is a correlation? I think, for example, you have a three cohorts placebo, 5 milligram, 10 milligram. Do you need to see the dose response among all these three cohorts in terms of a protein knockdown and also the correlation to the functional measurement? And I think you did mention two different important measurements based on the stage 2 and stage 3. And how would you look across different measurements, which will be the most important measurements 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 in 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 [indiscernible] [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. And I guess I was curious if you expect that trend to continue into Q2 or how you're kind of expecting -- like what the current status of Translarna is in Europe? And then how are you thinking about the timing of additional meetings with FDA regarding Huntington's and when do you expect to have alignment on a registrational path going forward there?

In Translarna in Europe, look, we are in a bit of a unique situation, right? We talked about expecting a European Commission action within -- typically within 60, 70 days of the CHMP opinion, I think on last count or 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's any action from the European Commission, the drug remains fully authorized in Europe. And so not surprisingly, there's interest in continuing to put patients on therapy and keep patients on therapy. We've talked a lot about the fact that 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 there's 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 continuing patients on. And then again, that's what we've heard is the desire of the physicians, that's the desire of the patients, it's may also be the desire of the commission as they're trying to find a way to keep patients on therapy. In terms of cadence of meetings regarding PTC518, after the data readout, I think it'll take time for us to absorb the package. We'll obviously work with our partner Novartis and the partnership is underway and we're quite excited of how well the teams are working. And one of the things that we talked about in selecting a partner for PTC518 is to have a team that can bring a lot of muscles to the effort and also have this as a priority program, and that's certainly what the partnership is demonstrating. There will clearly be a desire to understand that the PIVOT-HD data readout and of course then move as quickly as possible to understand from FDA the potential for accelerated approval. In parallel, all hands on our deck and all efforts are moving forward with that efficacy trial planning as we speak. Based on the data we've seen already from PIVOT-HD, there's clear evidence that the drug is working the way it needs to work in terms of target engagement, dose dependent Huntington lowering in the blood, what we're seeing in the CSF and the early signals of clinical effect. We have the data in terms of exposure confirming that we have the necessary biodistribution to have the efficacy effect over the long term that we fully expect to have. So regardless of how of the outcome of the PIVOT-HD interim data readout in the second quarter, it's full speed ahead now in planning for that efficacy trial, whether that's going to be a Phase 3 trial under a standard pathway or the confirmatory trial under the 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 on for Joe, and congratulations on all the progress in 2024. I guess you mentioned you’re looking into exploring business development opportunities in prepared remarks. How likely is this to occur in 2025 and is this continuing on all three therapies being approved this year? And then kind of building off that, do you -- how do you plan to balance that 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 I'll pass it over to Pierre. Look, we're incredibly excited to be in the position where we're in an incredibly strong position where we built a strong balance sheet with over $2 billion in cash now, steady stream of ongoing revenue and a number of very promising prospects for future revenue on the horizon, including PKU program, which we've talked about as really being a foundation for significant future revenue. We also have two valuable platforms, highly differentiated scientific platforms that we have again focused our efforts on, so we can leverage the full promise of that science. I think the PTC518 Novartis deal demonstrates once again the potential promise of splicing, small molecule splicing as being a transformative therapy. I'm sure everyone has seen the recent New England Journal of Medicine article that just came out on Evrysdi showing that a pregnant mother was given Evrysdi and the child was born without -- child was prenatally diagnosed with SMA, the child was born without any signs of SMA. And in two years there' no clinica signs of SMA. And so all of these factors really continue to confirm the promise and the potential for oral small molecule splicing for genetic disorders. We clearly want to continue to put our efforts and leverage the experience we have and the important learnings we've made. So as PTC has always done, we'll continue to populate our pipeline and commercial portfolio in a combination of our innovative products as well as things that we in license. And of course, as we said, as far as business development goes, we also are going to look to leverage splicing as a source of additional early stage strategic partnerships, because while there's certainly a number of indications where splicing is relevant that PTC could develop and commercialize, there's also a number of potential indications that are non-core, such as larger degenerative disease and oncology where there's a number of splicing targets and that could be a very valuable source of strategic partnerships. So I'll let Pierre talk about how we're thinking about business development priorities in terms of the commercial portfolio and the 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?

I think one of the important aspects of our strong cash position is that it was built with an understanding that we wouldn't have any Translarna revenue contributions from Europe in 2024 nor 2025. So in fact, what we've been able to continue to generate revenue for Translarna in Europe in 2024 and continue to see in 2025 is all upside from the very strong base capital position that we've established. So I think it's important as we sit where we are today with the strong cash position, the solid foundation of revenue we have today and the very important prospects of near term revenue in terms of the PKU program, which we've talked a lot about, potential for Friedreich's ataxia, the potential for Translarna in the US is all sources of strong future growth from that -- from where we sit today. And as Pierre mentioned in response to the last question, we also -- having this capital not only enables us to get to the cash flow breakeven and beyond without the need to raise additional capital, it also is sufficient to allow us to do strategic business development in a thoughtful measured approach to continue to augment near term commercial revenue as well as 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. Look, I think we've talked a lot about the essential elements to have a successful splicing molecule. One, having a high degree of selectivity and specificity for the target, having full brain bio distribution, which is incredibly important while Huntington's disease at certain stages is thought to be a disease of the [indiscernible]. And it's not -- it's a full brain disease. And if you're going to effectively leverage the benefits of Huntington lowering, you're going to want to have full brain biodistribution. So when we think about some of the more advanced therapies now, PTC518 is the only therapy that's oral, highly selective and specific for the Huntington target, as well as achieves full brain bio distribution. Now there are of course other therapies in much earlier stages with a long way to go. But I think right now we're quite confident in our leading position in the field in terms of HTT lowering and the significant differentiating factors that makes PTC518 unique and hold so much promise. And is the reason why to date we're seeing such important evidence of [Huntington] lowering effect as well as safety and tolerability. On the Translarna launch question, PTC has been commercializing DMD therapies for a long time and we were the first in the space of developing DMD therapy so that our roots are deep and we're incredibly well connected with the patient communities and the physician communities. In terms of specifically capturing the market, I'll let Eric talk about it. I'll just make one important [concept]. This is -- Translarna’s proven [indiscernible] would be the only genetically directed therapy specifically for nonsense mutation DMD patients. And there are a number of the mutations with nonsense mutation DMD that fall into exons that may be relatively contraindicated or contraindicated for the gene therapy. So we believe that there's definitely room for a nonsense mutation specific therapy. Eric, do you want to talk about our resources we have and how we would go about a launch?

We're very excited with the opportunity. And I can only say it's really plug and play, to Matt's point. We believe that already we 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 that -- of all these patients who have been treated with Emflaza that we can go back into and obviously provide genotyping and allow them to have access to it if they test for nonsense mutation. We also have close to 150 patients that are in our clinical studies and many of them have been on for almost 10 years. So they've been getting benefit from that. We would expect to convert them as well. So between the context of going into the existing database that we have, our experience within DMD and understanding that there's approximately 10% to 15% of that, of the prevalent population that could have nonsense mutation, we're already set to be able to provide the therapy to these patients in a very rapid manner. So 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.

[Technical Difficulty] touch based on published natural history, particularly on total motor score. Is that [indiscernible] 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 on natural history control?

We missed the first part of your first question. You didn't come through. Do you mind repeating that?

Just in the smaller cohort, the 12 months data, the placebo arm looked slightly worse than what we would expect on natural history, especially on total motor score. Does that affect how you're thinking about the larger cohort of patients and your ability to show the associations that the FDA is looking for?

So I think the reason we do placebo controlled studies is because they provide the best benchmark for the patients who enroll in the trial and are exposed to therapy, that's the whole concept behind a gold standard of a clinical trial is the patients would be identical except for the receipt of the -- or except for receiving the intervention, in this case, PTC518. So while it might be that the placebo group looked a bit different than natural history, I think it speaks to the fact that HD is a heterogeneous disease. And even if you have patients who are specifically stage 2, there's specific factors that could be driving their progression. And again, that highlights the importance of having a placebo group. One of the things we did do in PIVOT-HD was to stratify patients by what's known as the PIN score, which is a prognostic score of -- so that is predictive of how rapidly patients would progress. The reason we did that is because even within stage 2, there's a number of other factors that could impact, one, a patient's baseline status in terms of baseline TMS or other scores and two, how quickly they would progress. So I think we're not at all concerned regarding what the placebo group looked like. But in fact, we hold on to that as being very important, because it is a very good benchmark of how similar patients would have done if they did not receive PTC518. I think we're currently the only group in development right now that has 12 months of placebo controlled data, which again we think is very important. As we get out to longer terms, we could certainly think about the use of natural history to augment what we've observed over the first 12 months, and that's something we can certainly 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.