PTC Therapeutics, Inc. Price & Performance (PTCT)

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, Doctor. 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 $213,000,000 and full year 2024 revenue was $8.00 $7,000,000 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 $150,000,000 of the PRV received with the Kability approval we ended 2024 with over $1,100,000,000 in cash.

And following the closing of the Novartis PTC-five 18 transaction, we received an additional $1,000,000,000 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 and D platforms, and engage in business development activities to complement our existing commercial and R and 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. Capability for AADC deficiency, which was approved in November, CPAPAREN for PKU, which has a regulatory action date of July 29, 2025, Translarna for nonsense mutation DMD and vatequinone for Friedreich's ataxia, which was accepted with priority review and has a regulatory action date of 08/19/2025. These submissions create the potential to have four commercial launches in The U. S. Within twelve months. In addition, outside The U. S, we submitted a number of marketing authorization applications for Cepiotaren to support the plan global launch. In December, we announced a global development and commercialization collaboration with Novartis for the PTC-five 18 Huntington's disease program.

As part of the agreement, which closed in January, PTP received $1,000,000,000 upfront and is eligible to receive up to $1,900,000,000 in development and sales milestones. In addition, PTC will receive a 40% profit share in The U. S. And double digit tiered royalties for ex U. S. Sales. Novartis will assume all development, manufacturing and commercialization costs of PTC five eighteen following the completion of the placebo controlled portion Strong economics of this deal are commensurate with the promise of 18 as potentially being the first disease modifying therapy for HD. As we look forward to twenty twenty five, we anticipate several value creating milestones, including the global launch of Seagate CKD013, twelve month results from the PIVOT HD study at 18 PTC, and a number of regulatory decisions in The U. S. And around the globe. Starting with the global launch of C. Diff Tarrant, there's a great deal of excitement at patient and physician communities for cbioterrorin PTC the significant unmet need and the strong data package generated to date. We continue to collect data that support the potential for PTC to address all key patient segments, including therapy naive patients, patients not well served by existing therapies PTC patients who have failed existing therapies PTC.

Eric will provide more details on our global launch planning shortly. Also in 2025, we look forward to the potential launch of vidicquinone in [indiscernible] If approved, betequinol would be the first therapy for pediatric pediatric cataxi Turning to our PTC-five 18 Huntington's disease PTC, In the second quarter, we plan to share twelve month results from all patients in the Tivity [indiscernible] approximately one hundred and forty in total, which includes Stage two and Stage three 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, results of this study could support Huntington lowering as a surrogate endpoint for accelerated approval of PTC-five eighteen. 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 will now turn the call over to Eric to discuss our commercial performance. [indiscernible] Thanks, Matt. Our commercial team continued its strong performance in the with revenue results driven by our in line products. Including our DMD franchise despite significant challenges for both Translarna 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 [indiscernible] As Matt mentioned, Translarna is currently under review by FDA our experienced U. S. Team is well positioned to bring Translarna rapidly to patients. Pending potential approval.

Our Emplaza 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 Emplaza as we prepare to expand our neurology portfolio in The U. S. This year with two potential new product launches. Moving to septiotheran for PKU, We are actively preparing for the potential upcoming global launches in The U. S, Germany, Japan, 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 septiotherin access for a majority of these patients in the first twelve months of launch. The U. S. Represents the largest opportunity for septiaterin 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 highly restrictive diet. The clinical efficacy of septiotharone supports its potential to address all PKU patient segments, including patients who have failed current therapies PTC, patients who are not well controlled or tolerating current therapies [indiscernible] 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 septiotheran.

First, along with the newborn screening, there is a well diagnosed prevalent patient population and these patients are closely tied to centers of even if many are not currently on medical treatment. Second, with the vast majority of PKU patients who have poorly controlled PTC levels in need of effective therapy PTC, Septiotarone'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 Septitarin 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 septiaterin has been presented to many payers who clearly understand the value proposition of more effective fee control that can be measured rapidly via lab testing. Potentially reducing the time for patients to receive therapy PTC. With these pillars in place, and leveraging PTC's PTC global commercial infrastructure for rare disease, we believe septiotharone has the potential to exceed $1,000,000,000 in revenue opportunity. Now, turning to vadiquinone program for FA, where there is a significant unmet need for Our U. S. 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 six thousand patients. About one third of them are PTC. And for whom there is no approved therapy PTC. PTC has many years of experience in neurology, especially in raising disease awareness, which can increase earlier diagnosis, benefiting all FAA patients. With the potential opportunity to introduce vitiquinone as the first and only therapy for children with FA, we believe disease awareness and education will move diagnosis to occur [indiscernible] 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 vitikinone'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. 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 $213,000,000 including $144,000,000 from the DMD franchise.

From FLORIDA, net product revenue in the quarter was 94,000,001 in FLASA, our net product revenue of $50,000,000 For every B, fourth quarter global net revenue of approximately $415,000,000 was achieved by Roche, resulting in royalty revenue of $58,000,000 for PTC PTC. Our full year 2024 total revenue was $8.00 $7,000,000 exceeding guidance. This included DMD franchise revenue of $547,000,000 dollars and every deal royalty revenue of $2.00 $4,000,000 For the fourth quarter of twenty twenty four, non GAAP R and D expense was $116,000,000 excluding $9,000,000 in non cash stock based compensation expense compared to $113,000,000 for the fourth quarter of twenty twenty three, excluding $8,000,000 in non cash stock based compensation expense.

Non GAAP SG and A expense was $76,000,000 for the fourth quarter of twenty twenty four, excluding $8,000,000 in non cash stock based compensation expense, compared to $68,000,000 for the fourth quarter of twenty twenty three, excluding $8,000,000 in non cash stock based compensation expense. We have provided a wide initial total revenue guidance for 2025 of $600,000,000 to €800,000,000 including in line products potential new product launches and royalty revenue from Eviti. [indiscernible] 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 and D and SG and A million million dollars excluding estimated non cash stock based compensation expense of $75,000,000 Cash, cash equivalents and marketable securities totaled approximately $1,100,000,000 as of 12/31/2024, compared to $877,000,000 as of 12/31/2020.

As In addition, in January 2025, we received the $1,000,000,000 upfront payment as part of the PTC-five eighteen 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 and 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 and A. [indiscernible] Thank you. At this time, we will conduct the question and answer session To withdraw your question, Again, Our first question comes from Kristen with Cantor Fitzgerald. Go ahead Kristen.

Hi everyone. Thank you for taking the question. 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 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 Cepiaterin?

For the question, Kristen. You 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 take in more protein As we've talked about, one of the compelling parts of the PTC 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 I I'll give you a sneak preview and say that we're going to be able to show over ninety seven percent of patients in the food 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 were able to get to two times the RDA. What that means is not only are we enabling work [indiscernible] which is incredibly important for patients. Any amount of diet liberalization is incredibly meaningful. But we're able with secretarial treatment to enable many or the majority of the individuals to get beyond the [indiscernible] 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 PTC. P. H. E. P. H. Is that hearing anecdotes from patients saying they're having pizza and hamburgers and really changing their life significantly as a result of CBTAN therapy PTC. And that's what continued that evidence 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 classical BKU that end therapy naive. So again, we continue to collect these data and the story keeps getting stronger.

Thanks. Appreciate that. 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 a cadence of launch or anything that would be helpful for us as we think about modeling that? Thank you again.

Thanks, Kristen. I'll make it. Joe's statement and then 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 Friedreichotaxia patients, including pediatric patients for whom there's no available therapy PTC. 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 post 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 [indiscernible] therapy for all FA patients. Eric, do you want to talk a little bit how we're thinking about launch preparation and market dynamics? Yes. Thanks, Matt, and thanks, Kristen, for the question. 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 SA patients. In particular, I think we're looking 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. Pediatric neurologists. We know the key hospitals and 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 that 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 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 neurology experts as well understand that there is high unmet need in the adult population.

It's been two years since omad has been actually launched and there's still eighty percent of the patients who are diagnosed that have not had any treatment or have therapy. In addition to that, there are adults are poorly controlled and can't tolerate those. About a third of those patients actually off that Our next question will come from Eric Joseph with JPMorgan. Go ahead, Aaron.

Thanks and thanks for taking the questions. Congrats on the quarter progress. 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 U. S. Do you anticipate a formal PDUFA date in place ahead of decision. Second, Just as it relates to your top line guidance, consistent where it was in January. I guess how does that accommodate or or factor in Translarna maintaining authorization in the EU, to some extent do you think you should be thinking raising or trending kind of up the lower end guidance? And then thirdly, as it relates to [indiscernible] 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 three disease versus the initial twelve month readout last year?

Thanks for the questions, Eric. Let me I'll take one and three and then I'll pass number two to Pierre PTC.

So on number one, we know the review of Translarna is ongoing.

At FDA. We've that clinical site in inspections are moving along. And so it's clear that there is an active review process occurring. We don't expect there 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 Vodafone, we were planning in the second quarter to provide that update on the complete twelve month data from all subjects enrolled.

As you point out, that will include both Stage two and Stage three 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 relevance at different stages of disease. So for example, the total motor score is something particularly relevant for stage two patients.

In stage three patients, the CUH DRS 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 CHOOS, 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 two and early stage three PTC see if we see a different clinical signature. But the important point is we have the endpoints in place to capture [indiscernible] 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 [indiscernible] Translarna sales in Europe.

Yes. As it relates to our guidance for 2025, there's very limited Translarna 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.

Great. Thanks. And one quick follow-up if I could, on Pivot HD. I wonder whether there's the potential for a longer follow-up the set of interim Since that are patients reported in the interim last June, that is to say upwards of twenty four months follow-up, particularly when it comes to Huntington decline in the CSF in those patients? Thank you.

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 twelve 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 in understanding the effects on the biomarkers over time.

Thank you. Our next question comes from Kelly with Jefferies. Go ahead Kelly.

Thank you. Congrats on the quarter and thank you for taking my questions. I also have a couple for the PTC HD trial Firstly, from the twelve months to twenty four months, What kind of improvement do you expect on Total Motor Score and UHBRS. And maybe also the TFD, the total functional And also can you help us on the info regarding the Stage two and the [indiscernible] for this pivotal trial, is this relatively similar to the last interim update? Mid of last year? Thank you.

Thanks for the questions, Kelly. On your first question, as we move from twelve to twenty four months, what we would expect to see is continued benefit and continued slowing of progression on the TMS as well as the CUH UDRS and TFC. As with time. And this is the of course, we have the placebo group out to twelve 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 of a natural history of progression. Regarding the split of patients overall in the study, it's about half stage two and stage three. Now keep in mind, the data readout last June included only Stage two patients since the initial inclusion criteria of the study was for stage two and then we added the stage three patient later. So what you should expect in the readout in the second quarter this year is there'll be more [indiscernible] from Stage three that have new data, but the all twelve month data set that includes the initial subject from last June and this new readout will be a balance of two and three.

Thank you for the clarification. [indiscernible] Thank you.

Our next question will come from Thiago with Wells Fargo. Go ahead.

I just have a follow-up on PTC. One of the pushbacks we generally get from investors is that the low treatment rate for those patients I'm curious if you were to break down the $1,000,000,000 potential that you see in The U. S, part of that is an assumption on premium pricing, which we've kind of made clear 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 one being [indiscernible] Thank you. Santiago, it's a good question. And think one of the important things to understand is 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.

PTC 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 is 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 PTC tarrin not only in terms of phenylalanine lowering, but also in terms of dilaboratization. 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 Afiniti trial. 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, is therapy naive or how 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 the diet, which is what is an individual PKU really would want to have.

Understood. All right. Thank you.

Thank you. Our next question comes from Brian with RBC. Go ahead, Brian. Hi. This is Joanne for Brian. Thank you for taking our question. 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 products experience in other therapies? Thank you.

Thanks for the question, Joe. I'll let Eric talk about the work we've done with payers. Thus far. Yes. So we have had extensive discussions with payers. We've also done significant research with both U. S. And international payers They absolutely see the profile [indiscernible] 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 that we see with payers. Can you hear me okay? Yes, okay. Sorry. [indiscernible] 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 in those patients who are poorly who may be on the cost 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. Makes sense. Thank you.

Thank you.

Our next question is from Eli with UBS. Go ahead.

Hey, guys. Thanks so much for taking the question. Another couple on the PTC PKU launch. I guess how should we think about the size of the target prescriber base? And is this centralized or dispersed?

And in terms of the population, and I you mentioned this a little bit in terms of Tiago's question, the longer term. But in the near term, as we approach 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 correct you're talking about a potential premium pricing to Palantade? Just want to clarify if I heard that correctly and your latest commentary on pricing potentially in PKU? Thanks.

For the questions, Ellie. Let me I'll tackle the second one then I'll pass the other. To Eric.

Eric, I'll explain a little bit. We've clearly mapped these centers of excellence. And one of the that exists and one of the important things to bear in mind with PK is that we're coming into an established commercial infrastructure, right? There's centers of excellence, there's well coordinated patient community and such, which makes it the mapping exercise quite easy.

The other thing we've done is not only make contact with physicians, but also importantly, as Eric mentioned in his prepared remarks, nurse practitioners and dietitians who are incredibly important members of the care team and often make care and prescribing decisions. And so in We talked about contact with centers, there's physician contact yes, but there's also more importantly longer term connection with 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 messages we are able to access all of them. There's 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 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.

Yes. And actually have a tremendous feedback from these singers. We have profiled all 100, actually about 103 of these centers that that account for 90%. So it's very centralized at the time of when they're diagnosed at birth. And then as the continuity 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 with 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 goal and the diet liberalization that in turn leads to quality of life. So we've had a number of [indiscernible] a number of patients in operating switch patients And in addition to that, there'll be patients that are at the high unmet needs, the ones that haven't responded to therapy PTC. 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 of interest in utilizing this across a broad population.

Great. Thanks.

Thank you. Our next question comes from Gina with Barclays. Go ahead Gina.

Thank you. I have two questions. One is regarding ventricular in factors ataxia. Did FDA confirm that there will be no added account? And then my second question is regarding the pivot HD data in second quarter. Based on your FDA feedback, this will be important data set to show the correlation between Huntington lowering and the clinical measurement. So how would you define there is a correlation? I think, for example, you have three cohorts placebo, five milligram, ten milligram, do you need to see the dose response among all these three cohorts in terms of protein knock down and also the correlation to the functional measurement.

And I think you did mention two different important measurements based on the Stage two and the Stage three. And how would you look across different measurements, which will be the most important measurements for the FDA based on your feedback?

Thank you for the questions, Gina. For your first question, the FDA in the acceptance with priority review said they had not yet reached the decision on whether they'll convene an adcom or not.

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 HGC 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 HCT 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 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 [indiscernible] TMS and on COH DRS. That's really important because once that 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 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 what the data look like, but I think there's a lot of different sources of association between the ACT changes and clinical effect.

Thank you. If I can may just ask a quick question. Regarding the protein lowering, did SEED care more about the CSF Huntington protein lowering or blood hunting protein? Lower And so we discussed Huntington lowering as a general concept, clearly looking at both the blood and the brain is in 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 talked a lot about how the CSF is not a cellular compartment, but 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 that's looking both at the blood the brain and what that's telling us about Huntington lowering and then of course and looking at the associations with the clinical scores. Our next question comes from Joel with Baird. Go ahead, Joel.

Hi, thanks for taking the question. 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 bolus of patients waiting Could you help us think through the cadence of when those patients could start on therapy of SYMPIATARIN PTC maybe what the rate limiting factors are for that? Thanks for the question, Joel.

What we were alluding to is the fact that in general, we're seeing a significant amount of 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. Yes. 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 the centers we're going to be preparing for already have a significant amount of experience With PKU medical treatments, 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 PTC assigned for those who actually have sailed on previous therapies, who are poorly controlled That way we can minimize step edits and move directly into therapy PTC. 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 bonus.

And we're very confident with our previous experience in handling that within Plaza 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.

Thank you. Thank you. See here that you still have new patients 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 a have alignment on a registrational path going forward there. Thanks for the question, Sami.

In Translarna in Europe, look, we are in a bit of a unique situation, right? We talked about expecting European Commission action within typically within sixty seven days of the CHMP opinion. I think on last count, we're 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 PTC. 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 PTC. We've talked a lot about the fact that during this long press 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 PTC 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 [indiscernible] And continuing patients on and again that's what we've heard is the desire of the physicians, that's the desire of the patients. It 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 PTC-five 18 PTC, After the data readout, I think it will take time for us to absorb the package. We'll obviously work with our partner Novartis and the partnership is underway. And and we're quite excited of how well the teams are working one of the things that we talked about in selecting a partner for PTC-five zero eight 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'll clearly be desire to understand that the PivotH data readout and of course they move as quickly as possible to understand from the potential for accelerated approval. In parallel, I'll answer 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 bio distribution to have the efficacy effect over the long term that we fully expect to have.

So regardless of how the outcome of the PIVOTI HD interim data readout in the second quarter, it's full speed ahead now and planning for that efficacy trial, whether that's going to be a Phase III trial under standard pathway or the confirmatory trial under the accelerated approval scenario.

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

Yes. I think as you said, the partnership is about a joint development committee that's going to work together on these key elements. Great. Thank you. Thank you. Our next question comes from Peyton with TD Cowen. Go ahead, Peyton.

Good afternoon. This is Peyton on for Joe and congratulations on all the progress in 2024. I guess, you mentioned looking into exploring business development opportunities in prepared remarks. How likely is this to occur in 2025? And is this continued on all three PTC being approved this year? And then kind of building off that, do you how do you plan to balance that with the internal pipeline you plan to bring anything else from the internal pipeline into the clinic this year? Thanks for the questions, Payton. I'll make a few to Pierre. Look, we're incredibly excited to be in a position where we're incredibly strong position where we built a strong balance sheet with over $2,000,000,000 in cash now, steady stream of ongoing revenue and a number of very promising prospects for future revenue on the horizon, including the PKU program, which we've talked about is 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. Think the PTC-five 18 Novartis deal demonstrates once again the potential promise of splicing, small molecule splicing is being New England Journal of Medicine article that just came out on a RISD showing that a pregnant mother was given a RISD and the child was born without a child was prenatally diagnosed with SMA, the child was born with any signs of SMA a two years there's no clinical 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 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 strategic partnerships. So I'll let Peter talk about how we're thinking about business development priorities in terms of the commercial portfolio and the the additional milestones for this year. Yes. And as Matt mentioned, so BD has always been part of PTC's growth strategy.

We'll continue to do so. Think we still have a few cards to turn, obviously. You mentioned it, Patan, based on your question. Is it dependent on those three products approval? We will utilize BD. The question is 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 I 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 multi pronged approach. And let's turn a few cars PTC really see in which direction we go. Great.

Thank you, guys. Thank you. Our next question comes from Paul with Goldman Sachs. Ahead, Paul. This is Kalia calling in for Paul. Thank you so much for taking our question.

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. Guess the Translarna worries notwithstanding. I'm curious to hear like what your capital deployment plans are for the remainder of the year? Cleo, thank you for the question. I think one of the important aspects of our strong cash position is that it was built 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 up 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 talked a lot about. Potential for Friedreich ataxia, the potential for Transline in The U. S. 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 be 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.

Got it. Thank you. Our next question comes from Tazeen of Bank of America Securities.

Ahead.

Great. Thanks for taking my questions. 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 an early stage program I think it's five fifteen. And then I have a few questions on Translarna. How should we be thinking about the cadence of the launch of the approved in The U. S? 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 U. S. 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 [indiscernible] Thanks for the questions, Tazeen. So starting with the question about splicing modulation and competition. Look, I think we've talked a lot about the essential elements to have as successful splicing 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 PTC certain stages is thought to be a disease of the striatum.

It's not, it's a full brain disease if you're going to effectively leverage the benefits of Huntington Loring, you're going to want to have full brain biodistribution. So when we think about some of the more advanced therapies PTC, PTC-five eighteen is the only therapy that's oral highly selective and specific for the Huntington target as well as achieve full brain biodistribution. 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 PTC lowering and the significant differentiating factors that makes PTC-five eighteen unique and holds so much promise and is the reason why to date seeing such important evidence of Huntington lower effect as well as safety and tolerability. On the Translarna launch question, PTC has been commercializing DMD therapies for a long time and and we were the first in the space of developing DMD therapies. So 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, if approved in U. S, would be the only genetically directed therapy specifically for non sense mutation DMD patients. And there are a number of the mutations with nonsense mutation DND that fall into exons that may be relatively contraindicated or contraindicated for the gene therapy. So we believe that there's a 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? Yes. And Tasien, thanks for the question. Good to hear from you. 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, of all these patients who have been treated with Emflaza, that we can go back into and obviously provide genotyping and and allow them to have access to it if they test for nonsense mutation. We also have close to 150 patients that are on in our clinical studies and many of them have been on for almost ten 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 ten percent to fifteen percent 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 plug and play situation.

Thank you.

Our next question will come from David with Citi.

Ahead, David. Thank you very much for taking my question. 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 Thanks for the question, David. They were not prescriptive. The FDA was not prescriptive. What they said is they certainly appreciate the scientific rationale supporting HT lowering. As potentially or likely to provide clinical benefit given the fact that it's a monogenic disease. The disease is caused by the mutant hunting 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, they asked us was to look at the data that we're collecting and be able to show some association between changes in HDT levels and clinical effect. And so that they were not prescriptive in terms of key values, 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 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.

Got it. Thanks for that. 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 what 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 2050%. 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.

Thank you very much for taking the question.

Thank you.

Our next question comes from Joseph with Leerink Partners.

Go ahead, Joseph. [indiscernible] Based on published natural history, particularly on total [indiscernible] Does that affect how you're thinking about the larger cohort of patients and your ability PTC 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? Thank you.

I apologize, we missed the first part of your first PTC Just in the smaller cohort, the twelve month 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?

Cohort of patients and your ability to show the associations that the FDA is looking for?

Okay.

Thank you for the question. 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 of the patients would be identical except for the receipt of the or except for receiving the the intervention, in this case, 18. 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 specific stage two, there's specific factors that could be driving their progression. And that's again, that's highlights the importance of having a placebo group One of the things we did do in PIVOT HD was to stratify patients what's known as the PIM score, which is a prognostic score of that is predictive of how rapidly patients would progress. The reason we did that is because even within stage two, 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 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 PTC-five eighteen. I think we're currently the only group in development right now that has twelve 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 twelve months. 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, Doctor. Matthew Klein for 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 the number of catalysts coming this year and sharing them with you in continuing our growth and success. So again, thank you all for joining the call and have a good evening. This does conclude the program. [indiscernible]