PTC Therapeutics, Inc. Aktie

All right. Welcome, everyone, to this session of the Morgan Stanley Global Healthcare Conference. I'm Judah Frommer, one of the SMid Biotech analysts here. We're very excited to have Matthew Klein and Pierre Gravier with us from PTC. I'm just going to read a quick disclosure, and then we'll get started. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

So with that, welcome again, guys. Between your commercial products and pipeline, there's a lot to talk about. Before we dive in, maybe give the audience just a quick intro to the company for those who may be less familiar with the story and how PTC has evolved over the last few years?

Absolutely. First, Judah, thanks for having us. Great to be here. PTC is a global rare disease company that discovers, develops and commercializes innovative therapies for diseases of high unmet need. We have a robust commercial portfolio with 6 marketed products that we deliver to patients around the world as well as a broad R&D portfolio, including 2 scientific platforms, including our oral small molecule platform, which has already demonstrated to be quite valuable and well validated.

So far in 2026, we're off to a great start with the continued strong momentum of the Sephience launch that continues in the U.S. and worldwide. And we remain on target to achieve the important milestone of being cash flow breakeven this year. So I think that really is an important milestone for the company and it's something that we've been working for over the past couple of years as we transform PTC into a diversified sustainable, profitable rare disease company.

Great. It's been a big evolution that we've noticed. So maybe we'll start with that Sephience launch. We're a little over a year in. Sephience revenue is already annualizing above what we've seen for Kuvan and Palynziq in the PKU space. So what's made this launch different from prior PKU and rare disease launches? And have there been any surprises along the way for you?

Yes, absolutely. Look, we're incredibly excited about the success of Sephience thus far, and we remain incredibly bullish on the overall opportunity, and we're very much on track to reaching that $2 billion-plus level of revenue we've been talking about.

I think there have been a number of surprises for everyone. But I'd say, first and foremost, what we're not surprised about is the success. I think this marketplace was quite misunderstood, and there was a belief that since there were 2 approved therapies, that didn't reach that $1 billion mark. It was hard for a PKU therapy to get there, and that's simply not true.

The success is really attributable to a number of important factors. First, Sephience, the drug itself. It's a differentiated molecule with a dual mechanism of action that uniquely allows it to have benefit for the full spectrum of PKU patients regardless of severity, it's classical and nonclassical underlying mutation regardless of age as well as being oral, convenient and having a very favorable safety and tolerability profile. That's differentiated.

Second is the fact that all the pillars for commercial success were there. There's newborn screening, there's centers of excellence. It's a well-aggregated community. All that was missing was a therapy that could address the broad 17,000 patients in the U.S. and 58,000 patients in global markets where we could commercialize.

Next, is our team. I mean we are an experienced team in terms of delivering rare disease therapy to patients, not only in the U.S. but globally. We have a patient services team that's very well accustomed to helping manage through a competitive landscape, providing necessary patient support. And quite simply, we are very good at executing on commercializing rare disease drugs. So when you put that combination together of the landscape of the marketplace, the quality of the product and the execution of our teams that this is what you get. Okay.

Right. Okay. Great. And you guys had a significant presence at the SSIEM meeting last month, where you shared some new data and analyses for Sephience, including data on Phe normalization -- what were the highlights from your data? And what do they mean for PKU patients in the real world?

Yes. We were certainly excited to have 17 presentations to be able to continue to reinforce the differentiated nature of Sephience as well as to bring forward real-world evidence that's substantiating that Sephience has been able to deliver meaningful benefits, not only in terms of phenylalanine lowering, but diet liberalization, increased protein intake in the full spectrum of patients.

And I think a couple of things I want to point out. One is we're still early in this launch. And I think when we think about all the success we've had to date, we still believe we have a very, very long way to go just given the size of the population and the market opportunity. And the SSIEM and these kinds of conferences are part of the launch playbook. We basically come in a year into the launch and be able to continue to support product differentiation and help foster uptake for the large number of patients who we believe can benefit from Sephience.

So I think some of the key data points were the fact that we're -- people have asked, well, we know that any -- your data show that any individual, who is on sepiapterin or Kuvan branded a generic has a much better response with Sephience, whether in terms of Phe lowering or diet liberalization.

But what about more severe patients in your trial? We had an abstract that showed that in all of our studies, individuals who came in with an over 900 micromole per liter phenylalanine level had the same response rate as those who had lower. So really addressing that question, right? We then had real-world evidence showing that severe patients with classical PKU were able to enjoy significant Phe reductions and liberalized diet with significant protein intake. That was really important.

So it's just these opportunities to show again and again why Sephience can be an important therapy for the full spectrum of patients and also to support the Kuvan switching to reinforce the fact that if you're on Kuvan and getting any benefit, switching over to Sephience can bring greater benefit.

And then finally, you mentioned the normalization abstract. That was really cool. That was from some of our clinical trial data where we showed in those patients who respond, the majority of them are getting to normal phenylalanine levels. So we know that lower is better in PKU and just being able to have presentations not only by us, but by KOLs doing their own independent analysis of their data just further strengthen the value proposition of the therapy.

Okay. Great. And heading into the launch, you estimated about 70% of PKU patients had tried Kuvan. And you've seen Sephience uptake among both treatment experience and treatment-naive patients, including in adults. So how much of the PKU population do you think Sephience could ultimately reach?

That's a good question. So that segmentation is something we did early on. And I think a couple of very important things to note there. First, the fact that 70% of -- our estimates of 70% of patients trying Kuvan tells us that, that we should expect. That's why we say we've got a long way to go on this launch in the U.S. and worldwide. But what's also notable and to your first question about surprises is early on, we had a number of patients from the naive bucket, that other 30% who have been tried on the therapy. And I think that was a little bit of a surprise because a lot of KOLs who were interviewed prior to the launch said, "Oh, these naive patients are the more challenging patients. Many of them are remote to clinic, and we don't anticipate that they're going to come back to clinic."

And we ourselves believe that we could help these patients. We thought that, that we'd be penetrating that segment a little later in the launch. That's not what happened. We actually had about 30% of patients to date have come from that therapy-naive bucket, who tend to be the more difficult to treat patients, classical patients. That's why they're therapy naive because it was believed that based on their genotype of having BH4 nonresponsive mutations or classical mutations, they were not likely to respond to sepiapterin.

So therefore, they weren't tried. So I think what we're seeing thus far, the data we see and what we're hearing continue to support that Sephience can be a drug for the full spectrum of patients. And we're seeing this and we're hearing from prescribers saying that this is moving to become first-line therapy and standard of care.

We're also now seeing physicians thinking a lot about saying, okay, we have newborn screening for PKU. Maybe we should be now moving Sephience to be starting shortly after birth. We had a very young child start in the U.S. recently with a severe mutation with great result. We know in Germany, recently, there was the first patient who went from newborn screening directly to Sephience therapy.

So again, this is all really exciting for us and reinforces the value of -- the potential value of Sephience across the full spectrum of patients, whether you bin them by severity, by age or previous treatment experience.

Okay. Excellent. And you've achieved, I think you've said 100% penetration across the original 100 or so centers of excellence in the U.S. and you've seen prescriptions from other centers as well. So how much of the PKU opportunity is contained within these original 100 centers? How should we be thinking about penetration from a center perspective?

Good question. I think we had -- the estimates we had is that about 80% of patients were tied to these centers. And then we found that we had additional centers that weren't in the center of excellence. And again, this is what happens at the launch, right? You make new learnings. I think for us, some of the important factors getting to 100% COE penetration this early in the launch is great because in every launch, you deal with early champions and those who are -- it takes a little while to get on.

But being in every center allows you then to focus on a center-by-center basis and say, how do we penetrate deeper and deeper. And again, this is just stuff you do at a launch. We have an analytics team that now is able to say, okay, we're in 100 centers, and we can now map within these centers, what are the key points to reinforce in Center 1 and what about in center 6. And this is exactly the work we're doing in order to penetrate deeper and deeper into these different centers. And they come in different sizes.

And a lot of these centers, one of the other learnings we've made is that while physicians may be sort of the spokesperson for a center and the individual who gets interviewed in many of these centers, particularly the larger centers, the prescription decisions are being made by nurse practitioners and physician assistants. And then you also have dietitians who are a point of contact for those not getting medical care.

And so being able to understand that on a center-by-center basis helps us then cater our field tactics specifically to each center to help continue to drive penetration deeper and deeper and deeper and also understand, okay, in a center with 7 prescribers, 5 prescribing, why aren't the other 2? Okay, how do we -- what's the data now that our teams have to have to go in and get that. So not only do we think we're well poised to penetrate deeper into these centers, but we're getting smarter in a way of actually what is that tactical map to achieve that.

Okay. That makes a lot of sense. Heading into the second quarter earnings print, we sense a lot of consternation about discontinuation rates being at this point in the launch. But it seems like you guys clearly cleared your own internal bar, and I think investors part as well on that front. So maybe talk a little bit about discontinuation rates you're seeing in the real world, how those compare to what you saw in clinical trials? And do you have any anecdotal cases of patients returning to Sephience after having discontinued?

Yes. So we said coming into the launch that in our clinical studies, if you look -- if you set a bar of about 15% phenylalanine lowering, we had 75% of patients got to that level. So we thought all along that in the real world, our discontinuation rate would be in that 25% neighborhood plus/minus. And we got to Q2, and we said we're about 20%, which is really good for a couple of reasons.

One is we believe we're getting close to steady state. Two, as I mentioned, early on, we've had a number of these more difficult classical patients. And to be able to be having that level of adherence said differently than the other side of discontinuation is really impressive in the most difficult patients. And we know now in the next phase of the launch, we expect to be penetrating deeper and deeper into the switch opportunity.

And the switch patients, those who are on Kuvan have already demonstrated themselves to be adherent on a once-daily therapy. And so now you're basically going to be switching individuals from a similarly tolerated once-daily therapy to a superior one that with potentially superior efficacy. And definitionally, these should be more adherent patients.

So all this gives us a lot of confidence that we're getting to that flat part of the discontinuation curve, which is really great. I mean, especially in a disease like PKU, where patients -- first of all, you can objectively measure response, which you can't do in a lot of diseases. And second, patients therapy -- patients use very burdensome dietary supplements and diet restriction in the absence of a medical therapy. So they're only going to come on a therapy if they perceive that there's going to be some benefit.

So it's -- again, so it's not the kind of thing where people are going to just stay on the therapy because they have nothing else. In terms of coming back on therapy, we do have that. And so again, this is one of the things we talk to folks to say, well, how much further can this launch go? We're in the first inning, right? And one of the things you do in a launch and our teams do is we make learnings. So we've had discontinuations in 2 main buckets. One is lack of efficacy, we know that 100% of patients are not going to respond to Sephience.

And then we had other things like patient preference, taste and texture and things you commonly hear. So we were able to take that data point and get a couple of folks on our patient services team to focus specifically on taste, taste and texture.

So now we have programs before an individual prescribed Sephience, they can now talk about that. Talk about different foods you can mix with Sephience. And we've now had a number of patients come back on therapy. So I think that's just a great example of what an experienced customer-facing team can do as you go deeper and deeper into a launch, leverage learnings, bring that back and continue to drive adherence and penetration.

Okay. And maybe just the reimbursement component of compliance, how has that been trending?

Very good. I mean -- so the payer policies have been very favorable. Part of this is coming into the launch, we had the AMPLIFY study. The AMPLIFY study was a head-to-head study of sepiapterin versus Sephience, and it was a crossover study. So we were able to say for each specific individual, what we're seeing. And again, we saw that 100% of individuals who had a response to sepiapterin had a better response to Sephience we quantified that. It was 70% on average, 70% greater phenylalanine lowering.

We had a 100% (sic) [ 126% ] increase in protein intake. So to be able to go to a payer and have those data from a well-done study in hand goes a long way to addressing needs for step edits and things like that. And in terms of reauthorization criteria, we've seen it pretty broad. It could be phenylalanine response, protein response and also medical benefit. And that's super important because what we're hearing quite often now is that individuals on Sephience are enjoying some of the cognitive benefits, less brain fog, less anxiety, improved mood that may or may not directly correlate with phenylalanine lowering. So this is another opportunity to capture benefit aside from the 2 quantitative factors like Phe lowering or protein intake.

Got it. Okay. Great. And maybe can you help orient us on the progress ex-U.S.? It's kind of been fast and furious lately. So how many countries have Sephience launched in thus far? And where are we in terms of access and reimbursement there as well?

Absolutely, we said this was going to be a true global launch. And we had the benefit of already having global infrastructure with the exception of Japan, where we built that team and they were ready and did a lot of market development work. So we were able to be in a pretty special position that within 6 months, we had European approval, U.S. approval and Japan approval. The ex-U.S. launch is going great. We started in Germany. We're still in the process of finalizing pricing and reimbursement there, but the launch continues. And Germany represents a pretty large opportunity for us.

We expect that once we have a final agreement on the price that we probably will see another inflection in patients because there's a number of folks there who are waiting for an agreed-upon price before putting patients on Sephience because they worry that the companies aren't happy, they may pull out and they certainly don't want to start patients out. We're in named patient programs in a number of countries in Europe, including the France AP2 program and some of the countries in Southeastern Europe.

We're in pricing and reimbursement discussions are starting them in a number of the larger markets in Europe. We started the launch in Japan at the end of Q1. So some of the growth that folks saw in Q2 came from the strong early trajectory in Japan. And that's a great market. While there's maybe about 1,000 PKU patients there, we have an agreed-upon price for the next 10 years on par with the U.S. net price. So that's actually a great value for us.

We have named patient programs going on in Latin America. We have getting ready to launch in the Middle East and North Africa. We have patients on in Canada. Brazil, we got the approval. As you know, the Brazil access procedure takes a long time, but you also know that our teams are very experienced, currently markets 3 therapies in Brazil. We know very well how that system works. We've already laid the groundwork to get the first injunctions, which will lead to the first group purchase order. So we expect a number of these other markets to really start kicking in, in 2027.

Okay. So I guess on with that mentioned, near term, is ex-U.S. expansion the most important driver for new patient starts? Or what would you say is most important in the U.S. versus ex-U.S.?

It's all important. And we expect global growth. And we said that we expect the growth in the U.S. to be steady and consistent. Again, we've gotten over 2,000 start forms, the 17,000 patients in the U.S. 70% of patients were tried on Kuvan. There's a long way to go in the U.S. And we expect that switch dynamic to start coming into play more and more as we go deeper.

I think growth outside the U.S. is going to have -- it's going to be steady with a number of inflection points. Each time we gain access in the market, you're going to see an inflection of a larger number of new patients coming on. So again, we expect growth globally to continue for a long ways.

Okay. So maybe tying the success with Sephience back to the raised guidance that you provided for the full year. I guess how much of that is Sephience versus the legacy DMD franchise? Maybe speak to the high and low ends of the guide as well?

I mean when we came into the year, we were very clear, there was a lot of unknowns for the year. We were very confident that Sephience is going to do well, but we were a quarter into the launch. And we have the DMD franchise, which we know is declining. We just didn't know at what rate. And so we were very clear that as we move through the year that we would continue to raise guidance. And now we're at $850 million to $950 million. Obviously, a lot of that is Sephience and our confidence in continued Sephience growth. It's -- we still don't have clarity how much more we're going to get out of the DMD franchise the rest of the year.

We're looking at it for Emflaza, there's 10 generics. So it's just a matter of time before someone drops that price and then you get a race to the bottom. That doesn't happen, we'll continue to take along. And so that's sort of been where we are with the DMD franchise, but our confidence in the top end of guidance really comes from our continued confidence in Sephience.

Okay. Great. I wanted to make sure we tick through several of the pipeline programs. So maybe we'll start with vatiquinone, right? You were guiding toward initiation of a Phase III open-label study this quarter. Where do we stand on study initiation there? Can you remind us just quickly the purpose of the study given the history with this asset?

Yes, absolutely. Yes. So following the CRL, we met with FDA and they were quite clear that they wanted an additional study to support NDA resubmission. They offered the possibility of doing a study that was open label with a natural history comparator. We expect that's in part because we had some evidence of efficacy, the safety of the drug is very well established. And they've used the Friedreich's natural history registry as part of a previous approval for Skyclarys. So they knew that registry. They've actually invoked it as an example of a very well-done natural history registry.

And so we designed a protocol with a statistical analysis plan, and we met again with FDA to just make sure that they reviewed that and they were okay that we were doing the study just to make sure that this could support NDA resubmission. So they gave us some feedback, some things to address in the protocol and analysis plan. We were able to easily do that, and we're still on target to initiate in this quarter.

Okay. Great. And just given the different endpoints available in Friedreich's ataxia, we've talked about mFARS and the upright stability scale. mFARS being the primary endpoint for this study. What's the FDA going to be looking at in terms of primary and secondary endpoints that will give them comfort given that a matched natural history?

Yes. I'll try to make this as -- so look, the mFARS has 4 components, one of which is upright stability. That mFARS, each of those different components of the scale kind of move at different stages of the disease and different ages of patients. And so over the short term, in a younger population, short term, meaning 12 months, maybe up to 18 months, most people believe that upright stability is probably the best place you're going to see effect, and that's what we saw in MOVE-FA.

As you move out to a longer term, all of the natural history studies show that you start seeing as you get out to 1.5, 2 years, contributions from other components of the mFARS. So we designed a study that's single-arm versus natural history comparator. And so what we want to do is by using the mFARS endpoint, allow for the ability to capture benefit on any component of the scale, understanding that the natural history is likely to progress 2 to 2.5 points a year with contributions from different scales.

So really, it was some -- a lot of thought that went into giving us the best chance to win in the study. And I think from the agency standpoint, they want to see evidence of a statistically significant effect on disease slowing to really confirm in a way what we saw in a shorter time period in the younger patients in MOVE-FA. Okay.

Great. And at the front, you talked about your oral splicing platform. So maybe we'll switch to Votoplam for Huntington's. Maybe just remind us of the opportunity for this program and the 24-month data you reported earlier this year and kind of incremental excitement from those data?

Yes absolutely. So we're incredibly excited about the Votoplam program. We've talked a lot about how the preclinical and clinical development programs for Votoplam followed in that successful development path established by Evrysdi, our first oral splicing molecule. So the development program was really designed in Phase I to do typical Phase I stuff, safety, pharmacology as well as get evidence in healthy volunteers of target engagement in HTT, mRNA and protein lowering, which we did.

Then we moved to Phase II. And in Phase II, the first part was about, again, establishing PK/PD relationship in individuals with Huntington's disease. Ensure that we're getting adequate CNS exposure to reach the desired 30% to 50% HTT lowering throughout the brain. Safety, obviously, very important as well as to get early evidence of clinical effect and understand what the optimal clinical trial population would be because that's a very big issue we saw again last week in neurological disorders.

And so when we got -- by the time we got to the 24-month time point, we had a lot of really important boxes ticked, safe, well tolerated. Drug was doing what it's supposed to do in terms of dose-dependent Huntington protein and RNA lowering. We're getting excellent CNS exposure in line of what we needed to be confident we're getting the level of reduction in brain cells that we're seeing in blood cells. Against placebo at 12 months, we had evidence of dose-dependent benefit. And then at 24 months against a well-matched natural history, we saw that we're having 52% reduction at the 10-milligram dose level relative to natural history. I'll also point out that Novartis is able to look both at the trajectory of the placebo group to 12 months and the natural history group to 24 months, and they almost overlap.

What does that tell you? That gives you a lot of confidence that we have a well-matched natural history group and that we can extrapolate the placebo group now out to 24 months to add to the robustness and the reliability of the finding of 52% slowing out of 24 months.

Importantly, we also learned about the right population to study. And this isn't a small thing. The hypothesis going into PIVOT-HD was that the Stage 2 patients are probably the right group, especially if you're targeting HTT protein, which is a causative factor in the disease. So you're going all the way upstream in the disease, earlier-stage patients are likely to enjoy a benefit or a more detectable benefit in a shorter period of time than more advanced patients. And that's what really teed us up for the INVEST-HD protocol where we're focusing on early symptomatic patients who have a normal TFC. So really looking very much like the Stage 2 patients from the PIVOT-HD study.

Okay. Great. And you and Novartis, you are planning to engage with FDA later this year to discuss those data and a potential accelerated path. So I guess related to accelerated path in Huntington's and even rare disease more broadly, it's tough to handicap what anyone. So I guess how is Votoplam positioned for that discussion. Can you remind us of the potential path to approval? You do have a Phase III study initiating. So I guess what are the potential paths here?

Absolutely. Look, Novartis has been very clear that their base case remains Phase III. Now they've included an interim analysis that gives the opportunity to get to a win earlier on a smaller number of patients at an earlier time point. Nonetheless, FDA appears headed towards the precedent of accepting an application for approval for Huntington's disease based on cUHDRS as intermediate clinical endpoint.

And so if that's going to be the case, I think the PTC and Novartis teams believe it's worth having a discussion when we're able to offer a data package with much more -- many more patients exposed, having placebo-controlled data having biomarker evidence of target engagement and protein reduction that's dose dependent, a better characterized safety profile because more patients have been exposed, a therapy that in the worst-case scenario could be withdrawn because it's oral.

And as you mentioned, the INVEST-HD Phase III study has started. So -- but 100%, Judah as you said, I'm not here to predict what FDA is going to do. Everyone -- no one should be confident in predicting that. And but this is simply a matter of saying, hey, if this precedent is being established in CBER, then it's worth a conversation in CDER and in parallel, keep moving forward on the Phase III. And that's the situation. And we've commented and Novartis commented that, that meeting will occur. We expect that meeting to occur in H2.

Okay. Perfect. Maybe just sticking on Huntington's. You have another splicing candidate targeting MSH3 entering the clinic in 2027. I think you said could be developed in DM1 or Huntington. So from a mechanistic standpoint and also for commercial considerations, how might this program complement Votoplam?

So we're really excited about the PTC303 MSH3 program for a number of reasons. I think it's the product of our renewed focus of PTC on the splicing platform. We always knew the power of that platform as a differentiated RNA platform. But we have a lot more intention now and focused resources on trying to bring things forward and the MSH3 program is the first result of that. It's also targeting a novel sequence that there's never been a splicing molecule for. So a lot of exciting things.

And as you mentioned, we're targeting MSH3, but it has application beyond just one disease. So we're looking at HD and DM1, both where triplet repeat expansion is an important part of pathology. In terms of complementing Votoplam, you've heard us say that we believe it is complementary. Votoplam is targeting HTT reduction, the mutant protein itself, whereas PTC303 will be targeting somatic expansion, which is another element in Huntington's disease pathogenesis.

I also believe that juvenile HD, for example, might be a subset of the HD population that may be particularly well suited. Why? Because juvenile HD, these individuals have rapid expansion. That's why they get early onset severe disease. So if you have a drug that slows expansion, targeting a population that has rapid expansion kind of makes a lot of sense.

Okay. Great. And in terms of endpoints and what we could be looking for in terms of what might be meaningful derisking for the program? What should we be thinking about for this one?

So if Votoplam followed the Evrysdi playbook. 303 will follow the Votoplam/Evrysdi playbook. So we're right now doing the IND-enabling studies. So the plan would be to get into Phase I in 2027. And again, use the Phase I study to give us important information on pharmacology, but also substantiate CNS exposure and leverage, again, the fact that we have systemic exposure and can interrogate peripheral blood cells to confirm that we're having target engagement and the desired effect on MSH3.

We're again in a situation where based on our preclinical research and the published literature that we need to be achieving approximately 30% to 40% MSH3 reduction to deliver a therapeutic benefit. So in terms of derisking, it's seeing in that Phase I study that we're able to get to that level of mRNA protein reduction at doses that are safe and well tolerated.

Just again, going back historically, same with the SMA program early on being able to show that we were able to have dose-dependent increase in SMN protein, especially at doses that were safe and well-tolerated blood cells and we had CNS exposure. That ticked a lot of the key boxes. Votoplam Phase I, similarly, we will show that we were getting into the brain, getting adequate CNS exposure, had dose-dependent mRNA reductions in Phase I. So really, that Phase I study becomes important derisking of all the things we know that need to be in place to have clinical success.

Okay. Excellent. I want to make sure we get to ST-920, the gene therapy for Fabry that you recently acquired in the bankruptcy auction, if I'm not mistaken. So maybe just tell us a little bit about the stage of asset that you're acquiring here, why this was attractive to you, a bit about the development history for this one.

Absolutely. We were very clear that we have a significant cash balance of over $2 billion. We have global commercial capacity and the team has demonstrated that it can execute on rare disease commercialization. And we were interested in trying to find products that could deliver $500 million to $700 million top line revenue, so we can really accelerate top line growth as we cross over to profitability. This was not on the radar screen to be clear. But it came to our attention that it was going into bankruptcy, that it was BLA stage.

So the approval application had already been initiated and the company didn't have the resources to take it across the line. So we started looking at this and we said, first, does the drug work? And on diligence, it does. You're making the -- Fabry is a disease where the standard of care is enzyme replacement therapy. If you can provide the enzyme, there's clinical benefit that's been approved therapies on that. So we're able to see that the gene therapy is producing the enzyme, there's enzyme activity out to 5 years. It's safe and well tolerated. There's no need for immunosuppression. You're seeing benefits in terms of stabilization of renal function. Those who came in on our ERT are coming off the ERT, there's all that is really, really strong.

The CMC package, we have experience. We've got an AAV gene therapy approved. We know exactly what that takes. So we had comfort that we could get the CMC package where it needs to be for approval. And from a commercial standpoint, we're in an interesting situation where our head -- our Chief Business Officer, Eric Pauwels, our commercial group launched Replagal. We have several people in our team who are involved in the Replagal launch.

We have a Board member who launched Fabrazyme. So we've got a lot of in-house knowledge on Fabry. In fact, our folks help build that marketplace. So we're pretty confident on the commercial opportunity. The deal should close in the next week or so. We'll work to complete the BLA by the end of the fourth quarter. And if all goes well, this could be a commercial launch next year.

Okay. Great. So I guess post that acquisition, maybe just to round out the conversation, where does that leave you from a capital allocation perspective? How are you thinking about uses of cash? And is this transaction a good benchmark for what business development might look like?

Yes. So look, as Matt mentioned, we closed Q2 with $2.2 billion cash. The transaction was $111 million upfront. So we still have a lot of firepower available to us. Obviously, we're laser-focused on executing. We can develop our pipeline and then obviously continue to be opportunistic and be disciplined with external business development transaction. We have a global infrastructure. We can feed in assets in the orphan space, that's very important.

And we said we could be cash flow breakeven this year. We're still on track. And after that, we're going to manage, obviously, OpEx based on revenues. We want to -- we said all along since 2023, the goal is to build a global rare disease diversified and sustainable. You achieve that by being profitable, and that's how we're going to look at it going forward.

Okay. Great. Well, we could keep going, but we're out of time. So thank you very much for being here.

Thank you, Judah.

Thank you.

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics' Fabry Disease Transaction Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Dr. Matthew Klein, Chief Executive Officer. Please go ahead.

Thank you all for joining this afternoon's call. Before I begin, I refer you to our forward-looking statements on the slide posted on our website as well as our Risk Factors section in our most recent 10-K. I'm excited to share the details of our planned acquisition of the ST-920 Fabry gene therapy asset. This was an opportunity to advance our strategy of leveraging our accomplished existing rare disease global commercial infrastructure and accelerate short- and intermediate-term revenue growth.

Our customer-facing teams have repeatedly demonstrated the ability to deliver rare disease therapies to patients worldwide regardless of treatment modality, including oral small molecule, ASO and gene therapy.

The ST-920 Fabry gene therapy program provided a unique opportunity to acquire a potentially transformative therapy at BLA stage without the need for significant investment or build-out of development, regulatory or commercial capabilities. This is a potential value-accretive transaction that puts another innovative and valuable product in the demonstrated capable hands of our customer-facing teams.

In fact, we have several commercial leaders at PTC with specific experience in marketing the existing approved Fabry therapies. We see the potential here for significant return on investment without impacting our potential to reach cash flow breakeven in 2026.

PTC was selected as the winning bidder for the ST-920 asset through a competitive bankruptcy auction. The terms include $111 million cash payment at deal closing and regulatory milestones of $80 million for FDA acceptance -- FDA accelerated approval and $20 million for FDA full approval. Of course, deal closing is subject to certain conditions.

As one of the few companies to have gained FDA approval for an AAV-based gene therapy, we applied that knowledge and experience to a detailed diligence process. In addition to review of the clinical efficacy and safety data, our teams focused on the various aspects of product manufacturing and quality that we know are critical to regulatory approval.

We are confident in the demonstrated safety and clinically differentiated profile of ST-920 as well as in the manufacturing and related quality processes. In addition, we believe there is clarity on the regulatory path and that our experience in gaining FDA approval for an AAV gene therapy product increases the probability of success.

ST-920 is a onetime intravenously administered AAV gene replacement therapy that enables the production of the alpha-Gal A enzyme deficient in Fabry disease. Notably, treatment administration does not require pre- or concomitant immunosuppression.

The BLA for accelerated approval is based on the findings of meaningful effect on alpha-Gal A enzyme production, renal function and other aspects of clinical benefit recorded in the Phase I/II STAAR study. The STAAR study included 33 adults with Fabry disease, both men and women with a variety of subtypes and ERT treatment history. Based on discussions with FDA, the key efficacy endpoint for the BLA is the mean positive eGFR slope from baseline to week 52 following gene therapy administration.

The finding of positive eGFR slope over 52 weeks is differentiated from other Fabry therapies, which demonstrated improved renal function, but still negative eGFR slope from baseline. Furthermore, all 18 study participants on enzyme replacement therapy at study start were withdrawn from ERT. Durability of effect has been demonstrated with sustained increased alpha-Gal A activity maintained for up to 4.5 years for the earliest treated study participant with evidence of maintained improvements in renal function.

Importantly, ST-920 has been demonstrated to be safe and well tolerated. The most common adverse events in the STAAR study were fever, COVID-19 and headache. ST-920 has received regenerative medicine advanced therapy designation as well as orphan and Fast Track designations from FDA. As I mentioned, the BLA submission for accelerated approval is based on the intermediate clinical endpoint of annualized eGFR at week 52 as aligned with FDA, with 104-week results from the STAAR study planned to provide confirmatory evidence to support full approval.

The non-clinical and clinical BLA modules have already been submitted as part of a rolling submission, with the CMC package expected to be submitted in Q4 2026. PTC also plans to pursue regulatory approval outside of the United States, again, leveraging existing regulatory and commercial rare disease infrastructure.

From a commercial standpoint, we see this as a potential meaningful global opportunity. There are an estimated 11,000 individuals with Fabry disease in the U.S. and a similar prevalence rate worldwide in countries where we intend to pursue registration.

In addition, the disease community is well aggregated and there are Fabry centers of excellence where the majority of patients are treated. Furthermore, there are several U.S. states and countries in which Fabry disease is included as part of newborn screening programs.

In summary, we are excited to bring another meaningful rare disease therapy to patients in need worldwide. The terms of this transaction preserve our firepower as we pursue our strategy to leverage business development to complement our existing product portfolio and demonstrated rare disease development and commercial capabilities.

I'll now turn the call over to the operator for questions on this transaction. Operator?

And the first question comes from Kristen Kluska with Cantor.

Congrats on this deal. I wanted to ask, normally, when we see gene therapies approved for indications where standard of care is already existing, these therapies don't do as well as some of the ones where there's already -- where there's no options at all. Why not you believe this is going to be the case with this asset? Maybe it sounds like the kidney benefits in particular, are going to drive a lot of the events.

And then separately, does this program have rare pediatric disease designation? And is there potential for PRV associated with that?

Kristen, let me take the second question first and then the first question second. So the study included only adults, though we clearly realize that there is the potential and one of the things we'll think about as we advance the program forward is to go into younger Fabry patients, certainly adolescent patients. So for right now, the main study included adults that did not have rare pediatric indications -- rare pediatric designation, though again, I think we see a potential here to explore that following the completion of the transaction.

Fabry is a pretty diverse and large population that includes individuals on ERT, not on ERT as well as Galafold. And I think one of the things as we were doing diligence here that was very attractive to us is how differentiated this therapy is. And the trial included all patients with different ERT history, different genetic subtypes, men and women.

And as I mentioned in the prepared remarks, when we actually look at the patients who were on ERT during the study, 18 of them, they were withdrawn from the ERT during the study. So that's our way of saying that we believe this is a very differentiated therapy and has the potential to make meaningful impacts for all patients, whether those who are on existing therapies, not on existing therapies and have different treatment histories.

And our next question will come from Tazeen Ahmad with Bank of America.

I wanted to get a better sense about how you're thinking about eligibility of ST-920 based on patients who have pre-existing antibodies, level of severity of disease, if there is, like what proportion of the Fabry population do you think would be particularly amenable to 920? And what's your view of -- it seems like the low-hanging fruit would be switch patients, but how are you thinking about newly diagnosed patients and what it would take to make this the first treatment that they get?

Thanks, Tazeen. I'll start and then I'll turn over -- turn the part of the question over to Eric for his comments. I think if you look at the inclusion criteria for the clinical trial, they were pretty broad, again, in terms of treatment history, men or women, genetic background, and there were certain -- an important limitation as an AAV6 gene therapy. So clearly, if you have demonstrated history of AAV6 antibodies, you would not be eligible for the therapy, and the inclusion criteria also included those with GFR of over 40.

Now that's been clinical trial inclusion. Obviously, one of the things we'll do as we dig further into this and work on our commercial planning, we'll look to understand broadening potential eligibility, ensuring as always, which is very important with all gene therapies, that safety first. But we believe that given the differentiated characteristics of this therapy, it could have broad utility across the full spectrum of patients.

Eric, do you want to comment? I'll also comment that Eric himself has experience having launched Fabrazyme years ago, and a lot of his team is -- a lot of our existing commercial team, including leaders in market access and other parts of the organization, have specific Fabry gene therapy commercial experience, which, again, made this sort of such a nice fit for the company.

Tazeen, thanks for the question. Yes, I was involved in some of the very first launches, as you know, globalizing Replagal. And what I think Matt described is really begins with clinical differentiation. If we look at the data, the durability of kidney and cardiac is incredibly important and meaningful and there hard endpoints. This onetime infusion with no pre medication is also something critically important. And we see durable, meaningful improvements, both in the kidney and the heart.

And what we learned about Fabry is early diagnosis and early treatment means better outcomes. And that the data that we saw showed that this durability happens irrespective of sex, whether it's prior ERT, Fabry subtypes. So we believe that ultimately, the label will be the label, but we look at this in the long term as a broad use for Fabry patients.

Okay. And how are you thinking about switch versus newly diagnosed?

And to Matt's point, we looked at the market -- and the marketplace is really segmented with ERTs. In some markets, particularly if you look at the key ones, U.S., Japan, Europe, Latin America, particularly Brazil, about 2/3 of those markets are ERT, okay? And there's a burden behind that.

There's pre-medication. There are infusions that require every 2 weeks. There's people that have to travel to the clinics. Those are a number of different things that have to happen compared to a onetime infusion in the clinic. And then what you're doing is monitoring, if you will, kidney function and cardiac function.

So I think the target here is a broad use. We've been able to show that irrespective of Fabry subtypes that this is effective, and we will be looking at this in a broader context. I think ERT is potentially a lower-hanging fruit, but earlier treatment will be the better choice. And that's something we'll be going after.

And the next question comes from Eric Joseph with Citi.

Just two from us. I'm wondering if there's potential for -- as part of the planned BLA or completion of the planned BLA submission, I'm wondering if there's potential for perhaps full approval given that I think about 2/3 of patients have already completed their 104-week follow-up.

And just coming back to the point around expected durability, any thoughts on -- or could you share some thoughts on what you think the ultimate durability of ST-920 to continuously express alpha-Gal A would be, just appreciating that some other AAV programs have resulted in attenuated gene product expression over time?

Eric, so look, there was pretty good alignment with the FDA in our review of the regulatory documents that this would be an accelerated approval based on 52-week data. Those data, the clinical module has been submitted. I think once all the data are available longer term, there will obviously be a process of going through that, analyzing that and at the right time, discussing with the FDA.

I think our base assumption and operating case right now is continuing with the plan as it was designed, which is that this clinical set would serve for accelerated approval, and then we would look to bring the long-term data for full approval. Clearly, we'll get a better idea of what that time looks like and whether that could be accelerated as we go a little further into the process.

And as you know, typically in the BLA process, you'll have your mid-cycle meetings and other opportunities to share what data may be available that could influence how the agency thinks about it.

In terms of durability, look, we're -- what we've seen so far in this product is really encouraging to have the 4.5-year maintenance of enzyme production levels, I think, is really, really important. And while one could say, sure there could be changes over time, what we've seen so far has been really impressive to us. And again, that durability effect we've seen, I think, gives us greater confidence in the strength of this therapy and what it could provide for patients.

And the next question is going to come from Ben Burnett with Wells Fargo.

This is [indiscernible] calling in for Ben. We just have a quick one. So what kind of CMC information are you -- can you share with this asset? I assume that this is probably working with the CDMO, kind of what kind of information do you know?

Sure. Look, as I mentioned, having taken a gene therapy across the finish line for approval as we did with our AADC program, we have a very good understanding not only of the importance of the CMC package, quality characteristics, CDMO, all that, but how difficult and challenging this is. So clearly, one part of diligence that was particularly important to us was ensuring that the CMC package looked good, which it does. There's a very clear process with specifications well thought out and PPQ lots being conducted.

And then the CDMO. CDMO for the production of this product is Thermo Fisher, which I think is a best-in-brand CDMO. And again, not surprisingly, in preparation for the file, there's already been mock inspections, and we'll continue to do those and make sure everything is in order for any potential inspection.

But again, I think what we've seen of the CMC program based on our experience and the quality work that the Sangamo team has done gives us a lot of confidence on the CMC package, and it's always reassuring to have a best-in-brand CDMO responsible for the manufacturing of the gene therapy.

And the next question is going to come from Ellie Merle with Barclays.

Congrats on the deal. Just a question on sort of the commercial landscape. I guess, how would you characterize the heterogeneity of the disease severity in Fabry? And I think of the 11,000 patients you cited, I guess, which of those do you think would be the most interested in gene therapy? Is it patients that are progressing on their current ERT or Galafold or showing symptoms? Or is it more of the burden of administration of ERT? And if you can elaborate on sort of how you're thinking about that segmentation of the patients.

Thanks for the question, Ellie. Again, I think what we see here is a pretty broad opportunity that was one thing that came through in the clinical data. I'll let Eric talk a little bit about how his team is starting in these very early hours thinking about the population market segmentation and a plan of attack. Eric?

Yes. I think we said that -- thanks, Ellie, for the question. From the commercial landscape, first of all, we have a footprint right now across multiple markets, and we know how to market not only gene therapy but rare disease, but also really get inside these clinics. And these clinics have a variety of patients.

When I launched Replagal, we -- in the very early days, what we thought in terms of severity were males, adult males that had symptomatic. And what we found out over time was that this is X-linked and of course, females, perhaps less symptomatic were also on enzyme replacement therapy.

I think there's a natural progression to think that there is definitely severity, and severity will certainly drive this. But with the durability of this data and the durability that we see not only in kidney function and heart function, this really is for a broader use.

The Galafold, obviously, there's only a segment of the market that can actually utilize this. So there's only certain Fabry subtypes. So far, what we've seen is that vast majority of subtypes going to may be able to respond to gene therapy and have a durable treatment, not having to take oral therapy every single day. So again, all of these factors play into broad use for Fabry.

And our next question is going to come from Brian Cheng with JPMorgan.

Just a quick one. As we think about the launch, can you talk a little bit about how much work needs to be done for the build-out of the commercial capacity? Do you have a sense of the capacity that you will have in place at the time you launch this product?

Brian, for us, I think one of the key factors here is the fact that we have the existing infrastructure globally with capacity. Obviously, we have a number of different products in the commercial portfolio at different stages of their lifespan. And we really believe that we have the capability to really just set this in with the existing infrastructure.

And that includes -- it's not only commercial in terms of launch but also regulatory and global regulatory capacity and understanding because getting this across the finish line, we have that experience, and I think we're very well suited to do that.

So again, this was really -- this is what made this a pretty special opportunity for us. We have existing capacity, existing expertise, and this is something that we could set in to what we have without any significant build needed.

And the next question is going to come from Judah Frommer with Morgan Stanley.

Congrats on the deal. Maybe you could just help us with a little more detail on the process here and the due diligence, the competitive nature of the process. Did you have a chance to speak with Sangamo, or was due diligence done in sort of a clean room environment? And then what could FDA interactions look like from here? Did you get a good sense of what they were previously and what the next ones will be?

Jud, thanks for the questions. I'll say we did a pretty thorough diligence process here. There was a sufficient time prior to the auction. There are several weeks' time that -- again, this was a matter for us of taking our team who knows this stuff inside and out, clinical team, CMC, quality, CMC regulatory, all of those folks were involved. We had a number of conversations with the appropriate folks in the Sangamo team to get questions answered.

Again, we were very impressed by the Sangamo team who worked incredibly hard and passionately to get this program and product forward to patients. And we, again, we made the decision to participate in the auction and clearly to make sure we had the winning bid because we believed in the potential here.

We clearly -- we carefully considered the clinical data, the safety data, CMC package and the like, and we're very comfortable with the promise of this therapy and our ability to get this across the line based on the quality of the package, the data combined with our experience. So that was really an important part of it.

It was a competitive process. There were multiple bidders. In fact, the auction took over 2 days, just to give you an idea of how competitive it was and how much interest there was in this asset. And look, for us, as I said, this was really a pretty good opportunity, unique opportunity for us to say the ability to get this asset, we think that we can generate a significant, significant return on investment based on what we think the potential market opportunity here is.

We can integrate it into the existing teams and existing infrastructure, existing expertise, and again, have been one of the few companies who've gotten an AAV gene therapy approved. We have the know-how to navigate the regulatory pathway.

And I'll also -- I think the other thing that's attractive here is we're able to bring in such a potentially valuable asset while still maintaining a significant amount of our firepower given the economic upfront consideration.

In terms of FDA interactions, the process is going on. We obviously -- we carefully reviewed all the previous regulatory correspondences and that made us comfortable that there was an aligned upon path forward for the submission for the confirmatory evidence. And we expect going forward, the submission to get completed and that it would follow a fairly standard review process where you have the typical agency back and forth, sometimes information requests, formal meetings around mid-cycle or late cycle parts of the review period.

And the next question comes from Brian Abrahams with RBC Capital Markets.

So when you were able to review some of the FDA interactions, can you clarify just how much of the dialogue was with the contemporary administration versus in 2024, when Peter Marks was running CBER? Should we be expecting a potential AdCom? And then where do you stand on scale-up and materials here? Any expected pre-approval production costs that could impact the near-term R&D line?

Absolutely, Brian. So the -- this program -- the Fabry program has been in progress for a number of years. So there's FDA correspondence that goes back several years as well as correspondence with the current administration. In fact, I believe there's correspondence confirming with current leadership, the plan to submit the BLA based on the intermediate clinical endpoint of eGFR slope at 52 weeks as well as for the confirmatory evidence to be eGFR slope at 104 weeks. So again, we were comfortable there based on the correspondence.

In terms of predicting AdCom, I don't know. I can't really predict that. I think one of the things that's attractive here in our diligence is when you're dealing with things like eGFR slope, that's pretty objective. This is something that's calculated based on objective clinical data. So there's not a lot of room for interpretation. It's a pretty standardized calculation.

And I think when you look at the change in slope or the slope value from baseline to week 52, you see a consistent steady benefit emerging over the weeks post treatment. So that is to say this 52-week finding wasn't the single one that looked good.

Now this is a consistent -- you see exactly what you'd expect to see with an efficacious therapy that you have a gradual improvement in function over time. So a lot of that gave us comfort that these data are clear, consistent and interpretable, which, as you know, is always very important in considering the potential way that the agency could think about the review.

And the next question will come from Faisal Khurshid with Jefferies.

Two slightly related questions. We were trying to do the math on how large the market is U.S. versus ex-U.S. And it looks like the ex-U.S. market here is pretty considerable and larger than the U.S. market. I just want to see, is that true? And can you talk about the capability of filing this data package as it currently stands ex-U.S. and whether Sangamo had pursued any regulatory conversations related to that?

Sure. I just want to come back and finish answering the second part of Brian's question, sorry, Brian, and then Faisal I'll answer yours about scale up and production.

I think one of the good things here is as part of all the PPQ batches, we're getting enough supply to be ready to launch this. We'll clearly look at any additional supply that would be needed ahead of launch or near time for launch. But as we said, I think we're pretty comfortable that this doesn't change any of our thinking about expense and our ability to meet our goal of cash flow breakeven this year.

Faisal, to your question, sorry about that. Obviously, there's a large global market. There's patients in the U.S. And then when we look at our global capabilities and the presence we have from both regulatory and commercial standpoint in Japan and Europe, Middle East, South Africa, Russia, Commonwealth of Independent States, Brazil, there's a lot of patients here.

And one of the things we'll be doing now over the next few weeks is really finalizing our launch sequence and what comes along with that is our thinking about regulatory planning. And as we said, not only do we have commercial capabilities in all these regions, we have experience and regulatory teams -- and regulatory expertise that could allow us to be successful in getting this across the line.

I know there were some discussions that Sangamo had in Europe and with European authorities, but then one of the things we're going to be doing in our regulatory work stream here is understanding what data we have, what the regulatory path could look like, how do we leverage the U.S. data, how do we leverage U.S. approval for named patient programs, all the things we typically do in the PTC global rare disease playbook.

And the next question will come from Joseph Thome with TD Cowen.

Congrats on the transaction. You kind of addressed this maybe, but can you just maybe specifically talk about the meta-analysis that, I think, the FDA wanted to see from Sangamo comparing their data to prior Phase IIIs in the space and your level of comfort that, that was done maybe appropriately?

And then second, just on the milestones, I think, that are related. Can you go a little bit more detail as to what those are related to, if they're accelerated approval or full approval, U.S., international? Anything you can do to provide color on that would be great.

Yes, absolutely. So this was a gene -- single-arm Phase I/II gene therapy trial, and we found that the evidence here is very compelling for a number of reasons. One, you have the objective evidence of the improvement in the enzyme, the reduction in the deposit of the substrate that deposits in different organs causing organ damage, and then seeing the clinical benefit in terms of renal function also objectively related.

As you mentioned, Joe, there was a request in discussions with FDA to provide some context to the improvement observed in renal functions by way of having some sort of control or comparison of the data -- of the treatment data.

And again, this is very encouraging on several levels. First of all, the natural history of Fabry disease in terms of renal function decline is very well characterized. You lose renal function over time and you have a negative slope of annual eGFR.

And here, again, not only is there improvement here over what the natural history is, there's actually improvement as a positive slope over time. This also is quite differentiated from the other approved Fabry therapies, which slow progression in terms of loss of renal function, but there's still a negative eGFR slope. It's just less negative.

And again, this is just in such stark contrast that it's positive. And so the meta-analysis really took us -- tried to formalize this analysis. And again, as you expected, to us, it seems fairly clear here that you've got a group of folks who are negative slope and then you have a treatment as positive slope. It was pretty clear cut that this was a differentiated therapy, and we believe the team did a very careful and thoughtful job of doing the analysis.

In terms of the milestones, it's -- there's two of them. The first one is $80 million on accelerated approval in the U.S. The second is $20 million on full approval in the U.S. with no additional other regulatory milestones, no sales milestones and no royalties.

And the next question is going to come from Joseph Schwartz with Leerink.

This is Leona Nease on for Joe. Congrats on the update. Just a couple of things from us. What learnings from your prior gene therapy launches can you apply to ST-920? How much work do you need to do to activate centers and identify eligible patients? And then also, can you clarify whether commercial product will be manufactured by the same CDMO as what was used in the STAAR study?

Leona, thanks for the questions. On your first question, look, I think anyone -- there's not that many of you have gotten AAV gene therapies approved, but anyone who has it knows that it's a pretty big lift -- pretty heavy lift. Not only do you have the traditional clinical issues, non-clinical issues, but the CMC manufacturing quality, all of that is super critical.

And we have that same team here that brought the AADC product, Upstaza, forward all here, all brought that expertise to the assessment of ST-920 as well as have the confidence in continuing to work with the folks at Sangamo to get this across the line.

In terms of commercial preparation, I think this is not gene therapy specific. This is what we do in rare disease, and I'll let Eric comment on that.

Thanks for the question. I think what we've been doing over the last decade or so is we have a geographic footprint that helps look not only find patients, work with centers of excellence. But as gene therapy evolved, we look for the value proposition. So our market access teams have been able to negotiate not only favorable pricing and reimbursement, but also ensure that patients are able to be treated across multiple geographies.

As the previous question came up about how big is the Fabry market ex-U.S. is very important, and we have a geographic footprint that will be able to address that. Importantly, we also have the mechanisms such as named patient programs. So once the U.S. approval happens, we can begin that process in many of the countries to treat patients in Europe, in Latin America, in the Middle East, in Russia and different places right now.

So we're going to be applying a lot of what I think is the playbook that we have been doing for decades with the portfolio of drugs that we've had and especially applying a lot of what we've learned about gene therapy in terms of getting patients not only on drug, but getting access to these treatments.

And then Leona, let me answer your other question about product manufacturing. As I'm sure you're aware, which why you asked the question, a lot of gene therapies over the course of the development may have different manufacturers, different manufacturing processes, and this one did as well.

But clearly, one of the most important parts of our CMC diligence was this idea to ensure that the product that's been used in trials, the product that's been used in early parts of the trial, later part of the trial and in the commercial product comes from processes that are comparable.

So of course, we look through the comparability assessments, the comparability analyses. And again, this was an area where our team got confidence that, that very common feature of gene therapies would not be an issue.

And the next question will come from Paul Choi with Goldman Sachs.

Congratulations on the deal. Matt, I was wondering if you could maybe provide some framework for how you're thinking about potential pricing here versus multiple years of patients being on ERT. Is that maybe the right way to think about it? And as you look at sort of historical sales estimates for ST-920, do you find these estimates to be reasonable? Or how are you thinking about potential upside scenarios versus what had been sort of consensus estimates at the time?

Paul, let me take the second one, and then I'll turn it over to Eric and talk a little bit how we are thinking about pricing relative to the clear value proposition and differentiation here. We, of course, saw some of the previous sales estimates from previous analyst coverages. I would say, look, I think one thing that has certainly evolved over time and one of the things that PTC, we believe, can bring to the commercial opportunity is really the global aspect of this.

We're clearly aware from a commercial standpoint that there is a significant potential U.S. opportunity. And I think that's included in some of the previous analyst estimates, perhaps some are -- and incorporated global as well. But I think we really think about this as an important global opportunity much as we're doing with SEPHIENCE and the ability to bring this to Japan, which is a pretty special rare disease market. Obviously, we have Europe and we have LatAm, we have all the different regions.

So I think the opportunity and our team's demonstrated ability to execute here, I think, brings even greater value to -- potential value here to the opportunity. Eric, do you want to talk a bit about access?

Yes, Paul, thanks for the question. I think it all starts with differentiation. Pricing is going to be a very important component based on how we differentiate the product, the final label that we have as well as the addressable population. We'll be looking at all these factors.

And as Matt said, the U.S. will be our primary market, but we also see Japan as a very important market where we can get premiums. I don't think it's a bad thing to actually look at what ERT is doing over a period of time and look at where the durability of the treatment could be. So that certainly is an option.

And then as we demonstrate the value proposition, particularly around durability around the kidney and heart function, these are hard endpoints that Europeans really do like, and they want to see things that are going to be improving quality of life, replacement of various therapies, reduction in hospitalization and costs and infusions, things like that.

So developing the value proposition in many of these markets, which are what I would call HTA or health technology sensitive markets is going to be part of our strategic goal as well. And so for us, really, we believe that pricing will be a factor of all of these things. So stay tuned. We believe this is a really important opportunity for us.

And there are no further questions in the queue at this time. I'd now like to turn the call back to Dr. Matthew Klein, Chief Executive Officer, for closing remarks.

Thank you all again for joining the call today. As I said, we're incredibly excited about this opportunity. It really fits very well with what we've articulated as our strategy to leverage our accomplished rare disease commercial infrastructure, to accelerate short-term and intermediate-term revenue growth. I think there's some particularly unique characteristics of this opportunity that made it even more attractive to us.

We can -- we're able to generate, we believe, significant value creation here while leveraging the unique regulatory and commercial expertise that we have. We preserve significant firepower in terms of being able to continue to pursue business development as a component of our strategy of strengthening our product portfolio. And finally, we really look forward to an opportunity to bring something we believe could be a meaningful therapy to patients who really need one.

So with that, I thank you all, and I wish you a good evening.

I would -- this does conclude today's conference call. Thank you for participating, and you may now disconnect.

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics Second Quarter 2026 Earnings Conference Call. [Operator Instructions] 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' Second Quarter 2026 Corporate Update and Financial Results. I'm 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 website in conjunction with the call, which contains information about our forward-looking statements and our most recent quarterly report on Form 10-Q and 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 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.

Thank you all for joining today. I'm excited to share the results of another quarter of outstanding execution across the company. Starting with revenue, we achieved another record quarter with total revenue of $361 million, including $239 million of product revenue, driven by continued strong global supply and sales. Based on this performance, we are raising our full year 2026 product revenue guidance to $850 million to $950 million and now expect total revenue of $1.18 billion to $1.28 billion. In addition, with our continued effective management of expenses, we remain in a position to potentially reach the milestone of being cash flow breakeven in 2026.

I'll begin with an update on Sephience global launch. Momentum remained strong in the quarter with continued steady growth in the U.S. and accelerating growth internationally. Second quarter global Sephience revenue was $151 million, up 21% quarter-over-quarter, with the majority coming from the U.S. and increasing contributions internationally. And as of June 30, we had 1,647 commercial patients on Sephience globally. We continue to see broad uptake across all patient segments and age groups worldwide. There remains strong underlying demand for Sephience, and our teams continue to effectively execute.

In the U.S., we now have received prescriptions from 100% of the centers of excellence as well as prescriptions from other centers not previously designated as centers of excellence. This breadth of penetration this early in the launch is impressive, and we will now work to continue to penetrate deeper into these centers. We continue to see demand across disease severities and treatment histories, including treatment-naive patients, prior therapy failures and those switching from existing treatments.

Adherence rates remain strong, and we continue to hear reports not only of meaningful reductions in phenylalanine and increasing evidence of diet liberalization, but also of Sephience's benefits on mood, cognition and quality of life. These dynamics of strong demand and reported patients benefit reinforce our confidence in Sephience's long-term commercial opportunity.

In international markets, momentum for Sephience continues to build. Commercial sales in Japan began to ramp in Q2 following our first commercial sale in late March. We started expanded access programs in a number of European countries and have seen positive progress towards future revenue in Latin America, including Brazil, where Sephience recently received the highest classification for therapeutic benefit from the country's drug market regulation chamber.

As we have previously shared, we expect international revenue to increasingly contribute in late 2026 and into 2027 as additional markets come on board. Overall, based on the continued strong launch momentum and the persistent strong underlying demand, we remain confident in the $2 billion-plus global commercial opportunity for Sephience.

Turning to the votoplam Huntington's disease program. In April, we reported positive top line results from the 24-month interim analysis of the PIVOT-HD long-term extension study. At month 24, votoplam demonstrated dose-dependent slowing of disease progression on cUHDRS, including an average slowing of 52% relative to natural history in the 10-milligram Stage 2 cohort. Importantly, we continue to observe a favorable safety profile across doses and disease stages. These data support the potential for votoplam to provide long-term meaningful clinical benefit for individuals affected by Huntington's disease.

We also shared that Novartis has initiated enrollment in the global Phase III INVEST-HD study, which is being conducted and funded by Novartis. The study is expected to enroll approximately 770 individuals with early symptomatic disease, randomized 3 to 2 to receive votoplam 10 milligrams or placebo, and the study includes an interim analysis. While the Phase III study remains the base case for votoplam approval, the Novartis and PTC teams are finalizing a plan to engage with FDA in the second half of 2026 to discuss the 24-month results and potential accelerated path.

For the vatiquinone Friedreich's ataxia program, based on discussions with FDA, we have finalized the study protocol for the open-label trial with the natural history comparator arm to support NDA resubmission. We plan to initiate this study, PROVE-FA, in the third quarter of this year. The trial will enroll approximately 120 individuals ages 7 to 21 and the study primary endpoint is the change in mFARS from baseline to month 24. The study design reflects the key learnings from our prior development work and has understandably generated enthusiasm within the FA community, particularly because it offers patients the opportunity to access therapy without the uncertainty of receiving placebo.

We believe the study design, coupled with our experience in FA therapy clinical development, meaningfully enhances the probability of success of the PROVE-FA study and the potential to deliver an important new therapy for children and adults affected by FA.

Shifting to our other clinical pipeline programs. We have initiated the Phase I study of PTC612, our oral NLRP3 inhibitor and have completed several of the single and multiple ascending dose treatment cohorts. Notably, this healthy volunteer study will enroll a cohort of individuals with obesity and cardiovascular disease, which we expect will provide an early view of PK/PD effect. As we have previously shared, PTC612 is differentiated from other NLRP3 inhibitors in terms of potency, selectivity and chemical structure.

Later in the third quarter of this year, we expect to initiate a Phase IIa study of PTC844, our next-generation DHODH inhibitor. PTC844 is highly selective for the DHODH enzyme and benchmarks favorably to other DHODH inhibitors in preclinical potency models. The PTC844 study will be a 12-week PK/PD study in which we will assess treatment effect on biomarkers related to T-cell and B-cell immunity. The results of this study will help inform the ultimate target indications for PTC844.

We've also made a number of advances in our splicing platform. We recently selected a development candidate for our MSH3 splicing program, PTC303. MSH3 is increasingly recognized as an important target for triplet repeat expansion diseases, including Huntington's disease and myotonic dystrophy. As we have discussed, targeting MSH3 provides a complementary approach to HCT lowering in addressing the key pathological causes of Huntington's disease. The MSH3 program also further reinforces PTC's leadership in the discovery and development of oral small molecule splicing therapies. PTC303 is fully owned by PTC, and we expect it to be in the clinic in 2027.

Overall, the company remains in a very strong financial position. In June, we strategically managed the 2026 convertible note liability with the refinancing of the majority of the existing notes at a 0% coupon and 40% conversion premium to the stock's closing price at the time of the deal. We closed the quarter with over $2.2 billion in cash and remain in a position to achieve cash flow breakeven in 2026. In summary, I'm proud of our team's outstanding performance in the first half of 2026 as we continue to make significant progress across the business.

I will now turn the call over to Eric to provide a commercial update, including additional details on the Sephience launch. Eric?

Thanks, Matt. In the second quarter, our commercial team continued the strong global launch of Sephience, driving solid product revenue and reinforcing confidence in our growth trajectory through 2026 and beyond. Launch momentum remains strong, supported by sustained contributions in the U.S. and increasing contributions from international markets. And now we have 1,647 patients on commercial therapy globally on Sephience.

In the second quarter, Sephience revenue was $151 million, representing 21% growth over the first quarter of 2026. In the U.S., launch execution remains strong with steady demand. As Matt noted, all U.S. centers of excellence are now prescribing Sephience with adoption spanning the full spectrum of disease severity, all ages, including classical patients and a broad mix of treatment backgrounds, including therapy-naive adults, prior treatment failures and an increasing proportion of switches from existing therapies.

We are pleased to see persistent strong demand and to hear reports of the meaningful impact Sephience is providing children and adults on diet liberalization as well as mood, cognitive improvements and improvements in quality of life. With our increasing base of commercial PKU patients being treated with Sephience in the U.S., our customer-facing teams are focused on rapidly filling new prescriptions and successfully managing reauthorizations, refills and providing exceptional patient support.

Our customer-facing teams are dedicated to work closely with health care providers and the patient community to facilitate access to Sephience. These efforts will help support continued momentum and growth as we move further into the launch.

Turning to our patient advocacy support. We had a strong presence at the National PKU Association Conference in Chicago earlier this month, where we focused on connecting with patients and caregivers and understanding their unmet needs. At this meeting, we presented data from the AMPLIPHY study, demonstrating the ability of Sephience to reduce blood Phe significantly more than BH4 as well as new data on patients switching to Sephience in both pediatric and adult PKU populations.

We also held several engagement events with patient advocacy groups, including a symposium emphasizing the extensive real-world data and examples of patients who, in addition to seeing important reductions in blood Phe levels have also experienced significant improvement in their day-to-day quality of life on Sephience treatment.

Internationally, launch momentum continues to build. In Japan, the early launch results are exceeding our internal expectations with rapid uptake across many Japanese centers of excellence. We have secured pricing in Japan on par with the U.S. And importantly, this price is locked in for 10 years. As we observed in the early stages of the U.S. launch, we are seeing broad uptake in Japan across disease severities and age groups as well as treatment histories.

In Germany, we continue to see strong momentum in the quarter, especially with an increase in newly prescribed adult and naive PKU patients as our pricing and reimbursement discussions are continuing in the country.

In other European markets, we are leveraging early access and named patient programs effectively and are seeing accelerated demand in France, Italy and Spain.

In other regions, including Latin America and the Middle East, we are similarly leveraging early access programs as we grow the Sephience's global footprint and see important contributions to future commercial patients.

While the U.S. remains an important near-term growth driver, we expect global revenue to become an increasingly meaningful contributor in the second half of this year and well into 2027. As we discussed, there is a large addressable PKU population globally in markets where innovative treatments are reimbursed, and we expect to bring Sephience to as many of these countries as quickly as possible, reinforcing our confidence in achieving a multibillion-dollar peak revenue potential.

Looking ahead to our key event this summer. Our team is preparing for a strong showing at the SSIEM meeting in Helsinki next month. This being the largest global metabolism meeting of the year. We have 17 oral and poster presentations planned that continue to showcase evidence of Sephience's treatment benefit across the broad range of individuals with PKU based on new analyses of long-term trial data as well as reports of real-world evidence. Many of these presentations will highlight the positive impact that Sephience has had on PKU patients in countries around the world, with lower Phe levels leading to better diet, neurocognitive and quality of life outcomes for these patients.

Importantly, we plan to present new data demonstrating that treatment with Sephience's responders led to a substantial portion of participants achieving complete normalization of blood Phe levels of 120 micromoles per milliliter in a rapid time frame, including those PKU patients who are classical and BH4 nonresponsive. This impressive real-world data demonstrated that achieving Phe level normalization is an important key treatment goal for all potential PKU patients.

Now turning to our mature brands. In the second quarter, we continued to generate meaningful revenue despite challenges in the DMD franchise. For Translarna, we had continued sales in Europe and Latin America as well as the government order from Russia. In the U.S., Emflaza continues to see new prescriptions. And despite generic pressure, we see ongoing brand loyalty attributable in part to our programs and continued high-touch white glove services from our PTC Cares team.

In summary, our customer-facing teams delivered another strong quarter with another record revenue performance, once again demonstrating PTC's global rare disease commercial capabilities. We remain confident in our ability to grow and sustain our launch momentum of Sephience globally and firmly establish it as the standard of care for PKU patients.

With that, I will now turn the call over to Pierre for a financial update. Pierre?

Thank you, Eric. I will now share the financial highlights of our second quarter of 2026. Beginning with top line results. Total product and royalty revenue for the second quarter was $310 million and total net product revenue across the commercial portfolio was $239 million compared to $118 million for the second quarter of 2025, representing over 100% growth.

Second quarter 2026 product revenue includes Sephience net product revenue of $151 million and DMD franchise revenue of $67 million. Translarna net product revenue was $42 million, including a government purchase order from Russia and Emflaza net product revenue was $25 million. For Evrysdi, Roche achieved second quarter global revenue of approximately USD 628 million, resulting in royalty revenue of $71 million.

For the second quarter of 2026, non-GAAP R&D expense was $89 million, excluding $11 million in noncash stock-based compensation expense compared to $104 million for the second quarter of 2025, excluding $9 million in noncash stock-based compensation expense.

Non-GAAP SG&A expense was $68 million for the second quarter of 2026, excluding $13 million in noncash stock-based compensation expense compared to $76 million for the second quarter of 2025, excluding $10 million in noncash stock-based compensation expense.

Cash, cash equivalents and marketable securities totaled $2.23 billion as of June 30, 2026, compared to $1.95 billion as of December 31, 2025. In the second quarter of 2026, we repurchased the majority of our existing 2026 convertible notes and issued new convertible notes due in 2031 at 0% interest rate and a conversion price representing a 40% premium over the stock's closing price at the time of the issue. Our strong financial position gives us the flexibility to pursue business development opportunities that support future growth while advancing towards cash flow breakeven and future sustained profitability.

And I will now turn the call over to the operator for Q&A. Operator?

Our first question comes from Kristen Kluska with Cantor.

Congrats on a really strong quarter. I have 2 Sephience questions. The first is based on the patients on therapy and accounting for potential dropouts, my math is getting to about 10% or so of the patient population on the U.S. has tried the therapy. Curious if that matches what you think? And also what percent of patients you think may at least be open to trying a therapy, not saying we'll get on it and assume peak penetration there?

And then second, just thinking about the conference circuit, you just came off the biggest one for the patients in the U.S. and now you have a big medical focus. What are really the key drivers there? Is it awareness? Is it proving that the therapy works across a breadth of patients? What are the key goals you hope to learn?

Kristen, thanks so much for the question. So on the first question, look, I think the key take home that we see this early in launch is we're incredibly excited about the demand and the uptake thus far. But as you highlight, we still have a very, very long way to go, given the size of the population in the U.S. of 17,000 and the 58,000 patients we see in addressable markets worldwide.

I think when we look to metrics thus far and we see penetration into 100% of the centers of excellence, that's really an incredible milestone this early, and it basically puts us in the position we want to be with a strong base of patients to now go deeper and deeper into those centers of excellence. Usually at this stage of a launch, you're usually trying to get to all the centers of excellence. We're there. And now it's the task is to get deeper and deeper into those centers.

In terms of overall patients who may try the therapy, I think, the number we had always had is about 70%, 7-0 percent of individuals tried Kuvan. And that again suggests we have a very, very large number of patients who are yet to try Sephience. And we already know that we've seen patients who are therapy naive, that never tried Kuvan that are in that other 30% bucket who are coming back to clinic.

So again, it's hard to put an exact number on it other than to say we're still very early in this launch. We've had strong momentum at the start, but we have a very, very long way to go in terms of continuing to get much larger number of patients to try the therapy and of course, to stay on the therapy and enjoy the benefits, which I think goes then into your second question about our goal at these conferences.

It's multifold, right, manyfold. One is, look, there's a lot of patients and there's a limited number of clinics. And we know that means that it's going to be just a steady cadence over time given the strong underlying demand. What we do at these conferences is continue to promote awareness of the drug for those who may have been not on therapies or remote to care and are starting to come back or are curious about being on a therapy and then also continuing to let people understand the benefits we're seeing, that we're seeing benefits in patients who have classical PKU and non-BH4 mutations.

And you had in NPKUA, one of the care -- I'm sorry, one of the prescribers told stories about patients -- severe patients with classical PKU having significant responses. That's really important for patients to hear that they can get an oral therapy that allows them to lower phenylalanine and liberalize diet.

It's also really important to continue to reinforce the data and the messages around AMPLIPHY and patients who are on Kuvan, for example, where the brands are generic and to hear that 100% of those patients in our data have a much better response to Sephience are able to get even lower in phenylalanine and liberalize their diet even more.

So I'd sum it up by saying we're early in the launch. The response has been strong. The demand is really strong. But our teams still have work to do in continuing to reinforce the message, continuing to engage with patients, family members, caregivers, prescribers, letting them understand the benefits that they could enjoy with Sephience, so we can continue to get those trying numbers up to 70%, 80% or even higher.

Our next question comes from Tazeen Ahmad with Bank of America.

Matt, you've been really clear about defining how this launch is proceeding as very steady and consistent. So you have in the past talked about roughly adding about 140 new scripts per month. Can you just talk about whether or not you expect that to continue to be the cadence for the rest of the year? And if not, maybe just talk to us about anything that's changed? And then can you just give us a little bit more color about what you're seeing in discontinuation rates so far?

Yes absolutely. So Tazeen, we've moved now towards just really highlighting revenue in patients on drug because at this stage in the launch that you're starting to hear the global contributions and the prescriptions mean different things in different locations. I'll characterize things this way. I think we're continuing to see consistent demand. We believe in the potential for there to be steady growth, continued growth in the U.S. based on that demand and continue to expect accelerated demand outside of the U.S. And a lot of that is what underpinned our confidence in raising guidance to $850 million to $950 million that we believe that we can continue to have steady growth in the U.S. and accelerating growth outside of the U.S.

In terms of discontinuations, we continue to see very high compliance and very high adherence rates. Discontinuations now remain low at about 20%, which is really impressive at this point in the launch, given the fact that a lot of the early patients who came on drug were those more severe patients. And we also feel at this level that we're getting pretty close to steady state based on what we have seen from the clinical studies.

Importantly, the renewal rates on prescriptions is super high. It's over 90%. So overall, all these metrics look really, really good and again, support our confidence not only in our ability to raise guidance for this year, but in the long-term significant potential -- revenue potential for Sephience.

Our next question comes from Joseph Han with Barclays.

It's Ellie from Barclays. You mentioned several early access programs ex U.S. Just to clarify, are you recognizing revenues from these programs yet? I think you mentioned seeing accelerated demand in France, Italy, Spain, LatAm and Middle East. Can you maybe give some color or characterize the number of patients on all of these early access programs and how that might compare to the 1,600 patients on commercial therapy globally?

And then lastly, I think you've mentioned being launched in about 30 countries by the end of this year. So how should we think about which countries and when will contribute to revenues over the course of 3Q and 4Q?

Ellie, I'll give just some general comments, and I'll let Eric give a little bit more detail on early access. And so all those early access patients are contributing to revenue. And what's important to note is that this whole approach we're taking in a global launch is really a well-thought-out plan. First, we have the global commercial infrastructure in place and already been commercializing in 50 countries. And a lot of this is about understanding different markets, understanding sequencing of launch, understanding how we can maintain a rigid pricing corridor, which is more important now than ever.

And also with early access programs, it allows us to get drug into patients in countries. It also tends to be a lot of those prescribers who are the leading KOLs in certain countries. That's super important, because this allows those physicians to have positive experience with Sephience. And those are going to be the same physicians that will be called upon when HTAs are making assessments about access and pricing. They can go to these physicians who will have had firsthand positive experiences with the drug, which has obvious benefits in terms of access and reimbursement.

I'll let Eric talk a little bit more about just overall number of countries and how we're thinking about sequence and launch and [ recent ] revenue contribution. Eric?

Yes. Thanks, Ellie, for the question. As Matt said, the strategic plan is laid out many years ago actually because we are leveraging this infrastructure, which had a portfolio of products for over 12 years. So when we mapped out the sequence of this, we knew exactly that the U.S. Germany and Japan would be commercial launches. But we've also mapped out very carefully where early access programs would actually be implemented. We knew that there would be large addressable populations in Europe, in the Middle East, and Latin America, places where we could get innovative pricing and reimbursement and maintain, if you will, a price for that innovation and maintain a narrow pricing corridor.

So we've actually implemented programs in France right now in key major markets. France has already given us an HTA assessment, and that's completed, and they've approved our early access program, and we've seen an accelerated demand rapidly in France. We've also seen accelerated demand both in Italy and Spain and a number of Southern European markets as well as Central and Eastern European markets.

We're just in that process of beginning and implementing those in Latin America and the Middle East, where they will be meaningful contributors. We've said that there's up to 30 markets that could potentially provide revenue. Keep in mind, as Matt said, over the last 10, 12 years or so, we have actually been commercializing products in over 50 countries, and we have extensive experience. So we're going to bring Sephience to as many of these markets and as quickly as effectively as possible.

Our next question comes from Eric Joseph with Citi.

Congrats on the progress. Maybe just to pick up on the ex U.S. outlook. Can you talk a little bit about sort of the 30 global markets that you're pursuing, which are likely to have their own HTA review processes versus referencing other geographies to arrive at a pricing decision and also what HTA review time line might look like? And if I could just squeeze in a pipeline question. I'd be curious to kind of get a sense of time lines as it relates to the NLRP3 inhibitor program and what kind of profile might support later-stage development as those data read out?

Eric, let me -- I'll take the second question first, make a comment on the first and then turn it over to Eric. So we're excited about the NLRP3 program as we've talked about. We've done a lot of work preclinically demonstrating that this molecule is highly differentiated in terms of potency and being able to benchmark it against others. It has specificity for the target, and we talked a bit about how it's chemical backbone is a bit different than others that have been in development at worse and that others had some potential toxicity concerns that we don't think will apply here.

We've designed the Phase I study to answer the typical Phase I pharmacology biodistribution and safety questions, but also we're including a cohort of patients with sort of metabolic syndrome phenotype and inflammatory biomarkers so that we can get early confidence that the exposures that we're able to get exposures we can get safely, the level of inhibition we're seeing is associated with favorable biomarker effects. And we could have those data as early as the end of this year into early next year, and that would really put us in place then to move quickly into Phase II.

And so we're -- again, we're super excited about this program. We've talked about focusing on rare pulmonary disorders as a first set of indications, and that was based on the understood overlap between NLRP3 inflammasome and a number of pulmonary inflammation and fibrotic pathologies.

And the first question, let me just make a general comment that number of 30 countries, we had said between 20 and 30 and that was just in 2026. I just want to make clear that we expect this to be -- as the launch moves forward into '27 and beyond, there's many more countries we seek to get to and target that 58,000 global addressable market.

Eric, do you want to talk a little bit about the HTA processes?

Yes, Eric, thanks for the question again. HTA assessments are primarily in large Southern European markets. And I'll just give you a little color for that because those are the markets that are referenced pretty much around the world in international markets. So for France, the HTA assessment is complete. We've completed that. And the early access program has been approved in Q2. And as I mentioned, there's been a very accelerated demand by health care professionals for the early access program, and we're recognizing revenue there. The price is actually the German price.

But in terms of timing, pricing and reimbursement discussions are now ongoing, and we would expect that to conclude sometime next year in France. In Italy and Spain, again, key markets HTA process is still ongoing, and that's going to be going on for probably into the third and fourth quarter. However, we do have early access programs, again, being leveraged. Those are priced at the German price at this point in time. And then pricing and reimbursement discussions will be conducted with the authorities likely in the fourth quarter and should -- we are expecting that to conclude sometime in early 2027.

And as you already know, Germany, the HTA assessment was completed at the beginning of the year. And right now, from a GKV discussion, this is still ongoing. Pricing and reimbursement should be finalized before the end of this year in Germany.

Our next question comes from Ben Burnett with Wells Fargo.

I was wondering if you could maybe just talk to the revenue guidance. Great to see that increase. Just want to know what's considered in the increase. Is this mostly Sephience confidence? Or is this from sort of broader confidence with other programs?

And then just one clarification on the discontinuation rate. How is that defined?

So on your first question on the revenue guidance, look, when we came into this year, we said we had a lot of unknowns that we were dealing with. We were still very early in the Sephience launch. And we also, in terms of the Duchenne franchise, had significant headwinds with a significant number of generics now for Emflaza and headwinds in some of the larger countries where we get group purchase orders as well as the fact that we were -- we're still selling product in Europe without a license. Clearly, the Duchenne franchise has had a bit more durability than expected and the Sephience growth has been terrific.

So as we went and looked at revising the guidance as we did after the first quarter and now again after second quarter, it's based in large part on our confidence of Sephience and the ability for it to continue to grow in the way that we have seen it growing. And some of the widespread of the guidance range incorporates the fact that we could still see some contributions from the Duchenne franchise if Emflaza is able to withstand the continued generics, for example. But a lot of it's our confidence in Sephience with some confidence that we may get still some more life out of the Duchenne franchise.

In terms of the discontinuation numbers, we define that as going basically 60 days or 2 months with that prescription renewal.

Our next question comes from Brian Cheng with JPMorgan.

Congrats on the quarter. Maybe just first, heading into the discussion with the agency on votoplam later this year. Is the discussion going to enable you to talk about the ability to file for an accelerated approval based on the 24-month data? Is that one of the primary goals here?

And then secondly, we're seeing new patient add accelerated this specific quarter, and the revenue is not catching up as fast. So I'm curious if you can help us -- how do we best reconcile these 2 numbers?

Yes. Brian, in terms of votoplam, as we had said after we shared the data that we -- that our team and the Novartis team discuss whether we would review those data with FDA. Clearly, the FDA's seeming agreement to accept a filing from -- for the gene therapy on cUHDRS as an intermediate clinical endpoint was an important data point in our consideration of whether to talk to the FDA. So -- and I think the belief is that it's important to go and talk to them and talk to them about the data. And obviously, one of the important topics is going to be if there is a precedent for applications based on ICE in HD.

We believe our data compare quite favorably when you consider just the number of patients exposed, the dose-dependent effect seen in the Stage 2 patients, the fact that we have objective data of target engagement and mechanism of action with the dose-dependent durable lowering of blood Huntington protein as well as safety exposure in a larger number of patients in a drug that's titratable, reversible. And we have a Phase III study that's up and going and enrollment is underway. So we think all of those things allow for a really good discussion with FDA.

And obviously, Novartis has made the comment that they're still operating under the assumption that Phase III is the base case. Importantly, that study has an interim analysis, but they have also commented as we have that we could look for any chance we have to accelerate access to a potential disease-modifying therapy given the significant unmet need for Huntington's disease patients.

In terms of patient adds, look, I think what we're seeing, again, is what we said is consistent demand and consistent adds in the U.S. and increasing contributions now globally. Obviously, patient numbers come in different patient numbers and revenue may be different in terms of that patient weights may be different. There's a lot of variables that actually go into the amount of reimbursement. And obviously, all patients don't enter in a quarter at one time. Some can come in a lot early, then some can come in a bit later. So I think there's a lot of variables that go into it.

I think importantly, to your point, we see consistent demand. We see growth in patient numbers that we saw your early note is more than folks expected, and we expect that to continue. And we expect the revenue also to continue to grow over time, as we said, given the large number of patients. And again, what we've consistently said is a significant $2 billion plus multibillion-dollar opportunity.

Our next question comes from Judah Frommer with MS.

Congrats on the quarter. Are you able to add any guidance or detail on switching dynamics, patients that are switching from standard of care therapy to Sephience. Are there particular sales efforts that are generating success there? Is it word of mouth amongst patients? Anything anecdotal or tangible there would be helpful.

And then just on the peak sales opportunity for Sephience, any change in speed to peak as you're now through several quarters of the launch? Or do you expect things to kind of be in line with your original expectations as of now?

Thanks for the question, Judah. Let me take the second one first, and then I'll ask Eric to comment a little bit on what we're seeing in the switching dynamics and some of the data that's driving that and some of the dynamics of those patients.

Look, I think we've talked just generally about this being, call it, $2 billion plus, multibillion dollar, not in terms of specific guidance, but just to help people understand what we believe is the magnitude of this opportunity. Recalling that when we started the launch, we were getting ready for the launch, a lot of people were benchmarking this to previous therapies. I mean I think we are now at a full year run rate that exceeds what people -- many people thought the initial opportunity was for this product. So we thought it's really important to really say that there's no precedent -- there's no benchmarking this in terms of previous PKU therapies, but rather to benchmark in terms of what a differentiated rare disease therapy with a population of 17,000 in the U.S. and 58,000 in markets where we could access patients and get reimbursed for drug could bring.

I think as we get closer, as we get further into this year and into next year, we'll be in a better position to talk more about formal guidance. But again, we just have that number and have stuck to that number now just to hold out the fact that, one, it's a much larger opportunity, I think than many have initially imagined. Two, what we're seeing thus far in the launch does nothing but increase our confidence that this is the magnitude of this opportunity.

Eric, do you want to talk a little bit about the switching dynamics, some of the data and what that's looking like?

Yes, Judah, thanks for the question again. I think the first thing is that we said is we're really impressed after 12 months in the launch, that we were able to see a lot of the dynamics of those patients who are actually failed or poorly controlled. And we also saw that adults and naive have been coming in. What we thought may have been the case was that patients and physicians who are the highest unmet need would be the first ones treated. Now we have all centers of excellence who are prescribing.

And we're also seeing now a significant movement to change what patients are seeing in terms of Phe reduction. And I think we have a number of key programs that our sales teams, our medical teams are communicating about not just Phe reduction, but how lower Phe reduction is more important.

And what we'll be showing at SSIEM will be some very important data that talks about normalization, patients at 120 micrograms per milliliter. And when you think about normalization, that's incredibly important because we know patients who already respond to BH4 will have a much better response to Sephience and are likely to not only reach goal, but to reach normalization. And that's going to be a very, very important part of our communication and messaging as we go forward. And that's going to be supported by data as soon as next month at SSIEM.

So we have tailored programs from a medical perspective, and we're working with these centers. And as we thought, these patients who were the most severe were the first ones to come on to therapy, but now we're seeing more and more benefits from patients who are switching, and that dynamic will continue over time.

Our next question comes from Joseph Thome with TD Cowen.

Maybe the first one, I guess, in that upside scenario that the FDA is amenable to a filing for Huntington's, can you talk a little bit about where you are from a CMC perspective with votoplam and your readiness there?

And then second, maybe on the DHODH inhibitor program. I know it's been a while, but you also had PTC299. Can you talk a little bit about the differences between that older agent and your next-gen compound?

Yes, absolutely, Joe. So on HD, look, I think this is the benefits of, one, it's a small molecule and two, having a partner like Novartis, who is well equipped to move all of these things forward as quickly as needed. I think when we did the partnership back in '24 and then went through the official handover in early '25, it's very clear that their teams are all over every aspect of getting things exactly in order for FDA approval. So we have -- if we were given the opportunity based on the clinical data, I think we'd be very confident that that application could get there.

And of course, obviously, the confirmatory study is already up and running. In terms of DHODH inhibitor, I think PTC299 was really a legacy product. And as one would expect from a -- when you go from Gen 1.0 to, I would say, this is I guess technically 2.0, but it's more like a 3.0 or 4.0 in terms of how much more potent and specific it really is. And I think we had a lot of conversations internally about bringing this molecule forward.

But when we saw how differentiated it is and understanding that there have been other DHODH inhibitors that have been approved that have been viable commercial products and to be able to benchmark PTC844 to those, and we showed those data at our Research Day as well as 299 (sic) [ PTC299 ] and show the superiority in terms of in vitro potency as well as specificity for the DHODH target tells us that we're now able to target a mechanism known to be important and do so in a very selective, specific and potent way.

So now we look forward to the Phase IIa study. We're going to be doing that in a population of patients with significant inflammation with rheumatoid arthritis. That's not our intended indication, but rather, what we want to do is take a population in whom we knew would have a biomarker profile of inflammation that would allow us to establish the relationship between DHO levels and effects on biomarkers of T-cell and B-cell immunity that can then help us inform where we would go from there in terms of specific target population.

Our next question comes from Faisal Khurshid with Jefferies.

Just going to ask a couple of nitty-gritty commercial things, if you don't mind. Could you comment if there were any inventory effects for Sephience in the second quarter? And then can you also comment on how we should be thinking about and modeling things like gross to net and like net pricing and average patient rate? Have your assumptions there changed at all?

Yes. I would -- thank you for the question. I would say, Faisal, we've had no inventory effects to think about. Things have been fairly constant in that regard, I would say, as well in terms of patient weight, patient age, gross to net, all those things have been consistent. We haven't seen any real changes there.

Our next question comes from Brian Abrahams with RBC Capital Markets.

This is Nevin on for Brian. Just one more on Sephience. How are you kind of thinking about the split of revenues over the long term, especially just given that the ex U.S. is progressing so well and you seem to be getting pretty good reimbursement and pricing there and just given that there's kind of a larger population outside the U.S. as well?

And then I'm also wondering if you could talk about your updated thoughts on BD and if your kind of appetite has changed there, if you're looking at any specific programs or therapeutic areas? And what's the size of any potential deals that you might be able to do?

Sure. First, on the split, look, I think it may be a little early to give an exact breakout. I think we think that international can be a significant contributor here. Still the vast majority, I guess, will likely always be driven by the U.S., but I think there could be a significant contribution ex U.S. when you start looking at that number of patients and what we believe we're going to be able to achieve in terms of reimbursement. But it's a little early for us to give an exact breakdown there.

I'd say, for example, what we're seeing thus far in Japan has been really impressive. There's maybe 1,000 and 1,100 patients there with PKU, but we're seeing a lot like the U.S. There's early demand. There's patients not on therapy who are coming back in and getting on therapy, the centers of excellence. And as Eric mentioned in the prepared comments, there, we have a price on par with the U.S. price is set for 10 years. It's very easy for patients to get on drug. So again, there's a lot of these kinds of stories out there where we're seeing the international markets be able to start to make an impact that we expect will continue to grow in the latter part of '26 into '27 and beyond.

Pierre, do you want to talk a little bit about how we've been thinking about BD?

Yes, happy to. So first of all, I will say we closed the quarter with a very strong cash position of $2.2 billion. We work really hard to get there. And as we said, we -- our team has demonstrated their ability to launch products globally. That's a key strength of ours. They have capacity. So we're looking at BD in a number of ways. One, obviously, we're still laser-focused on Sephience. We don't want to distract the momentum at all. [ Are there ] ways to complement that very strong franchise for us? That's one bucket.

We're also looking at other areas in the rare disease space, late stage or commercial, again, to leverage that global infrastructure that we have. So that's how we're thinking about it. Again, we want to make sure we are very disciplined in any potential transaction to make sure that we create value for shareholders. You mentioned size. Again, we're not going to do anything where we will lever up and use all our cash in one go. So that's how we think about it.

Our next question comes from Luke Herrmann with Baird.

So now that you're established in all the centers of excellence for Sephience, has there been any shift in the proportion of new starts stemming from sort of a proactive visit as compared to a more typical checkup schedule? And sorry if you've already covered this, but to the extent you're able to qualify how have new starts tracked into July?

Yes. Thanks for the questions, Luke. I would say that we -- what we've been hearing from a lot of the KOLs is that most of the prescriptions are coming now as part of regular visits. So early on, we said in the first couple of months of the launch, there were a lot of folks coming in waiting list and a lot of attention in the first part, but most of the KOLs and prescribers have told us that somewhere late November or so, we saw a shift it's really as patients are coming in, they're looking to either start them on therapy or switch them, for example.

Now that being said, we still note that one of the questions earlier asked about what the effects of us going to conferences and the team -- the work that our customer-facing teams do in the field and our patient support and patient engagement work does. We know that the more messages -- the more patients hear about this, there still is a lot of patient pull and market pull to get into clinics and get on the drug.

In terms of starts into July, what we said is that overall, we continue to see strong underlying demand. We expect there to be consistent growth in the U.S., accelerating growth outside of the U.S. And a lot of that is what underpinned our or prompted our confidence in our ability to raise guidance to $850 million to $950 million.

Our next question comes from Joe Schwartz with Leerink Partners.

I guess, I have a question on Germany first. I think the pricing and reimbursement for Sephience was previously expected to be finalized this summer with other European negotiations advancing behind that. Why is it seeming to take longer? Are you getting the traction you expected? And will it hold up the -- any of the discussions with other European countries in any way?

Thanks, Joe. Eric, do you want to talk a little bit about the negotiations globally and particularly Germany?

Yes. And in fact, keep in mind -- thanks, Joe, for the question. Keep in mind that we've launched in Germany, and it has been just barely on the 12-month cycle. We have a number of what we call mandatory negotiation sessions and then there are informal ones with GKV. Clearly, those discussions have been productive. They've been cordial. We've been working on that. We've just now hit the summer months. So those discussions will continue throughout the summer.

It's likely that our pricing and reimbursement will be finalized sometime in the third quarter, but it could go into the fourth quarter. The list price right now that we have listed in Lauer-Taxe is very similar to the U.S. price. It has not affected any of the other markets. And in fact, Brazil, which CMED has referenced in terms of innovation status, the current Brazilian price is linked to the German price. So essentially, everything is going according to schedule, and we anticipate to have the final decisions sometime in the second half of this year.

Our next question comes from Paul Choi with Goldman Sachs.

Congratulations on the progress. I have 2 on Huntington's. Matt, I was wondering if you could maybe offer your preliminary thoughts on development of PTC303 as a monotherapy in Huntington's versus potential combination use with votoplam. Any early thoughts there would be great.

And my second one is Roche recently discontinued its tominersen studies in Huntington's and caveating for the usual cross-trial and cross-drug differences. Any thoughts there just on the implications just given what was early and promising biomarker changes versus what looks like less success on clinical endpoints? And just any thoughts on potential read-throughs there?

Yes, absolutely. So first, look, we're super excited about PTC303. We talked about it at R&D Day. And I think, again, this shows PTC's ability to leverage splicing to bring forward potentially valuable and impactful therapies. And PTC303 is one that can target several diseases characterized by somatic expansion. This is one that I think from conception to getting to a development candidate took our team probably a little less than 3 years, which is phenomenal. And really, I think, is an example of how we are getting smarter and using the tools we have to facilitate and accelerate small molecule splicing development.

As you pointed out, Paul, and we talked about on the call, HD is a disease of somatic expansion. Targeting MSH3 is probably now the hottest target in Huntington's disease drug development. We're very excited about votoplam. We think they could work together. And also, it could serve as a monotherapy, particularly in, for example, Juvenile HD, which Juvenile HD is a setting where there's a large number of triplet repeats and it's characterized by rapid progression.

What does that mean? There's rapid somatic expansion. So you would think that something targeting somatic expansion, you could see a signal sooner and maybe louder in a short amount of time in, say, a Juvenile HD population. But we're very excited to be able to have this as a potential therapeutic option. We look forward to getting all of the IND-enabling studies done and getting this into the clinic as quickly as we can in 2027.

In terms of tominersen, I think it's been quite clear for a bit of time now, probably ever since the GENERATION HD1 data were presented, and probably even before that when some of the earlier-stage data were presented, that a lot of the challenges with tominersen were not really a mandate or a reflection of the potential of HTT lowering, but a lot of it was associated with the limitations of the ASO modality here. As was noted in earlier studies with tominersen, particularly when there was a 4-week dosing arm, it had to be discontinued because of the significant amount of inflammation created in the CSF by the ASO.

And in fact, in the doses used in GENERATION HD1 as well as GENERATION HD2, you still saw white blood cells and protein markers of immuno-inflammatory response in the CSF of patients who received it. That's been noted. That's something that has always been a concern. If you think about it, you're taking 8 Huntington's disease patients and a lot of those patients were later-stage patients. So these are individuals who had brain inflammation and oxidative stress for decades and you are dropping an inflammatory stimulus into their CSF. And so what ends up happening is you can't actually, I think, readily or easily detect a favorable Huntington lowering response because it's confounded by a significant inflammatory response in that population.

And again, that's corroborated by the protein and white blood cells in the CSF as well as by some of the other issues with the CSF that were observed in that study. And of course, the association of certain points of NfL spikes following treatment. All of that put together is really where I think a lot of people are -- view the tominersen was -- experience as really a reflection of that drug and not HTT lowering.

We think that the -- and the Evrysdi paradigm is probably a better way to think about votoplam, right? Oral small molecule splicing agent gets full brain biodistribution, allow for titratability, allow to use the peripheral blood cells as a marker for target engagement and change of protein of interest. And then really allow you then to identify a therapeutic window so that you can deliver benefit along with safety. So that's how we think about it.

Thank you. I'm showing no further questions. I'd like to turn the call over to Dr. Matthew Klein for closing remarks.

Thank you again for joining the call this afternoon. We are incredibly excited about our performance so far in 2026, and we look forward to continued outstanding performance, not only with Sephience, but across the entire company.

Thank you all again for joining the call.

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

Okay. We'll continue with the next session. I'm Paul Choi, and I cover the SMID-cap biotech sector here at the firm. It's my pleasure to have PTC Therapeutics here. And on stage with me, to my immediate left, Dr. Matthew Klein, CEO; and to my far left, Pierre Gravier, CFO. I think what we'll do is what we've done in prior sessions, and we'll let maybe Matt kick it off maybe with some high-level comments on sort of the strategic priorities for the balance of the year and going into 2027. And then we'll go into Q&A after that.

Sounds great. Paul, thanks so much for having us. For us, 2026 so far has been really successful. We had a really strong first quarter with record product revenue of $226 million, total revenue of $273 million, fueled by the continued success of the Sephience launch. We announced launch in Japan late first quarter, which was great news and will really help accelerate the launch. We also shared positive top line data from the long-term extension of the votoplam Phase II PIVOT-HD study and that the Phase III trial is now underway and being enrolled by Novartis and continue to have nice revenue contributions from our more mature products.

We look forward to an exciting rest of 2026 into 2027. Clearly, the Sephience launch, the continued momentum of the launch is going to be an important part of the story. But we also are looking forward to a number of advances in our R&D portfolio. We've aligned with the FDA on the design for the next vatiquinone for Friedreich's ataxia study and expect to initiate the, what we're calling, MOVE-FA trial in the third quarter, which I know we'll probably talk a little bit about is open-label natural history comparator to provide additional data to support NDA resubmission.

We also look forward to initiating a Phase IIa study of PTC844, which is our next-generation DHODH compound. We've already initiated the Phase I study of PTC612, which is our NLRP3 compound, and we look forward to continuing to enroll that Phase I healthy volunteer study as well to collect data in the second half of the year. We expect to announce a development candidate for our MSH3 splicing program. We're really excited about this program. MSH3 is an important target for regulating somatic expansion, which is important in Huntington's disease, myotonic dystrophy as well as other disorders. And we look forward to announcing that compound and really continuing to lead the field of oral small molecule splicing.

And we also expect to have a development candidate from our ferroptosis platform for synuclein-targeted therapy that can be used in both Parkinson's disease as well as MSA. So really a lot going on at PTC. And also, as we've mentioned, we'll continue to look at business development opportunities given our strong cash balance and our desire to look at ways to augment the PKU portfolio as well as drive near and intermediate-term top line revenue.

Great. Clearly, a lot going on. So maybe we can start with the commercial piece. And I guess, either for you, Matt, or Pierre, how would you characterize the Sephience launch so far to date? How do you think about how it's done versus your internal expectations as we look at the sort of comps or historical comps in the category? And then I had a follow-up question after that.

Yes, absolutely. Look, we're really excited with how the launch has gone to date and for what we see as continued growth. We expect to have continued growth in the U.S. as well as later in the year contributions ex-U.S., given our global footprint and already the number of global approvals that we have.

Look, we were very clear from the beginning that we did not think comparing Sephience to the other therapies, PKU therapies, whether Kuvan branded and generic or Palynziq was really an appropriate comparator given the unique differentiated profile of Sephience. We knew coming into the launch that there's about 17,000 patients in the U.S., 58,000 in markets where we can commercialize globally. And despite there being approved therapies, there was really still a significant unmet need. We know that Sephience, given its oral well-tolerated profile, the fact that it has a dual mechanism of action, one is a precursor, a more bioavailable precursor for BH4.

The second is an independent chaperone that can provide benefit for non-BH4 responsive or classical patients that we, for the first time, had a therapy that could address the full spectrum of PKU patients regardless of age and regardless of severity. And the story of the launch thus far really is a story of breadth. Seeing broad uptake across all different segments, no matter whether you're talking about age segments of kids and adults, treatment experience, whether that be therapy naive, those who tried and failed other therapies or switches from existing therapies. We shared our Q1 earnings that at that point in time, we had over 90% of the centers of excellence in the U.S. have already prescribed Sephience and that we soon expect to be able to get that number to 100%. Which, again, after only 2 full quarters of launch is really a significant milestone.

We also talked about our team as being quite experienced in selling rare disease drugs, not only in the U.S. but also globally. We have a robust global commercial infrastructure. And we've talked a lot about how that team did really well with Translarna, which I think everyone could acknowledge was a much more -- had a much more challenging profile than something like Sephience. And with the approvals in Japan and Europe and Brazil and our ability to leverage early access programs in countries where we don't yet have pricing and reimbursement, really, we think that this is unique again in the category for being able to be start within the first year and have a true global launch.

And so overall, I think we're really pleased with how things have gone. We've been very clear that we expect continued growth in the U.S., accelerated growth outside the U.S., which we expect to really start having an impact in the latter part of 2026 reimbursement on board and position us really [indiscernible] and beyond.

Right. As you think about sort of the other launch dynamics, Matt, you touched on utilization both in treatment-naive, treatment experience and switch patients. Can you maybe help us understand to what degree is this, given the sort of -- that there hasn't been a new PKU drug in a while, how much of this is just sort of bolus driven versus how much do you think this is just sort of market expansion in the PKU category?

Yes, absolutely. Look, when we came into this launch, a lot of folks believed. And in fact, a lot of prescribers said that they thought the early part of the launch would be driven by switches. That's actually not been the case. One of the, I think, surprises early on is about 30% of patients from that therapy-naive bucket, and this is a bucket of folks who tend to have more severe disease, classical PKU.

The reason they're therapy naive is because they were never tried on other therapies because there wasn't a belief that they would work or that it would be well tolerated. And many thought that these individuals "lost follow-up, it would be very hard to get them on drug. And if you did get them on drug, that was going to be sort of a latter -- in the latter part of the launch years down the line."

That's not the case. And so we've had strong contributions from that segment. And probably the largest segment contributing is those who've tried and failed previous therapies with a smaller number of switches, which we expect to grow over time. So I think what we're really seeing is still steady, strong demand from a market or from a patient population that has real needs for a safe and effective therapy.

Great. You provided some nice numbers on where the patient growth and patient types are coming from. But either for you or for Pierre, have you sort of, I guess, based on this early launch trajectory, rethought the TAM here in PKU? I mean [indiscernible] billion plus on top of that the ex-U.S. opportunity. Have you sort of internally rethought about the TAM? And then I had a follow-up on that.

Yes, absolutely. So I think in terms of market numbers or population sizes, about 17,000 patients in the U.S., and we've said about 58,000 globally in geographies where we believe we can get access and reimbursement. And when you think about the fact that this is a therapy that has the potential to serve virtually all of those patients, we see this as a large market opportunity. And I think we've been now very clear that we believe that this is overall a $2 billion-plus global opportunity. We expect there to be strong growth in the U.S. and then again, the ex-U.S. contribution.

We've talked a lot about the importance of the international contribution here and being able to have that early in launch. I think at its peak, Translarna did something like $330 million. Again, we think the PKU profile is much stronger. Translarna was never in Japan. The PKU population is much larger. So when you just start thinking about that, you can see that the international contribution could be quite strong. And then in the U.S., given the differentiated profile, I think we could reach those $2 billion-plus numbers with modest penetration for an effective differentiated rare disease therapy.

Great. Since you mentioned the ex-U.S. markets, can you maybe give us sort of a current update on sort of where reimbursement is -- where reimbursement is? We've, I guess, in the past, talked about like AMNOG in Germany. You recently launched in Japan, just sort of those larger markets, maybe just give us an update there.

Yes, absolutely. So we'll start with Japan first because pricing reimbursement is done there. And given that Sephience is an orphan product, that price is set for 10 years, and there's no ex-Japan, there's no referencing done when we get pricing in other countries. So that list price is consistent with the U.S. list price. So that's a great place to be in terms of having that locked in for the next 10 years.

We're -- the negotiations are ongoing in Germany. As you know, it's a long process and a lot of back and forth. We were very encouraged by the early feedback we've received -- and the rating we received and the acknowledgment by GBA that they view phenylalanine, which was the primary endpoint of the clinical study as holding value, as having clinical meaningfulness. Which is really important because traditionally, they do not regard biochemical or biomarker data as support of clinical meaningfulness, and they do in this case, and they were very explicit in the initial feedback.

The other thing that's really helped us is being able to have the results of the AMPLIFY study available to be in the dossier, the pricing reimbursement dossier. AMPLIFY is a head-to-head study where we took individuals, they were randomized to either get BH4 then Sephience or Sephience then BH4, which allowed us to demonstrate in individuals the significant benefits of Sephience. And so overall, in that study, we had a mean benefit or mean greater -- mean reduction of 70% more with Sephience than for BH4.

So to be able to go and have payer discussions with a published manuscript that shows superiority over the other oral therapy, really puts us in a good position for reimbursement. So those discussions are ongoing. We're also recently announced that we have been able to get Sephience into the AP2 as Early Access Program in France. So we'll be beginning pricing and reimbursement discussions there as well as in Italy and other countries. We have mentioned that while we're doing -- going through the often lengthy pricing and reimbursement discussions, we've been able to, as we're doing in France, leverage early access programs.

And that has a number of advantages because being able to do early access at this point gets us patients on drug in countries. That's a price set by us pending agreement on pricing. And also puts the drug in the hands of the influential KOLs who can then participate in the pricing and reimbursement discussion. It's very common in a number of the countries that the ministries of health who make decisions around pricing and reimbursement, we will consult with expert physicians. Clearly, if they've had the drug in their hand and seen the benefits of that drug, that will certainly help as we seek to get a favorable pricing.

Okay. Great. I want to talk about some of the real-world feedback that you're getting now that you guys are commercializing Sephience here. And one of the things I picked up on social media was a patient talking about eating McDonald's chicken McNuggets, of all things, for the first time. And so I want to -- maybe just on that point of diet liberalization or increased protein intake. What are you hearing in the field? And I guess, this is something I think you're still continuing to prosecute in the clinic and follow up. And just how are you think -- what are you hearing from your sales force and just thinking about development of that aspect of the disease?

Absolutely. I didn't see the McDonald's comment, but I assume that was a kid, but I think the point which is super important is that these are individuals who have not had the benefit of having freedom to eat foods that other kids may eat or that their parents may eat or that the parent can eat the same meal as that they're serving their child. And we're continuing to hear these stories of really success of Sephience, success of allowing folks to have some diet liberalization, in cases complete diet liberalization, and that's super important. We hear that on social media, see them on social media, our field forces get feedback. And we also work very closely with the dietitians.

All these centers of excellence have a multidisciplinary approach to care of the PKU patient, which not surprisingly includes dietitians. Why? Because in the absence of a therapy, the mainstay is this highly restrictive diet. And what we've worked very hard on is as individuals start on Sephience that there is a plan to gradually increase protein intake and also some guidance on the right protein to take from a nutrition standpoint. But -- so we're getting a lot of feedback from dietitians as well as how well this is going.

We've also been hearing a lot about another benefit, which is super interesting, which is improvements in mood and cognitive function. We know that PKU can have significant effects on cognition, clarity of thought. And we also know that Sephience gets across the blood-brain barrier. And so we're hearing more and more about these types of benefits, decreased anxiety, increased executive functioning. And we shared some of these data that we collected from our open-label extension of the APHENITY trial, where we're able to show significant improvements on those points in the QOL assessment.

But as you alluded to, Paul, we're continuing to gather real-world evidence because these data, which capture different types of benefit. Obviously, we talk a lot about diet liberalization, but other things in terms of cognitive function and mood are incredibly important for generating market demand, market pull and also obviously, adherence and compliance.

Great. I think all biotech CEOs have a healthy sense of paranoia when they think about competition. And so as you sort of look at the competitive landscape, who do you -- who are you monitoring? Who do you think of as potentially next to market here? And what does that, I guess, in your mind, as you look at the market down the road, potentially do to pricing and sort of share in your mind?

Yes, absolutely. Look, I think there's been a lot of interest in the kidney-directed therapies that Jnana and Maze have. And I think the -- what we're hearing a lot from the physicians is a desire to combine those with Sephience to get even more benefits for patients. I think it's still -- while those are in clinical trials, I still think there's some questions out there in terms of what's the ultimate therapeutic window for these compounds going to be, who are they going to be most useful in.

Currently, all the clinical studies -- I mean, the Phase III -- the Phase III trial for Jnana, I think Maze just announced a Phase II study are in adults. So that's still leaving that huge pediatric and adolescent population without -- and the reasons for that, I'm not sure of, and we'll see how that goes over time. So I think from our standpoint, we're watching those. We'll have to see what the safety and efficacy are. But I think importantly, what we're hearing a lot is the desire to have combo therapies with Sephience. Sephience will be first line and then this could be added on to get even more benefit...

As a backbone?

Yes. And it makes perfect sense. This is a community that PKU patients, their daily life is combo cocktail therapy. That's how they live today. And so it's not surprising if you can have additional therapies that can get you even more benefit, that would be the ideal.

Great. Let's maybe turn to your pipeline and maybe starting with vatiquinone. Can you maybe walk us through your recent FDA dialogue and just sort of what drove the sort of change in perspective at the agency to allow your new trial design? And maybe you could just remind us what your new trial design is here.

Yes, absolutely. So look, we were clearly disappointed by the CRL last summer and believe that we had evidence of significant benefit in the younger patients who don't have -- currently don't have a therapy. And we had discussions with the FDA. And the interesting part here was they were the ones who suggested that if -- well when they said they'd like additional data, they were -- had suggested that we could do an open-label natural history comparator study to get that additional data to support NDA resubmission. Quite frankly, that was a little surprising to us in a good way. And I think it potentially reflects the fact that, one, the safety profile of the drug is very well characterized. It's very well -- it's safe and very well tolerated. So that's not a question now.

And in terms of efficacy, I think the FDA has long viewed the Friedreich's ataxia natural history database as being robust and reliable, and able to provide a reliable comparator to what would happen outside of therapy. There's a lot of -- without therapy, and there's a lot of reasons for that. The clinical trial sites tend to be the same sites who contribute to the natural history registry. So it's the same teams doing the same assessments on the same patients. I think also if you look at our MOVE-FA study, the placebo group's progression looked a lot like natural history, which also gives you confidence that you're seeing those 2 groups aligned and therefore, supports the fact that the natural history group can provide a reliable comparator in an open-label fashion.

So we've worked with them on the protocol. They've reviewed our protocol and analysis plan, and this is going to be about 120 individuals aged 7 to 21, consistent with the primary analysis population of the MOVE-FA study. It's going to be 24-month treatment period. There'll be a natural history comparator group from the robust and reliable Friedreich's ataxia natural history registry. We have a statistical analysis plan that is already specifying what the matching criteria are going to be, what is the matching model going to be and how we're going to account for any potential differences between those key characteristics that are most influential on disease progression.

We've shared that we believe we can get this study started in the third quarter. And obviously, what we've heard so far is a lot of excitement from the community to be able to enroll the study and get access to the drug without having to worry about being put on a placebo and therefore, delaying access to a drug that could slow progression, which is particularly important for younger ambulatory individuals.

Great. Maybe 2 mechanical questions. Can you maybe remind us in terms of like background or prior therapies, are patients allowed to be on CoQ10 or vitamin E or previously on SKYCLARYS. And then just on the matching dynamic, is that locked in as they're randomized? Or how does that process evolve during mid-trial or after treatment is initiated?

Yes, very good question. So we're fairly -- in terms of SKYCLARYS, they can't be on active SKYCLARYS therapy. We do have certain provisions if they were on it for a limited amount of time because there were a number of individuals who have tried and dropped off

[Audio Gap]

comes down to [indiscernible] whatever they have in the trial, the natural history subjects, right? So the real issue with SKYCLARYS, which we still have the MOVE-FA extension going on, and we have patients on both therapies, which a lot of the physicians want. But the registry doesn't have enough individuals who had enough SKYCLARYS experience that we could match. That's why we had to be very limiting in terms of how much SKYCLARYS you could have been exposed to. In terms of the mechanics of the matching, so what we've done, we will do the query of the registry once everything is done and the trial is enrolled.

However, we did prespecify exactly what are going to be the characteristics on which we're going to match. That was the key part. And there are the obvious things that you can imagine that are important in terms of influencing disease progression. So age, number of GA repeats, baseline mFARS score so that you're aligning the disease severity. So those types of things that will be influential of disease progression, we specified already how we're going to do that, what the procedure is going to be for querying the registry. And then once we do that, what are the details of the propensity match model, including all the coding and all of that has already been submitted before we start the trial so that there's integrity there in terms of sort of fixed process. Exactly right. Given the open-label nature, we wanted to make sure that all of that was fixed and aligned on ahead of time.

Okay. Great. As you think about your learnings from your previous MOVE-FA trial and just sort of what the real-world experience has been with SKYCLARYS, where do you think the biggest sort of unmet need is outside of sort of the pediatric or younger patient population, maybe just from a clinical benefit perspective as well?

Yes. So look, I think the pediatric and adolescent unmet need is significant, right? About 1/3 of the patients are in that age group. And if you think about a degenerative condition, it's quite clear you want to start treatment as soon as possible. And I think the -- we've talked a lot about the data from MOVE-FA and being able to show the significant benefit in the short term on upright stability, which has those items around balance and gait, which are clearly important to younger individuals who can still ambulate. So I think that, that is an important part of the population.

But then when you look to the adult population, there's a number of individuals who've tried and not stay on SKYCLARYS. And I think the ability to have therapeutic options is really, really important for patients. I mentioned as well that there's a number of physicians who want to combine therapies who also want to look at combining a therapy like vatiquinone with some of the frataxin augmenting therapies. Why?

Because even though the frataxin protein is deficient in Friedreich's ataxia, introducing a functional frataxin protein into a very broken cell will not work nearly as well as introducing frataxin protein into a cell where you can turn down the cell stress and inflammation. If you get the genetic machinery and other cellular machinery to be less inflamed and work better than giving exogenous frataxin will obviously work better. And this has been shown preclinically in a number of different diseases. So I would say kids and adolescents and then don't underestimate the importance of having a therapy that's safe, well tolerated, doesn't -- wouldn't -- is unlikely to have significant monitoring requirements as a therapeutic option for folks.

Great. Maybe one more on Friedreich's ataxia before we move on is, can you -- with an open-label natural history trial design here, can you remind us, is there an interim look built in? How does that work? If positive, how do you think about sort of timelines if you have after, let's say, half your patients enrolled or whatever the case may be or monitored? How does that -- how do you think about that?

So we thought a lot about that because it's -- whenever you start a trial like this and you have a high probability of success given the nature of the study, given the fact that we could have -- we're able to incorporate a lot of the learnings from our previous studies and what we have now, we believe is a very good understanding of the disease and the endpoint. But then we [indiscernible] really our last chance here. And if you believe in the drug, you've designed your trial well. We believe what made the most sense is let's not have an interim. Let's run it straight through 24 months with the full population because that's what's going to give us the highest probability of success. And so the plan is, at this point, not to have an interim.

And I think it's also important, given the open-label nature of it, that we have the largest data package we can, right? Because there's always questions -- that's part of the decision to go 24 months was because you want to make sure that, that placebo effect in Friedreich's ataxia, which is known to exist and known to be pretty fully washed out by month 6, you went up as long as time as possible to show that this is a credible -- this effect can be credibly attributed to the therapy and nothing else. And so when you put all that together, we said, look, high probability of success, let's get as many patients treated for the full duration and go with the strongest data package and get this across the line and approved.

Okay. Great. I want to maybe touch on Huntington's for a moment. Your program, which you partnered with Novartis has now transitioned to a Phase III. Can you maybe just remind us of what are your obligations, I guess, at this point as the Phase III now is underway? And just how should we think about updates from that program now that the asset is more or less fully in Novartis' hands given it is potentially a very big value driver for you in the future?

Yes, absolutely. Look, we're incredibly excited about the votoplam program, and we've talked a lot about -- from the beginning, this was following the path established by Evrysdi. How do you develop a small molecule splicing agent for CNS, mostly CNS disease. And everything we've done across -- along the way has followed that path. I think the PIVOT-HD data, the long-term extension data give both PTC and Novartis confidence that the Phase III trial is very well designed, includes early symptomatic patients.

The target enrollment is 770 patients approximately with cUHDRS as the primary endpoint up to 36 months. There's an interim analysis that will allow for an earlier look in a smaller number of patients. And this is fully in the hands of Novartis in terms of the technical execution. They're responsible for the enrollment and the conduct of the trial. And I have to say, as proud as I am of our team and the capabilities of the PTC team, Novartis was built to do a 770 individuals study. And I think that really increases the technical success of this study.

They're also 100% responsible for the funding of the study. And then according to the terms of the agreement, we still have about another $1.8 billion in sales and commercial milestones, and then there's the 40% profit share in the U.S., double-digit ex-U.S. royalties. So we're set up for significant financial benefit here if successful. And again, I think we -- both companies feel that if the long-term extension data play out in Phase III, then we could have the first disease-modifying therapy for Huntington's disease, which would be incredibly exciting.

Great. Maybe in our remaining time, as we turn to your earlier-stage pipeline, one of the things that I find most interesting is your NLRP program. A lot of interest in this area generated by the recent Ventyx data as well as the acquisition there. And so maybe just at a high level, could you point out some of the key differences and pros and cons for your asset versus Ventyx?

Yes, absolutely. Look, I think this is, as you mentioned, a hot area, inflammation and NLRP3, the NLRP3 inflammasome has been recognized as really an important hub, the NLRP3 pathway sort of a sensor of inflammation that propagates a further inflammatory response. We've been clear that we're interested early -- at this point in looking at pulmonary disorders where there's a very nice link between NLRP3, the NLRP3 inflammasome and pulmonary pathology. What we've been able to do, and we shared this at our R&D Day is really show that PTC612 is differentiated from some of the other therapies.

If you look at the Ventyx compounds, the obesity compound, we've shown that in an IL-1 beta assay, we have 50%, 5-0 percent greater potency. And then over -- we have almost 10x potency of their other compounds. So I think from a potency standpoint, we believe that we have a really differentiated compound. We believe we have a lot more specificity. And then its chemical structure is different as well. A lot of the existing NLRP3 therapies have a sulfonylurea backbone, which is responsible for some of the off-target toxicities. Ours doesn't have that. So its chemical structure is a bit different. It's got a good potency profile, and it has a -- we believe, more specificity for NLRP3. We mentioned

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SAD, MAD type things [indiscernible] and drug exposure, but we'll also be having an MAD cohort of individuals with a metabolic syndrome biochemistry that could give us a read in Phase I on some of the potential biomarker effects we're having on inflammatory markers associated with the NLRP3 inflammasome.

Great. Pierre has been very patient here background as Matt and I have chatted on the pipeline. But Pierre, I want to maybe ask you a little bit, you're having massive top line growth from Sephience here. You've sort of maintained your OpEx guidance for the remainder of fiscal '26. And so the company's sort of financial profile is in the midst of changing here to breakeven and eventually profitability. And so as you think about the shape and sort of velocity of the company's margin profile change, what would you sort of tell the Street to how to think about the balance of '26 and going into '27 and then the intermediate term?

Yes. So first of all, we're very excited to be here. We work really hard to get there. We're excited about, obviously, Sephience launch and continued growth in '26 and beyond. We talked about a $2 billion-plus opportunity, not guidance yet. And that obviously bodes very well with our OpEx management, which we have been very disciplined over the years to reduce that. And again, we're built globally. We talked about the launch. Commercial was ready, right, in Europe, in the U.S., in Japan, in LatAm.

And obviously, R&D, we're going to be very disciplined. We have a number of new products obviously coming in the pipeline, which we talked about a little bit. And both our platforms on both splicing and ferroptosis are very important to us. And then HD is obviously partner, so there's no OpEx for that. So that's how we think about the future. And obviously, we talked about a very strong cash balance where for the right opportunity, we will be ready to deploy additional capital. We have a commercial team available that demonstrated they can sell rare disease products globally. And so we think about how can we accelerate that top line [indiscernible] in a very disciplined manner and making sure we create value for our shareholders in an accretive manner.

Pierre, it's no secret you have a banking background. And so you've obviously looked at shopping for assets. And I guess, as you sort of think about the core competencies of the company, historically, it's been in things like splicing and so forth. You have a strong launch going on with the Sephience. But how do you sort of think about the landscape as you look for potential BD on the early-stage side versus something that might be closer to clinical trial completion or commercial stage?

So the #1 thing that is very important is we have flexibility, right? We don't have a rush to do one way or the other. And are there ways that could complement our approach? Historically, we're a small molecule company. So just if you look at modalities, but we could look at other ways to enhance the portfolio. Again, it's all about how can we complement both commercial assets, which are important. Are there things that could fit rare neuro, rare metabolic or neuro-metabolic. But again, we could build another adjacencies as long as it's rare disease, right? We're not going to start and do an oncology therapeutic area for us. That makes a very detailed sense for us.

So again, it's what are the areas where we are we're really the leader. And also, I will say, beyond commercial, we have global regulatory capabilities. We manage to push programs to the finish line that could be very attractive to companies. And so when we look at the landscape, if a company -- I mentioned the fact that we want to create value for our shareholders. If a company trades at 20x sales, good for them. That's not going to be something we will be looking at. But are there ways where we can find value? And again, there's also that global commercial capabilities. We could take ex-U.S. rights, for example, and start to market in Europe, in Japan, in LatAm in a very efficient manner.

Great. We're coming up on time here. So maybe one to close with you, Matt, which is if you were to direct investors to 1 or 2 things that you think are really key over the next 12 to 18 months, what would you highlight?

Yes. So clearly, having a product like Sephience that can be a multibillion-dollar rare disease product, the fact that we have a robust pipeline with the leading oral HD therapy in development with none of the costs but a significant back end, the ability to innovate and have a steady flow of pipeline assets and then sitting in a strong cash position with over $1.9 billion gives us flexibility to continue to augment, as Pierre said, both the R&D and commercial pipelines. I think -- and the fact that we're, as you mentioned, Paul, going to be vectoring towards being cash flow breakeven and profitable in the near future. It's a pretty unique setup for a company, and we're pretty proud of that.

Great. Okay. We're out of time here. So my thanks to Matt and Pierre for joining us, and thanks to PTC.

Thank you.

Thank you.

Welcome to our next session. We've got PTC Therapeutics presenting for the next 30 minutes sitting up here on stage with me are a couple of folks that you definitely would recognize, Matt Klein, who is, of course, Chief Executive Officer; as well as Pierre Gravier, who is Chief Financial Officer. We also have a couple of folks in the audience from the team as well. We might yell out to Eric during Q&A as well. So let's maybe just do a quick overview of the company for the few people who might not know about PTC, Matt, and then we can go into Q&A.

Absolutely. Thank you so much for having us, Tazeen. PTC is a global biopharmaceutical company that discovers, develops and commercializes therapies for diseases of a high unmet need. We have 6 marketed products that we commercialize ourselves around the globe as well as a robust R&D portfolio, including our validated and differentiated small molecule oral splicing platform. We're off to a great start in 2026. We delivered commercial revenue -- total revenue in the first quarter of $273 million with product revenue of $226 million, allowing us to raise guidance for the year. That was really led by our another strong quarter for Sephience, which we launched last year for children and adults with PKU. We did $125 million in revenue globally.

This is a rare disease launch that's leveraging our established global infrastructure. And as I mentioned, we're off to a strong start with strong momentum, and I'm sure we'll talk a lot about that during the fireside. And also, we've made a number of advances in our R&D portfolio as well, sharing the positive data from the long-term extension of our oral Huntington's disease therapy, votoplam, which is partnered with Novartis. We also shared that Novartis has initiated the Phase III HD trial, which is up and running. We also provided an update on our Friedreich's ataxia program, where we've discussed with the FDA being able to conduct an open-label versus natural history study to support NDA resubmission. And our NLRP3 program we shared is now in Phase I. So a lot of great progress across both the commercial and R&D portfolios.

Okay. Great. So yes, we wanted to talk a little bit about this new little launch you've got with Sephience, right? So we've covered this company, I've covered this company for quite some time now. So you've had an evolution. So you were originally known as a DMD company. And now you've got PKU and maybe just talk to us about the platform, how it's evolved and why you're excited about the early innings of the launch, and then we can talk about what your expectations going forward are?

Absolutely. So the company has its roots in DMD, which was started with DMD and actually being one of the first RNA drugs in development. And that experience with Translarna and then, of course, with Emflaza really allowed us to build a robust rare disease global commercial infrastructure with the ability to navigate regulatory authorities, pricing and reimbursement and sales all over the globe. And so as we've continued to do work and focus on both the discovery and development of important therapies for rare diseases, the PKU program with Sephience fit very nicely into that. And of course, we have a number of other programs in the pipeline that are moving through. And so when it came time to file for Sephience and get ready to launch, this was really -- we saw as an exciting opportunity, one, because the molecule -- the therapy itself, Sephience is highly differentiated.

It has a novel dual mechanism of action, which is capable of providing potential benefit to the full spectrum of PKU patients. PKU is a disease of approximately 17,000 individuals in the U.S., 58,000 globally in areas we could market the therapy. And despite there being approved therapies, there remains a significant unmet need for the vast majority of patients. So here we are with the opportunity to launch a product that has a highly differentiated profile, very strong safety profile, demonstrated efficacy across the full spectrum of patients, regulatory labels that are quite broad, a large patient population for rare diseases with significant unmet need and this global team that's very used to launching and selling rare disease drugs.

So we've been able to, within 6 months, get approval in the U.S., Europe and Japan. We have already launched in a number of countries. We said we should be up to 30 by the end of this year. That's really impressive for a company our size and for a rare disease launch. So I think it's really this combination of having a really good drug, a really experienced team that obviously, being in place allowed us to spend 1.5 years in market development, become very well integrated in the patient communities, understand their needs, have disease awareness and education programs like in the U.S., we had an opt-in program prior to launch, all these things that allowed us to hit the ground running as soon as we had authorization and I think you're seeing the products of that with the strong launch, not only in the U.S. but now globally.

Yes. So on the point of the strength of the launch, were you expecting a bolus when you first launched? And did you see that? And is that starting to fade?

Yes. So I think the term bolus to me -- so the short answer is we don't think we had a bolus because the bolus really means you had this lot of patients come in and then it dwindles off. What we certainly had was an acceleration phase in the first couple of months where since we had done so much work in market development and there were a lot of centers that had waiting list of patients to come in, we had a really strong start to the launch. And -- but we're still in a period of very strong momentum that we can maintain for the long term. So that's why we really use the term an acceleration phase where in the first 2 months, they're waiting list, the centers brought in a lot of patients and then somewhere around middle of the fourth quarter, we started seeing we're getting into this sort of sustained cadence whereas patients came in, they're being put on drug.

We also noticed that there are a lot of things in this launch that I think people misunderstood coming into it. One is I think there's a fundamental misunderstanding of the marketplace. A lot of folks thought that, well, we had the 17,000 patients, but a lot of patients are lost to follow up and you'll never get them in and maybe you'll just get the patients who are on existing therapy switching. And that's not what we observed at all. In fact, what we saw across centers of excellence is that there's a preference for getting those who are not on a therapy first, on a therapy first. And a number of these individuals who thought we lost to follow-up, such as adults, including those with classical or more severe form of disease, they're coming back to the clinic.

And so I think what we've been able to show early on is that the addressable market is the full patient population of PKU. These are people who want a therapy so long as it's safe, well tolerated and it can make a difference in their life. And so we've been able to really -- again, a lot of this was from the work we did beforehand, but we're already penetrated into over 90% of the centers of excellence in the U.S. Again, this early in the launch is pretty phenomenal, and we have penetration into all of the key patient segments, including those therapy naive, those who tried and failed other therapies, those who are switching from existing therapies. We've got infants on the drug. We have 80-year-olds on the drug. So we -- breadth is really the story of this launch.

And it's the fact that we have that breadth already no matter how you segment the population and the fact that the population is so large is what gives us the confidence that we're really in this period of sustained momentum in the U.S. And then outside the U.S., we're just getting started, right? So we've launched in Germany, that's going very well. We launched in Japan in March. And now we're seeing that sort of accelerated phase in these other countries. And that's what's so special is that we are now in a period with a strong start in the U.S., a strong base of patients with sustained momentum there and now accelerated momentum globally is really what we believe is going to take us to the levels that we think we could achieve blockbuster status, multibillion-dollar status as we've talked about.

Okay. So we are in agreement with everything that you said. We published a survey of physicians before you reported the quarter, which indicated strength in the quarter and beyond. But some of them -- some folks are looking at data points that we'd like to hear what you think of, for example, claims data. So some are of the view that claims data trends seem to indicate that there might be a plateauing of demand. So why would that be an incorrect interpretation?

Yes. I don't think the claims data are really reliable here for us. And then also people are looking at prescription sources, in fact we have 2 specialty pharmacies. There's a closed network, everything is confidential. So that's point one. Point two is that what we talked a lot about is we saw at the end of the year holidays into early part of the year, typical dynamics you'd see with holidays and starts maybe going down a bit and then shorter months in February, and then we see a really, really strong March, really strong April.

And there's no signs that this momentum is slowing. Yes, it's -- every week is not going to be the same. It never is in any launch. There's a lot of external factors. But if you can zoom out and look from around mid-November till now, it's pretty consistent, consistent with the number we gave. So I think people -- I know there's a lot of discussion about the first question, is there this bolus and now it's going, wait, no. There was this acceleration from all of the work we did, market preparation we did. And now what we're seeing over the past 4 or 5 months is sustained momentum that all the signals we have are going to continue.

So you've used sustain a couple of times in this conversation. You used it a couple of times on the earnings call. So as far as U.S., and then we'll talk about ex U.S. in a second, is this -- are you in a place where you think you'd start to feel comfortable providing like sales guidance?

Yes. So I think what we've talked about is we've typically had the practice of not giving guidance for the first year of a launch. And we've said that we see -- we believe we're in a period of sustain as, which means if things continue to go the way we imagine as we get later into '26 across the year point, and we have enough points on the map to give guidance, then we'd be ready to do it. No promises of exactly when, but obviously, we're tracking this. It's -- we're seeing such great trends, such strong trends, and we're still early launch. So we want to make sure, as always, when we give guidance, we believe in the guidance and can stick by it. But there is -- and I think we've been very clear, everything we're seeing reaffirms our conviction in this, one, the strength of the launch and really the strength of the long-term opportunity here for the product.

Yes. So you talked about long-term opportunity. So I don't know what the current consensus estimate is for peak sales. But as you look at number of patients in the U.S. and abroad, how are you thinking about what the TAM worldwide could be on sales here?

So we said that the market itself, we think is about 58,000. We've not guided to what that could translate into sales. Obviously, the price -- there'll be some variation outside the U.S. We're working very hard early on to maintain, as always, that rigid pricing corridor. We shared that we've got pricing in Japan on par with the U.S. back that's fixed for 10 years, really good and making very good progress there. Similarly, we have the list price in Germany is on par with the U.S. So again, we see 58,000, we said about 17,000 in the U.S. And we -- again, just where -- as we see this going, we've already in the first -- through the first quarter have over 1,200 patients on drug, and we see an ability just to continue to build that base. And that's really the key with good adherence and steady adds and accelerating outside of the U.S., that's how you get to that large opportunity.

What has early discontinuation rates looked like? And I think I asked this on the earnings call, but maybe we can go into a little bit more color. What's been the reason for discontinuation?

Yes. So we say we're in that low double-digit percentage, which is really strong at this point in the launch, especially when you consider what I said earlier, which is a lot of the early prescriptions in the U.S. were for those who are therapy naive, classical PKU, the more challenging patients. So if we're seeing really good adherence in the more challenging patients, knowing that a lot of the Kuvan switches, for example, are still to come, that gives us a lot of confidence in the long-term adherence rate because definitionally, if you've been on an oral therapy for years and know whether it's branded or generic, and you're going to switch to a therapy that's also once a day, let's just say, has equivalent tolerance, but superior efficacy, that bodes really well for the long-term adherence there. In terms of reasons for discontinuation, we have about half of them have been for clinical, which could be not effective for tolerability. Other is patient preference. We've seen a number there patient preference, which falls into any number of buckets.

So is there a particular profile of patients as this launch is progressing that you think would be particularly likely to respond? Or is it too early to know?

Well, look, I think we've said what we're seeing is response across the full spectrum, which is what's really, really important, again, going to the fact that we keep hearing stories of prescribers who put their most challenging patients on and hearing about phenomenal responses in terms of not only phenylalanine lowering with diet liberalization. Of course, we know from our data that any individual who's had any response to Kuvan branded or generic will have a superior response to Sephience. So that's very clear. Even if they were able to get to target Phe or some diet liberalization, one would fully expect that to be much better on Sephience.

So the good news is the word out there in the -- the experience in the real world is that we are having meaningful effect across the full spectrum of disease, which again continues to give us confidence to continue to penetrate these markets, right? If you're a prescriber and you put your challenging patients on the drug and you're seeing responses that just says, I'm going to keep going there. And then also, I have got these other patients that I can switch at some point. Just when you look at that across the board, you say, okay, that's why this has really long legs and a really large opportunity potential.

So in terms of treatment-naive patients who are experiencing Sephience for the first time versus switch patients from something else or as you described it earlier, patients who were initially lost the therapy and are coming back in. What do you think is the current split of that?

So right now, we have somewhere around 30% are treatment naive, which is a nice number. And then the switches and the tried and failed, it's a little harder to ascertain the exact numbers because it's not always fair if you've tried before. PFS doesn't always distinguish between the 2. But I think, let's call it, an even -- maybe -- actually, I think we have more tried and failed than on current therapies, again, because what we've heard is this desire to try patients who aren't on an existing therapy, which is why we believe we still have a very long way to go in terms of Kuvan switches.

Okay. And from the time a script is written to when a patient receives treatment, has that time period contracted as the launch has progressed?

Well, I think it started very strong. I think we were on an average of about 2 to 3 weeks when we started. We're probably still in that average range.

Do you expect that to be the normal range?

We think so. That's an average. Some can get on very quickly and some may take a little longer depending on their specific circumstance. And we now -- we said we now have policies with over 2/3 of American lives. The policies have been consistent in being very flexible with very few obstacles to getting on therapy. So all of that, we think, is going to continue to help.

Now what are you hearing about the qualitative measures like the quality of life measures like diet liberalization and things of that nature, which we have talked about prelaunch?

Yes. We're hearing great things. And we're seeing great things. In fact, on social media, it's so fun to see stories of kids eating certain foods for the first time. We saw photo of a kid eating a piece of steak off his parents grill and never having been able to do that before and hearing stories of families all being able to have the same meal for the first time. We're also hearing a lot about benefits on cognition and mood, which is super interesting because if you talk to families affected by PKU or health care providers, they'll talk a lot about the burden of anxiety, brain fog and cognitive difficulties. And we in our recent publication looking at the open-label extension for the Phase III study, we're showing on the QoL measures that we're having a good impact, a very favorable impact on anxiety, mood, other aspects of mood and cognition.

And these are things that go a long way for patients in feeling better. In fact, when we talk about the policy, the criteria for reauthorization include quantitative things like Phe lowering, potentially diet liberalization, but also overall medical benefit. And we're hearing from a number of folks that, I don't know my numbers are a little bit better, but I just feel so much better, my brain fog is gone. And that's really important because that's talking about quality of life, being able to -- we had the story of used to have to take a woman used to have to use GPS to get home from work, right, to be able to not have to do that, mood being better. All of those are really important favorable effects of the drug.

And as you talk to physicians, is there one thing in particular that they are impressed by? And I'm sort of trying to figure out sort of the depth of prescriptions. Are you still at the phase where doctors are trying it on a couple of patients and you keep getting new doctors that are adding a couple of patients? Or are you seeing more trying to use it in a more significant.

Yes. I think, again, we're in over 90% of the centers and the larger centers, and we've been in contact with the other centers and fully expect to get them onboard. Those are the late adopters as you typically would see any launch. But I think we've seen a variety. We definitely, the larger centers, what we're seeing is we're putting we're on. Just like we said we would, we're going to try all our patients on it. We've seen other centers that were maybe at first were a little skeptical and I'm going to try 1 or 2 more difficult patients and then they start to response, okay, now the floodgates open, and we're going to try to put everyone on. I think it's so those early -- that early experience in the more severe patients was so important to reaffirm that all patients should have the right to try this drug. It becomes the first-line therapy for PKU. And that's where we're going. And we're there in a lot of the major centers. And again, that's what gives us the confidence of the durability, I'll use the word sustain again, of the launch momentum.

Yes. Okay. And then as it relates to Europe, do physicians there have a similar view of science to how U.S. physicians think about it? I mean you guys have been in an unusual position of being able to market drugs in Europe for longer than you have in the U.S., you have that built-in expertise. So did you -- were you able to -- have you been able to capitalize on the infrastructure you have built out for Translarna for this launch in Europe?

Yes, absolutely. We have that playbook for Europe. We have it for LatAm with the approval in Brazil, and we're using a similar playbook that we're writing for the first time in Japan. And the experience in Europe and Japan are actually quite similar to what we're seeing in the U.S., right? Great enthusiasm on the part of the KOLs and understanding of the potential of the drug to treat the full spectrum of patients. It may differ center by center who may try first and how that works, but a lot of excitement. And we're also using that infrastructure we had in the Translarna playbook, we knew a lot about how do we leverage early access programs in a number of European countries, which we're doing while pricing and reimbursement goes on.

So that gives us the ability to sell the drug at the price that's consistent with the -- what we're maintaining for the narrow corridor, all while we're going through the period of formal pricing and reimbursement. Now to be clear to -- these early access plans, you're not going to get all the patients on. It's going to be smaller numbers. Once we get final pricing and reimbursement set, then you'll expect the large numbers to come in, but it allows us to one, start getting revenue in the country; and two, building up the physician and patient experience in those countries in a very positive way so that once pricing and reimbursement are in place, again, it opens that floodry and allows us to access the larger patient pools in all of these countries.

For Germany, in particular, I think for some launches, when they've gone particularly well, they've had to go back and take a price decrease. So what is your expectation of that happening post launch?

Yes. So Germany now has it's a 6-month repricing period, and that came to an end for us in January. We launched in July. And we're in the process now of going through the pricing negotiations. The initial assessments were quite favorable. A lot of that is because of the data we have and the fact that we had done a head-to-head study, our AMPLIFY study, which showed that on average, patients had a 70% greater lowering in phenylalanine versus Kuvan. That head-to-head data was super, super valuable. We saw them -- what they don't often do, but did in our case was recognize the biomarker fee being meaningful and having. So that's going very well. We expect there will be some discount. What it is, we'll know better as we play out in terms of the negotiation.

Okay. You mentioned phenylalanine. In the U.S., are doctors actually going back and measuring these levels in real time? I was just curious about that.

Yes, I think they do measure them. I think it's -- patients want -- well, the funny thing is if an individual PKU will tell you that their brain is like a PKU -- phenylalanine monitor. They know when their levels are high and levels are low. But the physicians do look at it and they do monitor it. And the patients do. I mean we've seen on social media, people posting their Phe results down 80%, which is really, really cool.

So that's another motivator for patients to stay on therapy, do you think?

Absolutely. Well -- and the way it works typically is you need to get to a certain level before technically you should be liberalizing the diet. And one of the things we've done in this launch, again, our experience in working with centers and prelaunch, making sure we understood the dynamics at each of the centers of excellence is the important role of the dietician, right? The last thing we want -- we're sitting here in Las Vegas, let's we want someone to start on the drug and went to the buffet and start eating everything, right? You want it to be a very thoughtful, measured approach.

And so we've been working a lot with the centers, and they've been working a lot with those who get on the drug to have a very measured approach to first establishing that you're having a certain amount of longer phenylalanine, then gradually increasing the diet. So there's a setup for success. And we avoid that risk that there's this expectation that, oh my god, I'm going to be able to lead everything in the first week on the drug, which probably is not realistic. So that's just another thing we're doing to make sure that we're set up for success and most importantly, that the patients are set up for success.

Okay. In terms of the competitive landscape, we talked about who you are currently competing against, but how do you see this over the next, I don't know, 5 to 7 years evolving?

Yes. I think right now, the next therapies in the pipeline are ones targeting the SCLA1A, I think transporter in the kidney. Very interesting approach that you think has the benefit that it's not -- it's agnostic to mutation. It basically tells the kidney, stop reabsorbing phenylalanine, pee it out and that should lower the levels. Again, interesting approach. The early data are looking encouraging. Still a lot of open questions, right? I think the current Otsuka trial is in adults only. And there's a lot of questions about long-term safety of lowering the other amino acids because this target is not specific to phenylalanine. It's all neutral amino acids. So there is this risk that if you have a lot of lowering of phenylalanine, it's going to be lowering a lot of other things as well.

What we've heard from a lot of the prescribers is they really would love to have this as an adjunctive therapy to Sephience to be able to say, okay, Sephience is doing great. We can add something on and maybe you can do even better. And of course, in a disease like PKU, the patients are already used to having cocktail approaches, right? They have cocktail supplements. So we see this as something that could be on top of Sephience, especially given the head start that we have. And there are some programs that are earlier on looking at specific mutations. But of course, there's like, I think, 10,000 different mutations. So I think that's -- we don't see that as a significant competitive threat. I would say the question -- this also show a safety and efficacy of the kidney-directed drugs, and we would see that being something on top of Sephience.

Okay. Maybe let's spend a few minutes that we have left, talk a little bit about the pipeline. So you just recently gave us an update on the Huntington's program. Can you just give us a quick recap of that and what the next steps are there?

Yes, absolutely. This was -- we shared the results of the 24-month long-term extension from the PIVOT-HD Phase II study. really great results. I mean the headline is that in the Stage 2 patients, which is the group that we along was the right clinical trial population, we had dose-dependent lowering of cUHDRS, 52% at the higher dose of 10 milligrams, 27% at the lower dose of 5 milligrams, good effect across 3 of the 4 subscales, slight numeric benefit on the fourth subscale, continued safety and tolerability, NfL at both dose levels below baseline. So when you take now the whole Phase II experience, what we've been able to show is that the drug is doing what it's supposed to do in terms of splicing and having dose-dependent lowering of the disease causing huntingtin protein.

It gets into the brain. We actually have higher exposure in the CSF than the plasma. We're seeing now like 24 months sign of dose-dependent clinical benefit on the disease rating scale. It's safe, it's well tolerated, and we also learned about the right population for Phase III. So in neurodegenerative disease drug development, we have ticked every box and now have a Phase III trial that's up and running that's really been derisked. It's really well supported by everything that's been done so far in Phase II. We mentioned Novartis, our partner is running that study. They're going to have about 770 patients, early symptomatic patients, 1 dose level of 10 milligrams versus placebo through to 2 with cUHDRS as the endpoint with a planned interim analysis for efficacy and futility.

And when do you think that interim could happen?

Yes. So on -- so I think Novartis said they expect the full trial to go until the end of '29. And obviously, the intent of the interim was to get a read sooner on a smaller number of patients. They haven't given the specifics yet of that. I'd simply say that they've been quite clear that if they can get this drug to patients faster, they absolutely want to do that.

So that would be by an accelerated path to approval?

Or well, the interim could be the total -- yes, or keep going we get approval of as you know.

Yes, right. And so if you think about the mechanism of this, Huntington's is an area of high unmet need, but for whatever reason, it's also been difficult to drug. Based on where this program has reached how are you thinking about -- what's your confidence that this is something that can make it to the finish line?

Yes. Look, we said all along, the playbook here followed the Evrysdi playbook. The first molecule that came from our splicing platform, where we early on tried to use the blood effects in the case of SMA, increasing SMA protein, then being able to use that to inform the dose, figure out then the clinical study to establish efficacy. Clearly, Huntington's is a bit more complicated just in terms of being a neurodegenerative disease with heterogeneity. But again, I think what we've been able to do thus far in a very thoughtful, systematic approach is tick all the boxes we need to along the way to inform the next step.

So to be able to enter Phase III, knowing that we've got a very -- a high degree of confidence we have the right patient population. We have the endpoint. We have a dose that has the biochem desired biochemical effect as well as signs of the clinical effect. I think in neurodegenerative disease is that's about as great as you can do. And we know the drug is working on something that means something, right? It's not like we're going to some protein deposits that maybe affect that cause. We're going to the underlying cause of the disease. So when you put all that together, it gives us a lot of -- as much confidence as you can have in neurodegenerative disease program. And we've got a partner, Novartis, who's built to do these long studies, long, large studies quickly and in a high-quality way.

And before we let you go, just what is the status in Europe?

Of the...?

Of how EMA will want you -- Novartis to study this? Are they...

Yes, yes, we're -- they've been working on global alignment for the clinical study. And it's going to be a global study with sites.

And then just remind us about the economics between you and Novartis.

Yes. So this is -- again, this was a really good partnership deal for us. We had $1 billion upfront. Novartis is now responsible for all of the development costs going forward. We have a 40% profit share in the U.S., double-digit tiered royalties ex U.S. and about $1.85 billion left in development and sales milestones.

Okay. And then, Pierre, what is the strength of balance sheet just based on what Matt just mentioned to us?

Very strong balance sheet. I mean you saw the evolution of PTC. Some things obviously hold true, patient-centric, global footprint, et cetera. But also we got financial discipline, right? We work very hard for that strong balance sheet. We closed the quarter with $1.89 billion cash. That allows us to develop all our programs, our highly differentiated platform on both the splicing and the ferroptosis inflammation and also gives us capacity to add potential products through business development in a very disciplined manner, number one; and two, what we saw highly creative transactions.

What types of products do you think would be what you would look for?

So rare disease is our DNA, right? We have a global infrastructure with capacity that demonstrated that we know how to sell drugs. We know how to launch globally in all geographies, obviously, U.S. Europe, LatAm and Japan. And again, rare will be core and rare metabolic for us DNA, but we're looking at other adjacent therapeutics as well.

Okay. Cool. With that, we are out of time. Thanks, guys. Appreciate you making the time.

Thanks.

Thank you.

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics' First Quarter 2026 Earnings Conference Call. [Operator Instructions] Today's conference is being recorded.

I would now like to turn the call over to Ellen Cavaleri, Head of Investor Relations. Please go ahead.

Good afternoon, and thank you for joining us to discuss PTC Therapeutics' First Quarter 2026 Corporate Update and Financial Results.

I'm 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 website in conjunction with the call, which contains information about our forward-looking statements and our most recent Quarterly Report on Form 10-Q and 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 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.

Thank you all for joining today.

We are off to a terrific start to 2026. We had a record quarter of product revenue, led by the continued strong momentum of the Sephience launch as well as contributions from our mature products. First quarter total revenue was $273 million, including $226 million of product revenue. With this revenue performance, we are raising our 2026 full-year product revenue guidance to $750 million to $850 million, with expected total revenue of $1.08 billion to $1.18 billion.

I'll begin by providing an update on the Sephience global launch. In the first quarter, the launch continued at a strong pace, with all signs indicating sustained growth and breadth of uptake. First quarter Sephience global revenue was $125 million, representing 36% quarter-over-quarter growth with U.S. revenue of $112 million. As of March 31, we had 1,244 commercial patients globally. And in the U.S., we surpassed the 1,500 patient start or mark in the quarter with a consistent cadence of prescription starts averaging 140 per month over the past few months. We see this robust cadence of U.S. starts continuing for the foreseeable future.

In addition to the sustained momentum in the U.S., growth is accelerating internationally through both commercial access and paid early access programs. We had our first Sephience sale in Japan in late March, ahead of schedule and remain on plan to have commercial sales in up to 30 countries by year-end. I'm incredibly proud of the execution of our global teams. Within 9 months, we have gained marketing authorization in the U.S., Europe, Japan, Brazil and several other countries and are well positioned to serve the global addressable market of over 58,000 children and adults with PKU, making Sephience a blockbuster rare disease product.

We continue to see broad adoption across age groups, disease severities and treatment histories, including treatment-naive patients and those who have not responded to existing therapies. We are also seeing rapid penetration into centers of excellence in the U.S., with now over 90% of centers having prescribed Sephience. Persistence remains strong, supported by high refill rates, underscoring the long-term commercial opportunity.

Feedback from patients, their families and health care providers continues to be positive. We have seen social media reports of meaningful reductions in phenylalanine and the ability to liberalize diet and enjoy certain foods for the first time. We also continue to gather, present and publish real-world evidence on success of diet liberalization as well as effects on other aspects of disease, including mood and cognition.

I'm also pleased to report that our manuscript describing Sephience's novel differentiated dual mechanism of action has been accepted for publication. This manuscript nicely details how the dual mechanism of action supports the ability of Sephience to provide greater benefit to those who have a response to BH4, as well as the potential for Sephience to deliver benefit to those individuals with more severe mutations not responsive to BH4, typically associated with classical PKU. Based on Sephience's highly differentiated efficacy and safety profile, the strong start to the launch as well as our ability to maintain momentum in the U.S. and accelerate growth globally, we remain confident in the $2 billion-plus global commercial opportunity for Sephience.

Turning to the votoplam Huntington's disease program. Last week, we reported positive top line results from the 24-month interim analysis of the PIVOT-HD long-term extension study. At 24 months, votoplam demonstrated dose-dependent slowing of disease progression on cUHDRS with an average slowing of 52% relative to a matched natural history cohort at the 10-milligram dose level in participants with Stage 2 disease. In addition, the safety profile continues to be favorable across doses and disease stages. These data support that the significant dose-dependent HTT lowering observed in the 12-month PIVOT-HD study are manifesting in dose-dependent clinical benefit over long-term treatment.

In addition, the interim study results give us increased confidence for the success of the now enrolling global Phase III INVEST-HD study funded and led by our partner, Novartis. INVEST-HD has a target enrollment of approximately 770 individuals with early symptomatic disease who will be randomized 3 to 2 to receive votoplam 10 milligrams or placebo. The study also includes an interim analysis. The PTC and Novartis teams are still reviewing the data from the Phase II long-term extension interim readout and will discuss potential plans to meet with regulatory authorities.

For vatiquinone, we had a Type C meeting with FDA in April to discuss the design of a new trial to provide additional data to support NDA resubmission. Based both on written comments and meeting discussion, we are moving forward with an open-label study with a matched natural history control group from the robust FACOMS disease registry. The study will have a target enrollment of approximately 120 individuals with Friedreich's ataxia from age 7 to 21. The primary endpoint will be a change in mFARS from baseline to 24 months. We look forward to initiating this study within the next few months and believe the design of the study, along with our learnings from previous studies, significantly increases the probability of success.

Turning to our earlier-stage pipeline. In the second quarter, we expect to initiate the Phase I study of PTC612, our oral NLRP3 inhibitor. While the majority of the study will be conducted in healthy volunteers, we will look to include a dosing cohort of individuals with elevated inflammatory biomarkers to enable an early assessment of PK/PD. As we have discussed, PTC612 benchmarks favorably to other NLRP3 inhibitors in terms of potency. We expect to develop PTC612 for inflammatory lung disorders, where there is overlap between the NLRP3 inflammasome and disease pathology.

We also continue to make good progress on our other pipeline programs, including our wholly owned MSH3 oral splicing program for HD and DM1. The MSH3 program for HD could complement the HTT reduction approach of the votoplam program as well as be particularly suited to target the juvenile HD population. We are also making good progress on several programs from our Inflammation and Ferroptosis platform, including our Phase II-ready PTC844 DHODH program, ferroptosis Parkinson's disease program and NRF2 activator program.

Overall, we're off to a great start in 2026. We look forward to the sustained momentum of the Sephience global launch over the course of 2026 and continued favorable developments in our R&D portfolio. Our strong cash position enables us to continue to support all current programs, as well as to look for accretive business development opportunities that can leverage the strength of our global rare disease commercial engine to accelerate short- and intermediate-term growth.

I will now turn the call over to Eric to provide a commercial update, including more details on the Sephience launch. Eric?

Thanks, Matt.

To start, we are very proud of our commercial team's performance as they continue to execute on the launch of Sephience with excellence. Our outstanding performance in the first quarter reached our highest level of product revenue in the history of the company and has laid the foundation for continued success in 2026. The global launch of Sephience continues to accelerate, driven by continued strong growth in the U.S. and growing contributions internationally.

First quarter Sephience revenue was $125 million, including $112 million in the U.S. and $13 million internationally, representing 36% growth from the fourth quarter of 2025. We continue to see growth with new prescriptions in all PKU patient segments, irrespective of age and severity and are seeing the rapid adoption of Sephience as we expand our global footprint with our experienced teams.

Since the initial launches in the U.S. and Germany last summer and as of March 31, 2026, our commercial operations have generated over 2,200 prescriptions worldwide. In the first quarter, we continue to see momentum in the U.S. in terms of new patient starts and low discontinuation rates. As Matt mentioned, uptake in the U.S. continues to be broad with over 90% of U.S. PKU centers of excellence prescribing Sephience. We are also seeing broad adoption across the full spectrum of disease severities, including classical patients.

We continue to see new patients with various treatment histories, including treatment-naive adults, past treatment failures and patient switches. Refill rates remain strong and discontinuation rates remain low in the low double digits, reinforcing our confidence in the sustained launch momentum.

U.S. payer dynamics for Sephience remain favorable. Most commercial and government provider policies are in place, covering over 2/3 of the U.S. population with limited restrictions and flexible criteria for reauthorization. The AMPLIFY head-to-head data demonstrating superior clinical benefits of Sephience versus BH4 continues to strengthen the value proposition with payers, further supporting broad access in the U.S. and ongoing pricing and reimbursement discussions in Europe.

Our Sephience launch momentum continues to build globally with the launch in Japan, which has progressed ahead of plan. We had our first commercial patients and revenue recorded in Q1, which was earlier than expected, and we are very pleased with the positive feedback from Japanese health care providers and patients in the early stages of the launch. We also secured Sephience regulatory approval in Brazil, where our local team is fully engaged in creating awareness for access via named patient programs while we finalize pricing in the second half of the year.

In Germany, we're seeing good progress, with centers of excellence accelerating new patient starts, including adults, while we finalize pricing and reimbursement this summer. In other European markets, health technology assessment dossiers are being actively reviewed with paid early access programs already in place, while pricing and negotiations advance in France, Italy, Spain and other key European markets. While the U.S. remains a key near-term growth driver, we expect international revenue to continue to ramp with commercial patients in up to 30 countries by year-end.

Sephience represents a significant global commercial opportunity long term. Its differentiated efficacy and safety profile and dual mechanism of action support broad adoption and positions Sephience as a potential standard of care, which gives us confidence to achieve multi-billion peak revenue. Going forward, as the Sephience business grows and diversifies globally, the launch metrics we provide will include only global revenue and the number of active patients on Sephience treatment worldwide. We believe these metrics will best illustrate the long-term trajectory of Sephience growth.

Now turning to our DMD franchise. We delivered solid first growth performance despite significant headwinds. Translarna revenue was driven by a large government purchase order in Brazil, and we continue to support nonsense mutation DMD patients on therapy across Europe. In the U.S., Emflaza generated $22 million in quarterly revenue despite multi-generic erosion, supported by strong brand loyalty and high-touch patient services. Our experienced global commercial team have successfully executed multiple rare disease product launches for over a decade.

Looking ahead, we are confident in our ability to drive strong performance and continued growth in building Sephience into a blockbuster brand for PTC.

With that, I will now turn the call over to Pierre for a financial update. Pierre?

Thank you, Eric.

I will now share the financial highlights of our first quarter of 2026. Beginning with top line results, total product and royalty revenue for the first quarter was $273 million and total net product revenue across the commercial portfolio was $226 million compared to $153 million for the first quarter of 2025, representing 47% growth. First quarter 2026 product revenue includes Sephience net product revenue of $125 million and DMD franchise revenue of $81 million.

Translarna net product revenue was $59 million, including a large one-time government purchase order. And Emflaza net product revenue was $22 million. For Evrysdi, Roche achieved first quarter global revenue of approximately USD 585 million, resulting in royalty revenue of $47 million. As a reminder, we continue to report Evrysdi royalty revenue in our financial statements. However, there are no cash proceeds to PTC.

For the first quarter of 2026, non-GAAP R&D expense was $90 million, excluding $11 million in non-cash, stock-based compensation expense compared to $100 million for the first quarter of 2025, excluding $9 million in non-cash, stock-based compensation expense. Non-GAAP SG&A expense was $74 million for the first quarter of 2026, excluding $12 million in non-cash, stock-based compensation expense compared to $72 million for the first quarter of 2025, excluding $9 million in non-cash, stock-based compensation expense.

Cash, cash equivalents and marketable securities totaled $1.89 billion as of March 31, 2026, compared to $1.95 billion as of December 31, 2025. Our strong financial position supports continued development of our commercial and R&D portfolios and preserves flexibility for strategic and disciplined business development to further enhance long-term growth.

And I will now turn the call over to the operator for Q&A.

[Operator Instructions] Our first question coming from the line of Kristen Kluska with Cantor Fitzgerald.

Congrats on the record quarter for the company. Now that you have a couple of quarters under your belt for Sephience, I was hoping you can give us a little bit more color and clarity about patterns that are emerging in the real world around making sure that patients and physicians are working conservatively in measuring Phe and slowly increasing the protein uptake and how that's been resonating in terms of compliance, long-term utilization and also how these patients that are staying on therapy, is it entirely driven by diet liberalization? Or are there in other instances, other factors that are playing a key role?

Kristen, thanks for the questions. Look, I think we're incredibly excited about the continued launch momentum we're seeing. We think we're in a stage now of consistent growth in the U.S. of acceleration ex-U.S., which is what's going to make this such a valuable product for us. And as a global launch, this is exactly what we've been working for and exactly as we expected. In terms of dynamics now a couple of quarters in, in general, I think, again, we're seeing this consistent theme of breadth, breadth of uptake across all patient segments, including those naive patients who many thought were lost to follow-up. It was really just a matter of being able to offer them a safe and potentially effective therapy, full age range, babies up to, as we talked about octogenarians and broad uptake across centers of excellence in the U.S. as well as outside the U.S.

In terms of folks staying on drug, it's a combination of factors. Of course, the ability for individuals on the drug to liberalize their diet and try foods for the first time, the things we're seeing all over social media are so incredibly impactful and so motivating not only for those individuals to stay on drug, but it's also continuing to increase the enthusiasm and desire of others to get on drug. I think that's really been an effective way in this launch that the demand keeps growing in the patient communities, which is great to see. We have, of course, worked very hard with the centers where, as you know, there's dietitians on staff. They're an important part of PKU management even when an individual is not on therapy. And so this idea of making sure that when someone gets on the drug that there's first evidence of Phe lowering and getting into that range where you can liberalize diet and then proceeding slowly so that we're set up for success.

I'll also add, we're hearing a lot about other benefits that have been really important for patients. And what's really interesting about this is for a lot of the prescribers and the patients, it's not necessarily about a number. It's about being able to liberalize diet. And others are saying, I just feel better. I have improved anxiety, improved cognition, less brain fog. And that's really also some of the impactful things that clients has been able to do.

And as Eric mentioned in his script and I did as well, these are things that we're codifying now in real-world evidence papers as well as presentations. We have a number of them coming up at the SSIEM in September, talking about all these different ways in which benefit is provided to patients and really supporting, again, not only persistent and in some cases, growing demand, but also adherence, which remains very high.

And our next question coming from the line of Tazeen Ahmad with Bank of America.

I have a couple. So when you talk about the cadence of around 140 new start forms, you've been careful to make sure you say this is consistent. So, do you expect this trend to continue? Or do you think this could accelerate, especially in the U.S. over the course of the coming year? And then can you also comment on discontinuation? So, you've talked about that a little bit, but for patients who are discontinuing, what's the main reason?

Tazeen, thanks for the questions. So in terms of the start forms, when we talk about the consistency of about 140 per month, that's going back to the later parts of 2025. As expected coming into the new year around the holidays, there was a bit of a decrease. It's completely expected with seasonal effects and all the things that everyone knows about. We had one of the strongest months in March actually. We're seeing that continued momentum into April.

So, we think that the 140 probably represents a reasonable run rate for the foreseeable future, knowing that there'll probably be ups and downs and things, and just the typical dynamics one sees in a launch, essentially being early on. But we believe that's a very solid number, and we're excited about being able to have those starts added to already a very substantial base of patients, which are maintained on the drug, which, of course, is a key to driving the revenue opportunity over time.

I'll make a brief comment about discontinuations and then turn it over to Eric for a bit more color on this. As he mentioned on the call, we're in low double digits at this point in the launch. We're starting to approach steady state. I think what's really encouraging is that we know that the earliest individuals put on Sephience were tended to be those not on a therapy, the more challenging patients, those therapy-naive adults. And so to be able to have this kind of adherence rate in the context of the most challenging patients coming on first is obviously incredibly encouraging for the strength and growth of the launch over time.

Eric, do you want to provide a little more color on what we're seeing?

Yes. Thanks for the question. In fact, I think we're very pleased because in the very first phase of the launch, we would call that an accelerated phase. The vast majority of these patients were the ones who actually in the real world were failed or had poorly controlled based on previous treatments. What we're seeing right now is that even that hard-to-treat group has benefited really well, and we have low double-digit discontinuations. And in fact, the amount of discontinuations is even lower for clinical reasons in terms of efficacy or safety. Some of the reasons are obviously because maybe patients don't respond or safety reasons, but it's very low.

The others are just patient choice. And that could be a variety of different reasons. But overall, when you think about the number of patients that have come in, we're building this very large base of patients. And as Matt said, it's an accelerated but a robust cadence. And as we build that, part of what we're going to do is sustain the momentum and continue to grow and maintain high refill rates and work very diligently on discontinuations and making sure they're very low.

And our next question coming from the line of Ben Burnett with Wells Fargo.

I wanted to ask about kind of what you're seeing in terms of average weight or average price. And as you kind of add Japan and some of these ex-U.S. territories to the mix, would you foresee any changes to kind of the long-term sort of average price estimate?

Ben, look, we said at the beginning, we expected average weight to be around 45 kilos and our studies had shown that we'd be somewhere in the 45 to 50 range. And I think we're very much in that ballpark. And as you alluded to, the international dynamics play into that as well, right? We have some adults who came on. We said that the average age now is around 17 or so globally, but different rates of patients in different regions in different areas. We're seeing very young patients be put on first, especially in some of the early access programs where there's a preference to get infants on drug because there's a keen concern for the neuroprotective effects or the neurodevelopment protective effects that we see with the drug.

And in an early access scheme, those are the kinds of things that could get someone on paid drug ahead of formal pricing and reimbursement. So, I'd say overall, we're still in the ballpark we thought we'd be in. We anticipate that for a while. But obviously, we'll continue to watch that dynamic as the launch plays out.

Our next question coming from the line of Eliana Merle with Barclays.

Just a follow-up question on how to think about the ex-U.S. opportunity and the near and long term for Sephience? I guess, specifically, how we should think about the pricing for Sephience

and then how we should think about the cadence of ex-U.S. sales over the course of the year?

Yes. Thanks, Ellie. And as we talked about, we've always been very intent on maintaining a rigid pricing corridor that went into our launch strategy. I'll let Eric detail that and talk a little bit about how we're seeing price globally and the cadence of contribution ex-U.S.

Yes. I think very importantly, the international business right now will be a very important future contributor to the revenues. However, the U.S. will still be the main driver at this point for this year. We know that each country that comes on incrementally up to 30 countries that we anticipate this year will be incrementally very important, but the U.S. is still our main driver this year. Japan, we got off to an early start. We're very pleased. And we're seeing a lot of the launch dynamics there. And we've been able to maintain pricing and reimbursement.

We were able in Japan to lock that down in Q1 and finalize pricing, and it will be locked down for the next 10 years during orphan exclusivity. Currently, we have pricing in HTA assessments in dossiers in Europe and where the HTAs are being assessed and pricing and reimbursement discussions would be finalized towards the second half of this year and early parts of next year. I think it's safe to say that the U.S. will be, again, the near-term driver in terms of revenue and will continue to play a very important role. However, over time, each one of these countries will be adding incrementally revenue in patients, and that will be important for the long term.

And our next question coming from the line of Brian Cheng with JPMorgan Chase.

Can you hear me?

Yes.

Congrats on the quarter. Matt, you sounded very confident in the 140 patient start forms per month run rate continuing and you see growth accelerating in your prepared remarks. You mentioned over 90% of the centers have now prescribed Sephience. So, what is holding back the remaining 10% of the centers? Just curious if you can talk a little bit about the phenotype of the center of excellence that's holding out. Is it just a matter of reaching out to those doctors and increase the touch points? Or is there something else that we should also consider?

Thanks, Brian. I'll start by saying that we are very bullish on the opportunity in the U.S. and globally, right? This is a true global launch, and we're at a point to be able to add, we believe, 140 starts per month on top of already a very strong base is why we believe we're going to reach the very promising revenue potential we think is out there for us. So, we're incredibly excited about that and everything we're seeing continues to support our confidence there.

I'll let Eric talk about the center dynamics, but I'll also say that we're now sitting here after the second full quarter of a rare disease launch. The fact that we have prescriptions from over 90% of the centers for us is the headline. That's incredible progress, thanks to all the work our team did in market development and establishing relationships with the centers. And as you can imagine, these tend to be the larger centers where we are. But I'll let Eric talk about the dynamic. But I just want to emphasize that we're incredibly proud to have that degree of penetration at this early part of the launch.

Eric?

Yes. This is a very strong penetration when you think about -- and the centers right now that are giving are obviously some of the ones that are in the large metropolitan areas. These are what I would call the Tier 1s who have already written many prescriptions and continue the breadth and depth of the prescriptions, particularly the new starts. But keep in mind, we're also -- these centers also have many patients on therapy. So, we're working not only to get new starts, but maintain many of these patients and get those refill rates high, make sure discontinuations are low.

When we look at just the remaining 10% or so, which are just a small handful, these are typically what we see with any centers. They're late adopters. They're probably smaller centers. We call on all of them, by the way. And in many cases, they're just not staffed adequately and they're not really proactive as much with patients. So when we go and we look at where the bulk of our prescriptions are coming from, 90% in those big metropolitan centers. They're working very hard right now. They're very strong and robust cadence from those centers.

Our next question coming from the line of Judah Frommer with Morgan Stanley.

Congrats on the progress here. Two quick ones for us. I guess, first, just on the guidance update. Can you separate out that one-time Translarna order from the rest of the guidance raise? And then just on vatiquinone, any indication within that meeting or written feedback as to how prior data would be treated, specifically subcomponents of the mFARS? Or should we think about this as kind of starting from scratch in a late-stage trial?

Judah, so on your first question, just looking at overall guidance, we came into the year and we said, look, there's a couple of things we know for sure. We are incredibly confident in the growth trajectory and strength of the Sephience launch, and we believe the vast majority of product revenue will come from Sephience. We also know that there's uncertainty in the mature products, specifically the DMD franchise. We have, in Translarna, business in Europe, which we're continuing to maintain without a license. So, that longevity is hard to predict. And we know that we're facing headwinds in some of the countries like Brazil, like Russia, where we get large purchase orders.

On the Emflaza side, we're already seeing in Q1, we are down from Q4 last year. There's 10 generics in the market. And while there's been no major price drops, we do expect erosion to continue. So, we basically increased guidance based on the overall performance of the quarter. And as we go forward in the year and understand better the trajectory of the science and understand what we get from other government orders for Translarna as well as the Emflaza erosion, we'll then be in a situation to raise or narrow guidance whatever is appropriate based on the dynamics that we're seeing.

On the Friedreich's ataxia side, look, I think we were excited to have gotten the suggestion from FDA itself that the additional data to support NDA resubmission could come from a natural history controlled study. Obviously, the safety profile of vatiquinone is very favorable and very well established. There's no need to have a placebo-controlled study to identify new safety signals. And the data from MOVE-FA do provide a signal of efficacy. So, this is really -- we view this as a way to get additional data that will support the already established data set of safety as well as signs of benefit, particularly in younger patients.

Now, I'll say that the endpoint selection here is really a function of duration of the study. The natural history of FA in young individuals has been very well characterized now in a number of publications. And it's clear that over the shorter period of time, about 12, up to maybe 18 months that the upright stability subscale is likely the most sensitive component of the mFARS rating scale to capture progression and therefore, treatment benefit.

We're now doing a 24-month study, and the literature clearly shows that as you get to 18 months out to 24 months, you start seeing other components of the mFARS scale capture progression and therefore, capable of capturing treatment effect. We actually saw this in MOVE-FA as well. Once we got to 18 months out to 24, we started seeing upper limb, lower limb start to contribute. So, this is really a question of choosing an endpoint that's most appropriate, yes, to our population, but also importantly, to the duration of the study of 24 months.

And our next question coming from the line of Geoff Meacham with Citigroup.

This is Jarwei on for Jeff. Maybe just thinking about the OUS opportunity. Maybe a 2-parter. First, if you can help quantify or help paint the picture for how the early Japan launch pattern has looked? Have you guys seen a similar uptick pattern from the early days of the U.S. initial launch?

And then also, I guess, as a follow-up to that, the second part. The U.S. launch has seen great

success with using social media as a leverage to gain awareness among patients. And I guess, can we expect similar success in other geographies just given maybe there are different patient to physician dynamics versus stateside?

And then third question, if I may, just real quick. Given vatiquinone's open-label study, the plans will be open label, I guess, how sensitive is mFARS to potential protocol deviations or data?

Jarwei, thanks for the questions. Let me take the third one first, the second one second, then I'll turn it over to Eric to handle the second and the first. Okay. Third one, look, I think the -- I'll say in general, FDA has very well thought out guidance if you're going to use a natural history comparator group as a control arm. And I think we know that the agency has used the FACOMS, the FA registry before to support regulatory decision-making in public forum. They held that out as a model of a patient registry where you can get quality data because that very well characterizes and captures disease progression.

Obviously, we had to set up the treatment portion of the study with vatiquinone to match a lot of the dynamics in the natural history registry, including timing of assessments and such. Obviously, again, in selecting natural history cohort from the registry, we're going to be sure to make sure that they do have the appropriate endpoint information at the key time points, clearly baseline, clearly 24 months and 12 months in the middle. So, these are all things that we are thinking of ahead of time.

We've included in the protocol, the statistical analysis plan to make sure that this we can get as robust a comparison as possible. And again, I think we're afforded -- we have the luxury that the FA community has developed such a robust and rigorously collected and protocolized natural history registry for the key endpoints that are relevant for clinical trials.

Your second question was about social media being so important in the U.S. and what's going on outside the U.S. Look, I think it's different use in different places. I think the important thing is that globally, there's well-aggregated communities that communicate with each other and there's global communities as well. So there's the flow of information not only in the U.S., what happens in the U.S., it goes outside the U.S. And social media is global. And then we also know that there's communities in other countries as well where there's sharing of information, whether that's on social media or other form.

Let me turn it over to Eric to talk a little bit about the Japan dynamics and if he wants to add anything to the question about social media.

Our Japanese launch is really off to a really great start, again, ahead of schedule. And we believe that this will be an important and significant opportunity for us. Keep in mind that we actually did get approval in December, and we were promoting and profiling a lot of the centers there. But in Q1, we actually did finalize the pricing and reimbursement, which, as I mentioned, has been locked in now with no price decreases for the next 10 years due to orphan exclusivity and no referencing. So, that's incredibly important for us in terms of that sustained business.

What we've seen in the early stages of the launch in Japan, and keep in mind, this is just early stages, is that there is some similarities to the U.S. There are patients who are seeking treatment that have failed or uncontrolled, but we are also pleasantly surprised that there are adults and naive patients that have come in. So, so far, we've seen a lot of the similar, what I would call, accelerated dynamics that we saw in the U.S., in Japan as well.

And our next question coming from the line of Brian Abrahams with RBC Capital Markets.

This is Kevin on for Brian. Maybe just on Sephience and payer dynamics there. I know you mentioned sort of increasing coverage there across commercial and government. Can you talk maybe a little bit about any -- the types of step edits that you're seeing or maybe you had anticipated at this point? And then just what percentage of prescriptions, if you can comment, are sort of currently facing prior authorization delays and maybe how you see that metric evolving from here?

Thanks, Kevin, for the questions. Eric, do you want to take those payer dynamics and then any challenges in authorization?

Yes. Absolutely. I mean, payer dynamics have been as expected. Prior authorizations are typically in place based on the label. And so most, if not all payers are requiring, obviously, PKU assessment and understanding requirements that are within the label. These are very simple and easy to get through. And right now, we've seen the vast majority of commercial payers as well as government payers have already written their policies. And it's really been very favorable with very few limitations, including step edits, very few step edits. And of course, the vast majority of patients have already some kind of documented history, either they've been on Kuvan or Palynziq, or they have actually failed on any of those therapies.

So, prior exposure is incredibly important for moving them through. Even it does require step edits, it's something that we can measure very quickly and sometimes days and in just a few weeks and provide that information to insurers. So right now, everything is going according to plan, and we see very few limitations. And in fact, our time from PSF to dispense has improved continuously because of those policies now being in place.

In terms of answering your question about the split, we've historically said it's a little over 2/3, 1/3. It's holding very well. In fact, in the last quarter, we had a slight tick up towards more commercial. We anticipate around 65% to 35%, being 65% commercial payers right now that are being covered.

And our next question coming from the line of Yifan Xu with Jefferies.

This is Yifan for Faisal. Congratulations on the quarter. Can you maybe provide some additional color on the PKU patient split? And for the current quarter, like what percentage of revenue like contribution from mild to moderate patients and what percentage for from classic PKU patients? And for your $2 billion peak sales guidance, how is that split?

So Yifan, in terms of the breakdown, we don't collect specifically whether you're classical, moderate or mild. What we have seen from the beginning and are continuing to see is up to 1/3 of the patients are treatment naive, and those tend to be the more classical patients who were never tried on other therapies that were not thought to provide benefit to classical patients. And then again, the remainder are between those who have tried and failed existing therapies or those who are switching from existing therapies. But I think we're seeing more tried and failed as we've heard from centers that at first, there's a priority to get those who are not currently on a therapy on to a therapy.

I think the important part of this is the feedback we are receiving and what we're seeing, which is that the more severe patients, as we expected, they're benefiting from Sephience. We have a number of these patients, which are showing significant reductions in Phe, diet liberalization. And so what we're seeing is consistency of effect across moderate, classical, mild, which is really, really encouraging.

And obviously, we're doing a lot of work with the mechanism of action paper to support why that's the case, the fact that there is this independent chaperone effect that provides benefit in the more severe mutations and obviously, as well getting the physicians to put together these real-world evidence studies that clearly document how these more severe patients and those therapy-naive patients, those that are thought to have lost follow-up are coming in and having important responses, including Phe reduction, including the ability to liberalize diet and then other benefits like we talked about in terms of cognition and anxiety and other things.

Eric, do you want to talk a little bit how we're thinking about the -- we said $2 billion plus, multi-billion. Those are the words we're using. So, I wouldn't limit it just to $2 billion.

But let Eric, do you want to talk a bit about how we think the splits can and contributions can play out?

I think the contributions are going to be consistent, with the U.S. being, again, the main driver longer term. So, we understand that the U.S. will play a very, very important role. However, we've always said that there are 58,000 addressable patients worldwide. That means that out of the 17,000 to 20,000 in the U.S., there's 2/3 of them that are available in many other markets. We'll continue to work very hard to ensure that there's a narrow pricing corridor, that access and reimbursement is available to as many of these countries. And as we bring these 30 countries -- up to 30 countries along, we're going to continue to add patients internationally as well as grow the business in the U.S.

One of the most important things is getting new patients in, but also building the base and maintaining that base. That's what we do in rare disease. And it's important that we continue to not only add new patients and add new countries, but also maintain patients with all the services, education and program that we can and at the same time, minimize any kind of discontinuation and maximize adherence and compliance. So overall, that gives us the confidence that we can actually build this blockbuster brand in multiple countries, and it will be truly a global launch.

And our next question coming from the line of Jacob Ormes with TD Cowen.

This is Jacob on for Joseph Thome at TD Cowen. I just wanted to ask, so regarding Sephience and time it takes for patients to get on drug, we're wondering if you had any insights on how that might differ based on geography?

Jacob, thanks for the question. I don't think you mean geography being country-wide within the U.S. or outside the U.S. I'll just say, in general, in the U.S., we're continuing, as Eric said, to get folks on fairly quickly. Some take longer, some take shorter, but on average, we're still seeing very, very rapid throughput.

Eric, do you want to talk a little bit about the global dynamics and in particular, why we say going forward, we're going to really focus on global patients given the complexities of the global dynamic?

Yes. And it's a good question given the fact that the complexity is now with multiple countries and everyone has their own unique systems for access. What we see in the U.S. is dispenses that can be just in a matter of a couple of weeks. And in some cases, just a few days depending on the insurance, the policy and the requirements. In Germany and Japan, likewise, it's just a few days because the products are either reimbursed and/or listed and available in the pharmacies.

As we get to the complexities of named patient programs in Southern Europe or Latin America or Middle East and others, the times can be days, weeks or it can be months. And each country is unique and different. But the most important metric is the prescription because our teams are really behind working with health care providers and centers and patients to ensure those prescriptions turn into commercial therapy and move those as quickly as possible. So it's very hard to tell you that there's an average out there, but certainly, named patient programs can take sometimes weeks or months in timing.

But in other cases, once pricing and reimbursement is finalized, you'll see a much more accelerated and rapid adoption. So, that's why we believe going back to those metrics of providing global revenue as well as the number of active patients will be an important metric to measuring our ability to get to that multibillion-dollar status.

And our next question coming from the line of Luke Herrmann with Baird.

I had 2. First on Sephience. A follow-up on U.S. reimbursement. Is there any sort of bolus of patients who haven't been able to get reimbursed yet that you think can be in the future? And then secondly, on vatiquinone, on the open-label study, can you just walk us through how you're treating Skyclarys use here? And do patients need to wash out for how long? Any details there would be helpful.

Luke, so let me take the second question first, and then I'll let Eric talk a little bit about the favorable payer dynamics that we're continuing to see. So on vatiquinone, one of the key things in this study was to make sure that if you're going to use a natural history comparator group that matches or that the treated patients would match the natural history, if you will. It has to match both ways. And given that there's not been an extensive experience with individuals on Skyclarys for a prolonged period of time, we can't allow concomitant use of Skyclarys as we've done in the open-label extension of MOVE-FA, for example.

So, there are going to be some provisions in the protocol for those who've been on it for a short amount of time and have washed out of it, but we can't allow concomitant use or long-term priority use of Skyclarys because we have to make sure that the natural history data we're using can accurately capture any other concomitant therapies. And again, Skyclarys is relatively new. So the natural history data don't have that well captured. And again, this is just an example. It's a really good question and a really good example of all of the thought, planning and alignment with FDA that's needed if we're going to go ahead and prospectively identify a matched natural history cohort and use that to support the resubmission.

Eric, do you want to talk a little bit about on the payer dynamics and questions about any areas we're seeing challenges?

Yes. In fact, there have been very few limitations. Things are going as planned with U.S. payers. In fact, I think what we're seeing right now is very few of these patients right now are being denied. If they are, they're not hard denials. It's to work through medical necessity. We do not have a bolus, or a very large number of patients that are either on patient assistance programs or bridge. And if we do, we work very carefully to ensure that we bridge them to commercial therapy in matters of days or weeks. So, there isn't a very significant number at all. There's a smaller number. And we've been very pleased so far that the time to dispense is becoming more and more efficient, and we're doing that.

We're seeing scripts being filled in a matter of a couple of weeks or less. And reauthorizations have not been onerous at all. They've been basically reauthorizations for 6 to 12 months. And we see that medical assessment of the physician and the patient along with Phe and -- Phe lowering and diet liberalization are enough for that patient to continue to get therapy. So overall, I would say the simple answer is the vast majority of these patients are actually on treatment.

Our next question coming from the line of Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. Maybe just one on the longer-term PKU competitive setup with oral genotypes independent SLC approaches now in late-stage trials, how are you thinking about the parts of the PKU market where Sephience is most defensible long term? Is the differentiation around Phe lowering, diet liberalization or physician comfort with this BH4 pathway or something else?

And relatedly, are there any patient segments where you think future oral competition could expand the treated pool rather than directly compete with Sephience?

Yes. Thanks, Jenny. While we acknowledge there's other therapies in late-stage development for adults, the Phase III study being done in adults, look, we don't -- we're not worried about a significant threat here. We have a significant first-mover advantage. We're very well penetrated into the market. And the general view in the marketplace, i.e., amongst the prescribers is they would be looking for something to add on to Sephience and not replace Sephience. And of course, in PKU, this is already a community where they're used to cocktail approaches. Their whole life is about supplements and mixing and matching different things.

So the idea of being able to add something on to Sephience to potentially even get even better benefit, whether that could be complete diet liberalization, Phe lowering -- additional Phe lowering in more severe cases. So, again, I think the view here is very much as it being complementary. Of course, if there are segments of patients, the small numbers who have tried Sephience and have not had the success with it in terms of efficacy.

We know it doesn't work for every patient. Clearly, we see those folks getting tried on the other kidney-directed drugs. But I think this is why when we talk about what we've been able to do in the launch, the penetration we have, this is becoming first-line therapy and standard of care. And anything that comes later would obviously be added on top of it or would be for those who aren't being served by Sephience.

And our next question coming from the line of Paul Choi with Goldman Sachs.

I wanted to also follow up on vatiquinone. And Matt, I was wondering if you could comment on since the MOVE-FA study and the commercial availability of Skyclarys, any changes in understanding of what the natural history in FA looks like versus when the other studies were run previously?

And then secondly, just on the cash balance, Matt, I guess, as you think about sort of the catalyst and data cards that have yet to -- won't turn over for a bit in terms of your late-stage pipeline, I guess, sort of what's the rate-limiting factor for additional business development here?

Thanks, Paul, for the questions. First, on vatiquinone, I think what's so interesting about FA natural history and the natural history registry, it's been incredibly well characterized and it's incredibly consistent. So if you look over time at the number of publications that have been done using the FACOMS registry, the rate of progression has been fairly consistent, 2 to 2.5 points a year on the mFARS. The components that contribute to that are -- as we talked earlier, are a function of age and a function of time. So even with approved therapy, that natural history has remained pretty consistent. And again, I think in the discussions with FDA regarding the use of FACOMS as a natural history comparator, it's that consistency over time. It's that robust data. It's the large number of patients and the completeness of that registry that have, I think, given them comfort that we can further substantiate efficacy with vatiquinone using this type of study design.

In terms of the cash balance, look, we've talked a lot about this. We're incredibly excited for having gotten the company into this position where we've been able to launch Sephience, which is clearly a foundational product for our growth. The launch is going very much as we hoped and anticipated, and we still expect very strong growth and for this to be a multibillion-dollar product. As you alluded to with FA now with what we view as a trial with a high probability of success coming later in the decade and of course, the PIVOT-HD data really derisking the Phase III trial that Novartis is now -- has up and running for Huntington's disease that does have an interim analysis. These are 2 really attractive potential commercial revenue contributors later in the decade.

There is an opportunity, and we have capital. And I think really what it comes down to is finding the right fit for us, something that we could bring in to set and leverage our existing commercial infrastructure and still remain in a strong financial position. So, I'd say the limiting factor is really identifying something that fits what we want to do in terms of the right size and something that we think we can set in. We're incredibly excited about our R&D portfolio.

As we outlined in the research -- in the R&D Day, we have a lot of exciting things coming. We're finally getting -- I think we're leveraging all the learnings we've made in splicing, and that's a truly highly differentiated mRNA therapy platform that we're now just really learning to apply and get therapies forward. So again, I think as we look at things now, I think the company is in an incredibly strong position. We have a number of opportunities, and we have the luxury to be able to find the right thing to set in to ensure that we're continuing to grow our top line in the short, intermediate and long term.

And I'm showing no further questions in the queue at this time. I will now turn the call back over to the CEO, Dr. Matthew Klein, for any closing remarks.

Thank you all for joining the call this afternoon.

Look, as I just stated in response to Paul, we're incredibly excited where the company is now. We work very hard to build PTC, to be in this position with a very strong launch for Sephience, a global opportunity that we're well positioned to take advantage of. And I'm incredibly proud of the team's performance, and we're positioned now to continue to grow in the U.S., accelerate growth outside of the U.S. and realize that multi-billion-dollar opportunity as well as all the advances in the R&D platform and the cash position, as Paul alluded to, which gives us the ability to continue to drive value in both the short and intermediate term.

So, thank you all again for joining the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics PIVOT-HD Long-term Extension Study Top Line Results Call. [Operator Instructions] Today's conference is being recorded. I would now like to turn the conference over to Dr. Matthew Klein, Chief Executive Officer. Please go ahead.

Thank you all for joining the call today. We are excited to share the positive and promising top line results from the 24-month interim analysis of the PIVOT-HD long-term extension study. The findings of safety and treatment effect I'll share today give us confidence that votoplam has the potential to provide long-term meaningful effect in slowing the progression of Huntington's disease.

Before I begin, I refer you to our SEC filings for a full description of risks and uncertainties. As a reminder, the Phase II PIVOT-HD trial was a 12-month placebo-controlled study of votoplam at 2 different dose levels in individuals with Stage II and III disease. Following the 12-month placebo-controlled phase, all participants were eligible to enroll in a long-term extension study in which those initially randomized to receive placebo would be rerandomized to receive either high or low dose of votoplam.

Importantly, all study participants and investigators remain blinded to treatment assignments. As we shared last year, PIVOT-HD achieved the primary endpoint of blood HTT protein reduction at week 12 with evidence of durable dose-dependent lowering of HTT protein at 12 months. At that 12-month readout, there was early evidence of dose-dependent benefit on the cUHDRS rating scale for the Stage II participants, along with evidence of safety and tolerability without any treatment-related NfL spikes.

Today, we will share results from the 24-month interim analysis of the long-term extension study. The long-term extension study was designed to assess safety, clinical and biomarker effects of votoplam over time. This interim analysis assessed the long-term effects of votoplam treatment on disease progression as assessed by the cUHDRS and its subscales as well as long-term safety and biomarker effects following 24 months of votoplam treatment.

Given there was no placebo group after month 12, the long-term extension protocol specified that a well-matched natural history cohort from the ENROLL-HD disease registry would be used to contextualize votoplam treatment effect at month 24. This table summarizes the baseline characteristics of the Stage II and Stage III study participants included in the 24-month analysis.

I want to point out that these are the participants who were initially randomized to receive votoplam at 5 or 10 milligrams at the start of the placebo-controlled phase of PIVOT-HD for whom we now have data following 24 months of votoplam treatment. The key points to highlight on this table are that as expected, the Stage III participants tended to be older, with evidence of decline on the total functional capacity or TFC scale, which is a hallmark of Stage III disease in Huntington's disease.

As I mentioned, in order to contextualize the votoplam treatment effect following 24 months of treatment, a natural history cohort from the ENROLL-HD Registry was developed. ENROLL-HD is the largest HD disease registry, with over 30,000 patient records and includes data for all the key inclusion criteria of PIVOT-HD.

Here are the key matching variables used to identify the natural history cohort, the key factors that influence disease progression. This slide summarizes the key baseline characteristics of the votoplam-treated subjects and the natural history cohort. As you can see, the natural history cohort is well matched with regards to the key variables that may influence disease progression with no relevant differences across the group.

Now here are the results. First, for the Stage II participants, I am pleased to report that at 24 months, votoplam demonstrated dose-dependent slowing of disease progression relative to natural history on the cUHDRS scale, with a mean of 52% slowing versus natural history at the 10-milligram dose and 28% at the 5-milligram dose level.

Notably, from months 12 to 24, we see the curves continue to diverge from natural history, supporting an increased treatment effect over time. While the differences did not reach statistical significance, there is a trend with a p-value of less than 0.10 for the 10-milligram treatment effect.

Next, in looking at votoplam treatment effect on the 4 individual cUHDRS subscales, we see evidence of benefit for both dose groups on several of the subscales. Importantly, at 24 months, we continue to see no evidence of NfL spikes and for both the 5- and 10-milligram groups, NfL levels are below baseline, which is a departure from the understood natural history of progressive NfL increase over time.

Now moving to the Stage III participants. As we have discussed, when we initiated PIVOT-HD, we understood that individuals with Stage II and III disease may progress at different rates and anticipated that the Stage II subjects may be the population in whom disease progression could be better captured over the 12-month course of PIVOT-HD.

Now at 24 months in the Stage III participants, we are beginning to see signals of potential favorable treatment effect. Looking first at the TFC scale, which is a particularly relevant cUHDRS subscale for Stage III patients where by definition of a stage of functional decline, we see benefit relative to natural history at both dose levels.

On the cUHDRS as a whole, we observed a trend of benefit for the 5-milligram dose level at Month 24 with what may be an early signal of slowing of progression from months 12 to 24 to the 10-milligram dose level. For NfL not shown here, there were no treatment-related spikes in the Stage III participants with median levels below baseline for both 5 and 10 milligrams at month 24.

I'm also pleased to report that the safety profile of votoplam remains favorable after 24 months of treatment. There are no new adverse event signals identified and the overall profile is consistent across both dose levels in both stages at month 24 as well as consistent with what was observed in the placebo group. On this adverse event table, we show the adverse events from the first 12 months of PIVOT-HD here on the left side of the slide, with the events for months 12 to 24 in the open label extension on the right side of the slide.

As you can see, the AE profile is quite consistent over time and across dose levels. In a long-term extension, all grade 3 and 4 AEs and SAEs were deemed not treatment-related. These safety and efficacy data, particularly those in the earlier-stage participants provide us increasing confidence in the design of the Phase III INVEST-HD global trial which Novartis shared earlier today is now enrolling.

This study will directly assess the long-term efficacy of votoplam in earlier symptomatic individuals with a normal TFC score of 13. Participants will be randomized 3:2 to receive 10 milligrams of votoplam or placebo. Target enrollment is approximately 770, and the primary endpoint will be change from baseline up to 36 months on the cUHDRS rating scale. This study will also include interim analyses for both efficacy and futility.

As we have shared previously, this registration study could serve as a confirmatory study in the context of potential accelerated approval. In conclusion, in PIVOT-HD votoplam demonstrated statistically significant dose-dependent reductions in blood HTT levels. And now at 24 months, votoplam has demonstrated dose-dependent slowing of disease progression relative to natural history in Stage II participants with an average slowing of over 50% at the 10-milligram dose level.

At 24 months, there remains no evidence of NfL spikes with NfL levels below baseline. The safety profile continues to be favorable across both dose levels and disease stages. These clinical findings support that the effect on HTT lowering demonstrated in the placebo-controlled PIVOT-HD study is manifesting in early signs of clinical benefit that will be assessed in the now enrolling Phase III INVEST-HD study.

In terms of next steps, the Novartis and PTC teams will continue to review the data from the interim analysis and then will align on plans for potential regulatory interactions to discuss the results.

Thank you. And I will now turn the call over to the operator for questions. Operator?

[Operator Instructions] Our first question or comment comes from the line of Kristen Kluska from Cantor.

Congrats on the strong data today. Two questions for me. Just thinking about the primary endpoint on the Phase III, the language is up to month 36. So even if there isn't a potential for accelerated approval on these data sets, is there a potential for this Phase III to do either an interim analysis or wait until a certain number of patients potentially reach that 36-month endpoint?

Kristen, thanks for the question. I'll say that I want to compliment our partners at Novartis as well as the joint development committee. The protocol is very well thought out, very well designed and the results we shared today really support that design, which is obviously very encouraging. The study does have an interim analysis for efficacy, which in -- has the potential then to take an early look and potentially, depending on what those data show, could accelerate a time line for approval.

Okay. And have you guided what that specific analysis is or it's confidential at this stage?

Yes. The details of that haven't been shared yet. As you can imagine, as you think about an interim analysis, it would clearly be at a point that would be allowed for an early look, understanding that the primary efficacy analysis is up to 36 months.

Okay. And then my second question is just understanding how you did this comparison. Obviously, FDA has been pretty outspoken that they're supportive of natural history comparators, but they need to be done in a thoughtful and appropriate manner. So if you could just help us understand your confidence in why the natural history group that you used is indeed a good comparison and why it holds to the strong integrity that FDA is looking for.

Yes, absolutely. It's a very good question. And clearly, there's been a lot of discussions about natural history and natural history comparator groups. And look, first, it started with the fact that in the long-term extension protocol, we had prespecified that we would be leveraging the robust natural history registry, specifically ENROLL-HD to generate a natural history comparator group. So that's one thing that FDA really likes to do is specify that ahead of time and to -- as well as have an analysis plan that would prespecify the matching criteria that would be used, and that was done for this study.

I think in terms of registries, the ENROLL-HD has a large number of records as we shared and a very thoughtful approach was taken to ensure that we have a registry that includes all of the key inclusion criteria for the PIVOT-HD in open and long-term extension study as well as ensure that we matched -- we generated a matching group that had similarities in terms of the key factors that drive disease progression. And as you can see from the slide we shared today, the cohorts are well matched for those key variables really with no meaningful differences between treatment cohorts and natural history cohort.

Our next question or comment comes from the line of Ellie Merle from Barclays.

Just a couple for me. Maybe first on NfL, I guess, how do you interpret the data on NfL? And why do you think it wasn't dose dependent and your perspective on how to interpret what was seen in year 1 versus year 2 for NfL? And then I have a follow-up question after that.

Ellie, so look, at NfL, the exact relationship between specific NfL levels and disease progression, I don't think is that well understood for HD. What's generally appreciated is that over time, NfL should be increasing. I think we referenced the recent study that was done published in 2024 saying that, that could be anywhere around 13% a year increase. So I think for us, what's most encouraging is that we see in both dose groups that there is a reduction relative to baseline, which supports that we are having an effect on -- potentially on neuronal biology and neuronal sparing. So I think it's really supportive evidence that there could be an overall favorable treatment effect on disease pathology despite not being dose dependent. I think, again, the key thing is that we're below baseline.

Got it. And just in terms of the next steps with the FDA, just if you could give us any more granularity on when you plan to meet with the FDA? And I guess how we should think about the time lines for when on our side, we could hear more about the potential filing strategy? And then lastly, just a housekeeping question. I know for the Phase III, you said early HD. Just can you clarify if that includes both Stage 2 and Stage 3?

Yes, absolutely. So let me take the second question first. So it's early symptomatic individuals with HD. So it would be Stage II and also very early stage Stage III. Those individuals would have to have a normal TFC score of 13, which I think is an important factor in consideration. And as you can imagine, the decision for the enrollment criteria, the design of the study, all took into consideration the things that we were observing in PIVOT-HD.

And looking at the data today, I think that's what's so encouraging to see that the data we're presenting support the plan, the design and all the thinking that went into the design of that INVEST-HD study. In terms of next steps, as I mentioned, and I think Vas mentioned on the Novartis earnings call this morning, the key next step now is for the teams to go through all the data, understand what data we have and then align on what would be an appropriate next step, including potential regulatory interactions. So I think right now, we want to go through these data. And of course, the team working on Phase III is full speed ahead on getting that trial going. And then we will, as partners, discuss what the appropriate next steps would be.

Our next question or comment comes from the line of Tazeen Ahmad from Bank of America.

This is Jeremiah on for Tazeen. Congrats on the update. We were wondering if you could just help us contextualize the benefits associated with some of the changes on the cUHDRS subscales, maybe specifically as it relates to impacts on patients' quality of life. Just given some of this therapy will be dosed chronically, I'm just wondering what you guys' expectations are on like a real-world adherence.

Yes. Absolutely, Jeremiah. So look, I think the reason that the cUHDR scale is really favored as an endpoint in Huntington's disease is because it assesses many different components of the disease, including motor function, cognitive function and then ultimate functional -- decline of functional capacity. And so it really is able to capture a number of different relevant signs and symptoms of the disease, including those that would be particularly relevant to how individuals can feel or function in everyday life.

And obviously, as you go deeper into each of these scales, there are different items that can capture different things. So for example, the cognitive functions on the Symbol Digit Modalities Tests can get into really elements of cognition that are particularly important to individuals with HD. As you look at the TFC scale and start looking at things that relate very closely to activities of daily living. All of those things should translate quite well into quality of life.

In terms of your second question regarding long-term adherence in the real world, look, I think one of the clear advantages of votoplam is that it's a single once-a-day small molecule that so far is demonstrating to be safe and quite well tolerated. So the ease of administration, the ease of use, especially if we're able to continue to demonstrate efficacy, I think it would be certainly something that should have very high adherence given its tolerability, safety profile and ease of use.

Our next question or comment comes from the line of Judah Frommer from Morgan Stanley.

A couple for us. You mentioned, Matt, on the kind of the slope of those lines widening or the difference between the lines in cUHDRS widening as you got to 24 months. Now the error bars are wide, but it does look like part of that is that the votoplam 10 mg line is flattening out. So is there anything to read into potential improved effect over time there?

Judah, it's a good question. I think we're all starting -- we're still in the process of learning what can happen over time. Clearly, it's encouraging, as you say, when we look at the difference in the slope from 0 to 12 months and 12 to 24 months, we certainly see some -- at the 10-milligram dose level, we certainly are seeing some flattening there.

You could also say a similar thing is being observed on the TFC subscale. In fact, it may be that flattening on TFC that could be driving the flattening we're seeing on cUHDRS. I think the encouraging thing for us is that as we are taking -- observing these individuals for more times, we're seeing continued benefit that seems to be increasing in magnitude.

I think we understood all along in complex neurodegenerative diseases that are heterogeneous, it takes a longer period of time to clearly understand treatment effect. And I think that's why we're encouraged now looking at 24 months, we're seeing what we believe are stronger signals than we saw at 12 months, which is exactly what you want to see and quite frankly, expect to see if you have a therapy that could ultimately provide disease modification.

Okay. Great. And then just on the crossover patients, those patients that crossed over from placebo in the first 12-month period, are they included anywhere in these data or anything you can tell us kind of directionally about those patients as they reach 12 months?

Absolutely. So the readout here that we're sharing is focused on those who have had 24 months of treatment, again, to help give us an idea of what we observed at 12 months in PIVOT-HD in terms of HTT lowering are we starting to see greater signals or stronger signals over time of efficacy. I would say on first look at those crossover patients, it appears that a delay in getting the drug could have an impact, but the teams are still working through to understand those data because they're also very small numbers.

Our next question or comment comes from the line of Brian Cheng from JPMorgan.

Can you walk us through how we should view the changes that you are seeing at the subscale level? Because it seems that the Symbol Digit Modalities, the SDMT subscale seems to be the one driving most of the impact that we're seeing on the cUHDRS score and also the dose response we are seeing here, too. So how should we view the response in the individual subscales and also the reliability of the SDMT subscale when it comes to the Phase III INVEST-HD trial?

Brian, thank you for the question. So I think one of the -- again, as I mentioned, HD is a heterogeneous disease and individuals with HD may have different manifestations, they progress at different rates and they progress on different aspects of the disease at different times. And so one of the strengths of the cUHDRS is its ability to assay different aspects of disease progression and thus also simultaneously assay drug treatment effect on these different aspects of disease.

So I would think as we look at the cUHDRS subscales, what we're seeing at the 10-milligram dose level is contributions from several of them, which tells us that we are impacting for individuals what may be what is important aspects of the disease to them. So I would say we're not reading too much in depth to what one individual scale is saying here, particularly in these Stage II individuals, where I think getting an understanding that we're seeing contributions from different scales is really good. And the fact that we're seeing it across several scales also supports that we're seeing a real treatment effect at the 10-milligram level.

Our next question or comment comes from the line of Mr. Ben Burnett from Wells Fargo.

I wanted to just clarify and come back to one other point, just around the regulatory path. I guess understanding that you will align with Novartis about plans to sort of have interactions with the FDA. But I guess is the -- is accelerated approval still on the table with these data?

Yes. So Ben, I think as we've talked about and both companies have talked about, there's a strong desire to get this drug to individuals with HD as quickly as possible. I think we clearly -- there's a clear appreciation of the unmet need. I think both companies believe that all options remain on the table. It's just that we want to look through the data, have a very thoughtful plan about when and how we would engage regulators in discussing the data. So I think it's more a matter of -- it's not a matter of saying something is off the table or on the table. It's really a matter of saying, let's be -- we have data to go through, let's be very thoughtful about how we want to approach things. Let's leverage learnings from our own study, leverage learnings from other things going on in the environment.

And then as we -- we're just analyzing the top line now as we get deeper into the data, then I think we'll be able to, as partners, align on those best next steps, the best timing and how that -- how those interactions could be most successful for getting the program forward.

I got you. Okay. That's very helpful. And if I could just ask one follow-up. Just about the efficacy you're seeing. And if you're seeing any correlation with any of your sort of natural history variables, like do you see any efficacy correlation with like the number of CAG repeats or TFC at baseline or anything else?

Yes, it's a good question. We haven't really looked -- I'm not aware that that's really been looked into quite yet. I think the focus thus far was to ensure that we had those variables, and we were trying to get as close to apples-to-apples comparison as one could be. I think one of the things that was encouraging to us is looking at the trajectory of the natural history in the first 12 months and placebo in the first 12 months that they're fairly close. They're directionally in the same way and numerically quite similar and consistent, which is a really good sign. But again, as we looked at the variables, it was more about making sure that we had an apples-to-apples comparison and haven't really looked at any of the individual factors being a correlate or predictor of response.

Our next question or comment comes from the line of Mr. Geoff Meacham from Citigroup.

This is Jarwei on for Geoff. Two questions from us. Maybe first, could you remind us why you guys chose the TFC subscale as the enrollment criteria in Phase III? I totally understand that, that is a good predictor of disease progress in cUHDRS, but it does seem like perhaps some of the other ones could portend perhaps efficacy as well. And then the second question is, do you guys have any emerging correlation data between the degree of HTT suppression and maybe magnitude of benefit on cUHDRS?

Jarwei, thanks for the questions. Let me start with the first one. So I wouldn't say that TFC was the criteria -- that wasn't the driving criteria of the enrollment for the trial. The idea was to go into early symptomatic individuals with HD that consists of Stage II -- those with Stage II disease and early Stage III with a TFC score that's normal. That was more of a way of having a cutoff of severity, again, to account for the population in whom we think we're likely to have the greatest chance of impacting disease progression.

So I think it was really learning from the data that we had. There were a number of important criteria. The TFC score I mentioned, an independent score of greater than 90, total motor scores between 7 and 25, CAP-100 greater than 70. So there were a number of criteria that were developed, and they were really well thought out, again, based on the team's understanding of the disease progression was understood based on natural history and obviously, what we've observed thus far in PIVOT-HD and the long-term extension.

Again, I think that's why when we look at the data we shared today, we feel that they really support the design of the Phase III trial because, again, we're seeing a lot of the thinking and assumptions that went into design that trial get verified in a way when we see the treatment effect we're observing thus far. In terms of correlations between HTT lowering, I will say at a larger level, we're dealing with small -- still relatively small subject group numbers.

So I think it is encouraging to see that the treatment difference at 24 months on cUHDRS at 10 milligrams is 52% and at 28% as observed at the 5-milligram dose level. So we're seeing that about half the dose level is getting us about half of the slowing of progression. Now again, these are small numbers. But I think for us, that dose dependency is an encouraging sign that the differences in HTT lowering could manifest in a differential impact on disease progression. But we've not dug yet into doing any deeper associations.

Our next question or comment comes from the line of Brian Abrahams from RBC Capital Markets.

I guess have you looked at caudate volume changes out to 24 months and any trends emerging there? And then secondly, the ENROLL-HD derived natural history control parameters look just subtly different here versus in the prior 24-month interim cut. So just wondering how the criteria for, I guess, propensity matching may have changed between then and now?

So on the first question, Brian, in terms of the MRI data, we're still -- the teams are still in the process of analyzing those. So we don't have those data yet. And then in terms of the natural history, look, I think there's many different ways to approach how you do the specific natural history analysis. In this particular case, as we shared, there was a desire to ensure that we were matching on the key variables. There was then a new assay of the ENROLL-HD database that yielded the comparator group that we used here.

Our next question or comment comes from the line of Faisal Khurshid from Jefferies.

I wanted to ask, did you have a chance to look at the reduction in HTT levels out to month 24? And was there any meaningful difference in what you saw at the earlier time points?

Yes. So here, we're just looking, Faisal, at the clinical data at the 24-month time point as we reported in PIVOT-HD, the focus really there was in the primary endpoint was the reduction in blood HTT levels. We saw the dose dependence that hit the primary endpoint at 12 weeks. We saw that we were at the steady state at around 9 months. And then at 12 months, we saw that continued dose dependence. So here is basically looking at did those changes we observed in 12 months, are they starting to manifest over time in clinical benefit.

Our next question or comment comes from the line of Mr. Joseph Thome from TD Cowen.

Just curious, how many sites were patients identified at for this study? And maybe how many sites are planned for the Phase III? I guess, related to the question, I guess, how much site-to-site variability is there in the assessment of some of these measures, if at all? And then obviously, I know you're focused on MSH3 as well internally earlier in the pipeline. I guess, mechanistically, how might that target be differentiated? Any thoughts on that versus the data you're presenting today?

Yes. Yes, absolutely, Joe. So this PIVOT-HD was obviously a smaller study than INVEST-HD with 770 -- target enrollment of approximately 770 individuals in 30 different countries. I'll say that one thing, and I think there'll be probably approximately 200 sites or so for Phase III. I think the -- I'll say first, I think the Novartis team has done an outstanding job in moving quickly to get this Phase III study started from what was in discussion with the FDA in the fourth quarter on study design to getting the study up, getting it running, getting enrolling.

It's been really incredible to see, and we're very grateful to have them as a partner, and this is exactly the type of muscle they bring to this necessary large and complex study that we think heightens its probability of success there. And again, the key will be to work with centers that are expert in these assessments that most of them will ENROLL -- participate in ENROLL-HD and contribute to the natural history registry.

And you could be sure that there is -- will be great efforts to ensure the quality of assessors so that we have the greatest consistency as possible in -- across sites. In terms of your second question, the MSH3 program, we have shared that we have -- we're moving towards drug development candidate in our internal MSH3 program. That's another aspect of -- that can impact disease progression.

We've always thought that targeting MSH3 could be complementary with huntingtin lowering. It's really tackling 2 different aspects of the disease. one, the pathogenic mutant huntingtin protein as we're doing with votoplam and the somatic expansion, which is another aspect of disease progression. We've also shared that we thought it's possible that the MSH3 program could also -- MSH3 molecule could also be particularly suited for juvenile HD, where there's more rapid somatic expansion. So we're excited to be able to apply our splicing capabilities to really attacking the disease in 2 different meaning -- what we believe to be meaningful ways.

Our next question or comment comes from the line of Luke Herrmann from R.W. Baird.

Just following up on the flattening of the functional curves in the Stage 3 group at 10 mg. Can you just clarify the statistical modeling for dropouts and whether that 24-month time point was maybe just less affected by patients who are in steeper decline at the 12-month cut?

Yes. So I would say, Luke, that this is -- these are as observed data. So there's no modeling here. And we've not had -- very few dropouts. There's been actually quite very high adherence and individuals sticking in the trial, high compliance. And so this is really those who came in and observing them over time.

Great. And then on the MRI data, is there any idea of when we should expect to see those?

Yes. I don't -- I can't guide to that. I know we're sharing the top line data today. The plan will be to share a more full data set, obviously, once the analyses are completed at an academic meeting, a scientific meeting. But obviously, I think the Novartis team will determine when the right time and the appropriate meeting to share those data would be.

Our next question or comment comes from the line of Paul Choi from Goldman Sachs.

My first question is with regard to the Phase III INVEST-HD trial design. Matt, can you clarify if the study is based on the natural history decline on the Unified Huntington's Disease Rating Scale. The reason I ask is, since we don't have multiyear placebo-controlled data, your Slide 10 shows about a 0.6 decline at 1 year for the natural history cohort.

But I think in your prior update, you showed a smaller decline for your placebo-controlled arm at the time. So any clarity there would be helpful. And my second question is, does the Phase III initiation trigger any sort of milestone from a financial modeling perspective?

Yes. Thanks, Paul. So let me take the second question first. Yes, there's a $50 million milestone tied to the initiation of Phase III. In terms of your question, look, I think the trajectory of what we've seen when we look at 12 months with placebo relative to natural history are actually quite close. There's a very clear trajectory. I think -- so that's one point. And the -- there may be numerical differences, but I think importantly, they're both declining and appear to be relatively consistent in that regard. But in terms of the design of the Phase III study, this was more not about tracking progression, but zooming out and understanding what we think would be the key variables at the key stage of disease where we think progression is occurring at a rate that we could be best suited to capture treatment effect over the course of the trial.

It's also influenced by what we've seen not only in the preparatory work going into PIVOT-HD, but what we have seen thus far in the data. And obviously, we're going to continue to analyze the data from this interim analysis, and we'll continue to learn and we'll continue to enhance our understanding of these different factors and patient populations.

I'm showing no additional questions in the queue. At this time, I would like to turn the conference back over to Dr. Klein for any closing remarks.

Thank you all again for joining the call today. We are clearly very excited about these data. The PIVOT-HD study showed us that we have a drug that's doing what it's supposed to do in terms of splicing and reducing toxic huntingtin protein levels. It's getting where it's supposed to get in the CNS with better CSF levels or higher CSF levels in plasma. We're now seeing that those changes in HTT or lowering of HTT is manifesting at 24 months with dose-dependent benefit on cUHDRS.

And taken together, these data not only support the promise of votoplam to be a meaningful therapy, but are also clearly supportive of the study that's -- the Phase III study that's been designed and now initiated by Novartis. We look forward to continuing to review the data and working with our partners on determining the next steps, including any regulatory interactions. So we thank you all again for joining the call this evening.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.

Great. Well, good morning, everyone. Thank you for joining us on day 2 of the Barclays 28th Annual Global Healthcare Conference here in Miami. Very happy to have PTC Therapeutics here with us today. And I'm Ellie Merle, one of the biotech analysts here at Barclays. And joining us from PTC is CEO, Matt Klein; and CFO, Pierre Gravier. Thank you both so much for joining us.

Maybe to kick it off, let's start with Sephience, which is a launch that I think a lot of investors are closely following. Can you give us a high-level overview of PKU as a disease and why this could be such a meaningful opportunity for Sephience?

Absolutely. Thank you so much, Ellie, for having us. So PKU is a rare disease where individuals are born without the ability to break down the amino acid phenylalanine. This results in accumulation of phenylalanine in the body and has devastating consequences for brain development, neurological function and a whole host of other symptoms. That's why there's newborn screening for PKU so that once diagnosed, individuals can start on a highly restrictive diet that keeps them from ingesting protein. So you can imagine a very challenging life where you either have very little protein or you suffer severe neurological and other consequences if you have protein in your diet. There's about 17,000 individuals in the United States with PKU. [indiscernible] to say about 58,000 in countries around the world that we intend to market Sephience, our therapy for kids and adults with PKU.

And we see this as really a significantly large opportunity because there's 17,000 individuals with this disease. They're diagnosed at birth. And while there, prior to Sephience were 2 approved therapies, the vast majority of patients weren't served by these therapies, and there remained a significant unmet medical need for folks who desperately want a therapy that's safe, well tolerated, can help them feel better and have more freedom with their diet.

Yes. And I mean, I think that investors still very much underappreciate the market size, I think, in part, given some of the experiences seen with Kuvan and Palynziq in terms of the total -- like from a sales perspective, opportunity that was seen with those drugs. Maybe can you walk us through in more detail some of the differences between Sephience, Kuvan and Palynziq and why you think Sephience can unlock this broader population, whereas we haven't seen this, frankly, from Kuvan and Palynziq.

Yes, absolutely. And that's such an important point. When we started the launch, there was really this misconception that since the vast majority of patients weren't on a therapy, perhaps kids and adults with PKU didn't want to be on the therapy. That's just wrong. What really was the situation was that they want to be on a therapy that's safe, well tolerated and effective. PKU is a little bit different than other disease areas in which we work because if you think about diseases like Duchenne muscular dystrophy or spinal muscular atrophy, without a therapy, there's nothing these individuals can do except suffer the consequences of the disease.

So there's a high willingness to try a therapy and even stay on it if it may not be that effective or there's no perception of effectiveness. That's not the case in PKU. You're diagnosed at birth and you start on a lifelong highly restrictive burdensome diet. So your standard approach to dealing with this is already very restrictive and something you're already taking. So if you're going to take a drug on top of that, it's got to change something. You've either got to feel better or you can not -- you can ease off on that highly restricted diet. That's why if someone goes on an oral therapy like Kuvan branded or generic and doesn't perceive a benefit, phenylalanine is not getting lower, diet can't be loosened. There's no motivation to stay on it.

Similarly with Palynziq, which has been demonstrated to be effective, but has very significant tolerability -- a very challenging tolerability and safety profile, it's hard to stay on it and have an impact on your already very restrictive life. So all that is to say, this is a different disease state. And if a drug is not working for you where you can't tolerate it or has a safety profile that's difficult for you, you're not going to stay on the therapy. And that's why people took this idea that not staying on that therapy meant patients didn't want a therapy. No, no, no. They want a therapy. They want a therapy that can change their current management and that they can tolerate and have diet freedom, feel better and have a better quality of life.

And so that's why we're so enthusiastic about the opportunity of Sephience. It's an oral therapy once daily. The clinical studies have shown that patients have significant reductions in phenylalanine. The long-term extension studies are showing that patients are able to liberalize their diet and the Phe tolerance substudy of our Phase III study, 97% of patients were able to increase protein intake. 70% of patients were able to reach the recommended daily allowance of protein intake for someone without PKU and still control -- maintain control of phenylalanine levels. The safety and tolerability profile is very strong.

And what we're seeing in the real world are these benefits come to life for patients. We're hearing stories of individuals being able to have foods that they never had before, kids able to sit at the lunch table and have the meals that other kids are having, adults who talk about being able to eat with others at work that they were never able to do before, being able to drive home in the car without brain fog because your mental clarity is better because your phenylalanine is lower. And these benefits are being delivered in the context of a very favorable safety and tolerability profile. And that's why we say that we really view the potential addressable market here as the full population of PKU patients because our data demonstrate that we're having significant benefit in folks with the full spectrum of disease, including those with more severe PKU known as classical PKU.

So I think we're I hope people are slowly appreciating that this is a disease where those affected desperately, desperately want to be on the therapy. They just have to perceive that there's benefit and that it's safe and well tolerated in order to stay on it.

Absolutely. And you've seen some encouraging launch metrics out the gate. Walk us through what's been seen with the launch so far, both from a start form perspective as well as revenue.

Absolutely. So in the first 5.5 months, we had over 1,100 starts. And in the first 5.5 months, we had over $110 million in revenue, and that's mainly U.S. with some small contributions in Germany. We started the global launch towards the end of Q3 last year with approvals in the U.S. and Europe. We've recently got an approval in Japan in December. We'll be launching there in early Q2 in Brazil. And I think this early success is really a testament to both the significant unmet need and the strong desire of patients to get on this therapy.

And of course, also a credit to our teams. I mean, we did a lot of work for a year, 1.5 years prior to launch, mapping out the 104 centers of excellence, getting to understand who are the decision makers and what are the dynamics at each center. For example, many of the PKU centers, the prescription decisions are driven not necessarily by the physicians, but by the nurse practitioners and the physician associates and also dietitians. They're a really important part of the care team because, of course, in the absence of a therapy and sometimes even in the presence of a therapy, diet is still a really important part of management of PKU.

Absolutely. And in terms of who's getting the drug, Sephience, I mean, we're seeing a lot of Kuvan failures are out there, and then there's patients that aren't treated. How are -- what are you seeing in terms of who's starting on Sephience and where you're seeing the most uptake initially?

Yes, absolutely. One of the clear themes of the launch thus far is breadth. We've had two month old prescribe the drug and 80-year-olds prescribe the drug, full spectrum of disease severity. And then across all key patient segments. We've described the segments as being those who are currently on therapy, whether that be Kuvan branded generic or Palynziq, those who've tried and failed, which is probably the vast majority of individuals with PKU and those that are therapy naive. And that's often individuals who have what are known as non-BH4 responsive or classical PKU who are never tried on Kuvan because there was a belief that since their mutations don't respond to BH4, they were unlikely to have benefit.

And what we've seen early in the launch is the majority of patients getting prescribed the drug are those who've tried and failed other therapies, whether it's Kuvan or Palynziq and we've seen a number of the therapy-naive patients also get the drug, including adults who I think, again, this is one of those prelaunch misconceptions that there was this group of patients who were never tried on drugs, who are remote from the centers who are never going to come back in and they're coming back in. We're seeing adults who are therapy naive come back in. And then we're seeing a smaller number of switches thus far. It seems that the dynamic that's been playing out in these early days of the launch is that the centers are looking to put those who currently aren't on a therapy first rather than switching someone who is on the therapy.

And our data have been very consistent in showing that if you have a response to sepiapterin and Kuvan, you're going to have a much more significant benefit from sepiapterin. And I think 100% of the patients who've been in our studies have shown that. And in our AMPLIPHY head-to-head study, we were able to quantify that relative benefit. And we had, on average, 70% percent greater reduction of phenylalanine with Sephience relative to sepiapterin, which again just speaks to the fact that when patients are switched, they're going to stay on the drug and enjoy greater benefit. But again, I think the priority has been to first get those who don't have a therapy right now tried on Sephience.

That's interesting because I would think that the Kuvan patients would almost be the lowest hanging fruit of like you know they respond and then there's a drug where they'll respond better and have more dietary flexibility. And we've heard that from some of the doctors that we've spoken to. Yes, how do you think about that?

I think that's another example of how a lot of the preconceived notions about the marketplace, if you will, prior to launch may not be playing out exactly as people thought, right? Number one was, these folks don't want to be on drugs. That's why the peak revenue for the existing therapies was so low. No, no, they want to be a drug that's safe and well tolerated. Okay. Well, the low-hanging fruit is going to be -- in the early launch is going to be driven by switches. Why? Because there's 100% guarantee they're going to be better on this drug. And a lot of physicians interviewed prior to the launch said, well, my intent is to switch the 80-plus percent of my patients over to Sephience and I'll then try it in a more severe mutations. It hasn't played out that way. It actually has played out that there's been early experience with more severe mutations.

There's one very prominent physician who a lot of people interviewed who, I think early on was a little bit skeptical about the effect in classical patients. And she said, I tried one of my classical patients on the drug. There was, I think, somewhere like a 90% very rapid reduction in phenylalanine and I'm sold. Now all my patients are going to get tried on it. And that's just not that at that center. That's a theme we're hearing consistently. And so once the prescribing pattern shifted to trying all patients on it, there was priority given to those who don't currently have a therapy prior to doing the switches, which I think bodes very well for the sustainability of the launch because if you're thinking about the 100% guaranteed responders and 100% definitionally adherent population that have stayed on oral therapy, and those -- we haven't really penetrated deeply into that segment yet, that's still to come. But that's really good news for the launch.

I'll say the other thing that's been really impressive early on, we shared this on the call last month or earlier this month, we've gotten more than one start form from 80% of the centers of excellence. That's kind of odd at this stage of launch. As usually, it's the other way around where you are -- maybe it's 20%, maybe it was the investigators in your trial who are the first ones to try it. And now it's gone the other way. We're just seeing this such broad uptake and broad interest. And so now that as we move -- we're still early days in the launch. But as we continue to move through it, it's just -- the story is going to be about penetrating deeper and deeper into existing centers where they're prescribing and continuing to penetrate deeper into these segments where those aren't on therapies. And slowly, I think we'll start to see the switches come as we move through the year into next year.

Absolutely. And so patient start form, that's certainly something that people will be tracking. You had about 1,100 exiting December. So if we're doing our math correctly, that's about 200 a month from the last update that you had around 500 exiting September. How should we think about the cadence of new starts from here? It seems like you're seeing a sizable breadth in prescribing, certainly a large number of centers. How should we think about this?

Yes. I think where we are now somewhere around -- out of the gate, super duper strong. I mean those first months, there was such incredible enthusiasm. And I think demand has remained. The patients want to get on the drug. We -- as we headed into the fourth quarter and into the fourth quarter of last year, what we started to see is the centers were saying, okay, we got to get to a steady cadence here where we can continue to prescribe. We can't spent all day long putting patients on Sephience as much as they want to be on it. And so I think we hit that point late last year where we were seeing now this sort of steady state where as patients were coming into the clinic, they were being put on the drug. And now we're also moving into a part where we're adding countries outside the U.S.

So patient numbers now won't -- there's not start forms in countries in Europe. And as we launch in Japan, there won't be start forms, same with Brazil. So I think the metric as we move further into the year is going to be patients on drug. That's going to tell the full story as we get more centers outside the U.S. So the story of '26, we believe, will be continued momentum in the U.S. and then the addition of ex-U.S. patients coming on board. And we've said by the end of 2026, we expect to have commercial patients in 20 to 30 countries. So we're really excited about this being truly a global launch and being able to get the drug to as many individuals as we can who might benefit.

And another question we get from investors is around the adherence that we'll see for Sephience, just given if patients say are nonresponders, do they stay on? How are you thinking about that? And what are you seeing in the real world? And your expectation for will there be discontinuations if patients they don't respond?

Yes. It's early days. So it's hard to have a clear sense of what this is going to look like at steady state. We shared that through Q4, the discontinuation rate was really low. We said low single-digit discontinuations and very few of those were for nonresponsiveness or not having an effect.

I think we'll see that reach slightly higher than low single-digit discontinuations as you'd see with any drug. But I think the fact that we've seen in the studies that we have response rates of 70% to 75%, depending on how you define response, bodes very well for what we'll see in practice because in reality, the stories -- the anecdotes we're hearing, the data we're seeing from prescribers is suggesting that we're seeing what happened in the trials play out in the real world, that there's responsiveness among the full spectrum of severity, that there's patients who are under very careful management able to begin to liberalize their diet and looking on social media and seeing individuals posting their Phe levels dropping.

And these include those with severe disease, talking about having foods that they never had for the first time, as I mentioned earlier, that's really what we're hearing across the board. Those aren't one-offs. And that really is consistent with the experience in the clinical trials.

Absolutely. Pierre, I guess, in terms of the guidance, I mean, we've gotten questions around, is the guidance conservative? Can you walk us through sort of what is baked into the guidance for the Sephience launch versus some of your other products?

Yes, of course. Absolutely, I'll break it into the multiple products. So the guidance on revenues is $700 million to $800 million on product revenues, excluding Evrysdi. In terms of revenues, the vast majority is Sephience. As Matt mentioned, we believe, right, in the strong momentum that is continuing in 2026 and the global opportunity is really $2 billion -- at least $2 billion plus worldwide. In terms of the rest of the portfolio, right, the mature business, the DMD franchise, Translarna and Emflaza, look, Emflaza, we now have 10 generics. And so we will expect continued erosion there. And then Translarna is unique. If you think about last year, Q1 had full sales in Europe before the license was removed.

Now in Europe, obviously, we said we could maintain about 25% of our sales. And this is very unique. We sell without a license. You don't know how long it's going to be. And then ex Europe in LatAm and Russia, CIS, those are government orders, and it's unclear for how long we could maintain that. So the way we see this is mature business with continued erosion and then obviously, Sephience being the vast majority contributor here. And that's how we guided at the start of the year. And obviously, if we see less erosion, we have opportunity to obviously update guidance.

All right. That's helpful. Turning to Huntington's disease, which certainly has been an area of a lot of focus. Remind us where you are with your program and the data update that we can expect this year?

Absolutely. The Votoplam Huntington's disease program is continuing to move forward. We had shared that along with Novartis, there was a meeting with FDA in the fourth quarter of last year that there were two main objectives. One was to get alignment on the efficacy trial, a Phase III trial of Votoplam and alignment was reached and that protocol has been finalized and Novartis is moving very quickly to get that study up and running. That's an efficacy-focused study that could serve as a confirmatory study in the context of potential accelerated approval. And otherwise, it could itself be a registration trial, and we've shared that there's a plan to have an interim analysis in that study that could also provide another opportunity and an early look at data for potential accelerated approval.

So Novartis is working very quickly to get that up and running. We said over 700 subjects in over 30 countries, there'll be centers. So it's going to be a very big trial and really something Novartis can manage quite well. In terms of the PIVOT-HD Phase II open-label extension, that study is ongoing as well. And we expect a readout in the first half of this year once all participants cross the 24-month time point. And so that will be coming up this half. And we've been clear that if those data looked supportive, that could allow us to have a discussion with the FDA about potential accelerated approval.

And I'm not going to ask you to comment on sort of what's happened recently with the FDA and uniQure. But maybe commenting on your own program, sort of what are the reasons why you think your data set would be supportive potentially of accelerated approval?

Yes. And I appreciate that. We're in a very different context, right? It's an oral therapy. We had a placebo-controlled initial study. We have an open-label study prespecifying that we were going to use an external comparator group. We also have the evidence in the blood of target engagement in dose-dependent lowering of Huntington protein. So we're in a much different framework and in CDER, which is also a different center in the agency. So what we believed all along is that Huntington protein itself has the potential to be a surrogate endpoint, likely to predict clinical benefit. The mutant Huntington protein is the causative disease protein and being able to lower it should have benefit. And by the way, there's a number of studies supporting that.

So we have already a prespecified primary endpoint successfully achieved in PIVOT-HD of statistically significant lowering of Huntington protein that was dose dependent. So the idea is, okay, can we have data from the longer-term study that can support the notion that those changes observed early on in Huntington protein are likely to [indiscernible] to long-term clinical benefit. Now at 12 months in the Stage 2 patients, which is going to be the patients who make up -- more or less make up the Phase III study, we showed dose-dependent benefits relative to placebo at 12 months. And in the initial 1/3 of patients who reached 24 months, we saw dose-dependent benefits on cUHDRS, TFC, single-digit modalities test relative to natural history as well as a dose-dependent change in NfL.

So again, we'll see what the data look like in the first half. But if we can have clinical data that maintains dose dependency, which suggests that there is a relationship between the amount of Huntingtin lowering and clinical effect and could have biological support from something like NfL, that's a marker of neuronal injury. That could be a package that -- well, we believe it's a package we could -- we would certainly feel comfortable talking to the FDA about and could be one that could allow us to leverage the surrogate accelerated approval path that's been used in the neurology division before.

Interesting. And what's your expectation for how the data at 24 months would compare to the data at 12 months? Do you expect continued stability, continued separation versus the natural history comparator? How do we think about that?

Yes, absolutely. So at 12 months, we benchmarked to placebo. And when we looked at the first group at 12 months and then that initial group out at 24 months, we saw continued trends of benefit both on the cUHDRS scale and some of the subscales. Those are small numbers, about 12 patients -- 10 to 12 patients in each group. We'll have a much larger, about twice that number now. And I think what we'd really be looking for is that continued trend of benefit that's dose dependent. And we have ways of also thinking about leveraging that placebo data to get a sort of a better match in the natural history group that more represents what a true comparator population should look like for the treated patients.

Okay. And so then after the data, sort of a fair assumption you'll speak with the FDA again?

Yes. I think depending on what the data look like, if the data look good, we'll work with Novartis and make and make a plan for regulatory discussions.

Great. Just quickly, I know you have a lot of other programs in the pipeline, including some interesting early-stage programs that you had an R&D Day on last year. Maybe if you could give us kind of the high-level overview of those programs.

Yes, absolutely. So we do have a lot of exciting programs. We also had the update with -- discussing with FDA about the potential of the next study for vatiquinone for Friedreich's ataxia, which they wrote to us that they believe that could be an open-label study with a natural history comparator. So we'll discuss and finalize those plans. And then we worked very hard to evolve the splicing platform. It delivered Evrysdi, which was incredibly valuable Votoplam program. And now we have a number of preclinical splicing programs. We highlighted our MSH3 program, where we plan to have a development candidate this year, another way of approaching Huntington's disease that can be complementary to HTT lowering.

And our inflammation, ferroptosis platform also has a number of promising therapies. We expect to start our Phase I study for our NLRP3 inhibitor, PTC612, which is a highly differentiated potent molecule in the second quarter, we'll be starting that. And then also look forward to advancing our Nrf2 activator program and ferroptosis, Parkinson's disease program. So a lot of excitement early on of molecules that we think can be really meaningful coming closer to the clinic.

Great. Well, Matt, Pierre, thank you so much for the time, and thanks, everyone, for joining us.

Thank you, Ellie.

Thank you.

Welcome, everyone, to our chat with PTC Therapeutics. It's my pleasure to host Matt Klein, CEO; and Pierre Gravier, CFO. Thanks so much for joining us.

Thank you, Joe. Glad to be here.

So Matt, can you start us off with a quick level set and briefly touch on your recent accomplishments and goals for this year?

Yes, absolutely. We're coming off a very strong 2025, which was highlighted by the initial global approvals of Sephience, our drug for kids and adults with PKU as well as a strong start to the launch. We had over $111 million in revenue in just the first 5.5 months. And that performance really speaks to the highly differentiated profile of Sephience, the significant unmet need for a safe and effective therapy in the PKU community as well as our team's ability to execute our experienced customer-facing teams around the globe.

Overall, in '25, we had a strong revenue performance, exceeding guidance. Our expenses also came in below guidance, and we ended the year with approximately $1.95 billion in cash, which sets us up well to continue to support our commercial and R&D portfolios as well as to continuing to build the company forward the way we wish. We also talked about this year being a year of revenue growth driven by Sephience.

We expect continued strong momentum in the U.S. and so that by the end of the year, we expect to have commercial patients on drug in 20 to 30 countries. We explained that with our revenue guidance and expense guidance, we're in a position to potentially be cash flow breakeven this year, which would be a significant milestone for the company.

We also made significant advances in our R&D portfolio, including our oral small molecule splicing platform, which first brought forward Evrysdi, followed by votoplam for HD, and now we have a number of programs in earlier stages of development. So overall, we're really well positioned for continued growth and continued success.

Great. Okay. Thanks. So at this stage, how much Sephience demand is coming from different patient segments? And how do you expect that mix to evolve over the next 4 to 6 quarters?

Yes. I think one of the early strong signs from this launch has been its breadth. We've seen breadth in terms of patient age with kids as young as a few months old, adults as old as 80 getting on drug. We're seeing broad uptake across all patient segments, including those who are therapy naive, those who have tried and failed previous therapies and those switching from existing therapies.

I think one of the early surprises in the launch is that we are seeing a number of patients who are naive and adults who were thought to be lost to follow-up and people wondered if they'd ever get on drug. And if so, it would probably be later in the launch. I think there was this belief that the early momentum would be driven by switches, and that's not been the case, in fact, we've seen lower number of switches and rather, it seems like centers are putting an emphasis on trying to get patients on drug who currently on one -- who aren't on one before doing switches.

Nonetheless, we have seen some switches, both from Kuvan and Palynziq, but early on, this has been about patients who tried and failed previous therapies. I'd also say we're seeing breadth in terms of center participation. We shared by the end of Q4 last year, we had more than one prescription from over 80% of the centers of excellence.

Again, that's unique at this point in the launch. Usually, it's a small number of centers and you have to work to get other centers on board. But at this point, we have 80% of centers and whom we can continue to penetrate as we move deeper and deeper into the launch.

Okay. And what are the most important data points you're tracking internally to determine whether the Sephience franchise is shaping up to be durable and not just another switch cycle?

Yes, absolutely. Look, I think by all measures, $111 million in 5.5 months for a rare disease launch is outstanding. And that was a tremendous early performance. And as we've talked about, we really see us being in a period of sustained momentum as we continue to move forward. And part of that, again, is this breadth, right? We're seeing patients with classical PKU who are more severe patients who are getting tried and staying on drug.

We're seeing patients who, again, were therapy naive or tried and failed others coming and staying on drug. And the fact that we haven't seen a large number of switches yet from Kuvan and all of our data show that if you have a response to Kuvan, you're going to have a much greater response to Sephience.

Those are patients who tend to do quite well on our drug and tend to be adherent. Those -- we haven't even begun to go into that segment yet. So all of that suggests we have a very long way to go in this launch. You consider a population of 17,000 patients in the U.S., 58,000 worldwide in markets in which we would commercialize and hearing feedback from prescribers that their intention is to try all their patients on the drug, we've got a very, very long way to go.

And we're seeing very high rates of adherence, large very high rate of prescription refills. So again, all signals suggest that we -- we're off to a strong start, and there's continued momentum, and we have a very long way to go and which is why we've been quite clear that we see this as at least a $2 billion-plus global opportunity at peak.

And how do you expect responsiveness to look in the real world relative to your clinical experience?

Thus far, it seems to be lining up very well. Of course, we don't track it as much in the real world as we do. So the idea that it's tracking -- it's doing well is what we're seeing and hearing from prescribers as well as patients.

I think there's nothing more gratifying and probably no greater statement of support for the potential transformative value of Sephience in social media posts where we see kids talking about being able to have meals with the rest of their family, the same as the rest of their family for the first time, having pizza at a party, trying steak off the barbecue for the same time, parents being able to say they're having the same meals with their kids, getting reports of people having better brain fog, not needing the GPS to get home from work. All of those things are suggested that we're seeing the continued benefits observed in the trials in the real world.

Okay. So then what kind of a response rate metric would that entail?

So in our trials, we had about a 70% to 75% response rate in terms of pure quantified Phe lowering. We know that benefit is defined by both payers and prescribers in different ways. There's Phe lowering where the percentage threshold -- the percentage to define response may vary based on your baseline Phe because clearly, 15% to 20% or 30% lowering for someone who has a phenylalanine of 1,200 looks a lot different than someone who has a phenylalanine of 400 at baseline, for example.

We know the ability to increase protein intake is really important. We know for others, the numbers matter, but just feeling better, having less anxiety, having clear cognitive function, clear executive thinking, that's a real benefit that really matters to the patient and in fact, we've talked a bit about how we've gotten policies from payers that are covering about 200 million lives, so about 2/3 of the population in the U.S.

And there's been no step edits required and response has been defined as quantitative lowering of Phe or increased protein intake or overall medical benefit. So we're seeing these different definitions of response being applied broadly.

Okay. And how are -- how is uptake and persistence comparing in pediatric versus adults?

So it's early days, and I know you've heard me say this before. We said by the end of Q4, we were seeing low single-digit discontinuations, which, again, it's early days, and we don't know that it will stay that low, but we expect there to be a high rate of adherence. It seems to be fairly consistent between adults and pediatric patients.

I think we've said that the main reason that we were seeing withdrawals tended to be concerns about taste and texture of the medication from adolescents. So that was sort of the one early sign that stuck out. But across the board, we're seeing very good adherence and consistence.

And I'll also say that we also have been working on as part of life cycle management, getting towards a tablet formulation as well. So ultimately, we'll be able to address any concerns someone might have with the formulation.

Can you go into that a little bit more? What are your plans on that front?

So clearly, when you have a product that has the potential of Sephience and the success we've had, we're actively thinking about life cycle management and life cycle management involves thinking about evolving formulation. We've guided that we have IP protection out to 2039. But of course, we're always looking to expand the IP portfolio and get greater duration. So those are just very standard life cycle management things that you would do when you have a valuable therapy like Sephience.

Okay. And at what point will you be able to -- or will you be able to detect from like refill rates at some point. What the response rate is tracking in the real world relative to the clinical experience?

Yes. I think we're going to have to get a little further into the launch. As we've said early on, we're seeing the low discontinued rates and very few of them have been cited as lack of response. So I would imagine we're going to need to be at least a few more months into this to get to a real hand on it. But again, all signs now still looking like very high adherence rates and refill rates.

Yes. Okay. Great. And then can you talk a little bit about the payer requirements for staying on therapy? I think unlike BioMarin, you're not providing drug for free during the trials. So people jump through all those hoops upfront. On the one hand, that might like lower the the desire to switch after they've gone through all that effort. But on the other hand, I'm just wondering what payers are requiring.

Yes. The payer feedback has been very positive. And part of that is because they understand that you can tie value to lowering and to have been able to enter payer discussions already having in hand the AMPLIFY study, which shows as all of our other studies did that 100% of patients who responded to Kuvan respond to Sephience better. And we quantified that as having an average of 70%, 7-0 percent, greater lowering in phenylalanine with Sephience relative to Kuvan.

With those data, we've not had the requirement imposed any of the policies of a step edit because it's very clear that there's significant greater benefit with Sephience.

Furthermore, about the testing, if you look at the Kuvan data in their studies, they did a response as we did to identify responders and the responder rate in that study is about 20%. For Sephience, we were closer to 70%. And so that is why we didn't feel it's necessary to give free drug. When you have 4/5 of patients not responding, you may need to give a free test. But when you have the vast majority of patients responding as with Sephience, we didn't see that need to test to prove that it's going to work because it does for the majority of patients, including both classical and nonclassical patients.

Okay. And what other data will you be generating either in the clinic or in the real world going forward?

Yes. So we have the open-label extension from the Phase III AFFINITY study, and we recently shared an interim cut of those data, which showed patients are able to liberalize their diet. We reported that 97% of patients in the Phe tolerance protocol were able to increase protein intake. 70% of those patients were able to get to the recommended daily allowance of protein at some point in the protocol. Those are really compelling data because we know that ability to loosen the diet is so, so important to patients.

We also had an early look at some of the QOL data showing the ability to have improved executive functioning, decrease anxiety and increased mood symptoms. So those were good early data points, and we're going to be continuing to look at those over time.

We have a separate study looking at neurocognitive function that's being done as part of the pediatric investigator plan agreement with Europe and then a number of investigator-sponsored studies looking at different things like response rates as well as some of these other important aspects. So we look forward to having continued data that are supporting really the value of Sephience for patients.

Okay. And then what data do you have to demonstrate that patients can get to certain levels of Phe? And how robust is the ability of Sephience to get patients to meaningful levels, meaningful improvements where their Phe is really under control?

Yes. And I think that was one of the most important data points from the Phase III study that 84% of patients were able to get to below 360 micromolar per liter, which is really the target Phe level and the level at which most feel comfortable starting to increase protein intake. So 84% is a very high number, and that included a number of patients who started with Phes at 800, 900 and 1,000. So we're seeing this, again, for the full spectrum of patients.

And then within that substudy, as I mentioned, once you got below 360, we were seeing that 97% of those folks were able to increase protein at all. And 70% were able to get to a level of protein intake that would be recommended for you and I, someone who does not have PKU, that's a lot of protein.

And if you think about the lives of people with PKU, being able to even have one meal or one part of the day where you could have increased protein intake is transformative. A kid who can go to school and have lunch with the other kids or go to a birthday party and have what the other kids are eating, an adult who can go to the office and have lunch with other folks and not have to have their restrictive diet. That's life changing. And that's where a lot of the adherence here comes from is the ability to really favorably affect people's lives in a meaningful, meaningful way.

Yes. That was impressive clinical data. I think there were not that many patients with classical disease and very high levels of Phe. I think they were a little bit lower than what we saw in the Kuvan studies, for example. Are you going to be generating any more data, so we can understand how well Sephience works in the classical population, which makes up the majority of patients?

Yes. Well, absolutely. So I think we can debate numbers majority and break down. We had capped the enrollment in the study at 20% classical and saw a very good response in those patients. I think you did a great interview with the KOL who had pointed out that they were initially skeptical and put one of their most severe patients on who had severe classical and had a 90%, 90% lowering phenylalanine right away. And that's really what had everyone understanding they need to try all their patients on the drug.

And we'll be publishing very soon our mechanism of action paper, which is showing the ability to affect the non-BH4 responsive, these classical mutations, both in vitro, in vivo and in the clinic.

And what's really interesting about the Phase III trial, Joe, is if we take the metabolic definition of classical, you're right, the numbers were low in the trial because we capped at about 20%. But it turns out 70% of those carried a mutation that's associated with non-BH4 responsiveness. We've gone back to the genotype data, which is the purest way to understand a classical presentation of disease and actually had a very, very high percent of the "non-BH4 responsive classical mutations " So that will all be coming out soon and really establishes that if you look purely at the genetics that we are having very strong responses in a lot of these classical patients.

Okay. Good. I look forward to that. So then I guess, longer term, how are you thinking about defending the Sephience franchise some new approaches emerge that might work in even more patients?

Yes. I think let's be careful. We don't -- everything looks good early on. So I think what's well understood -- first of all, the launch is getting off to a strong start. We expect very strong penetration before any therapies reach the market. And I think the next therapies in line are some of the kidney-directed therapies, which are still a bit early in terms of having broad efficacy and safety demonstrated and understanding what their role can be.

The feedback we've gotten from a lot of folks in the community is people think we're headed towards a cocktail approach where you're going to be able to have more than one therapy to get folks even closer to complete diet freedom. In fact, I think if you look at the Otsuka trial with the first kidney-directed therapy and their inclusion criteria allowing folks who are on an oral therapy to stay on it, which already anticipates the fact that this is something that's going to be added on top of therapy for a lot of patients.

Okay. Great. So assuming Sephience becomes a solid backbone for the company, which pipeline program has the clearest path to becoming the next meaningful source of value creation?

Yes. I think, look, as we said, we're enthusiastic about Sephience. We believe that alone can get us to cash flow breakeven potentially even this year and certainly to sustainable profitability. I think looking at our existing portfolio now, in addition to the commercial products we have, with the recent feedback we've gotten from FDA on the vatiquinone program and the potential to be -- to have additional data to support resubmission coming from an open-label natural history controlled study, I think, would be something we'd look forward to doing.

We were very clear that we'll meet with the agency to get alignment on that protocol and analysis plan before initiating the study. But I think we would view that as a very high probability of success study and also very clearly could be a significant revenue contributor given the unmet need for pediatric and adolescent patients with FA and I think the clear need for alternative therapies or additional therapies for adults with Friedreich ataxia.

I think we also see the votoplam HD program, while we partnered with Novartis, the economics of that deal have significant upside for us with a 40% profit share in the U.S. And I think that clearly can be a very meaningful revenue contributor either through an accelerated pathway of available or a standard approval pathway.

Yes. Great. So let's touch on both of those. And I guess on vatiquinone, you've elected to move forward with a new trial following that regulatory feedback you alluded to. What specifically gives you confidence that the -- that this incremental investment makes sense? And what is similar or different in the design or degree of regulatory alignment that you have now versus previously?

I think our confidence comes from the MOVE-FA study where we showed over 72 weeks in a placebo-controlled study, significant effect on the upright stability scale, which was the only subscale of the mFARS on which the placebo group progressed over 72 weeks. So basically, you're saying the only place you could have shown significant slowing of progression, we did.

And then when we look longer term after 3 years, that same approximately 50% slowing of progression we saw over 72 weeks was maintained after 3 years when looking at a well-matched natural history control. So being able to take those data and all the learnings we've made and apply it to a study, again, if we're able to align on the protocol and analysis and setup of that natural history match external control study gives us a lot of confidence.

We know very well how a natural history control group should progress. I think part of the reason FDA has traditionally supported the use of the Friedreich ataxia registry as a source for external control data is the fact that there's a very clear, consistent predictable rate of progression of roughly 2 to 2.5 points a year.

So knowing how your control arm is going to perform removes one of the major questions you have going into a clinical trial. And so knowing that and what we've seen in terms of vatiquinone's ability to slow progression over a similar time period that is -- if we see what we saw before in the study, that should set us up very well for success.

Okay. And how do you feel, given the use of external synthetic control arms are a little bit of a hot topic nowadays at the FDA. Does that give you any pause heading into a strategy that might emphasize that?

So I think it's always important to have alignment with the agency before you start a study, how you're going to design it, how you're going to match things and how you're going to analyze it. That's straight out of the FDA guidance for 2023 on the use of external controls. So I think that's why we want to be super sure that we're aligned with the agency on both the essential elements of the protocol, how a match cohort would be identified and how the analysis would be done.

I think it's also important to note that this would be being done on top of a placebo-controlled study that showed benefit, and the study is being offered to provide additional data that would support resubmission. So while we're always wanting to be sure that we're aligned with FDA in writing align and clear, what we're going to be doing, I think the context here is also very different from some of the recent discussions that have gone on regarding external controls.

Okay. Great. And then given -- that's probably a good segue to my next question, given what's been going on in Huntington's disease, does that -- do those events influence your views at all about your Huntington's program that's been partnered with Novartis.

It is the recent experience with the gene therapy and FDA. Yes. Look, we've said all along that we have a very different program in terms of mechanism. We've had a very different development program where we've been able to provide objective evidence of target engagement and mechanism of action. We've had a placebo group. We've prespecified in the protocol, the intent to use an external control group long term to contextualize clinical benefit.

So I think we're in a very different context. We're in a different part of the FDA. I think the one thing that remains consistent is what has been very clear as a significant unmet need from a patient for a patient community that very much wants a therapy that can be safe and effective for them. So I think that's where things are consistent, but I think the programs are very different. The data packages are very different. And I think both our partner, Novartis, and we look forward to availing ourselves of an accelerated path if we believe the data warrant that.

So then just following up on that a little bit more, what would you hope to see that could make that -- bring that closer to reality?

Yes. So we're expecting to have in the first half, the interim data analysis of the -- where all the participants from PIVOT-HD crossed 24 months in the open-label extension. What we've already learned is that the -- we believe the optimal responder population is that Stage 2 patient group. In fact, the Phase III INVEST-HD, which Novartis is working very quickly to get up and running is going to be really focused in that earlier stage group of patients.

So what we would like to see now is in addition to already having hit the primary endpoint of Huntington lowering in these patients, seeing after 24 months continued evidence of dose-dependent effects on some of the clinical scales, including cUHDRS and the TFC subscale and also seeing in addition, if we can continue to see those trends in dose-dependent trends in NFL lowering, which provides some biological support that you're having a favorable effect. So I think it's -- again, it will be a package where we'll be looking at the effect on Huntington lowering combined with the clinical data at 24 months.

Okay. And it seems very important to the FDA that things are prespecified in order to be able to allow them to entertain whether or not they'll entertain having conversations around a potential accelerated path. So what's your strategy on that front?

Well, I think it's a strategy that started before we started the study. So right, the initial PIVOT-HD study was clear and prespecified Huntington lowering as the primary endpoint. There was an analysis plan, that endpoint was hit with statistical significance. The protocol for the open-label extension specified the intent to compare the cUHDRS and the subscales to external control registry, the natural history registry. And before the study is unblinded, there's a statistical analysis plan that outlines the strategy for modeling and matching as well as the analysis plans.

Yes. Yes. I know there's a ton of data out there available to sponsors in Huntington's disease to be able to do really rigorous comparisons. And what have you seen as far as the correlation between the Huntington lowering and the functional changes?

Yes. I think what we've seen, which has been very compelling is the fact that we're seeing these dose-dependent changes on the clinical scales. We saw that at 12 months in the placebo-controlled phase. We're seeing it out in the first data cut of the Stage 2 patients out at 24 months. That was about 1/3 of the patients where we saw those dose-dependent effects on cUHDRS on TFC, on the single-digit modalities test, which is the cognitive scale.

I think in these smaller patient numbers, being able to see that dose-dependent function is really valuable because it suggests that if you're lowering Huntington protein twice as much, you're seeing greater clinical benefit, which I think really supports the concept that Huntington lowering could provide long-term clinical benefit.

Okay. And then let's talk some more about the rest of your efforts given you held a nice event recently to talk about the deeper pipeline. What's your strategy there going forward?

Yes. You're referring to our R&D Day in December, which we were really excited to present. And in part, we wanted to spend some time talking about a lot of the advances we've made in the splicing platform. I think the RNA splicing platform is a highly differentiated validated platform as being incredibly valuable, again, yielding first Evrysdi, which is now the leading therapy for SMA and the HD program, which is the leading oral disease-modifying therapy in Hunting -- for Huntington's disease patients.

And we've made a lot of advances just in understanding how many more potential splicing targets there are. We've been able to integrate our knowledge about these potential targets, the biology of these targets, our proprietary library to develop something we call PTSeek, which is sort of a high throughput way we can match these and both facilitate and accelerate the discovery and development of splicing molecules.

We were able to share a number of the programs, preclinical programs in splicing that are moving forward, including our MSH3 program for Huntington's disease and DM1 for which we expect the development candidate this year. We also spent some time talking about our inflammation platform, where we have our NLRP3 program, which we expect to be entering Phase I in the second quarter of this year, our Ferroptosis Parkinson's program where we expect the development candidate this year as well as our Nrf2 activator program.

So a lot of exciting programs targeting aspects of biology known to be very important in diseases and doing so with highly differentiated molecules, whether as a function of specificity or potency or in the case of the splicing platform, leveraging our decades of expertise in splicing molecules.

Yes. And what's the strategy for taking them forward on your own versus would you be open to partnering any in particular? How are you about that?

Yes. We've been very clear that certainly things that are in the rare realm certainly fit very well in our capacity to develop and commercialize, and we'll definitely look to do that. There'll be other therapies. I think Parkinson's disease is one where we're certainly very comfortable taking that into Phase I, looking at different biomarkers to get an early read on important pharmacodynamic effect. But that's really something that I think would be better suited for a partner who has the muscle that you really need to do a Parkinson's disease program well.

We've also talked about having an interest in using the splicing platform also as a source of earlier-stage partnerships where there's certainly splicing targets that could be very valuable in larger neurodegenerative disease or oncology spaces where PTC is unlikely to be developing and commercializing, but nonetheless, our science can play an important part. So we think a lot about sort of these dual tracks where we can identify promising therapies that we can develop and commercialize, but then also still leveraging the potential of partnerships for noncore therapeutic areas.

Okay. Great. Well, thanks for the update. It looks like we're about out of time. Appreciate it.

Thank you, Joe.

Ladies and gentlemen, thank you for standing by. Welcome to PTC Therapeutics Fourth Quarter and Full Year 2025 Earnings Conference Call. [Operator Instructions] 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 2025 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 website 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 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. 2025 was a year of many significant successes for PTC, positioning us well for 2026 and beyond. I'll start by reviewing the highlights in 2025 and then share our key objectives for 2026.

The main highlight of 2025 was the initial global approvals and launch of Sephience for children and adults living with PKU. As we have discussed, Sephience will be the foundational product for PTC's near-term growth. In 2025, we gained approval for Sephience in the U.S., EU, Japan and other countries, all within several months. The global launch is off to a strong start with broad uptake across all key patient segments and age groups.

In 2025, we also made a number of advances in our R&D pipeline including achieving positive results from the Phase II PIVOT-HD study of votoplam and progressing a number of early-stage programs, including those from our RNA splicing platform.

And in 2025, we delivered another year of strong revenue performance. Fourth quarter net product and royalty revenue was $263 million, and full year 2025 total net product and royalty revenue was $831 million, exceeding guidance of $750 million to $800 million. Total revenue includes $587 million of net product revenue with solid contributions from our mature products and from the early Sephience launch. For Sephience in the fourth quarter, we achieved $92 million in revenue and for 2025 since launch, we achieved $111 million, a really impressive start.

In addition to the strong revenue performance, non-GAAP R&D and SG&A OpEx for 2025 was $728 million, coming in below our guidance of $730 million to $760 million. With our strong commercial execution, disciplined OpEx management as well as the monetization of the remainder of the Evrysdi royalty for $240 million in December 2025, we ended the year with $1.95 billion in cash. This financial strength will enable us to continue to support our commercial and R&D portfolios as well as engage in strategic business development.

For 2026, we are providing product revenue guidance of $700 million to $800 million, with the majority coming from Sephience. This guidance represents 19% to 36% in year-over-year product revenue growth. The 2026 revenue guidance excludes Evrysdi royalty revenue given the sale of the remaining portion of the Evrysdi royalty. We are providing expense guidance of $680 million to $720 million. And based on our revenue and expense guidance, we have the potential to reach cash flow breakeven in 2026, a significant milestone for the company.

As we move into 2026, our main focus will be continuing the strong momentum of the Sephience launch. To date, we have seen broad uptake across all disease severities and age groups. This year, we expect revenue growth through increased penetration in our current markets as well as expansion into additional geographies. By the end of 2026, we expect to have patients on commercial drug in 20 to 30 countries across multiple regions, including Japan, where we gained approval in December and expect to launch in the coming weeks.

Based on Sephience's highly differentiated profile, the large unmet need for adults and children with PKU and the early broad uptake into all patient segments, we believe Sephience has a potential multibillion-dollar global revenue opportunity. In 2026, we also look forward to progress across our R&D portfolio. For the votaplam Huntington's disease program and then the Phase II meeting was held with FDA in the fourth quarter of 2025, where alignment was reached on the Phase III study design.

Novartis will be initiating the Phase III trial INVEST-HD in the first half of this year. This trial could serve as the confirmatory study in the context of accelerating approval or as a registration trial. We also expect to have results from the Phase II PIVOT-HD extension study in the first half of 2026 once all participants cross the 24-month time point.

For vatiquinone, we had a Type C meeting with FDA last December, where we discussed potential next steps in the development program following the CRL for the vatiquinone NDA. FDA has indicated that additional study will be necessary to support NDA resubmission and stated in the meeting minutes that this study could be a single-arm study with a natural history comparator group. We plan to meet with FDA in the second quarter to align on the protocol for this open-label study, including a matching strategy for the natural history control arm.

In 2026, we expect to advance several programs from our innovative R&D platforms, RNA splicing and ferroptosis inflammation. We expect to elect a development candidate for MSH3 program for HD and myotonic dystrophy as well as to advance some of our earlier preclinical programs.

From our inflammation platform, we look forward to initiating the Phase I study for our NLRP3 program by midyear and to potentially elect a development candidate for our ferroptosis Parkinson's disease program as well as our NRF-2 activator program. In summary, with our robust commercial engine, innovative R&D programs and strong financial position, we look forward to a successful 2026.

I'll now turn the call over to Eric to discuss our commercial performance, including details on the Sephience launch. Eric?

Thanks, Matt. We are incredibly pleased with the strong launch of Sephience reflecting its differentiated safety and efficacy profile and the experience and preparation of our global commercial organization. The PTC team has delivered on all key aspects of the early launch.

Our customer-facing teams engagement across all key segments, including Centers of Excellence, health care providers payers and patient advocacy groups has accelerated adoption of Sephience following FDA and EMA regulatory approvals. The breadth of adoption we are seeing across all patient segments in the first few months of the launch is highly encouraging.

In the fourth quarter of 2025, global Sephience revenue was approximately $92 million including $81 million in the U.S. and $11 million ex U.S. Sephience generated $111 million in revenue worldwide in 2025 since launch, and is expected with the U.S. accounting for the vast majority of the revenue. As of December 31, 2025, we had 946 patients on commercial therapy worldwide and in the U.S. received 1,134 patient start forms.

As Matt mentioned, we are seeing uptake from the full spectrum of the disease severity and patient age, including therapy-naive adults. We are also seeing breadth in terms of prescription base with 80% of PKU centers of excellence in the U.S. having written prescriptions for one or more patients. We are hearing positive feedback from health care providers highlighting broad adoption and have seen many patients of various disease severities, treatment histories and all ages from newborns to 80-year olds.

We are pleased to see that treatment-naive adults, many who have been called loss to follow-up or those who have tried and failed therapies in the past have actively been seeking suffice in the initial stages of the launch. While it's still early, we continue to see high refill rates and low discontinuation rates which we view as an important sign of building on the launch momentum. Importantly, the PKU community has been very active on social media, playing a meaningful role in sharing real-world experiences driving awareness and influencing other patients to engage earlier with their health care providers.

We continue to see favorable payer mix dynamics with the majority of prescriptions covered under commercial payer plans. Importantly, the AMPLIFY head-to-head study demonstrated significant superiority over BH4 has been well received by payers who are supporting open Sephience access with very few barriers, including no step edits and 12-month refills before reauthorization.

Our teams are also working on geographic expansion of the launch outside the U.S. We achieved regulatory approval in Japan in December and are finalizing pricing and reimbursement. While the U.S. continues to be the main driver for growth near term, we expect Sephience commercial patients to come from 20 to 30 countries by year-end, steadily building international presence in terms of both revenue and patients.

In Europe, we have submitted health technology assessment dossiers for pricing and reimbursement in key markets. and are leveraging paid early access programs for PKU patients to receive treatment as we finalize pricing negotiations. As we accelerate the launch in 2026, we believe the long-term opportunity for Sephience remains significant. In the U.S. alone, there are approximately 17,000 patients and new patients being identified via newborn screening with the majority of these patients tied to PKU Centers of Excellence.

The clinical data package of suites highly differentiated efficacy, safety and dual mechanism of action supports broad penetration across the PKU population and position Sephience as the potential standard of care. These compelling data and the large orphan patient pool create a significant runway for the future growth of the brand.

In the fourth quarter and throughout 2025, we continue to generate revenue from our more mature products. including the DMD franchise, given our ability to successfully defend Translarna and Emflaza despite significant headwinds. In conclusion, we are very pleased with the exceptional results delivered by the customer-facing teams in 2025. We are excited by the early launch Sephience metrics as we continue to build and execute on a world-class rare disease product launch.

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 2025. Beginning with top line results. Total net product and royalty revenue for the fourth quarter was $263 million, including Sephience net product revenue of $92 million. GMV franchise revenue for the quarter was $66 million with Translarna net product revenue of $39 million and Emflaza net product revenue of $27 million. For Evrysdi, Roche achieved fourth quarter global revenue of approximately USD 584 million, resulting in royalty revenue of $79 million.

Our full year 2025 total net products and royalty revenue was $831 million, exceeding guidance. Total product revenue for 2025 was $587 million including $111 million of Sephience revenue and $382 million of DMD franchise revenue. For Evrysdi, full year royalty revenue was $244 million.

For the fourth quarter of 2025, non-GAAP R&D expense was $124 million, excluding $9 million in noncash stock-based compensation expense, compared to $116 million for the fourth quarter of 2024, excluding $9 million in noncash stock-based compensation expense. Non-GAAP SG&A expense was $87 million for the fourth quarter of 2025. Excluding $10 million in noncash stock-based compensation expense, compared to $76 million for the fourth quarter of 2024, excluding $8 million in noncash stock-based compensation expense.

In December 2025, we sold the remainder of our Evrysdi royalty to Royalty Pharma for $240 million upfront and up to $60 million in sales-based milestones. Importantly, we maintain the right to receive $150 million milestone from Roche based on single year Evrysdi sales of $2.5 billion. Based on the prior accounting method for the royalty, we will continue to show Evrysdi in our financial statements. However, there will be no cash proceeds for PTC.

We have provided product revenue guidance for 2026 of $700 million to $800 million. This represents 19% to 36% product revenue growth from 2025. We anticipate non-GAAP R&D and SG&A expense for the full year 2026 of $680 million to $720 million. Excluding estimated noncash stock-based compensate expense of $95 million. Based on this revenue and OpEx guidance, we have the potential to reach cash flow breakeven in 2026.

Cash, cash equivalents and marketable securities totaled $1.95 billion as of December 31, 2025, compared to $1.14 billion as of December 31, 2024. Our strong financial position provides a solid foundation to pursue our strategic objectives including supporting our commercial and R&D programs as well as potentially pursuing business development opportunities.

And I will now turn the call over to the operator for Q&A. Operator?

[Operator Instructions] And our first question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on a really strong start for the Sephience launch. So first question for me. I just wanted to ask what's baked into your internal and external guidance for Sephience sales this year? Understandably, most of the sales will come from the U.S. But I would imagine if you're going to be in 20 countries versus 30, that will have an influence as well. So anything you can guide us for what's baked in and if you would consider this conservative at this stage?

Yes. Kristen, thanks so much for the questions. So as you indicated, the total -- so the revenue guidance this year is strictly product revenue, as we highlighted in the call of $700 million to $800 million, which is 19% to 36% growth over last year. We expect the vast majority of it to be from Sephience. The remainder, obviously, from our more mature products, as we said, we'll continue to have headwinds on the DMD franchise, including a larger number of generics in the U.S. for Emflaza and such. So we've been conservative in that regard of understanding where that could go. And as usual, as we get more visibility into DMD franchise as we move into the year, we can always adjust and raise guidance as needed.

On the Sephience front, we expect the majority of revenue to come from the U.S. with contributions ex U.S. that should -- as Eric and I both highlighted, we expect to have commercial patients in 20 or 30 countries by the end of the year, but we'll expect those revenue contributions to come later in the year. And I'll let Eric go into more detail on those dynamics in just a second, but I'll say that again, we're still very early in the launch with 1.5 quarters as we ended in 2025 with an incredibly strong start. We continue to see great momentum. And with just 2 points on the line thus far, obviously, we'll make adjustments to guidance as needed as we continue to move in the year and have greater visibility on the revenue trajectory.

Eric, do you want to provide a little bit more color on the rollout globally and the contributions to overall revenue?

Yes, and thanks for the question Kristen. I'll just add, Matt said a lot of different things here. And I think it's really important that you know that the U.S. will continue to drive the vast majority of our revenue during the course of this year. We continue to see very nice momentum in Germany as well, and we have prepared HTA dossiers in Europe as well. So much of this pricing and reimbursement will take place during the course of the second half of the year. We're also really excited that we have the Japanese launch that's coming up in the second quarter.

We finalized pricing and reimbursement. We will do that in the next few weeks and anticipate revenue to start in Q2, but more meaningful revenue in the second half. The good news as well is we had approval this week in Brazil, a very important market as well, and we'll begin processes with the named patient programs. And then as Matt said, when you potentially add 20 to 30 countries during the course of 2026, incrementally, they will be contributing over the course of the second half of this year, but really set us up nicely for 2027.

Go to office in the past? And maybe if you could just comment on some of the trends you're seeing within each of these specialty centers uniquely, like some of the feedback we hear is physicians are trying it on their more difficult patients first. And if they respond well, then kind of encouraging others to consider treatment as well.

Yes, thanks. Kristen, you've captured a number of the complex dynamics that we're seeing early on. So let's first start with this lost to follow-up bucket, which I think was a term, I think that really started with the physician saying that there's a lot of adults that they don't see who are not on therapies and they don't see them in clinic. And what we've learned is that there's a number of these adults out there who still have -- some of them still have associations with the clinic, whether it's periodic with dietitians or nurse practitioners and others who maybe not are associated with the center.

But I think what they have in common, and I believe this came out in your session today, with the MPQA, adults want to be on therapies. And so I think what was a little bit misunderstood early on is lots of follow-up and not coming to see a doctor was equated with not wanting to be on therapy. And that's not the case. I mean it's 2026 now, social media, people are plugged into what's going on in the community.

And I think as you talked about as well, what we see is a lot of activity on social media sharing the transformative benefits a lot of the patients have had with spine, including being able to try foods for the first time having fee control overall feeling better. And this gets out there. I mean there's actually social media influencers in the PKU community. So there are -- just because someone is not seeing a doctor doesn't mean the they are not -- that doesn't mean that they don't want to be on the therapy. And I think what we're starting to see is engagement of these folks as the new therapies available that has demonstrated to be safe ease of use and is able to deliver benefits that are so important to patients.

In terms of the center dynamics, it's not a one size fits all necessarily. But we are seeing early on that centers are tending to want to try those who are therapy naive or tried and failed other therapies before those are on therapies. And as you pointed to, we've heard from a few centers they're trying -- some of them are more challenging patients who desperately need a therapy. And the feedback there has been really positive with some of the more severe patients having really strong responses, which is really helping to put Sephience right there as first-line therapy to try for all patients regardless of severity. And then, of course, if it works in the most severe patients, there's greater confidence over time that those who are on current therapies, including oral therapies, could get switched over.

So overall, it's been a very strong response. And I would point out this lost to follow-up, doesn't mean loss to follow-up, but just one of those lessons that when a drug is launched and you're out in the real world, the dynamic play out as the dynamics are not always as the docs may have predicted. And again, overall, it's just been really impressive to see that those hardest to treat patients and hardest to reach patients are being reached and helped so early in the launch.

Our next question comes from Tazeen Ahmad with Bank of America.

I wanted to get a little bit of color on vatiquinone. So FDA has asked for an additional study for FA. Can you provide any color on details? So do you know what kind of a study you would need to run? How many patients over what time period? Any kind of color that you could provide would be great here.

Yes. Sure, Tazeen. Thank you for the question. As we've talked about before -- and is visible to everyone, it's public, the CRL for vatiquinone was really based on statistical considerations. We had demonstrated significant effects on the upright stability scale, which is the most relevant and meaningful scale for the young patients enrolled in that study. This drug continued to show to be safe. And I think in our discussions with FDA, this may be FDA giving us an opportunity to provide additional data through an open label or single-arm study within natural history control.

And I think that, again, this speaks to the potential need to just have some additional evidence beyond what was there in MOVE-FA to provide the totality needed to gain approval. So we obviously want to meet with FDA as they have suggested we do to go over that open-label protocol, go through all the details of the matching criteria with the FA COMS natural history database. As we talked about before, Friedreich's ataxia in the FA community has done a great job of building a rigorous and robust natural history database that was used by [indiscernible] for approval.

So this is a regulatory precedent using it. And so we will, again, be using that. And we're just in the process now of finalizing what the subject number would look like and duration of treatment. So more to come on that. We expect to meet with the FDA in the second quarter. That meeting has been requested and scheduled so that we can get final alignment, then we can share those details and look to get this study started as quickly as possible. Obviously, we're excited to have an opportunity to do a study like this that wouldn't subject younger patients to a placebo and really allows us to get that additional treatment evidence that we would need for approval.

So then just a follow-up on that. Since they gave you a suggestion, should we just assume that that's what you are planning on doing? And is that also baked in to your OpEx guidance for this year, OpEx expenses for this year?

Yes, absolutely. They had written into the minutes that this was an option for us to take, to collect the additional evidence. And so that will be what we'll pursue discussions would be on that protocol. There is some OpEx for the FA study, and there'd be no change to that. It's entirely possible with an open-label study, may obviously be less costly. It's a little less involved than having to manufactured placebo and all the blinding and some of the logistics required in the CRO operations. But no -- for sure, no increased OpEx related to doing this time.

Our next question comes from Ellie Merrell with Barclays.

On Science, first, just what are your expectations for the discontinuation rate commercially? Specifically, how long do you think physicians will wait to see if patients respond or not and I guess, the threshold that physicians view for response.

And then just a separate question, just in terms of the cadence of new starts from here. Are you seeing a steady number of new start forms this year so far? Or did you see a bolus upfront? And if you could just talk to sort of how you see the rate of new starts evolving, I guess, in the U.S. over the course of the year.

Thank you very much for the questions, Ellie. I'll just start and I'll pass it over to Eric. As we talked about thus far, it's still early days in the launch, and we're seeing very low numbers of discontinuations very high prescription renewal rate. It's still early days, but it's obviously very encouraging.

Eric, do you want to talk a little bit how we're thinking about that dynamic over time and cadence of starts going forward?

Yes. I mean on the discontinuation rate, that's really important because, obviously, part of what we're doing is building a prevalence and were discontinuation rates as well. as refills are something we're watching very carefully. As we've mentioned before, we have very low dropouts single digits. And usually, these are based on patient decisions, not necessarily for clinical reasons, safety or efficacy, which is incredibly encouraging.

With regards to Cadence, we see we have gone through. And of course, we've gone through the course of the 5.5 months of the launch. We continue to see very nice momentum with new patient starts. And we anticipate that cadence to continue throughout. It is a combination of consistency of bringing in new patients and maintaining the base of patients that we have by ensuring that our case managers and our teams are involved in making sure that medical education awarenesses, reauthorizations, dose adjustments and all of that are taking place.

So we're very, very confident that not only the momentum that we've had that we started in the first 5 months will continue, but adding 20 to 30 countries over the course of the second half of the year, we'll bring in meaningful revenue to this truly global launch.

Our next question comes from Brian Cheng with JPMorgan.

How should we think about the fine growth in Europe once we reach the end of the 6-month free pricing period specifically, how the negotiated price balance out the projected uptick in the market.

Thanks very much for the questions, Brian. And Eric, do you want to talk a little bit about German dynamics and pricing.

Sure. First of all, we're really pleased with the launch because the vast majority of the centers of excellence in Germany have prescribed suppliance. So we have an incredibly experienced team that's been managing that process. Keep in mind, we've also had a number of products that we've launched. And we've gone through this process right now to get pricing and reimbursement. We have already gotten the assessment from GBA and AMNOG on the benefit rating. And we're in this process right now for pricing and reimbursement.

We've submitted our HTA dossier. It has a very strong clinical package right now that includes both all of the affinity data as well as the AMPLIFY data which will give us a lot of really important strength in terms of supporting the highest possible price. These discussions are ongoing, and they will be going for the next 5 to 6 months before we finalize pricing and reimbursement with the AMNOG process. So I think we need to stay tuned. But we're anticipating with the strength of the data that we'll be able to maintain the highest possible list price and lowest rebate.

Our next question comes from Judah Frommer with Morgan Stanley.

Maybe just a follow-up on Sofia. Anything you can point to in reimbursement dynamics that have kind of shifted as we move through the initial stages of the launch, maybe specifically for those patients getting approved to be on first-line therapy with Sephience.

And then separately, just on the comments around potential to pursue business development. I guess, how do you think about prioritizing the internal early-stage pipeline and bolting on to that versus kind of going in alternate directions.

Yes. Thank you for the questions, it. I'll let Eric talk a little bit about the color on reimbursement dynamics and hear briefly on BD. So Eric, you want to go first?

Thanks for the question,. First of all, we're really pleased with the interactions that we've had with both the U.S. commercial payers and the government payers. I mean we've had some pretty experienced teams of our field-based teams with both MS cells as well as market access that they have met with payers now that cover more than 250 million lives. We've been leveraging again the AFFINITY data. But more importantly, the AMPLIFY data has really, really opened up a lot of good discussion in terms of policies.

Government and commercial policies have been written. It shifted in the positive sense in the context that -- where they've been written, they've been favorable to Sephience. They're primarily prior authorization to label. They're either limited or no step edits with refills from 6 to 12 months. And some of the biggest commercial payers have finalized their policies with refills to 12 months and no step edits. So that's very encouraging.

In terms of reauthorization, the processes seem to be very straightforward and generally positive. After 6 to 12 months, the criteria seems to be fairly consistent with our with our clinical results. So they're looking for fee reduction, goal attainment for dietary needs as well as potentially the physicians or health care providers judgment on clinical improvement. So all in all, I think the shift has been very quite positive, and we're seeing now a number of plans, both at the government and commercial level that have been favorable to survive.

And on BD, first of all, we're in a strong financial position with $1.5 billion cash as we start the year. Sephience is off to a great start, and we see it to be a multibillion dollar opportunity. We're obviously focused on the launch and continuing to expand globally as well as develop our internal R&D pipeline.

Rest assured, we have enough cash to do both at the same time, no problem. But we're open to accelerate top line growth via business development opportunities. We will be disciplined, and we will make sure to always look at maximizing shareholder returns.

Our next question comes from Ben Burnett with Wells Fargo.

I wanted to ask also about science. Just what kind of Q1 dynamics should we expect? I guess, any color on kind of discounting or any other sort of typical Q1 dynamics that we should be modeling?

And then also, like where do you expect kind of the majority of the demand to kind of come from going forward? So kind of talked about some of these lots of follow-up patients. But is going forward, are the switches kind of the more important group? Or do you see kind of adoption from both?

Thanks for the questions, Ben. Let me grab the second question -- take the second question first. Look, I think one of the things that has been impressive to us early on in the launch is the breadth of uptake, both in terms of age with patients as young as a couple of months of age up to 80 years as well as the full spectrum of severity, seeing less severe patients, classical patients with non-DI responses in different patient segments, those that are currently on therapies with those who are in therapy and I just talked about. And I think we had the majority thus far coming from those who've tried and failed previous therapies.

Being that we're still in the early stages of the launch, I think what we expect in the short term is continued broad penetration as we go deeper and deeper. There's no reason to see a slowdown in those that have tried and failed coming on, those that may be therapy naive. And I think over time, we'll probably see more of the switches that goes on therapy for the simple reason that what we're hearing is there's a preference at the centers to try to get those who don't have a therapy right now or trying filter to get on therapy first before switching.

Of course, the AMPLIFY data shows as well as on other studies continue to show every patient who's been on BH4 generic or branded has a much better response to Sephience whether that's in terms of fee lowering or fee lowering and diet liberalization. So time and time again, that is the case. And there's awareness about that in the health care provider community, which is why we expect over time, we'll see those switches come. But for now, I think the story is going to continue to be breadth but in terms of the segments, breadth in terms of severity.

And the other thing I'll point out that early on, as Eric raised in his comments, we've gotten prescriptions from over 80% of the centers of excellence. And at this stage of the launch, it's usually the opposite, it's usually 20 a prescribed and you're trying to get into the larger numbers. What we're seeing again is a story of breadth of getting penetration into these expert centers, which again, we expect will continue over time.

Our next question comes from Clara Dong with Jefferies.

This is [indiscernible] on for Clara. I just wanted to ask for Sephience. As you think about Japan and Brazil and these other ex-U.S. EU markets that you could launch in, how would you kind of force-rank those by revenue contribution potential? And then also on time line to kind of contributing meaningfully.

Great. Thank you for the question. As we said, we expect going forward, the majority will continue to come from the U.S., but we'll start seeing those contributions from ex U.S.

And Eric, you want to talk little bit how we're thinking about timing and contribution.

Yes. Timing and contribution in those key markets are very important. We're already getting to the very end of this quarter, and we will have price negotiated pricing and reimbursement in Japan. I think we're really pleased with the approval there. It's a full and broad label. Our staff is already on the ground. They're fully trained. They're profiling the centers of excellence. And we anticipate first commercial sales from Japan in the second quarter, with more meaningful revenue in the second half.

I want to remind you, there's about 1,000 PKU patients in Japan. However, it's a very, very high priced and premium-priced market with 10 years of orphan drug exclusivity. So we've got a long runway and a very experienced team there. We're also really pleased with the dynamics of Brazil because Brazil has over 5,000 diagnosed patients, and they're concentrated in major cities. We're pleased because our team there is incredibly experienced. They've launched multiple products in the rare disease space. They know how to navigate the named patient program aspects in Brazil.

So the team has gone through already for more than a year, profiled a number of the centers of excellence, health care providers, KOLs and the advocacy groups. And the named patient programs are in place and ready to go since the approval this week. So we have a number of patients already identified.

Pricing submission will take place shortly in the coming days. And we anticipate, again, more meaningful revenue because the name patient programs do take a little longer to go through in Brazil, but we would anticipate more meaningful revenue towards the end of this year.

Our next question comes from Brian Abrahams with RBC.

This is Joel on for Brian. I wanted to ask on votoplam. Can you walk us through the Phase III study design? How are you thinking about potential approval pathways there what might be some scenarios that could enable approval prior to primary reading out? And separately, can you also quickly comment on your net pricing expectations for Sephience?

Sure. Joel, thanks for the questions. Let me take the first one, and then I'll turn it over to Pierre to talk about net pricing. So this -- as we talked about, we -- there was an FDA meeting in the fourth quarter, where the key focus of that meeting was achieving alignment with FDA on the design of this Phase III study, INVEST-HD.

As you know, this will be conducted fully by Novartis, funded fully by Novartis, but obviously, we participate as a member of the joint development committee. And the idea was to set this study up to either serve as a confirmatory study in the context of potential accelerated approval based on the PIVOT-HD open-label extension data. or itself as a registration study. And as we shared at JPMorgan, this will be a placebo-controlled study with a 3 to 2 randomization of going to plan to placebo and a targeted enrollment of approximately 770 participants in over 30 countries with the primary end point in change in CUHDRS.

There is an interim analysis planned for both efficacy and futility. So there is that potential that if accelerated approval is not achievable based on the PIVOT-HD study with an interim analysis that could potentially bring an earlier approval prior to the completion of all patients getting through that INVEST-HD study.

Pierre, you want to talk a little bit on net pricing.

Yes, absolutely. The interesting dynamic in the PKU pricing is 2/3 of the patients are commercial which is very rare and usually in some other settings, for instance, Duchenne, it's 50-50 split. And we said we expect the gross to net between 15% to 25%. At the start of the launch will be in the lower hand of that side. And as we get to steady state will increase over time.

You next question comes from Joseph Thome with TD Cowen.

Maybe to follow-up on the Huntington's program. I guess now that Novartis is in charge of the program, are they also in charge of any further disclosures from Phase I/II program? Or should we expect anything in May of this year? Kind of how does that work? And then I guess is there another planned FDA meeting on the data that you have right now, I guess, to use that package for accelerated approval? Just trying to understand that component. And then lastly, in the Phase III, what triggers that interim analysis?

Thanks for the question, Joe. So the -- as we talked about the other objective of that fourth quarter FDA meeting was to just have a high-level discussion around the potential for accelerated approval and not surprising the neurology division in Cedar is open to that potential given the significant unmet need for those living with Huntington's disease. I think it's quite clear from the comments we've made publicly and Novartis has made publicly that there's a great enthusiasm in both companies to pursue that pathway based on the data, if that's possible.

Clearly, the next step is the analysis of the open-label data, which will occur once all subjects across 24 months. That would give us an opportunity to look at those data, make a decision through the joint development committee consisting both of Novartis and PTC, whether we believe we have data there worthy of discussion about accelerated approval. And then as you can imagine, there would be a subsequent needed regulatory and feeding to get an alignment with the division about the data and the potential for accelerated approval.

That analysis will be done by Novartis as they're overseeing the program now. We would expect that we would have a disclosure. The details of that will get worked out. as we go through the analysis. And as we said, that analysis will occur in the first half of this year. So we would expect to be sharing in the data. Those details are still to come. In terms of triggering the interim, those details haven't been disclosed as of yet.

I think the idea, though, is to make sure that there is a sufficient number of subjects that have gotten through a significant duration of treatment to allow for an opportunity to understand if there's a sufficient efficacy signal that could allow for potential stopping or at least a data cut and analysis to support discussions around accelerated approval.

Our next question comes from Sami Corwin with William Blair.

Congrats on the progress. I was curious how we should interpret the Translarna sales allowance in France? And if we could see a similar adjustment in the future. And then regarding the vatiquinone, did the FDA have any recommendations or input as to whether you could use upright stability as the primary endpoint? Or if they prepare you to use mFARS

Thanks, Sami. On the first question on the Translarna France allowance, this was kind of a unique thing to France. It's a onetime France specific thing that we had sold Translarna there under an early access program since the beginning of time where we set the price when the license wasn't renewed, France ended the early access program and set their own price and they issued a charge for the difference. So this is a something specific to the France early access system. In fact, it's something specific to Translarna that I think would never happen again for any other drug in and it was a onetime thing.

On vatiquinone, so I think one of the questions in terms of what the end point is will be based on the duration of that study because 1 of the important findings we had in the MOVE-FA study was that certainly, over the short term, 12 to 18 months that upgrade stability is clearly the endpoint that could capture is most sensitive to capture treatment effect in the population we enrolled in MOVE-FA, which would be consistent with the one that we would enroll in this new study.

However, what we saw in the data is that by 18 months and certainly as we went out to 36 months, we continued to record significant effect on slowing of disease progression. But now that slowing was captured on the other subscales as well, including lower limb and upper limb. So that's why I say that depending on the duration of the study, if we're looking at something a little bit longer than 18 months that it would probably make the most sense to have the NFRs as the primary endpoint. Because really, the goal here is to demonstrate significant effect on slowing of progression and how that's done with mFARS and the subscale is based on the patients and the duration of the study.

Our next question comes from Geoff Meacham with Citigroup.

This is [indiscernible] on for Geoff. Maybe going back to Sephience and thinking about OUS geographies A lot of the early trends that we've been seeing in the U.S. are pretty encouraging with regard to capturing the loss to follow-up patients and some of these early start trends and also awareness on social media. So maybe thinking about Japan and Brazil and other geographies you're thinking about. Could these trends also be similar or is your internal expectation, that is just too early to tell.

Thanks, [indiscernible], for the question. I would say that it's probably a little early to tell, but what we do know is true is that patients regardless if they live in the U.S., if they live in Brazil, are they live in Germany, are they live in Spain? Or are they live in Japan, UAE, their networks, their social media networks everywhere. There's patient organizations, there's aggregation of patients. And so the -- these communication channels like we're seeing in the U.S. that drive awareness that enable patients to share the stories of success in trying fees for the first time and such. We see that globally.

What may differ [indiscernible] in country to country is a little bit of just the dynamics of patients attached to centers. For example, I already talked about the number of patients in Japan 1,000. It's much more concentrated in about 12 centers of excellence as a number of centers of excellence in Germany where things are concentrated. So the dynamics in the segments may differ a little, but I think there is in common in some of these countries, there's a higher attachment to the centers of excellence and social media channels.

And I think the dynamics in Brazil may be different yet. But as Eric pointed out, our teams have a lot of experience working in all of the different regions in states of Brazil, understanding the dynamics of patient organizations, the importance of local governments and advocacy groups, how do you establish access, what's necessary to leverage the utilization process or early treatments while still trying to get access and reimbursement to see that in [indiscernible]. So I think this is where having that experience in understanding the dynamics unique to certain geographies will allow us to have early success as we launch.

Maybe one follow-up is that you mentioned earlier that about 80% or maybe slightly over 80% of centers of excellences in the U.S. have prescribed Sephience. So maybe just thinking about the remaining 20% of the pie, what do you think they need to see in order for them to get on board Sephience proven efficacy and excellent tolerability and safety profile.

Yes, I'll let Eric talk about that. I mean we -- because this is a unique dynamic at this age launch to be in 80/20 instead of the 20/80, but Eric...

I mean to Matt's point, it's remarkable to have after 5 months, 80% of your centers that have written multiple prescriptions in the U.S. And we have seen the same dynamics in Germany in these centers of excellence. So that's very encouraging. It means that the efficacy -- clinical efficacy of the product in the real world experience is playing out.

Of course, there's always going to be a few laggards. We have a number of key things that we're doing in the field. We have frequent touch points with all of the centers of excellence on either daily or weekly basis. And with those few laggards, we're doing a number of key medical education programs that peer to peer. We have newly published data that is now going to be in peer review, obviously, with the affinity, the long-term extension, Amplify the mechanism of action, a number of these things that we can bring forward.

But I think one of the main points is patient demand, social media, and the push through that these inquiries will have on these centers to accelerate adoption. I think these patient testimonies from other centers that have utilized this will move those remaining few laggers.

Our next question comes from Luke Herrmann with Baird.

Just another on vatiquinone. Are you able to share some additional color on your base case for the external control matching strategy in order to maximize the likelihood of a statistical hit. And I guess, what are the key features you need to align on with FDA at this point?

Thanks for the question, Luke. Obviously, we have experience from the MOVE-FA study of having done this natural history match on key factors that we had aligned with FDA on as part of the statistical analysis plan and had 50% slowing over 3 years relative to natural history. So I think we've got a good sense as does FDA on those matching factors and the things exactly that you'd expect, age of onset based on mFARS scores, things that get at making sure that you have similar baseline severity as well as similarities and things that drive progression.

Again, we're fortunate to be in a situation where there's regulatory precedent for using these natural history matching with the National Registry. We've done it ourselves and FDA is familiar with it. So that really helps. So really what comes down to the alignment is making certain that the FDA is comfortable with this matching approach, details of the model, statistical aspects of the model, how we're going to do the analysis and duration of study and subject numbers.

So really those key points. So as we move down what is a relatively unprecedented path for a neurological disease having this opportunity to do it have an open-label [indiscernible] comparison to allow for us to file. We just want to make sure that everything is buttoned up from whereas line as much as possible prior to starting that.

Our next question comes from Joon Lee with Truist.

Congrats on the strong quarter. This is [indiscernible] on for Joon, just a couple from us. So firstly, Palynziq has an upcoming PDUFA for adolescent coming up in the next week. Is that something that we should be paying attention to? And just quickly on the gross to net, the move towards the 15% to 25% range you previously mentioned, should we expect that this year?

Thanks for the questions, [indiscernible]. So the first question is the potential label expansion of Palynziq to adolescents. Look, I think as we've talked about, one thing that's becoming clear to us is suffices reaching that point where it will become the first line of treatment. It will be the first line of care, given that it is oral, convenient, strong safety tolerability profile and demonstrated efficacy across the full spectrum of patients.

And I think even if Palynziq is approved in younger patients, I think given its history of safety tolerability challenges with administration duration for lengthy time for titration to get to a dose that may be effective and safe. All of those things, I think, will keep it as sort of second line behind finance.

As you can imagine, for adolescents, there would be a lot of benefits to being having an effective drug that's oral, strong safety and tolerability record versus one that may have more challenges in that regard. Your question on GN, 15% to 25%, Pierre, do you want to follow up on that?

Yes, absolutely. I think, as I mentioned, we're on the lower end, and it will take multiple quarters to reach the top bank. So it's going to be a slow and it will not be our expectation to hit the top end of this year.

Our next question comes from Joseph Schwartz with Leerink Partners.

It's Jenny on for Joe. Just one question from us. At R&D Day, you highlighted your new splicing and inflammation programs. what are the first clinical proof-of-concept milestones that would provide validation and/or how do you view the catalyst path for these programs? And how are you prioritizing capital allocation as you target cash flow breakeven for these.

Thanks for the question. I think, first of all, in terms of splicing, we can confidently say that has been a well-validated platform. I think certainly, both rise the success of Evrysdi and the success of votoplam certainly substantiates the potential for Splicing to deliver transformational and very valuable therapies. So I think as we move through in terms of specific program validation, as we move forward, we look -- as I mentioned in the prepared remarks, we look forward to bringing that the MSH3 molecule to development candidate status this year and then as quickly as we can trying to get that into the clinic.

So the next step really is making sure we have all the necessary preclinical work done in IND-enabling studies done to allow us to move that into the clinic. Similarly on the inflammation proptosis platform. There, we've got some clinical stage programs, as we talked about being able to move into Phase I within our NLRP3 inhibitor program, which we expect to do by mid-year the next big stage gate there are your typical Phase I type things of being able to understand the safety and the pharmacology.

We also have the potential to start the Phase II program for the D2H inhibitor this year and in the early stage programs I highlighted both the Parkinson's ferroptosis program as well the NRF-2 activator program and both are nearing that DC stage. So we're still at that point where we're ticking the boxes to make sure we have all those gating nonclinical toxicology and pharmacodynamic study is done to allow us to move those forward. So we look forward to hitting those milestones and being able to get these programs forward as quickly as possible.

Pierre, do you want to talk a bit about capital allocation?

Yes. I will mention a few things. Number one, we demonstrated over the last few years that we're very disciplined an OpEx management. You see revenue increase and strong space launch and OpEx over the years. We've been very disciplined. We'll continue to be that's important to us to reach cash flow breakeven and be cash flow positive after that. we are highly focused on the momentum of fiance and expanding globally. That's important to us.

You mentioned R&D Day and our R&D programs, which will continue to develop both on the splicing platform as well as ferroptosis and information. And finally, we're open to look at the opportunities, as I mentioned, on ways to accelerate top line growth.

Our next question comes from Paul Choi with Goldman Sachs.

Congrats on all the progress. And I also wanted to ask on the early-stage pipeline as well, Matt, which is just with regard to your FRP program, as you mentioned. Is there a particular area of fibrosis, which, in your view, allows for the shortest clinical development time and time to market. And then for your NLRP3 program, I think you guys were still in the stage of indication selection. Can you maybe just comment on what your latest thoughts are on that program and just sort of where your target focus might be.

Just to clarify your first question is, I mean NRF2 program, is that correct?

Yes. Just sort of what area of fibrosis or fibrotic disease, I guess, provides you the sort of the easiest or shortest path to market.

Yes. So I think the way we're thinking about it for both programs is 2 things, right? One is where can we see overlap between the target pathway, the mechanism drug? and disease states. And then the second is how do we think about that in terms of efficiency and moving things forward. When you talked about the R&D day, how our NRF2 activator program is pretty unique in that it has a differentiated mechanism of action that has what we like to consider comprehensive NRF2 activation which modulates both the cellular stress response as well as inflammation pathways.

So we're able to see effects and as we share data from both kidney studies, and I believe lung studies as well showing great activity and benchmarked to others. So I would say at this point, well, we're still doing indication selection there. We should have a beat on that soon. But where we want to go is understand where there's been a clear evidence that by targeting NRF2 the way we can that we can deliver clinical effect.

And obviously, we're going to be in the rare disease realm. And as usual, from a developability standpoint, we'll look for things that have allow us to have objective biomarkers or clinical effect that can not only facilitate the development program, but also get to that acceleration piece you talked about, get confidence early that we're having a meaningful effect that could either open up an accelerated approval portal or allow us to move forward faster in initiating a registrational study.

On the NLRP3 front, as we shared at the R&D Day, PDC612 has demonstrated really strong potency due to its selectivity and we benchmarked it to a number of of compounds as we shared that day with favorable potency. We talked a bit about that day and continue to believe that our initial targets will be lung inflammation of fibrosis, given the overlap between the NLRP3 pathways and lung fibrosis. So we are still honing on final indications, but I think our first goal will be a pulmonary fibrotic conditions.

Thank you. I would now like to turn the call back over to Dr. Matthew Klein for any closing remarks.

Thank you all very much for joining the call today. 2025 was a really successful year for PTC. We're excited about the Sephience launch, the R&D platform, our strong financial position. all of which really sets us up for great success in 2026 and beyond. Thank you all again, and have a great evening.

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.

Good morning, everyone. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. At the podium, we have the CEO of PTC Therapeutics, Matt Klein. I'll now pass the mic to Matt for a short presentation, followed by a live audience Q&A.

Thank you, Brian, and thank you, everyone, for joining us this morning. Last year, I stood on this stage and talked about how 2025 was going to be a year of focus and execution for PTC, positioning us for future success. We set a number of objectives for the year, including gaining the first approvals for Sephience for the treatment of children and adults of PKU, ensuring a strong start to the Sephience global launch, continue to drive revenue and effectively manage expenses as we continue to move the company towards cash flow breakeven and advance our innovative early-stage programs, including the votoplam Huntington's disease program. I'm pleased to report that we achieved all of these objectives.

We gained approval for Sephience in the U.S., Europe, Japan and a number of other countries in just 6 months' time. The Sephience launch is off to a strong start with broad uptake across all key patient segments. We had another year of outstanding revenue performance and effective expense management and closed the year with over $1.94 billion in cash. And last May, we shared the positive results from the PIVOT-HD Phase II study of votoplam in Huntington's disease patients, as well as advance a number of our early stage programs, including those from our RNA splicing platform.

Overall, 2025 was a year of many significant successes. This morning, I'll review our 2025 performance and provide an outlook for what we expect to be a very exciting 2026. As I'll be making forward-looking statements this morning. I refer you to this slide as well as our recent SEC filings for a full explanation of risks and uncertainties.

I'll start with our 2025 revenue performance. Our revenue for the year was $823 million, exceeding our guidance of $750 million to $800 million. This outstanding revenue performance included $588 million of product revenue, driven both by our Sephience launch revenue as well as our more mature products.

For Sephience, in the fourth quarter, we achieved $92.5 million in net revenue, bringing the total since launch to $112 million. As of December 31, we had 946 patients on commercial therapy worldwide. And in the U.S., we had 1,134 patient start forms with a payer mix of approximately commercial. We continue to see contributions from every patient segment as well as the full range of age groups from infants to older adults, as well as the full spectrum of disease severity.

In addition, while still early days, we're seeing very high prescription refill rates and very low discontinuation rates with low single-digit percent in the U.S. This strong start to the Sephience launch reflects both the highly differentiated safety and efficacy profile of Sephience as well as the outstanding performance of our field teams and our PTC Cares case management team. I'll be providing more details on the Sephience launch and the overall market opportunity later in the presentation.

As we move into 2026, we're providing revenue guidance of $700 million to $800 million. We expect the majority of this to come from Sephience as we continue the strong launch momentum with smaller contributions from our more mature products. I want to emphasize that our product revenue guidance for 2026 does not include Evrysdi royalty revenue as we sold the remaining portion of the Evrysdi royalty for $240 million in milestones to Royalty Pharma as we shared in December of 2025. This product revenue guidance represents a 19% to 36% year-over-year growth from our product revenue of 2025.

In terms of expenses, we're providing OpEx guidance of $680 million to $720 million. The midpoint of this guidance represents an approximately 6% decrease from the midpoint of OpEx guidance in 2025. Looking at product revenue guidance and OpEx guidance, it's clear that PTC has the potential to reach cash flow breakeven in 2026, which would be a significant milestone for the company and position us for the potential of sustainable profitability in the future.

In 2026, our main focus is going to be continuing the strong sufficed global launch momentum. We also look forward to continued progress in the votoplam Huntington's disease program as well as to a number of our early-stage R&D programs. We'll also continue to work to move the company towards reaching that significant cash flow breakeven milestone.

Let's dig deeper into this 2026 outlook, starting with Sephience. As we've discussed, Sephience is the foundational product for PTC's near-term growth. The launch is off to a really strong start, with over $112 million in revenue and over 940 patients on drug within just the first 5.5 months. And every sign points to this strong momentum continuing into 2026 and beyond.

One of the factors supporting the broad uptake of Sephience and its potential to become the standard of care for PKU is its highly differentiated dual mechanism of action. This dual mechanism of action allows for the benefit in the -- for the full spectrum of PKU patients. even those with more severe subtypes known as classical PKU. The first mechanism of action is Sephience's ability to serve as a precursor to BH4, which is the cofactor for phenylalanine hydroxylase, the enzyme implicated in PKU pathology.

Now if one were to give BH4 itself, whether in the form of KUVAN, branded or generic, it gets oxidized in the GI tract and a lot of it gets excreted. So there's very little that is bioavailable to the cells. This is not the case for Sephience. Sephience is rapidly absorbed from the GI tract intact, actively transported into the cell where it's converted into BH4, achieving very high levels of intracellular BH4.

This is the reason why we continue to see in all of our clinical studies, that any individual who has a benefit from KUVAN, either branded or generic, has a much greater benefit from Sephience.

The second mechanism of action is Sephience's ability to serve as an independent chaperone, binding to the phenylalanine hydroxylase enzyme and stabilizing its shape which then augments enzyme function. It's this second mechanism of action that allows Sephience to have meaningful benefit in individuals with what is known as non BH4 responsive mutations such as those associated with classical PKU. The evidence for the broad meaningful benefit that Sephience can provide continues to grow.

We recently shared the results from the AMPLIFY head-to-head study comparing Sephience with BH4. In this study, as in all of our previous studies, we again see that any individual who has a benefit from KUVAN, branded or generic, has a much greater benefit from Sephience. In this crossover study, Sephience provided in over 70%, 7-0%, greater lowering in phenylalanine as compared to BH4.

These results not only resonate with prescribers, but are also very important to payers and HTA authorities. We've also recently shared the continued evidence of Sephience's ability to allow for diet liberalization. Probably the most meaningful endpoint for individuals with PKU. In the fee tolerance protocol of our affinity long-term extension study, virtually every subject was able to increase protein intake while maintaining control of phenylalanine. 69% of participants were able to reach or exceed the recommended daily protein intake for an individual that does not have PKU.

Now why these numbers sound great, and they certainly are great, perhaps even more meaningful are the stories we continue to see on social media of kids and adults with PKU being able to enjoy foods they never had before, like hamburgers and pizza and steak. We even see stories of moms who say, for the first time, they're able to have the same breakfast with their child. These are incredibly impactful stories and probably provide no greater endorsement of the potential transformative benefit that Sephience can provide for individuals of PKU.

We're also continuing to see important effects on other meaningful aspects of disease, including improved cognitive function and mood as well as improvements in a number of different aspects of disease-related quality of life. Importantly, all these meaningful benefits are being delivered in the context of a consistent safety and tolerability profile, which is quite favorable.

When one considers the highly differentiated Sephience mechanism of action, the evidence of meaningful treatment benefit across all age groups and disease severities and the consistent favorable safety and tolerability profile of Sephience, it's clear that Sephience has the potential to address each key segment of the market including individuals currently on treatment, those that have tried and failed existing treatments and those that are therapy-naive.

Thus, the total addressable market is nearly the entire population of PKU patients, which is 17,000 in the U.S. The evidence of early penetration into each of these segments thus far in the launch, supports that physicians similarly see the potential for Sephience to be first-line therapy for PKU and become the standard of care.

This market size, the significant remaining unmet need for PKU patients, even though they are approved therapies and our commercial team's ability to execute all add up to a very large potential commercial opportunity for Sephience. In 2025, our launch efforts are really focused in the United States and in Germany. And as we move into 2026, we expect to significantly expand the global Sephience footprint. We're expecting to launch in Japan in Brazil as well as a number of other countries around the world and will also continue to leverage early access programs where possible. Our customer-facing teams around the world stand at the ready to be able to deliver Sephience to any individual with PKU who may benefit.

So in summary, the Sephience launch is off to a really strong start. We see no evidence of this momentum slowing as we move into 2026 and beyond.

We also expect a number of activities from the votoplam Huntington's disease program in 2026. Votoplam is the leading oral disease-modifying therapy in development for Huntington's disease. Votoplam is a highly differentiated molecule that was discovered from PTC's splicing platform and was partnered with Novartis in December of 2024.

In May of last year, we shared the results from the positive PIVOT-HD Phase II study of votoplam. The study met its primary endpoint with durable dose-dependent lowering of blood Huntington protein levels. Favorable and dose-dependent clinical effects were demonstrated at month 12 relative to placebo. And at month 24, we demonstrated dose-dependent significant effects relative to a well matched natural history cohort.

In addition, at month 24, dose-dependent effects on NFL were also recorded. Importantly, votoplam continues to be demonstrated to be safe and well tolerated with no evidence of NFL spikes. In the first half of 2026, we expect the next data update from the open-label extension of PIVOT-HD as all participants cross the 24-month time point.

In the fourth quarter, an end of Phase II meeting was held with FDA where alignment was reached on the Phase III study of votoplam. This study can serve as a registrational trial or in the context of accelerated approval serve as the confirmatory study. The INVEST global HD study will be a double-blind randomized controlled study with target enrollment of approximately 770 participants from over 30 countries.

The primary endpoint will be change in the cUHDRS scale from baseline up to 36 months and an interim analysis is planned for both efficacy and futility. Per the votoplam licensing agreement, Novartis will be responsible for the conduct and full funding of this study.

At the end of Phase II meeting, we also discussed with FDA the potential for accelerated approval. As expected, FDA was supportive of the potential accelerated approval pathway given the significant unmet need for Huntington's patients. Based on the evidence of safety, early clinical effect and biomarker effect, we remain enthusiastic about the potential for votoplam to be the first approved oral disease-modifying therapy for Huntington's disease.

I'll now provide a brief update on the vatiquinone Friedreich's ataxia program. Vatiquinone is an oral small molecule with demonstrated safety and efficacy in both children and adults with Friedreich's ataxia. The MOVE-FA Phase III study demonstrated a significant vatiquinone treatment effect on the upright stability score, the most sensitive and meaningful endpoint for children and adolescents with Friedreich's ataxia for whom there remains a significant unmet need.

In the long-term extension study from MOVE-FA, significant effect was demonstrated on slowing of disease progression with a 50% slowing of progression relative to a matched natural history cohort after 3 years. Similarly, in the analysis of the long-term extension of an earlier placebo-controlled study in ambulatory and nonambulatory adults, vatiquinone similarly demonstrated a significant effect in slowing long-term disease progression.

Following the CRL for the vatiquinone NDA, we held a Type C meeting with FDA in December to discuss the potential next steps in the vatiquinone program. Discussions with FDA are ongoing at this time as the agency has asked for additional data and information from the MOVE-FA study before providing guidance on the next steps.

And finally, in 2026, we look forward to advancing our early-stage R&D programs. As we shared at our R&D Day in December, we have a number of innovative programs from our 2 scientific platforms, RNA splicing and inflammation and ferroptosis.

PTC pioneered the field of oral small molecule splicing the success of Evrysdi for spinal muscular atrophy and the early successes of votoplam for Huntington's validate the potential for the splicing platform to produce highly impactful and valuable therapies for diseases of unmet need. Our teams have made a number of learnings from the early programs that have fortified our position as the leaders in small molecule splicing.

Our learnings have allowed us to significantly expand the universe of potential small molecule slicing targets far beyond what was ever imagined. In addition, we've significantly enhanced our small molecule chemical library with what we consider splicing centric chemical motif. We've combined our decades of know-how the expanded list of potential splicing targets and our chemical library with advanced bioinformatics to develop PTSeek. PTSeek is a proprietary platform engine that will facilitate and accelerate the next set of small molecule splicing programs for a variety of indications.

As we have discussed, we expect the splicing platform to be a source of both PTC developed and commercialized therapies as well as a source of strategic partnerships for noncore therapeutic areas such as oncology and larger neurodegenerative diseases. The PTSeek approach has already yielded a number of exciting and innovative programs that will look to advance in 2026, including our MSH 3 program for Huntington's disease and myotonic dystrophy and earlier stage programs such as our sickle cell disease program and neurodegenerative disease program.

We also look forward to advancing programs from our inflammation and ferroptosis platform. As we discussed at the R&D Day in December, this platform includes a number of innovative programs with differentiated molecules that target aspects of inflammation in oxidative stress closely linked to a number of different disease pathologies, including our ferroptosis Parkinson's disease program, our NRF-2 activation program and our NLRP3 inflammasome program.

In conclusion, over the last 2 years, we have transformed PTC into a strong, innovative execution-oriented global biopharmaceutical company. With our robust global commercial engine, including our foundational products, Sephience, our innovative R&D platforms, including our RNA splicing platform and our strong financial position with over $1.9 billion in cash and the potential to reach cash flow breakeven this year. We are well positioned for success in 2026 and beyond. Thank you.

Thank you, Matt. Thanks so much for the presentation. Let's start off with the Q&A. For those who are in the audience, if you have any questions, feel free to raise your hand. For those joining us virtually, you can submit questions on the portal.

Matt, I want to start off with just the fourth quarter number for Sephience. Where are we now in the launch? What is in line with what you expected before the launch? And were there any surprises now that you're looking back at the third quarter and the fourth quarter performance?

Thank you, Brian. Let's make no mistake about it. This launch is off to an incredibly strong start with $112 million in just 5.5 months. Now we understood from the beginning that there was a significant opportunity for Sephience.

As we've discussed and shared in the presentation, PKU in the United States, there's a population of approximately 17,000 individuals. While there are approved therapies, both have significant limitations such that there remains a significant unmet need for PKU patients.

Our data package substantiates what we understood to be true from the mechanism of action that we have the ability to provide benefit to the full spectrum full spectrum of PKU patients, including those with more severe forms of the disease as classical PKU. I go back to this slide on mechanism of action, which nicely explains how based on the ability to be a more bioavailable precursor we're able to provide superior results than just giving BH4 alone.

And then we have the second mechanism which then allows us to address more severe mutations, including those that have the most severe genotype, phenotype scores. And then importantly, this is an oral once-a-day therapy that's very well tolerated, easy to use and has a strong safety profile.

And I'd say the last part, Brian, is our team's demonstrated ability year-over-year to successfully commercialize, let's just say, more challenging products that don't have the efficacy differentiation of Sephience. So when you put that all together, we believe this could be a big opportunity, and we still do, and we're off to a strong start. And look, we see no evidence of this launch momentum slowing.

And I'd say in terms of surprises, I think only -- I'd say the only thing we're seeing now that maybe we didn't expect to see right away is the uptake by adult therapy naive patients. We knew that, that's a significant unmet segment. We knew ultimately, we would penetrate that segment, but I think we're seeing that earlier in the launch than we thought.

And so when you think about those segments, I highlighted those on existing therapies, those that are therapy naive those that have tried and failed. We're penetrating each of these segments. And the fact that we're penetrating each of these segments, and we're hearing time and time again from physicians their desire to try every 1 of their patients on Sephience tells us that we're just at the beginning of this launch, and we've got a long way to go in penetrating each of these segments, and that's what gives us the confidence that this momentum is going to continue far into 2026 and beyond.

And that's true for the United States. And as we continue to launch in more and more countries around the world and that global footprint increases, again, that's why we say we see this as a very significant potential revenue opportunity.

Great. I think we should just go ahead and address one of the most frequently asked question this morning from their press release. Can you walk us through your thinking behind the guidance that you have laid out for 2026?

I think there's certainly that question of what do you expect coming from the DMD franchise for 2026? And certainly, there's also a question of whether there's a different way of thinking in terms of your way of guiding for 2026 versus how you guided for 2025. So maybe just walk me through those pieces so that people understand how you're thinking about the guidance number as we're heading into 2026.

Yes, absolutely. So look, we start 2026, what do we know to be true. We know that and we fully expect continued momentum from the Sephience launch continued linear growth as we're seeing in the Sephience launch. And we are also expecting to unfortunately see some continued erosion in the DMD franchise. Emflaza now has 6, 7 or 8 generics in the market. I'm very proud of the revenue that we've been able to maintain probably a level of revenue that people didn't expect.

And similarly for Translarna. I mean we had the withdrawal in Europe that happened at the end of the first quarter in 2025. And we've since seen an erosion of revenue not only in Europe but in areas outside of Europe, and we fully expect then erosion to continuing the DMD franchise.

What I can't say for sure is how quickly that erosion is going to occur, what's the extent of that erosion and also what's going to be the upward trajectory in the Sephience launch. We're 5.5 months in, we're still relatively early. And I think that's why most folks don't typically guide for revenue -- product revenue in the first year of the launch. We have to understand the dynamics better.

But again, what do we know for sure? We see no signs of slowing in the Sephience launch. We see the evidence of the ability to continue to penetrate all those key segments and for this to be a very, very large opportunity, and we expect to see continued erosion in the DMD franchise.

So the specific product revenue guidance of $700 million to $800 million reflects sort of what the knowns and the unknowns. And as always, as the year goes on and we learn more and understand where we find guidance. U.S. had as compared to last year. If you remember, in 2025, give really wide revenue guidance because, again, we sat there at the beginning of the year, expecting a significant decline in the DMD franchise that, quite frankly, didn't materialize as much as we thought.

And if that's the case this year, then look for us to adjust revenue up. But again, we can only deal with what we know to be true, which is the strong potential for Sephience and the declining contributions of the DMD franchise.

And how much potential erosion could we expect from the DMD franchise? And how does that balance out with -- the -- I think you said that there's no evidence of the launch momentum slowing. So how do we estimate both of those?

Yes. Again, we gave the guidance of $700 million to $800 million. I'm not going to be able to give you any more exact numbers. For Emflaza, we said all along that rare disease drugs typically don't fall off a cliff. They have a slower erosion, but we're starting to see sufficient numbers of generic entrants that, that could slow more.

And I don't know that anyone has heard of a drug not being licensed in Europe and still having the revenues that we're having with Translarna, which makes it really hard to predict what's going to happen next. As we said, we expect that could decline over time. We expect generic entrants in other regions of the world, we can see continued decline. We don't have exact numbers on that.

Brian, I think our range was the best effort to understand there's going to be puts and takes in the revenue. We're going to continue to do our best and get it, as we always do, to drive revenue as far and as fast as possible. And as we learn more -- as we move into the year, we'll continue to refine the guidance.

And then when it comes to the fourth quarter number, can you talk a little bit about the holiday impact that you potentially saw. Was there a holiday impact? Because I remember that coming out of the third quarter, that could be one of the swing factor when we think about the number. So what did you see in the fourth quarter?

We did see impact. We did see some impact because for the obvious reasons, right? Clinics in the U.S. tend to close the week of Thanksgiving and the 2 weeks around Christmas and the New Year.

We also heard that there were a lot of dietitians and physicians who said, look, there's so many meals and holiday things. This is not the context in which to introduce a therapy, we'll wait until the new year. So I think what makes the revenue performance in all the more impressive is it's in spite of those small holiday headwinds. Again, which is why we're confident that we're going to continue to see growth and success in 2026 and beyond.

Okay. In your prepared remarks, you said that the payer mix is currently at 70%. I remember last year, you have guided around 65% to 35%. That's the mix ultimately you think will land at for the Sephience franchise. Can you comment on the gross to net here? And are we still moving towards that 65%, 35%? And when do you think we'll ultimately get there?

Yes. The short answer is yes. We are still moving towards that 2/3, 1/3, which is the payer mix profile for PKU. And then again, we'll expect the gross to net to move into that neighborhood that you typically see somewhere in the 20% to 25% range. We're clearly not there yet, but that's where we think we'll be when we reach steady state.

Any questions from the audience? Okay.

There is a question about whether -- how we should think about the trajectory? I think there's always a question of, is there a bolus effect. What's your take on that? It's -- I know that we only have 2 data points, right? So -- and what's your take on that? I'm really curious how we should think about that.

Yes. We have 2 data points that make a very nice line that we're intent on continuing that trend. Look, I think bolus means different things to different people. Did we see a lot of enthusiasm early on because there's a lot of individuals wanting to get on a therapy that could safe, well tolerated and allow them to change their lifestyle? Absolutely.

But to me, a bolus means you had a shot of patients in and now it's going to just die down. And that's not what we're seeing at all. I think we saw a lot of early enthusiasm and we're seeing continued enthusiasm. Look, I go back to this observation that we're seeing penetration into each of these segments in a really nice -- and we haven't given the exact numbers. I think it's still too early to do so.

But the fact that we're touching each segment now, and we're seeing very high refill rates and patients staying on the drug suggest we have a very long way to go in penetrating each of these segments. And again, we're also hearing from so many physicians their intention to trial all of their patients on Sephience. That's becoming the first-line therapy. That doesn't mean all our patients are going to get tried on therapy tomorrow or in January.

It means this is going to be a long goal of continued penetration with what we're seeing is very high compliance adherence rates, which makes us bullish about the overall opportunity over time.

On Slide 17, you have this fantastic slide. You're comparing the geographical expansion of the Sephience franchise compared to 2025. Outside of the U.S. Just when you look at the international contribution, which geographical region do you think will make the most sense for investors to focus on? Which one has best potential to give you maximum growth potential?

I think, honestly, Brian, the strength is in the breadth and the fact that we have demonstrated capabilities in so many different countries and regions. So clearly, if you think about rare disease markets, the 3 largest countries are thought to be the U.S. Germany and Japan. I think those will continue to be important markets for us.

But we've also done very well with our other products in Latin America and in Brazil, in Russia and the Commonwealth of Independent States, Middle East and North Africa. And we've got teams in each of these countries that are well experienced in both regulatory in regulatory, commercialization and dealing with governments and payers.

And that's why we're attacking this from 2 different angles. One is, okay, where are countries where we can get approvals launch quickly and we think can be very valuable markets, such as the U.S., such as Japan, such as countries in Europe, where can we leverage early access mechanisms where we can get patients on maintain the narrow pricing corridor that we've already said very clearly is a priority while pricing and reimbursement discussions are ongoing.

So again, yes, there's -- again, I would say the most valuable markets are likely to be the U.S., U.S., U.S., and then Japan and parts of Germany and other areas in Europe. But the strength here is in the breadth and our demonstrated capabilities to really execute and commercialize therapies worldwide.

And I'm very proud of what the company has been able to do over the years with Translarna, but I'd point to that and say that's not an easy out. And the success that we've had with Translarna globally, we're putting Sephience to the hands of those same teams and that just bodes really, really well for the global prospects.

I have a question in my e-mail inbox. That question is related to your Huntington's partnership. How should we think about the accelerated approval path? You could be at an early stage of understanding what the agency wants. But help us maybe paint a little bit about what we could expect.

Absolutely. I think the first point, which is probably clear to everyone, is that the agency is, of course, interested in leveraging these types of pathways for significant diseases of unmet need. We had talked about before this FDA meeting that our expectation was the neurology division, which has leveraged this pathway for other severe diseases like ALS, like Alzheimer's, would likely be open to doing so for Huntington's and that's what we confirmed in our meeting.

Now FDA knows and we know that there's the next data readouts coming in the first half of the year. And I think both the PTC and Novartis teams remain similarly enthusiastic about the potential for accelerated approval and remain committed to trying to get votoplam to patients as quickly as possible.

We'll clearly undertake the analysis in the spring, look at the data that we have in terms of evidence of target engagement with the dose-dependent blood Huntington protein lowering, having evidence of placebo-controlled benefit in the short term, then being able to have evidence in the long term against natural history, which was a strategy that was prespecified in the study protocol.

Bringing that all together as well, quite honestly, is the legacy of Evrysdi, which was another oral small molecule splicing therapy that came from our platform that's well known to the agency and being able to provide a safe and efficacious therapy for severe disease. So that's how we think about it. And I know the Novartis' team's comments have been very clear. They're enthusiastic about starting the INVEST-HD study as quickly as possible.

Why? Because if we're thinking about an accelerated pathway, getting that price potential confirmatory trial started is really smart. And in the event that the accelerated approval portal isn't open with the PIVOT long-term extension data there will be interim analysis in INVEST-HD that could allow for accelerated approval. And then, of course, just starting that study sooner gets to the finish line sooner if there's no accelerated path.

Great. Well, that's all the time we have. Thanks for joining us. Thank you.

Thanks very much, Brian.

[Audio Gap] My name is Geoff Meacham. I'm the senior biopharma analyst here, and I have Jarwei Fang from my team on here as well. We're thrilled today to have PTC Therapeutics. With us on stage is Matt Klein, CEO. Matt, welcome. Good to see you.

Thanks Geoff. Great to be here.

So lots of questions on Sephience and on your R&D Day. But maybe just for those on the webcast, just give us a bit of a quick background or overall, and then we can get right into it.

Yes, absolutely. So PTC is a global biopharmaceutical company. We are focused in rare diseases and other disorders of high unmet need. We have a robust commercial portfolio with 6 products that we market around the globe as well as an innovative R&D pipeline highlighted by our differentiated oral small molecule splicing programs.

2025 has been an incredibly successful year for us, highlighted by the U.S. and EU approval of Sephience, our oral therapy for PKU. As we shared at Q3 earnings, the launch is off to an incredibly strong start. And I'm proud to report we're seeing continued strong momentum into the fourth quarter. And as we've described, this is really a foundational product for PTC that will lead us to cash flow breakeven and beyond in the near future. So really excited to get into the questions and talk about the launch.

Yes. Yes. Let's do that. So when you think about PKU and the 341 patients on therapy, it looks pretty good for the first quarter, right? So what were the -- I know you had from the clinical development, a pretty good idea of the backlog of patients. But help us with kind of the execution of the early part of the launch with the time from diagnosis to script to getting a paid for to delivering drug. How seamless are you? And where could you go?

Yes, absolutely. So we've said all along that we believe that the opportunity in PKU for Sephience was pretty unique. It's a rare disease in the U.S. There's about 17,000 patients. And despite there being 2 approved therapies, there remains a significant unmet need for the vast majority of patients. So in one way, you have a lot of the pillars for commercial success already in place with newborn screening, centers of excellence identified, a well-aggregated patient community, given the fact that there have been previously approved therapies, you have payers that understand the disease. They know how to tie value for a product to phenylalanine lowering.

And this is the context we walked into with Sephience, which is a highly differentiated product. It has a dual mechanism of action, allowing it to have effect in those who may have benefited from the oral therapy, sepiapterin. And also, given the second mechanism of action as a chaperone allows us to have benefit in the more severe patients, classical PKU patients who currently aren't met by the existing oral therapy or not met by the injection therapy, which has a challenging tolerability and safety profile. And so we basically had a drug that could be for the full spectrum of patients which obviously, in this context of 17,000 patients with large unmet need, really represented a big opportunity.

I would also add that we have a commercial team, customer-facing teams that's well experienced in rare disease drug launches. We understand what it takes to get patients on drug, keep them on drug, actively engage with the patient community. We have our PTC Cares team, which is our patient services team, which provides the necessary white glove service from PSF to prescription fill to refill. So that's really the backdrop that we -- the launch had.

And so when we see the early success, for us, it really wasn't surprising. It was really a product of the context of the commercial landscape, a highly differentiated product and a really experienced team. And so with the early launch numbers being so strong, we see continued momentum into the fourth quarter, and we'll obviously give the next update at JPMorgan, but we're continuing to see strong enthusiasm from the prescriber community across all patient segments, including the most severe patients, strong enthusiasm from the patient community and simply looking on social media and hearing patients tell the stories about being able to have foods that they never tried before, what that means to kids, what it means to adults, what it means to families. These are incredibly compelling stories that continue to fuel the interest to be on Sephience.

In terms of the time, you had asked about the time it's taking to get on drug. We're seeing -- in the early days, it's been quite fast. I think we said on average, we're seeing 2 to 4 weeks from PSF to getting on drug. Those numbers are continuing thus far. And again, we think part of that is the the fact that there is this unmet need. We have an experienced team that knows how to get PSFs in, get them processed quickly and get to patients quickly and also knowing how to appropriately work with the prescribers' offices and work with payers and things so that if there are questions or if there is a need for a prior auth, if there's a need for a letter medical exception, that can all get accomplished pretty quickly.

Let me follow up on that. So if you have prior auth or step edits or a letter of exception, are there success stories that maybe to go through that at an accelerated path that you can maybe translate as you roll out across the U.S. and more -- maybe on a more global basis?

Absolutely. So first, a couple of things. One is the prior auths, we're getting a prior auth to the label. The label is incredibly broad. It's basically 1 month of age and above. That's in the U.S.. Outside of the U.S. and Europe, there's no lower age limit. So a prior auth to the label is really easily achieved. In terms of other things that we have in cases of -- we haven't really seen step edit issues. One of the important data pieces we have is our AMPLIFY study. And this was a study we shared the results from -- in September at the International Metabolic meeting. This was a head-to-head study with BH4. It was a crossover study.

So while in our Phase III study, we had very good data on patients who had been on Kuvan previously generic or branded, showing superiority with Sephience, while based on mechanism of action, it's very clear that if you have a response to sepiapterin, you're going to have a much greater response to Sephience. This was a head-to-head study.

So we could say within each subject, how does Sephience perform. And the key data result from that was the fact that we had 70%, 7-0 percent greater lowering with Sephience relative to BH4. So when you have that data piece and you could give that to a payer, it substantiates that we have a highly differentiated therapy and that an individual who may have been on Kuvan brand that are generic or had not tried it is going to do better on our therapy.

So maybe on the differentiated data, you mentioned that there is extreme -- a lot of excitement on social media for Sephience and also among docs that we've spoken with, right? There's a pretty high awareness of the product. I'd love to hear your thoughts on how adoption patterns are looking across different patient segments, whether it be classical versus nonclassical, naive versus switches and how the conversion and persistence may be differ by the different segments of patients?

Yes, absolutely. I think one of the things we shared at Q3 earnings at the first update that was really exciting is in these early days of the launch, we're seeing uptake across every segment. We are seeing some switches from Kuvan. We've even seen switch or 2 from Palynziq, which was not expected early on. We're seeing therapy-naive patients who maybe weren't tried on existing therapies because they had mutations that were thought to be "non-BH4 responsive". And with the data we have showing ability to treat those patients, they're getting on drug.

We've had patients as young as 2 months of age. We had a 79-year-old get on drug. And all of these things really go to say -- go to substantiate this idea that we have the ability to address the full spectrum of disease. We're seeing early uptake from the full spectrum. We're getting patients. We're getting feedback, social media, physicians giving feedback saying, "Look, I'm trying my more severe patients on first." We had one prominent KOL talk about a severe and classical patient had 90% reduction in Phe very quickly. So those stories go a long way in continuing to drive enthusiasm for each of those segments.

I think it's also important to highlight that the early success, the early numbers were not driven solely by Kuvan switches. A lot of people said, oh, that's going to be the low-hanging fruit because, of course, if there's any response at all to Kuvan branded a generic, there will be a more -- a greater response, whether that be in Phe lowering or Phe lowering and diet liberization. And afore, that made that easy population to get on drug because you'd be swapping one once-a-day for a more effective once-a-day therapy.

The fact that these early numbers weren't driven by that really supports the fact that we've got a long way to go in penetrating each of these segments, which again gives us the tremendous enthusiasm that this is going to be a very successful product, certainly when you consider the size of the population and what one would think about in terms of potential penetration for a differentiated rare disease product.

So you mentioned that one of the patients were in their 70s, which is honestly incredible, right? Because a lot of times in these rare disease spaces such as PKU, if patients aren't well controlled, they kind of just drop off and they are not followed up anymore. And the fact that you guys were able to get somebody like that is pretty astounding, really. And then you also mentioned that you have diet liberalization data.

So maybe tell us a bit about how getting those loss to follow-up patients and how dilberalization data, how do they all tie in together to help get patients that maybe you didn't initially plan on capturing so early?

Yes. I think, Jarwei, this concept of loss to follow-up, I think, is a little bit -- I think it's a misconception. I think we hear -- I can say this as a physician. Physicians like to talk a lot about patients are lost to follow-up. And one shouldn't confuse someone not coming to clinic with not being interested in being on a therapy that could help them. The reason they don't come to clinic is because they're not getting something from the clinic that's helping them.

In fact, if you listen to some of the adult patients who are thrown in that loss to follow-up bucket, they'll say, "I'm not lost, I'm right here. I have social media. I actually want to be on a therapy. And I don't go to the doctor's office because I don't want to be yelled that for having Phe levels that are out of control." Many of them will say that while I don't see the physician, I'm in touch with the dietitian because they really help me manage my diet.

And so I think this concept of this loss to followup bucket is a little bit of a construct of docs thinking just because someone doesn't see them doesn't want me they want to be on therapy. Now admittedly, these are -- we would not have thought that, that was the -- I also hate the term low-hanging fruit, but let's just say the first layer of patients to get on a launch, but what it speaks to, I think, is what we knew to be true. that there's a strong desire for folks to get on a drug that can make them feel better because having lowering phenylalanine can help in terms of neurological function, executive function, cognitive function, and as you alluded to, the potential to liberalize your diet.

In PKU, if you're not on a therapy and even if you are on one, really your standard of care is a highly restrictive onerous diet. And so the ability to get on a drug like Sephience that has the potential to allow you to start to scale back from that and enjoy foods that you never enjoyed before. I think it's so hard for us to imagine what that's like. And you look on social media and you see these stories of kid eating a cheeseburger for the first time, a mom talking about being able to have breakfast, the same breakfast with their kid for the first time, these are transformational stories. These are really meaningful testimony that not only supports the benefit of the drug, but also helps spread the word about the benefit and obviously garners tremendous interest for individuals with PKU to try the drug.

Matt, I wanted to ask you, as you think about the globalization of the launch, so Europe, maybe Brazil, Japan, broadly, what are the nuances in each of the markets from standards of care that you'll have to navigate that -- obviously, you have a super experienced commercial team, but that's going to have to be part of the conversation, right?

Yes, absolutely, Geoff. And we spent a lot of time planning for this launch. We said this would be a global launch. And in fact, we launched in Europe and the U.S. almost the same time, which is pretty unique, but we have the infrastructure, the experience to do it. We mentioned that later this year, I know we're in December, but we're still expecting before the end of the year approvals as well in Japan and Brazil, where we have infrastructure and teams ready to go in terms of launch.

And we've been very thoughtful about price corridor. That's something that we take very seriously always. And I think in the era of MFN, it's something that we have to really think about, and we said that we have a price in the U.S. and Germany that are currently on par. We have patients outside of Germany who are looking to get on drug through early access programs, again, where we can help control the price as we go through pricing and reimbursement negotiations. And it may be in certain countries, to your question that we'll have to have discussions around price and volume and are there going to be certain patients who may get covered, may not get or get covered at different levels. And those are all things that we'll navigate in Europe.

In Japan, this is a country where Kuvan and Palynziq, it's called Biopterin and Palynziq in Japan are actually priced at a premium to the U.S. And so again, in terms of maintaining the corridor, we expect to be able to do so there. And in Brazil, our teams have a lot of experience. I mean we market Translarna, Tegsedi, Waylivra there. And so introducing Sephience and understanding the dynamics and our teams there are fantastic. They've already done a great deal of work mapping different clinics, understanding where -- which are the patient groups that we think we could access early on through the judicialization process before we get formal access and coverage. And so we have all of that mapped out.

Do you have to navigate guidelines or quality analyses like as you look to some of these markets?

I think the big thing here is there are guidelines. And again, this is when we talk about coming into a well-organized community, it includes having guidelines in terms of targets for Phe lowering. In the U.S., the target for Phe lowering is 360 like the [indiscernible] leaders. Yes. And so -- and that's why in our trial being able to have 84% of patients get below 360 is really a strong data point. In Europe, it's 600 in some cases. So these are -- so that number is out there, and that's the threshold.

And the other trick question in Europe is, in many cases, medical foods and formulas are. So having, Jarwei, as you mentioned, the diet liberalization data where we had 97 patients -- 97% of patients in the open-label extension be able to liberalize their diet at all, 2/3 of patients being able to get to levels of protein beyond the recommended daily allowance allows us to say when we talk to go through payer negotiations in Europe that we have data to say that this drug will actually lower the need to support medical foods in part. So that becomes an important part of the discussion.

Yes. And just in that same context, what investments -- have you seen the early part of the launch here? And I imagine you see the anticipated future demand, what investments incrementally are you investing in manufacturing, supply chain kind of thing, just to make sure that you can meet the demand?

Yes. This is I'm smiling as I answered it because these are the kinds of things we do in-house, right? We say what -- I'm very -- our teams and management teams what could go wrong from day 1 and have plan A, plan B, plan C, plan D, right? We're always thinking about these things. And so clearly, when we -- as we think about the tremendous potential demand for the drug, having supply is key, right, maintaining supply.

So we've done this. We started with initially API manufacturer. We've now expanded to 2. We're going to be looking to possibly add a third. We have additional drug product manufacturers, making sure that we can meet what we believe will be very strong global demand.

And so maybe thinking about what you mentioned earlier about the different guidelines depending on country. So as you begin to engage with the regulatory entities in each of those geographies, what part of the data packages of Sephience do you think will be important to highlight? Would there be differences in Japan versus EU versus Brazil and...

Yes. I think one of the beauties of the Sephience data package -- of the regulatory package is just how strong the data are. I mean it's -- we look at it and see the primary endpoints and secondary endpoints with less than 0.0001 significance, right? I mean that's -- the whole package is so strong and the fact that we can -- we have data that speak to Phe lowering being incredibly strong, Phe lowering across the full population, the proportion of patients, we -- over 75% in the trial would have met the definition of responder with over 15% reduction.

Then being able to bring in the guidelines, 84% getting below 360 micromolar per liter, then the diet liberalization data being able to show this proportion of patients has significant lowering and being able to say that we're seeing these benefits in every age group. So in a way, no matter what a regulatory agency may want to see, I think we have the luxury with the strength of this data package to be able to address any concern that comes at you. And I think we've all been around long enough. That's a pretty rare situation to be able to do that. And that's part of why this has been so exciting for us.

And I think earlier, it's apparent that excitement for Sephience on social media is quite large. And -- but maybe help us understand how -- I don't want to say ramping, but how wide is the awareness perhaps on a global scale, right? Is it just U.S.-centric? Or will social media help drive awareness of Sephience and its benefits on a global basis as you guys begin rolling out?

So the short answer is it's strong globally. In the U.S., we've done a lot of work. We've got -- and part of this is the drugs incredibly -- has an incredibly strong track record thus far. And there's no better spokesperson for the drug than someone who's been on it and had benefit. And so it's 2025, right? Social media and patient-to-patient communication is a very, very strong component of -- I'll put marketing in quotes, but just getting the word out about the therapy.

But we're seeing as well that there's well-aggregated patient communities globally. We've been -- we went to the ES PKU meeting. Our teams were there in Hamburg, Germany in September, a very well-organized community in Europe. And then in each country in Europe, there's PKU groups. And again, I think this is something that having an experienced team that's a patient engagement team, global patient engagement team and understanding how important it is to work with the community and work with the community in a way that's not really -- it's not only about Sephience, it's about truly helping the community, helping with disease awareness, understanding what's important. All of those things go a really long way in igniting patient awareness and enthusiasm.

Matt, I want to ask you just -- you have some very good market data from the entire clinical development path and then the duration of therapy. But are there other insights you can gain from pre-approval that the development, things like what helps to keep people on compliant persistence rates, things like that?

Yes, absolutely. So we know that what really helps with adherence is one, do you feel better, which I know sounds obvious. But for a lot of individuals with PKU, they will tell you that their brain is like a Phe monitor. And when their levels get different from what they're used to or they go higher, they'll have brain fog. We had one individual who is speaking with us who said, she knows on days that her Phe levels off. She just used the GPS to get home from work, which just tell you, they know things.

The other part is knowing the Phe levels lower and then, of course, diet liberalization, being able to liberalize diet is incredibly important. And we're continuing to garner data as well. For example, at the International Metabolism Meeting in Kyoto in September, we presented some QOL, quality of life data that included evidence of significant benefit after a relatively short period of time on executive functioning, on cognitive function, on mood. And these are things that are really, really important for individuals with PKU.

Yes. Makes sense.

So Matt, maybe thinking about the strategy of -- or maybe the future development of PKU treatment. Obviously, with Sephience, that's a novel new asset that's being marketed now. But there are other mechanisms such as SLCA or SLC6A19 my gosh, what a mouthful, inhibition that may be coming. Maybe help us understand where that might fit in the paradigm of PKU treatment and how maybe it may even be paired with Sephience use for...

Look, there's 2 therapies targeting that renal transporter of amino acids. I think it's a very interesting approach. Clearly, like most things early on, things could look good, but there's still a lot of questions, for example, what -- given the fact that this is a transporter in the renal tubule that's not only responsible for phenylalanine reabsorption, but all branch chain amino acids an important open question about potential effects of causing depletion of other amino acids that could be important. So that's an open question.

And certainly, the Otsuka trial, I believe, is being conducted now in adults. So there's an open question, will it be in children? What's that about? And their protocol, in fact, allows for using that experimental therapy on top of existing therapies, Jarwei. So I think that answers your question. I think this is envisioned to be something that can be used on top of an existing therapy.

Clearly, a lot to be learned a long way to go. We're also comforted by the fact that we're going to be well into our launch before these products come to market. So I think it could be an opportunity to see how they are on top of Sephience, but I expect by the time they come to market, we'll have very broad penetration.

We do want to give airtime to other parts of the business. But maybe, Matt, if you could talk through just the R&D Day, kind of some of the high-level takeaways, and then we can get into maybe Translarna and other elements.

Yes, absolutely. Happy to talk about the rest of the business. Clearly, the #1 focus for us inside PTC right now is, of course, the Sephience launch and continued execution on that launch because as I said, we think this is going to be incredibly successful for patients and for us.

But we do have other parts of the business, and we do have the R&D Day. And part of that was to basically say, look, I think people have been paying a lot of attention to our focus and execution on the late-stage programs on the commercial front over the past couple of years. But behind the scenes, we've also been doing some work. Our R&D teams have been doing work to advance a whole new set of programs.

I think one of the most exciting things that we were able to share at R&D Day is the incredible, really incredible evolution of our small molecule splicing platform. This 20 years ago, and we started working on small molecule splicing seemed like this radical concept that you would use an oral molecule to affect RNA, basically doing genetic manipulation with a pill seem crazy. How could you ever get the necessary sequence specificity and such? And now that's clearly a very well-validated approach with the success of Evrysdi, which was the first compound we discovered.

Now Votoplam, which is in Phase II, which is the leading oral therapy for disease-modifying therapy for Huntington's disease. And so while the world has been focusing on those 2 drugs and their success, we've been able to make a number of important advances in the lab, the most significant of which is saying, while initially, we focused on a very small as a target for both Evrysdi and Votoplam, we've now found that there's about 256 additional sequences that could be targeted for small molecule splicing. That was something we elucidated. And we've also now gone and seen that we have chemical matter possibly talk to those new targets.

So what we have basically is a highly differentiated, valuable small molecule RNA platform that we think holds tremendous potential to be a really incredibly important source of impactful and innovative therapies that PTC can develop and commercialize, but can also be the source of strategic partnerships because we know, for example, there's important splicing targets in oncology. There's important splicing targets in neurodegenerative disease. And so those may be areas where we're not going to go as a company, but we have certainly the ability to think about strategic partnerships.

So as we think to the future of the company, clearly, we're focused on the Sephience launch and execution there, but we also have sort of a goose that's laid 2 golden eggs already that we've only gotten smarter and better at learning how to leverage for future therapies.

So I guess that's the follow-up is that the filter is rare for you'll keep in-house and opportunities outside of that more likely to out-license?

Absolutely. We shared a number of programs the other day. We shared 5 new splicing programs. They're all early stage, and we have small teams working on those. We also shared programs from our inflammation platform, which some targets that are very familiar to people that we have a very differentiated approach to. And the same thing there. There will be some that will be for us and some.

Do you have a number in mind in terms of the R&D and the D capacity? Is it 1 IND per year? Is it 2? So that used to be an old metric, right, but now people are talking about that.

Yes. Again, I think -- so I think we don't have a specific limit in mind. However, we -- I want to be very clear that one of the things that we've been extraordinarily thoughtful and careful about is managing our expenses. And that's something we're going to continue to do. We've committed the company 2 years ago, I stood up and said we're going to move to get to cash flow breakeven in the near future. I stand by that. We'll update that guidance at JPMorgan.

Again, with a focus on the success of Sephience, that's going to drive our top line. We've said that we plan to reduce OpEx in '26 relative to '25. Very simple math tells you we're going to be getting very close to that point. And we're going to manage our expenses in the earlier parts of the pipeline to make sure that we're not violating that. And I think that's where this model of partnership as well as internal development, balancing that is one way to ensure that we're bringing things forward, but we're not overburdening our expense or our corporate focus.

And as you've had to invest in R&D, manufacturing and have had to acknowledge the MFN. Tell me about your engagement with the administration, how over the course of this year has it evolved?

With the...

White House.

White House?

Usually, that's a large-cap conversation. But you guys are a global company and you've hitting all the right use of elements.

And we're quite aware of these things, right? I mean we have a very -- look, we have a very active government affairs team. We all spend a lot of time in D.C., making sure we're well aware of how specific topics can impact our business. We've taken the approach with MFN, as I mentioned. In fact, it wasn't a stretch because, again, our commitment to maintaining a narrow corridor really was consistent with what one would think about in MFN capacity.

I mean there's other things that are very important to us as well. In rare disease, the renewal of the voucher has been something that's been very important. And with the House passing what we think will be a bill that will get through the Senate to renew the priority review voucher, that's very important to us. There's something about R&D amortization. Those types of things have been areas of active engagement for us as well. So we have been active on all those fronts. I don't expect we'll be...

Probably not on the radar...

Exactly. Yes. I think there's a lot of important things going on right now. I think the FDA, the commissioner has been quite outspoken. He was here a couple of days ago, reaffirming his commitment to flexibility and innovation, explicitly calling out neurology, I believe, as an area where the agency has to be forward thinking, and that's obviously near and dear to us with several things at FDA.

And so we've been quite active, I'd say under the radar. But I think we've been making sure that we partner with the appropriate people where there's shared agendas to ensure that we can not only help our business but the global community.

So I think that would be a great segue over to Votoplam and the Huntington's disease program that you guys have partnered with Novartis. I mean, like you mentioned, Commissioner Makary highlighted that the agency is now very committed to increasing flexibility to get these drugs for high unmet need indications to market, and Huntington's is a great example of that, isn't it?

And so as you guys are engaging with them, planning for Phase III and then maybe even potential for an accelerated approval pathway, how do you think this increased flexibility and then also your existence of placebo-controlled data differentiates Votoplam from maybe some of the other programs out there?

Yes. I think it's incredibly important to highlight how differentiated Votoplam is and from gene therapy, which may be what you're alluding to that there was news on this morning. I mean we have an oral small molecule. We have placebo-controlled data. We have a study with -- a Phase II study with open-label extension with over 140 patients. We also importantly have objective measurement of target engagement mechanism of action, which is really, really important when you think about the accelerated approval framework, right? Because an accelerated approval, the idea is you have to demonstrate that you have data to suggest that you're likely to have subsequent definitive clinical efficacy.

But one important component of that is being able to show that the drug is working the way the drug has to work in order to register the efficacy. And so one of the primary endpoint of the Votoplam Phase II trial was Huntington lowering. Why? Because that's how the drug works. And if we're not -- if we're going to have ultimate clinical efficacy, we have to be having evidence that we're lowering Huntington protein, and we did. We had dose-dependent lowering and lowering with 2 different dose levels of a magnitude that has been associated with clinical benefit. So all that is to say, I think we have a very differentiated program that would address a lot of the concerns one may have had in looking at the gene therapy. So we're very -- we're differentiated.

And then the second part is, I think Novartis shared they had a recent Meet the Management event in November, and there was a separate neurology group discussion, and they emphasized there how constructive our discussions with FDA have been and how there's a very clear shared view of the significant unmet need for Huntington's disease. And of course, I think the neurology division in Cedar has been -- has demonstrated itself to leverage flexibility certainly when it comes to devastating neurodegenerative disorders like ALS, like Alzheimer's.

So we're excited to continue to work with them. Novartis also shared that they're full speed ahead on getting that next trial started, whether that's going to be a confirmatory study in the context of a potential accelerated approval or a registration trial if the accelerated approval portal is not available.

Can you just characterize maybe your level of engagement with them on trial design, regulatory strategy? I wasn't sure if it's more proactive, passive, active, like just help talk about that.

Yes. I think it's been an incredibly productive collaboration, Geoff. I think we -- from a corporate leadership level, I think we're very aligned in terms of our shared enthusiasm for Votoplam, our desire to move forward as quickly as possible. I think this is one of the things that we valued in selecting Novartis as a partner. And then the working groups, the joint clinical development teams work very closely together.

And I think it's a great example of how I think the best of both companies comes together. There are certain strengths that I think PTC has and there's absolutely strength that Novartis has in experience and execution and thinking about a development program of things that you can do in parallel that may have been cost prohibitive for a company like PTC to do in parallel, they can deal in. And so I think we have a really promising molecule, a great collaboration and really a strong desire to bring this forward.

And I think the recent news and the concern in the community with the discussions with uniQure and FDA, which have brought a lot of concern about the regulatory potential and also about whether there can be a drug for HD. I think, again, given the fact that we're in a much different context with this molecule continues to have us be very enthusiastic along with Novartis that there's a potential path here that we're keen to drive through.

Great. And so maybe in the last 5 minutes, we can switch over to vatiquinone and then maybe real quick on Translarna at the end. So vatiquinone, we know that the CRL definitely was a disappointment. I'd love to hear your thoughts on were there any elements from FDA's feedback that surprised you given, again, like you guys hit on mFARS subdomains and upright stability with stat-sig. And then in your continued engagement with the agency, what have your feedback had been on maybe the path forward and how might perhaps a new Phase III be different from MOVE-FA?

Yes. I would say the CRL was disappointing, but the reasons for the CRL were not surprising in that we knew all along the major question in this review was whether they would say that the evidence of statistical significant benefit with the upright stability scale, though not prespecified as the primary endpoint, would it be sufficient to provide substantial evidence of effectiveness and approval. That was the question going into it.

And I think if you look at the CRL, that was really the main point in the CRL. There are a few other things they threw in there were other sort of, let's just say, statistical pile on, but the real issue here was you prespecified the whole scale, you didn't prespecify upright stability you missed. And that's really interesting because that basically says this was -- not that the drug didn't work. It was that there was something about that endpoint that wasn't learned until after we started the Phase III trial. And it was the old thing if we knew now -- if we knew then what we knew now, we would have done things differently.

And that was the discussion with FDA that ultimately led them to say, yes, let's -- you should submit. And this will be a review issue because it was very clear that the upright stability scale is the most sensitive and meaningful component of the mFARS for the pediatric and young adult population enrolled in the MOVE-FA study. And that was really driven home by the fact that when you looked at the placebo curves, the placebo group had no progression, no progression on 3 of the 4 scales.

The only scale on which the placebo group progressed was upright stability. This wasn't a chance finding. It was the only subscale in which you could register disease -- slowing of disease progression because it was the only scale in which patients would progress. So that was all the evidence that led to FDA agreeing that these would be review things that we should submit.

We look forward to having a meeting with FDA in the fourth quarter. I know we're December, but we're still in the fourth quarter, and there's still some quarter to go. And I think we look forward to those discussions to say, is there any other potential pathway here? Could upright stability be an intermediate clinical endpoint. If we're doing another Phase III trial, what would they like to see? And if the answer is it has to be another placebo-controlled trial, that's something we will look at. We'll look at -- do an assessment of the marketplace, the commercial opportunity today, the commercial opportunity when that study will be done, the cost of the study, whether we -- what we think is the likely outcome. So the typical things you would do in assessing initiation of a trial before we make the final decision.

And so just real quick, sorry. Maybe thinking about a global perspective, could there be a possibility that maybe other regulatory agencies, maybe EMA might be more amenable to move that data and perhaps you can progress there before a new Phase III were to start in the U.S.

Yes. Those are all things that we'll look at. I think what we -- we had had initial feedback from FDA and EMA, and we decided that the initial FDA feedback supported filing in the U.S. So we prioritize that. We will, of course, have conversations with EMA and FDA as we plot the next steps.

And last minute or last but not least, Translarna in Europe. Just tell us kind of the next steps from here.

Absolutely. So in Europe, we're in a unique situation where we have a therapy that's not licensed, but we're continuing to sell. And I hold that out as further evidence of the strength of our customer-facing teams. I mean the ability to be on the ground and understand how to navigate local regulatory authorities, be able to continue to manage selling a drug where it's not approved.

We said that we expected in the short term to be able to maintain about 25% of the European business. That's what we're seeing. The drug is now available in about a little more than half of the countries in Europe. Over time, we'll see. We expect heading into '26 to be able to continue that momentum.

One of the factors to watch is the availability of other therapies. There are no other genetic therapies targeting nonsense mutation. There was the potential theoretically for the gene therapy, but the CHMP gave that a negative opinion, so that's not coming. So there's not really another viable genetic targeted option in Europe, and we'll continue to work and keep patients on therapy as long as we can.

Okay. Thank you very much.

Thank you. Thank you both.

Okay. Good morning, everyone. Thank you for joining us at PTC's R&D Day. Thank you for those who are joining us live here in New York at the Yale Club as well as those who are joining us virtually online. I'm joined today by our Chief Scientific Officer; [ Neal Olmsted ]; our Chief Medical Officer, Lee Golden, members of our R&D leadership team, who will be presenting today as well as members of our IR team.

For the past 2 years, a lot of the focus on PTC has been on our late-stage programs and commercial products which makes a lot of sense. However, over that time, we brought the same emphasis on focus and execution to our earlier-stage R&D programs. When we did a restructuring a couple of years ago, we made the decision that we were going to focus on small molecule therapies as well as focus on science that PTC can uniquely leverage to deliver transformative therapies for patients with diseases of high unmet need. Specifically, this meant we were going to focus on our small molecule splicing platform as well as our ferroptosis platform. And we look forward today to sharing a lot of the progress that we have made over the past couple of years.

PTC currently has 2 laboratory facilities, 1 in New Jersey and 1 in Northern California. The majority of our splicing work occurs in New Jersey. And our inflammation of ferroptosis program work, most of that occurs in our Mountain View, California location. However, there is a lot of collaboration between the teams. In fact, we have certain specific areas of expertise at each facility that's leveraged by the entire PTC research organization.

So today, in terms of agenda, the first part of the morning, we'll be focused on our splicing platform. We'll give you a sort of deep dive into the science around splicing and highlight some of our recent programs. Then we'll have a deep dive into our inflammation and ferroptosis programs. And we'll have time for question and answer after each part of the presentation. I'll mention that we'll be limiting the Q&A to just topics that are covered today, not the Sephience launch, which is going great and other things, but this is really a day focused on PTC's early stage R&D platform.

As we will be making forward-looking statements, we -- I refer you all to our statements regarding forward-looking statements, risks and uncertainties that's on this slide as well as our SEC filings. Before I get started and turn the platform over to Dr. Trotta and Bhattacharyya, I'm going to just give a sort of simple readers digest overview of RNA and splicing to provide a foundation for some of the deeper science that will be covered this morning.

This central dogma that many of us learned in high school biology that DNA is transcribed into RNA, which gets translated into protein was described almost 7 decades ago by [ Watson and Krick ]. It's now quite clear that this is an oversimplified if not in complete description of how protein is generated. A critical insight into understanding how protein is generated from DNA came with the concept that DNA is first transcribed into a pre-mRNA that contains coding sequences called exons and noncoding sequences called introns. And then a process known as slicing occurs to splice out those introns to form the messenger RNA that will ultimately get translated into protein.

Splicing is really the key of how we're able to get 1 million proteins from just 20,000 genes. This important work on splicing earned [ Roberts and Sharp ], the Nobel Prize in 1993. Now splicing is an incredibly complex entity. There are many important participants. This spliceosome, as it's called, contains a number of protein or mRNA and enzyme interactions. There's also enhancers, inhibitors and modifiers that all contribute to the splicing process that, again, takes us from that pre-mRNA to the mRNA. And of course, all of these different aspects of the spliceosome represent potential drug targets.

Now the earliest attempts at targeting splicing were done with oligonucleotides, which makes sense because it was believed to affect these splicing processes, you needed the sequence specificity that was believed could only be provided by oligos. However, we know very well that oligos have drawbacks. They're not orally bioavailable. They are not easy to get biodistribute in the brain because if you want to treat a CNS disease, you often rely on intrathecal or intraparenchymal administration, and that really is not an optimal solution if you're trying to treat a whole brain disease, where whole brain biodistribution is necessary.

We were interested in trying to use oral therapies to target splicing. This made sense. I mean after all, in small molecule drug development, we often need specificity for enzymes in order to have an effective drug. And of course, we know very well that oral molecules have a number of advantages over oligos. They're easily administered, much easier to manufacture. You're able to get full body, systemic biodistribution. And particularly, if you want to treat CNS diseases you're able to get full brain biodistribution. And finally, titration is a lot easier to achieve with an oral small molecule than it is within oligo.

PTC pioneered the field of oral small molecules splicing. I think everyone is aware of our first 2 programs, one to treat spinal muscular atrophy and another to treat Huntington's disease. Evrysdi, which is commercialized by Roche is now the global leading SMA therapy and votoplam, which we partnered with Novartis is the leading oral therapy for Huntington's disease. We're incredibly proud to have pioneered splicing. And these 2 programs not only serve as the incredible innovative compounds that prove that you can get meaningful therapies with oral splicers, but they also provided us a number of important learnings that we'll be discussing today that have allowed us to greatly expand our efforts as well as the efforts of others in trying to develop oral small molecule splicing agents.

So how do these molecules work? Well, as I mentioned, there are these coding sequences of exons and noncoding sequences of introns. And our initial efforts focused on the elements of the spliceosome that defined the 5 prime splice sites on the exons. In nature, more than half of these U1 5 prime slice site interactions are known as canonical, which means that there's a perfect complementary fit between the U1 spliceosome component and the 5 prime splice site on the pre-mRNA. This strong interaction leads to the inclusion of exons in the final mRNA. About 45% of these interactions are noncanonical were weak. And when you have a weak U1 5 prime slice site interaction, you do not efficiently get exon inclusion. So you typically will not have that weak interaction results in the inclusion of a sequence in the final mRNA.

So our strategy was to develop small molecules that can specifically target these weak interactions, turn these weak interactions into strong interactions and affect the inclusion of exons in the final mRNA. And this is what was done with both of Evrysdi and votoplam. In the case of Evrysdi, we forced exon inclusion to increase the SMN protein, which is deficient in patients with SMA. In the case of Huntington's disease, we forced the inclusion of essentially a stop codon that prevents the translation of the full-length Huntington protein to decrease that toxic protein that causes the disease.

So let me describe a little bit further how these therapies work. Let me start with SMA. So SMA is a disease caused by a deficiency in spinal motor neuron protein or SMN. The majority of SMN protein comes from the SMN1 gene. Now there's a second gene that's quite similar, the SMN2 gene which differs, as you can see, in just a single nucleotide here in exon 7. That single nucleotide change leads to a weak U1 interaction and as we discussed, that weak interaction does not lead to efficient inclusion of that exon. And as a result, you get very little functional SMN protein from the SMN2 gene the majority of which you get is a truncated unstable protein.

Now in the disease states, there's mutations in the SMN1 gene that results in a significant decrease in the availability of SMN protein. So our therapeutic strategy was to target the U1 binding site on that exon 7 with a small molecule that could again -- sorry, that could turn that weak interaction into a strong interaction, force the inclusion of exon 7 into the mRNA that would then get translated in increase the amount of the deficient SMN protein. I think we all know the punchline here, this worked. These data are important -- were important proof-of-concept in vivo data, which demonstrates dose-dependent increase in SMN protein in the SMA mouse model. You can see that we were able to achieve levels of the SMN protein that were equivalent to those that would result in being phenotypically normal.

Also importantly, in these early in vivo studies, we were able to demonstrate that we were getting uniform biodistribution, uniform increase in SMN protein in both the CNS and the blood. And we'll be coming back to these types of figures time and time again throughout the presentation today because these are really important proof-of-concept data that substantiate that we're having the desired target engagement and dose-dependent splicing activity and dose-dependent change in the target protein. From these in vivo data, again, we've -- development was completed. And as I mentioned, Evrysdi is now the leading global SMA therapy.

So this program not only brought a transformative therapy to individuals with SMA, but also provided us with a blueprint of how to successfully discover and develop an impactful therapy -- splicing therapy, particularly for CNS disease. A number of critical elements in turn, including the need for sequence specificity, selectivity adequate blood-brain barrier crossing not being [ a flux ], all those critical elements that we learned from the SMA program were brought forward to our next program, which was the votoplam program for Huntington's disease. Now this is the pre-mRNA of the HTT protein. And as you can see, there is a pseudoexon that lives between exon 49 and exon 50 of the HTT transcript. And then without compound in the normal state, the pseudoexon is not included in the final mRNA and therefore, you get production of the full length HTT protein.

And with votoplam, what we do is we force the inclusion of that pseudoexon, which then acts as -- or basically induces a nonsense mutation or act as a stop codon to stop the translation and formation of HTT protein. So again, what we've done here is the other side of the corner, what we did with SMA. And in SMA, we used splicing to increase the levels of a deficient protein. And in the case of Huntington's disease, we're using splicing to decrease the production of a toxic disease-causing protein. Again, these are the data that -- those important proof of concept data showing that we're getting dose-dependent decreases in Huntington protein production, and we also have demonstrated and we've shared these data before that we get full brain biodistribution, equal amounts of HTT lowering in each region of the brain and consistent lowering both centrally in the brain tissue as well as peripherally in the blood.

We are incredibly proud to have pioneered field of oral small molecule splicing. What seemed like a heretical concept 2 decades ago, that we could use small molecules to drug RNA has now been validated as a powerful source of drug development. Over the past 2 decades, you'll see -- and you'll hear this from Dr. Trotta shortly, our teams have made a number of important learnings that have allowed us to significantly expand the universe of potential druggable splicing targets. We've augmented our small molecule library and we have advanced our screening tools to build something that we call PTSeek which is a powerful platform engine that we believe has the potential to lead to the development of a number of innovative and impactful therapies for a variety of different diseases.

So with that brief introduction and overview of RNA biology and splicing, I'll now turn the platform over to Dr. Chris Trotta. Chris?

Okay. Thanks, Matt. That was a very thorough overview of our splicing efforts at PTC. And as thorough as you might feel that was, I'm going to take us a little bit deeper and get really into the science. And I think one of the themes here is that we've learned a lot from these first 2 programs, and I really want to give you a sense of what we learned at the time and how we brought that forward to PTC, and I'll go through that in detail.

So I don't know if I introduce myself. I'm Chris Trotta, and I'm the Senior Vice President of the discovery splicing team at PTC Therapeutics, with over 2 decades of experience in drug discovery my multidisciplinary team of scientists has established PTC as a pioneer in targeting RNA and splicing to discover novel small molecules. It's been appreciated that targeting RNA and specifically RNA splicing has opened the door to important targets that lay outside of the traditional areas of drug discovery that target proteins and enzymes. While much of the validation, as Matt said, it was done by antisense oligos or siRNA, PTC has taken a different approach, and we focus on discovery of small molecules as a modality with a proven track record in drug discovery.

In my talk this morning, I will walk you to through these learnings from our efforts in targeting splicing. And I will -- and how we leverage these insights to develop the PTC platform. This has opened the door to take aim at the vast amount of targets that are found throughout the genome with our efforts to be able to develop novel small molecule therapies to target genetic disorders, cancers and other diseases, a few of which we will showcase today for you. I will begin by taking you deeper into the science behind the discovery of small molecule splicing modulators.

So we start with splicing. So what is splicing? Matt laid this out, but I wanted to give a better picture of this. This is really the -- captures the complexity of splicing. And so basically, splicing is the process that a cell utilizes to take DNA and turn it into a functional protein. And so this is a pre-messenger RNA. In this case, we're looking at the Huntington gene. And you can see -- this covers about 180,000 nucleotides within the genome and there are 67 exons and not introduced exons, which in this depiction, are the dark purple segments of the gene of the pre-mRNA. In light purple, are the introns.

And so splicing is the -- the challenge of splicing is to remove the intronic sequences and join these exons to produce the mature mRNA. And you can see that there's a lot of sequence needs to be removed. So this process is required for a majority of genes throughout the human genome, where there can be anywhere from 20 to over 200 exons in a pre-mRNA transcript. Processing of the pre-mRNA with such a vast amount of real estate within the transcript into a mature RNA requires precision. And I think Matt alluded to this precision. Recognition of the boundary between the exons and the introns occurs at locations known as the 5 prime and the 3 prime splice sites. The first step of splicing is accomplished by the U1 ribonucleoprotein particle called here the U1 snRNP or as I will refer to it throughout the talk -- sorry, the U1 snRNP or as I will refer to it throughout the talk is the U1 snRNP.

Once the U1 snRNP is bound to the 5 prime splice site, this complex with pre-mRNA is then recognized by the spliceosome, which will subsequently identify the 3 prime splice site that is found at the end of the intron. The splices all functions as a single turnover enzyme as it assembles onto the complex and catalyzes the reactions that will produce, remove the introns and join the exons to produce the mature mRNA product. This process occurs for each exon in a pre-mRNA. The recognition step serves as a gatekeeper and represents a crucial step in splicing. And this comes from literature and splicing as well as our appreciation of just the dynamic nature of how U1 is interacting at the 5 prime slice site.

Identifying the correct site among hundreds of thousands of nucleotides found within introns requires a high degree of specificity. If we zoom in to U1, so going from the cartoon picture on the left here, to yet another illustration of U1 interaction. However, we represent it as a zipper. And so the interaction between the U1 snRNP and the RNA -- pre-mRNA at the 5 prime splice site intron, exon boundary is basically accomplished through base pairing and base stacking interactions between the snRNA part of the U1 snRNP and the pre-mRNA. So when there is a perfect match between these 2, the complex is stable. The interaction is stable and will lead to engagement by the spliceosome, allowing the reaction to proceed to intron removal and joining of exons.

As Matt mentioned, there are -- however, for more than 50% of splice sites throughout the genome, this is not the case. These are called noncanonical 5 prime exons because they do not have a perfect match at the 5-prime slice site. And in particular, at the last several nucleotides of the exon here shown in dark purple. And so this results in a very weak association of U1 with the 5 prime splice site and often leads to dissociation of the U1 snRNP as the spliceosome is trying to recognize. And as such, it will be -- this exon will be failure to splice.

So for these cases, splicing has evolved several strategies to enhance the interaction between the U1 snRNP and the weak noncomplementary 5-prime splice sites. One of the main strategies is the use of cellular proteins called exonic splicing enhancers. These bind to specific sequences found within the exon. Once they are bound to their target sequence, in some cases, they will interact directly with the U1 snRNP, effectively clamping it into place at the 5 prime splice site. This will inhibit the dissociation of U1 and allows the recognition complex by the spliceosome, which leads to splicing and inclusion of exon into an mRNA. This is a critical mechanism that the cell uses so it can sample 5 prime splice sites throughout the large number of exons that are found in any given gene. Doing this accurately and correctly is critical to being able to splice properly.

A well-understood example of this comes from SMN. -- specifically the SMN1 gene which encodes the -- as we heard, encodes the SMN protein. Exon 7 of this gene carries a noncomplementary 5 prime splice site. So its interaction with U1 is already somewhat compromised. And so the way the cell has dealt with this is there is an exonic splicing enhancer binding site in exon 7. Once bound, this exonic splicing enhancer protein can stabilize U1 binding at the 5 prime splice site and activate inclusion of exon 7. This leads to constitutive production of SMN protein from the SMN1 gene, as we know, SMN is a critical protein required for motor neuron function.

Mutations or deletions in SM-1 gene drastically reduced the production of the SMN protein in patients with the disease SMA, the production of SMN becomes predominantly dependent on SMN2 gene, which is nearly an identical copy, as Matt discussed, of the SMN1 gene. This arose -- millions of years ago when human and chimpanzee lineages diverged. So SMN2 carries this critical sequence change. It's a cytosine to [ eurocell ], this is the binding site for the exonic splicing enhancer, and as such, SMN2 exon 7 is poorly included into mRNA. And this is the reason for the disease is that functional protein coming from SMN2 is very low.

So with this clear understanding of the splicing and how an enhancer can regulate the slicing in exon 7, PTC embarked on a molecular based screen. So we took this into account when we developed an HTS screen to screen for small molecules that could target this activity and reverse the week interaction between U1 and the 5 prime slice site. We're basically asking the question, could a small molecule function as a 5-prime splice site enhancer? Our efforts led to the discovery of a small molecule splicing enhancer that could modulate splicing of exon 7 and SMN2, allowing SMN protein expression to near wild-type levels from the SMN2 gene. And through optimization of this hit molecule, it led to Evrysdi, which is a first-in-class, first in mechanism, small molecule therapeutic that is the leading treatment of spinal muscular atrophy globally.

Evrysdi functions as a sequence-specific splicing enhancer, it represents a groundbreaking finding in splicing as it's the first demonstration that a small molecule could function as a splicing enhancer by directly targeting the interaction between the U1 snRNP and a week 5 prime splice site, and it was a breakthrough in drug discovery, where a small molecule splicing modulator could be advanced to a therapeutic treatment for patients with a devastating genetic disease. As these findings were emerging from our SMA program, we applied these learnings to accelerate our efforts to target the expression of Huntington gene to lower repeat expanded mutant Huntington protein as a treatment for Huntington's disease.

Our strategy to target expression of the Huntington protein utilized our compound library, which at this point now contains a splicing centric chemical scaffolds to identify a brain-penetrant small molecule that could knock down the Huntington mRNA, thereby lowering mutant Huntington protein. These screening efforts led to discovery of the second small molecule splicing modulator, which we demonstrated promotes the inclusion of a previously unknown exon in intron 49 of the Huntington pre-mRNA. This event is very rare -- this exon is very rarely incorporated into the Huntington mature mRNA. In fact, a survey of hundreds of publicly available RNA seq data sets reveals that the presence of this exon within the mature Huntington mRNA is ultra rare. It's almost never seen, but it actually is seen. So this is a biological process that the cell can use to regulate gene expression.

And this is basically due to a combination -- and Matt highlighted this, a combination between the week 5 prime splice site, where U1 will not productively interact and the presence of a stop codon. So even when this is sliced in occasionally, this stop codon will cause translation termination, which will lead to decay of the mRNA through a cellular process known as nonsense mediated decay. votoplam functions as a 5 prime splice site enhancer to target the conclusion of exon 49 A, which shifts the splicing to an isoform that will be subject to nonsense mediated decay and with the end result being a lowering of the protein production. This was a foundational discovery by PTC and established a new modality for the regulation of gene expression through splicing. The use of a small molecule modulator to tap into a splicing regulatory mechanism to lower protein expression.

When we compare the activity of PTC's 2 first-in-class splicing modulators for SMA and Huntington's disease, a second fundamental insight jumped out immediately. There is a high degree of selectivity of each molecule for their target sequence. This was achieved through lead optimization of the initial hit molecules that led to elicit sequence specificity. We refer to these exons as compound induced exons or i exons. These 2 programs demonstrate the ability to target the inclusion of exon in mRNA to either promote protein production as in the case for SMN protein with Evrysdi or to decrease protein production as in the case of votoplam for HD.

Several published studies in our own internal work suggest that these small molecule splicing enhancers function through direct binding of the interface between U1 and the pre-mRNA highlighted here in orange. If we look at the interface, this interaction occurs between the U1 snRNA and the last 4 nucleotides of the 5 prime splice site of the targeted i exon. As this mechanism became clear to us we got very excited and realized we were just at the tip of the iceberg. When you think about a splicing modifier as targeting the last 4 nucleotides of an exon, if you do the math, there's 4 to the fourth potential targetable sequences or 256 potential targeted sequences. Each of these sequences can be considered a distinct class of 5 prime splice sites with i exon throughout the transcriptome.

As demonstrated on the wheel to the right, which represents with each sliver of the pie representing a different sequence, SMN2, exon 7 and HTT exon 49 represent the first 2 sequences that can be specifically targeted by small molecule. Taking our learnings from these 2 programs, we asked 2 key questions. First, how broad is i exon regulation of gene expression? In other words, how many and in what genes do i exons exist? And second, can we systematically discover distinct small molecules for each i exon sequence class found at the 5 Prime splice site. We reason that success within these 2 efforts combined would open up the ability to target a wide range of therapeutically relevant i exons in targets of high interest to human disease.

To uncover the extent of i exon regulation, I'm showing here one type of experiment where we did this. We've also, as I mentioned, looked at RNA seq data sets, but we directly interrogated the transcriptome to understand the true scope of i exon inclusion. And the way we did this was we genetically modified the snRNA from U1 to each of the potential 256 sequences. So as depicted here as the ends, basically, we had a U1 variant that would match each of those 256 sequences. When we did this, we then treated cells and we look to see what exons were affected. We started, we looked at SMN2 and HTT, the genetically modified U1 variance for those 2 indeed induced in i exon class that matched the 5 prime splice site that we see Evrysdi and votoplam respectively, affecting.

Upon expanding this analysis to the remaining 254 sequences, we found evidence for i exons for all 256 sequences. Furthermore, amongst all the i exons observed, we estimate that there are i exons covering a majority of genes throughout the genome, including numerous genes of therapeutic interest. This insight into i exon regulation was pointing us directly at numerous druggable targets and led us to tackle the next and probably more important question, can we actually find molecules that can do this? So can we systematically discover small molecules that target the novel 5 prime splice site sequences as hit molecules for i exons that we could develop in exactly the same way we achieved with SMN2 and the Huntington pre-mRNA but within new therapeutic targets.

So to accomplish this, we built off the foundational discovery, some of which Matt and I have outlined today as well as we just saw a moment ago, and we developed what we call PTSeek. This is a novel platform that utilizes transcriptome wide interrogation. So directly looking at splicing, transcriptome wide and we use a innovative screening tools and some and informatics insights that we have gained from understanding the 5-prime splice site enhancers and work that we've -- of targeting splicing over the last several years. We couple this with PTCs custom design library of novel small molecules that cover unique splicing centric chemical space, which has been built over the last 2 decades.

To be clear, our efforts to this point led to the discovery of an entire universe of targetable i exons. And with PTSeek, we now had a small molecule strategy to uncover novel splicing modulators. Employing PTSeek for several years has led to just that, the discovery of dozen and counting novel chemical scaffolds that target novel 5 prime splice site sequences within i exons. As with Huntington and SMN splicing modulators, these novel scaffolds have a distinct structure sequence relationship. So each novel molecule targets a very specific sliver of the pie here. And this -- and as such, they all -- from the beginning, they demonstrate a high specificity for a novel target sequences. Equally important and many of these targetable i exons, many of these i exons are found in therapeutically relevant targets, some of which my colleague Anu will be presenting shortly.

So connecting these 2 -- connecting the discovery of a dozen novel molecules that target distinct sequences that are found in i exons of therapeutically relevant targets is unprecedented, and it really positions PTC to advance numerous splice modulators into the clinic over the next several years. As a sneak peek to some of the data Anu will discuss, I want to highlight another significant advantage of the PTSeek approach. The molecules that we have discovered are high-quality hits. Since these molecules are derived from splicing centric scaffolds, we have found that progression from a hit through early lead and lead optimization has been greatly accelerated relative to our initial efforts targeting splicing exemplified here by comparison to the SMA drug development time line. This has allowed us access to more targets and a quicker path to a development candidate.

So with that, I will sum up. PTC's efforts to target splicing have led to tremendous success in building a sustainable drug discovery platform, first, through a targeted high-throughput approach for SMA and HD, where fundamental insights into the innovative mechanism of targeting splicing with small molecules [ mods ] splicing modulators has led to the establishment of a platform approach, which focuses on transcriptome wide discovery of small molecules from PTC's proprietary splicing library. PTSeek is a best-in-class discovery engine. And over the past 3 years, has and continues to deliver novel small molecules that target a wide range of therapeutically relevant targets implicated in diseases of high unmet medical need.

I would now like to turn the podium over to Anu to take us through some of the exciting emerging programs from our efforts to target RNA splicing.

You can all hear me, right? Thanks, Chris. Good morning, everyone. My name is Anu Bhattacharyya. I have been at PTC for more than 18 years. I lead our splicing programs team. Chris just did an excellent job in describing how we have ushered in the next generation of splicing programs. I'm going to -- I'm sorry, these programs have this opportunity to deliver novel splice modulators like Evrysdi and votoplam across a wide array of indications. So I'm going to talk to you about a few of these programs really highlighting the great work that our fantastic splicing cross-functional team has done. The first 3 are late stage and the last 2 are early-stage programs. And in some cases, you will note that we're not going to disclose specific targets to maintain competitive advantage.

So the first program targets a key driver of disease pathology across a group of indications called nucleotide repeat disorders or NRDs. In nucleotide repeat disorders, individuals have a segment of DNA repeats in a given gene that is usually longer than what is typically seen in unaffected individuals. Right after birth, these repeats cause no symptoms. As the individual ages, the repeats expand further, especially in affected tissues. This expansion phenomenon is called somatic expansion and somatic expansion has been documented in almost all nucleotide repeat disorders. Our initial target indication for this program are Huntington's disease and myotonic dystrophy 1, or DM1, and we will focus on these 2 indications first.

For Huntington's disease, this is a differentiating approach from what we're targeting in the votoplam program. And this approach of targeting somatic expansion is complementary to Huntington lowering. So let's dig a little bit deeper into this phenomenon of somatic expansion. The rate of somatic expansion is key here. If the rate of expansion is faster, that will result in earlier disease onset and faster disease progression. On the other hand, when the rate of expansion is slower, patients will have delayed onset and slower disease progression. So there is a strong correlation between the expansion rate and disease onset and progression.

And this expansion rate is primarily driven by a family of proteins called mismatch repair or MMR proteins. Therefore, lowering the levels of these MMR proteins will slow down somatic expansion, which was significantly delayed disease onset and progression. Our program objective is to use PTC splicing technology to modulate the levels of these MMR proteins and target the rate of somatic expansion. Now of all the MMR proteins, MSH3 has really emerged as the most promising target in the past 5 years and the data is specifically strong in Huntington's disease and DM1.

As I said, MSH3 has very strong human genetics evidence. Here, mother nature has done the work to validate a correlation between MSH3 levels and disease onset and progression. As you see here in the table, there are HD patients who have these different variations in their MSH3 gene. As a result of these variations, these patients have reduced levels of MSH3 protein. Now when this is plotted out in there on the right, you see a clear linear correlation between the extent of MSH3 reduction in these HD patients and their disease onset. Now not only does this human data validate the therapeutic potential of MSH3 reduction, but it also values MSH3 protein as a potential surrogate biomarker. A similar trend in correlation between somatic expansion and disease onset was also observed in DM1 patients.

So our program objective was to use our splicing technology defined novel molecules that will lower MSH3 levels. And I'm very happy to report that we have identified novel splicing modulators that lower MSH3. The mechanism, as laid out on the slide is similar to what Chris described earlier for Huntington lowering. In this case, the molecules target a novel sequence distinct from the SMA and HD molecules, and they target a different gene, MSH3. These novel molecules promote inclusion of an exon bringing in a premature stop codon in the MSH3 mRNA. This induces degradation of the mRNA and reduction in MSH3 protein levels. So we have been using our in-house splicing expertise to significantly expedite both drug discovery and optimization processes.

Here is a snapshot of the results of that work. Now the data shown on this slide represents a lot of hard work from our very experienced splicing cross-functional team. We have identified novel compounds that are highly potent and selective. Here are some key pieces of data from one such compound. As you see here on the left, the compound shows a robust and correlative dose-dependent lowering of MSH3 mRNA and protein levels in cells. And this data is validated in animals as shown here in the middle. You see a nice dose-dependent reduction of MSH3 protein levels. Just as we have done in SMA and HD, we optimize these small molecules to cross the blood bring barrier not be e-fluxed and show uniform distribution throughout the CNS. We established a robust PK/PD relationship in this program. From our previous experience with SMA and HD, strong PK/PD data generated in animals transits very well to the clinic.

Next, as proof of concept, we tested our compounds in a specific expansion model. This was to see if MSH3 lowering has an effect on somatic expansion. As you see here on the right, we were able to show that 30% to 50% lowering of MSH3 levels significantly stalled expansion in this model system. This is in line with what's been reported and it represents what will be our target lowering in the clinic. This is a very promising program because it's built on a strong scientific foundation. By targeting MSH3 lowering, we can tackle what's been shown to be a key driver of disease pathogenesis in repeat disorders like Huntington's disease and DM1.

Again, in HD, this approach of MSH3 lowering will be complementary to HTT lowering. And this could be particularly appealing for juvenile onset HD because this population is linked to higher levels of somatic expansion. Our molecules target a novel splicing event that results in reductions of MSH3 mRNA and protein levels. They have favorable drug-like properties for CNS indications, such as Huntington's disease, our plan is to select a clinical candidate in the first part of 2026 and be Phase I ready by the end of the year.

Next, we're going to provide an update on our SCA3 program. SCA3 or spinocerebellar ataxia 3, is a monogenetic neurodegenerative disorder. It primarily affects the cerebellum, brainstem and spinal cord. Balance problems and in coordination are typically the first visible symptoms of SCA3. And currently, there are no disease-modifying therapies. Now in SCA3 patients, the mutant ataxin-3 protein is the primary toxicity driver that leads to neurodegeneration. Our therapeutic strategy is to lower ataxin 3 level, utilizing our splicing technology. We have identified novel splicing modulators that skip or exclude exon 4 in ataxin-3 pre-mRNA. This is a different mechanism from what I described earlier for MSH3. Now this is a great example of how different splicing mechanisms can be leveraged to modulate protein production. Here, the molecules skip or exclude exon 4 and that breaks the frame of the ataxin 3 mRNA, which creates an mRNA with a premature stop codon that then gets degraded. This results in reduction in ataxin-3 protein levels.

Here are some key results of our lead compound. As you see here, the compound shows a robust dose-dependent reduction in ataxin-3 mRNA and protein levels in cells and animals. Just as we have done in other CNS programs, the molecules in this program were optimized to cross the blood brain barrier and not be e-flexed and the extent of ataxin 3 lowering, we observed in animals is in the range believed to be needed for functional benefit. So for the SCA3 program, we identified a novel splicing event that results in ataxin mRNA and protein lowering. We demonstrated robust in vitro and in vivo activity and optimal drug-like properties. Similar to our MSH3 program, the plan is to select a clinical candidate in the first part of 2026 and be Phase I ready by the end of the year.

Next, I will talk about a program that targets brain tumors and metastasis. This is another great example of the utility of PTSeek in identifying novel splicing modulators across different indications, including oncology, which can be a partnership opportunity for us. This oncology target is an interesting one. It has a dual role. It promotes cancer cells to grow, and it suppresses T cells from being activated. So lowering it will have a dual effect. It will block the cancer cells from proliferating and it will enhance T cell function to kill those cancer cells. Also, it's been shown that the lowering of this target will synergistically enhance the anticancer effects of immune checkpoint inhibitors. The molecules we've identified in this program have excellent CNS exposure, which makes them suitable for targeting brain tumors.

As I mentioned, we have leveraged PTSeek again to identify this novel class of splicing modulators. These molecules modulate splicing of the target, promoting inclusion of an exon. And this induces mRNA decay and lowers protein levels. Again, similar to what I described for MSH3, but now with a different class of novel molecules. Here, I'm showing you an example of a lead compound that is very potent in reducing mRNA and protein levels in cells. This reduction in mRNA and protein levels leads to T cell activation as evidenced by a significant increase in cytokine levels, which is shown here in the middle. This brain penetrant compound also shows a robust lowering of the target in animals shown here on the right. In summary, we made excellent progress on this program. We have identified a novel class of splicing compounds that have great activity and selectivity. By lowering the target the compound activate T cells, they have great brain penetration.

Next, we're going to assess the compound synergy with checkpoint inhibitors. Our plan is to select a clinical candidate early 2026. Now I will shift to some of our earlier stage programs. First, I will start with the program that targets sickle cell disease and beta thalassemia. Now sickle cell disease and beta-thalassemia patients share a common pathology. They make defective adult hemoglobin. One therapeutic strategy that has emerged to be the most promising is induction of fetal hemoglobin levels in these patients. Again, mother nature has validated our therapeutic strategy. Sickle cell disease and beta-thalassemia patients with increased levels of fetal hemoglobin show significantly reduced symptoms. And this process of fetal hemoglobin induction is regulated by multiple proteins that we believe are great splicing targets.

So we have leveraged the PTSeek platform to look for novel molecules that will target these key proteins. PTSeek, again, has enabled us to identify novel splicing molecules that target one of these key inhibitors of fetal hemoglobin. These molecules modulate splicing of the target again, by promoting inclusion up in exon, as shown here on the slide. This induces mRNA decay and lowers protein levels. Now reduction of this key inhibitor will lead to an increase in fetal hemoglobin, and that will be disease modifying for sickle cell disease and beta thalassemia patients. As you see here on the slide, one of these early molecules shows a nice dose-dependent reduction of the target inhibitor which in turn induces fetal hemoglobin levels in adult blood cells in the therapeutic range. This is an early stage program. And as you see here on the right, the extent of fetal hemoglobin induction is already very encouraging. We will continue to identify and optimize these small molecules for potency, efficacy and drug-like properties and move this program as quickly as possible.

Next, I will talk about another early-stage program that has application in multiple neurodegenerative diseases. Now with SMA and HD, we targeted a single gene to address disease pathology using splicing. This is another example like MSH3, where splicing can be applied to target specific protein and targeting this specific protein will have a huge impact on a key pathway implicated in disease pathology across multiple indications. And this is a new powerful way we can use our splicing program.

Here, our therapeutic strategy is to mitigate the neuronal dysfunction that results from protein aggregation. And this is a common pathology of many neurodegenerative diseases. Again, with PTSeek, we can identify novel splicing modulators that can specifically target key proteins in this pathway. Our program's objective is to have a single therapy that has broad utility across multiple disorders. We have been able to identify novel splicing modulators that target one of these key proteins. This program is early but already our fantastic splicing team has done a tremendous job in identifying compounds with good activity and selectivity. As you see here from the green arrow, we are already seeing target modulation in the range that is deemed therapeutic, and it's just the beginning. We will continue to identify and optimize molecules for potency, efficacy and drug-like properties and move this program also as quickly as possible.

So as Chris and I showed you today, we have truly pioneered splicing drug discovery and development. It started with our groundbreaking work in SMA that led to the development of Evrysdi, which was then followed by our HD program and development of votoplam. We use the learnings from these programs to develop our innovative PTSeek platform. This platform is built upon decades of experience that allows us to expedite the discovery and development of novel splicing molecules. Now what's really exciting about PTSeek is that it unlocks a whole new therapeutic space by selectively targeting RNA and it gives us the advantage of delivering therapies that can't be addressed with traditional small molecule approaches. It also positions us to broaden the scope and continue to deliver best-in-class splice modulators like Evrysdi and votoplam in a wide array of indications. Thank you so much for your attention.