My name's Jeff Beach. I'm the senior biopharma analyst there, and I have Jar Wei 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.
Thank you. Great to be here.
Lots of questions on Translarna and on your R&D day, but maybe just for those on the webcast, just give us, you know, a bit of a quick background or overall, and then we can get right into it.
Yeah, 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 six 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 break even and beyond in the near future. So really excited to get into the questions and, and talk about the launch.
Yeah. Yeah. Let's do that. So when you think about, you know, PKU and the 341 patients on therapy, it's pretty good for the first quarter, right? So what were the, I know you had from the clinical development a pretty good idea of, you know, the backlog of patients, but help us with kind of the execution of the early part of the launch, you know, with the time from, you know, diagnosis to script to getting it paid for to delivering drug. You know, how, you know, seamless are you and where could you go?
Yeah, absolutely. So we, we've said all along that we believed 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 two 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, Sapropterin.
And also, given its second mechanism of action as a chaperone, it 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 can 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 a PTC Cares team, which is our patient services team, which provides the necessary white glove service from PSF to prescription fill to refill.
That's really the backdrop that the launch had. And so when we see the early success, you know, 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 J.P. Morgan, 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 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 two to four weeks from PSF to getting on drug. Those numbers are continuing thus far. You know, again, we think part of that is the fact that there is this unmet need.
We have an experienced team that knows how to get PSFs in, get them processed quickly, get drug 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's a need for a prior auth, if there's a need for a letter of medical exception, we that can all get accomplished pretty quickly.
You know, 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 in an accelerated path that you can maybe translate as you roll out, you know, across the U.S. and more maybe on a more global basis?
Yeah, a-absolutely.
Yeah.
First, a couple things. One is the prior auths for getting a prior auth to the label.
Okay.
The label's incredibly broad.
Yeah.
It's basically one month of age and above.
Yeah.
That's in the U.S., outside of the U.S., In Europe, it's. 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, we haven't really seen step edit issues. One of the important data pieces we have is our Amplify study. This was a study we shared the results from in September at the International PKU meeting. This was a head-to-head study with BH4. It was a crossover study. 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 Sapropterin, you're gonna 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% 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 than an individual who may have been on Kuvan branded or generic, or had not tried it is going to do better on our therapy.
Maybe on the differentiated data, you know, you mentioned that there is extremely a lot of excitement on social media for Sephience and also among docs that we've spoken with, right? There is pretty high awareness of the product. I'd love to hear your thoughts on, you know, how adoption patterns are looking across different patient segments, whether it be, you know, classical versus non-classical, naive versus switches, and, you know, how do conversion and persistence maybe differ by the different segments of patients?
Yeah, absolutely. I think one of the things we shared 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 two 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 two 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 a lot of 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 PKU. I'll talk about a severe and classical patient, had 90% reduction in Phe very quickly. You know, 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 gonna be the low-hanging fruit," because, of course, if there's any response at all to Kuvan branded or generic, there will be a more substantial, a greater response, whether that be in Phe lowering or Phe lowering and diet liberalization.
And therefore that made that an easy, you know, easy population to get on drug because you'd be swapping one once-a-day therapy 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 gonna 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? 'Cause a lot of times in these rare disease spaces such as PKU, if patients aren't well controlled, they kind a 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. You know, and then you also mentioned that you have diet liberalization data. So maybe tell us a bit about how getting those lost to follow-up patients and how diet liberalization data, how do they all tie in together to help get patients that maybe you didn't initially plan on capturing so early?
Yeah, I think, Joey, this concept of lost to follow-up is a little bit. I think it's a misconception. I think we hear, you know. 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, right? In fact, if you listen to some of the adult patients who are thrown in that lost to follow-up bucket, they'll say, "I'm not lost. I'm right here. You know, I have social media. I actually wanna be on a therapy.
And I don't go to the doctor's office because I don't wanna be yelled at 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 dietician because they really help me manage my diet. And so I think this concept of this lost to follow-up bucket is a little bit of a construct of docs thinking just 'cause someone doesn't see them doesn't mean they wanna be on therapy. Now, admittedly, these are. We would not have thought 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. You know, in PKU, if you're not on, if you're not on a therapy, and even if you are on one, really that 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 diet and enjoy foods that you never enjoyed before, I think it's so hard for us to imagine what that's like.
You look on social media and you see these stories of a kid eating a cheeseburger for the first time, a mom talking about being able to have breakfast, the same breakfast with her 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, you know, broadly, what are the nuances in each of the markets from standards of care that you'll have to navigate, that, you know, I'm obviously you have a super experienced commercial team, but that's gonna have to be part of the conversation, right?
Yeah, absolutely, Jeff. We spent a lot of time planning for this launch. We said this would be a global launch. In fact, we launched in Europe and the U.S. almost at the same time, which.
Yeah.
For, you know, it's 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.
Yeah.
Where we have infrastructure and teams ready to go in terms of launch. We've been very thoughtful about price corridor. That's something that we take very seriously always. I think in the era of MFN, it's something that we have to really think about. 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. It may be in certain countries, to your question, that we'll have to have discussions around price and volume and are there gonna be certain patients who.
Yeah.
may get covered, may not get covered 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 US. And so that, you know, 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 to SUS. We leverage 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 digitalization process before we get formal access and coverage.
And so we have all of that mapped out.
Do you have to navigate, you know, 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.
Yeah.
Micromoles per liter. Yeah. And so, 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's out there and that's the threshold. The other question in Europe is, in many cases, medical foods and formulas are reimbursed.
So, having, Joey, 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, two-thirds of patients being able to get the levels of protein beyond the recommended daily allowance allows us to say, you know, when we talk to go through payer negotiations in Europe, that we have data to say that this drug will actually lower the need for to support medical foods in part. So that becomes an important part of the discussion.
Yep. Yeah. And just in that same context, what investments have you seen in the early part of the launch here, and I imagine you see the anticipated future demand. What investments incrementally are you investing in the manufacturing supply chain kind a thing just to make sure that you can, you know, meet the demand?
Yeah. This is, you know, I'm smiling as I answer it 'cause these are the kinds of things we do in-house, right? We say, you know, our teams and management team is very big on what could go wrong from day one and have plan A, plan B, plan C, plan Z, right? That we're always thinking about these things. And so clearly, when, 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 one API manufacturer. We've now expanded to two. We're gonna 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.
Yeah. 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, you know, what part of the data packages of Sephience do you think will be important to highlight? You know, would there be differences in Japan versus EU versus Brazil and et cetera?
Yeah. 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, you know, we look at it and see the primary endpoints and secondary endpoints with, you know, 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, you know, we, over 75% in the trial would've met the definition of responder with over 15% reduction. Then being able to bring in the guidelines, 84% getting, below 360 micromoles per liter. Then the diet liberalization data being able to show a 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, you know, address any concern that comes at you. And I think we've all been around long enough, you know, that's a pretty rare situation to be able to do that. And that's part of why, you know, this has been so exciting for us.
I think, you know, earlier, you know, it's apparent that excitement for Sephience on social media is quite large. But maybe help us understand how, I don't wanna say rampant, 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, you know, on a global basis as you guys begin rolling out?
The short answer is it's strong globally, you know, in the U.S., We've done a lot of work. We've got, and part of this is the drug's, you know, 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, you know, it's 2025, right? Social media and patient-to-patient communication is a very, very strong component of, you know, I'll put marketing in quotes, but just say that getting the word out about a therapy. But we're seeing as well that there's well-aggregated patient communities globally. You know, we went to the ESPKU meeting. Our teams were there in Hamburg, Germany in September, you know, very well-organized community in Europe. And then in each country in Europe, there's PKU groups.
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 wanna ask you just the, 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, you know, pre-approval that, you know, the development, things like, you know, what helps keep people on, you know, compliant persistence rates, things like that?
Yeah, absolutely. So we know that what really helps with adherence is when 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 usually are used to or they go higher, they'll have brain fog.
Yep.
We had one individual who was speaking with us who said she knows on days that her Phe level's off, she has to use the GPS to get home from work, which just to tell you, they know when things are. The other part is, knowing the Phe lowering is Phe level's 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.
Yep. Makes sense. So Matt, maybe thinking about the strategy of, or maybe the future development of PKU treatment, you know, obviously with Sephience, that's a novel new asset that's being marketed now. But there are other, you know, mechanisms such as SLC6A19. Oh my gosh, what a mouthful. In addition, that may be coming. Maybe help us understand, you know, 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 two therapies targeting that renal transporter of amino acids. I think it's a very interesting approach. Clearly, like most things, you know, 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 branched chain amino acids, there's 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, what, you know, will it be in children? What, what's that about? And their protocol, in fact, allows for using that experimental therapy on top of existing therapies, Joey. 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. You know, clearly a lot to be learned, a long way to go. We're also comforted by the fact that we're gonna 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 wanna give airtime to other parts of the business. So, but maybe Matt, if you could talk through just the R&D day, you know, kind of some of the higher level takeaways, and then we can get into, maybe Translarna and other, you know, other elements.
Yeah, absolutely. Happy to talk about the rest of the business. Clearly, clearly the number one 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 gonna be, you know, incredibly successful for patients and for us, but we do have other parts of the business, and we did 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 commercial, 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, you know, 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, you know, what 20 years ago when we started working on small molecule splicing seemed like this heretical concept that you would use an oral molecule to affect RNA, you know, basically doing genetic manipulation with a pill seemed crazy. How could you ever get the necessary sequence specificity and now that's clearly a very well-validated approach with the success of Evrysdi, which was the first compound we discovered. Now branaplam, 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 two 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 sequence as the target for both, Evrysdi and branaplam, 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 to s and seen that we have chemical matter to possibly talk to those new targets.
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 'cause 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 gonna go as a company, but we have certainly the ability to think about strategic partnerships. As we think to the future of the company, you know, clearly we're focused on the Sephience launch and execution there, but we also have, you know, sort of a goose that's laid two 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 it. You'll keep in-house and opportunities outside of that, you know, more likely to out-license it?
Absolutely. We shared a number of programs the other day. We shared five new splicing programs that they're all early stage. You know, we have small teams working on those. We also shared programs from our inflammation platform, which, you know, some targets that are very familiar to people that we have very differentiated approach to. Same thing there. There'll be some that'll be for us and some that we'll be.
Do you have a number in mind in terms of the CapEx R&D and/or the R&D capacity? Is it one IND per year? Is it two? Is it? So that used to be an old metric, right?
Yes.
But now people don't really talk about that.
Yeah. Again, I think so. I think we don't have a specific limit in mind. However, we wanna be very clear that one of the things that we've been extraordinarily thoughtful and careful about is managing our expenses.
Yep.
That's something we're gonna continue to do. We've committed the company. Two years ago, I stood up and said we're gonna move to get to cash flow break-even in the near future. I stand by that. We'll update that guidance at J.P. Morgan. Again, with the focus on the success of Sephience, that's gonna drive our top line. We've said that we plan to reduce OpEx in 2026 relative to 2025. Very simple math tells you we're gonna be getting very close to that point. We're gonna manage our expenses in the earlier parts of the pipeline to make sure that we're not violating that. 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.
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, you know, how the course of this year has it evolved?
With the White House.
White House.
Yeah. The.
Usually that's a large cap conversation.
Yes.
You guys are a global company and you're hitting all the right.
Yeah, and absolutely.
Elements.
We're quite aware of these things, right? I mean, we have a very active government affairs team. We all spend a lot of time in DC making sure we're well aware of how specific topics can impact our business.
Yep.
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 an MFN in 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, you know, R&D amortization that 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 in.
Probably not on the radar as much.
Exactly.
Much bigger.
Yeah, and I think there's a lot of important things going on right now. I think, you know, the FDA 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, you know, forward-thinking. And you know, 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, you know, not only help our business, but the global community.
I think that'd be a great segue over to Votoplam and the Huntington's disease program that you guys have partnered with Novartis. I mean, you know, like you mentioned, you know, Commissioner Makary highlighted that the agency is now very committed to increasing flexibility to get these drugs for high unmet need indications to market. Huntington's is a great example of that, isn't it? As you guys are engaging with them, planning for phase III, and there may be even potential for an accelerated approval pathway, you know, how do you think this increased flexibility, you know, and then also your existence of placebo-controlled data differentiates Votoplam from maybe some of the other programs out there?
Yeah. I think it's incredibly important to highlight how differentiated Votoplam is then from, you know, 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, you know, 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? 'Cause in 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. Well, 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 that efficacy.
One of the, you know, the primary endpoint of the Votoplam phase II trial was Huntington lowering. Why? Because that's how the drug works. If we're not, if we're gonna have ultimate clinical efficacy, we have to be having evidence that we're lowering Huntington protein. We did. We had dose-dependent lowering and lowering with two different dose levels, of a magnitude that has been associated with clinical benefits. 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. We're very differentiated. 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, you know, we're excited to continue to work with them. Novartis also shared that they're, you know, full speed ahead on getting that next trial started, whether that's gonna be a confirmatory study in the context of a potential accelerated approval or a registration trial in if, 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, you know, if it's more proactive, passive, active. Like, just help, talk about that.
Yeah. I think it's been an incredibly productive collaboration, Jeff. 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's certain strengths that I think PTC has, and there's absolutely strengths that Novartis has, in experience and execution and thinking about a development program and things that you can do in parallel that may have been cost prohibitive for a company like PTC to do in parallel, they can do.
And so I think we have a really promising molecule, a great collaboration, and really a strong desire to bring this forward. I think the recent news and the concern in the community with the discussions with uniQure and FDA, which have, you know, brought a lot of concern and about 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 five minutes, we can switch over to vatiquinone and then maybe a real quick on Translarna at the end. So, you know, vatiquinone, you know, we know that the CRL definitely was a disappointment. Love to hear your thoughts on, you know, were there any elements from FDA's feedback that surprised you given, you know, again, like you guys hit on mFARS's subdomains and upright stability was stat sig. And then, you know, in your continued engagement with the agency, you know, what has your feedback been on, on maybe the path forward and, and how might perhaps a new phase III be different from MOVE-FA?
Yeah. 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 statistically significant benefit with the upright stability scale, though not pre-specified as the primary endpoint, would it be sufficient to provide substantial evidence of effectiveness and approval? That was the question going into it. And if I think if you look at the CRL, that was really the main part purpose, you know, main point in the CRL. There were a few other things they threw in that were other sort of, let's just say, statistical pile on. But the real issue here was you pre-specified the whole scale. You didn't pre-specify upright stability. You missed.
That's really interesting because that basically says this was, you know, 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. That was the discussion with FDA that ultimately led them to say, "Yeah, let's, you should submit." 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.
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 three of the four 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 'cause it was the only scale on 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. There's still some quarter to go. I think we look forward to those discussions to say, you know, is there any other potential pathway here?
You know, 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, you know, 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, you know, what we think the likely outcome. So the typical things you would do in assessing initiation of a trial before we make a final decision.
And so just real quick, sorry. Maybe thinking about a global perspective, you know, could there be a possibility that maybe other regulatory agencies, maybe the EMA might be more amenable to MOVE-FA's data and perhaps you can progress there before a new phase III were to start in the U.S.?
Yeah. I those are all things that we'll look at. I think what we had initial feedback from FDA and EMA, and we decided that the initial FDA feedback supported filing in the U.S., so we prioritized that. We will, of course, have conversations with EMA and FDA, as we plot the next steps.
Last minute or last but not least, Translarna and Europe, just tell us kind of the next steps from here.
Yeah. Absolutely. So in Europe, we're in the unique situation where we have a therapy that's not licensed, but we're continuing to sell. And I, 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. I, you know, we, we expect heading into 2026 to be able to continue that momentum. One of the factors that to watch is the availability of other therapies.
There are no other genetic therapies targeting nonsense mutation. You know, there was the potential theoretically for, 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.