Hi, good morning, everybody. Welcome to day three of Cantor's Global Healthcare Conference. I'm Kristen Kluska, one of the biotech analysts here. Very happy to be joined on stage with the PTC Therapeutics team. We have Dr. Matt Klein, the CEO, and Pierre Gravier, the CFO. Thank you both so much for being here. Thank you, Kristen. Always a pleasure hosting you. It feels like every year you give me more to talk about, yet we only have the same amount of time. Let's see what we can cover today. Sounds good. But maybe just to kick things off, do you mind starting with a high-level overview? Yeah, absolutely. Look, I'll say that 2026 has been a great year so far for PTC. We're continuing to build towards being that differentiated rare disease company that we've been setting out to do. SEPHIENCE launch is going incredibly well, and we see no evidence of slowing down and remain confident in meeting our objectives of this being a $2 billion-plus opportunity, and a product that this year will get us, we believe, to the cash flow breakeven milestone and set us up for future profitability. We also are continuing to execute on all fronts across the company, continuing to succeed from a commercial standpoint, remain with a strong balance sheet of over $2 billion in cash. A number of exciting programs coming through on the R&D front, including our recent planned acquisition of the gene therapy for Fabry, Huntington's disease program progressing well, as well a number of our inflammation programs. So a really exciting time for us as we continue to build towards future success. Okay. I think I'm going to try to talk high level about several programs today. So let's start with SEPHIENCE for PKU. I think investors have recognized this launch is going better than they expected. Big picture, what do you attribute to be the biggest drivers that led to this? There's several factors. First of all, it's a great therapy. It's a highly differentiated oral therapy with a dual mechanism of action that allows it to provide benefits of phenylalanine-lowering, diet liberalization, CNS benefits, a whole host of benefits for the full spectrum of PKU patients. While there are previous approved therapies, the vast majority of patients still needed such a safe, well-tolerated, and efficacious therapy. We saw this opportunity as quite large. Not only in terms of being able to provide a therapy for those who currently on the oral therapy of sapropterin, but those who are therapy naive, those who've tried and failed the oral therapy, those different severity of disease in the full age spectrum. We saw this as the ability to really deliver meaningful therapy to individuals with PKU. In addition, several of the important pillars for commercial success were already in place. There's newborn screening, there's centers of excellence, there's a well-aggregated patient community, and we have an experienced global customer-facing team that can deliver rare disease therapies to patients. I think when you have a great therapy, a significant unmet need, an identified, well-aggregated population, and a team that knows how to deliver, that really sets you up for success. What we're seeing is just that, an incredibly strong start. You've heard me say time and time again, the theme of the launch thus far has been breadth. Breadth in terms of accessing all the patient segments, including adults who are remote to care and therapy naive, those on existing therapies, the very young newborns up to. We've had patients up to age 80. Really the full spectrum of patients, and we really see continued growth, sustained growth in the U.S., accelerating growth outside the U.S. as we continue to bring more countries on board. We've pointed out that this really was a global launch where we were able to launch in the U.S., launch in Europe, launch in Japan, all within several months time, and now we're going to go through the work of getting approvals, access, and reimbursement in regions throughout the world as we continue to grow the global business. Okay. There are still questions as to whether there's a bolus effect or that all the patients interested would just get this therapy right at the beginning. Yeah leading to less growth over time. What have you seen from the launch to prove this theory wrong? Yeah. I never heard of a launch that peaks in year one or that all 17,000 patients show up at the clinic and get a drug day one. That would be a new one, and we didn't expect to see that here. What we've seen is absolutely acceleration in the beginning because there's such a significant pent-up unmet need. What we heard somewhere around November of 2025 in the U.S., a lot of the centers start to say, "Look, we're just going to start seeing patients as they come in every six months or every three months for their visits to start putting them on therapy." That's the sustained cadence we've seen really since the latter part of 2025 into 2026 and what we expect going forward. Look, there's 17,000 patients in the U.S. We've gotten over 2,000 start forms. We have a long way to go here. Yeah. What we've said and been very clear on is we expect to have sustained growth in the U.S., and we stand by that. We believe in that. Again, one of the early stories of launch was getting into some of the segments people thought we would get to later, like therapy-naive patients, those who've tried and failed therapy, and we still think we have a long way to go in those segments, but also in the switch population. There's probably still about 2,500 patients on Kuvan brand that are generic that physicians and other prescribers have said we expect to approach those folks about switching. Now, we don't expect all of them to switch, but that just tells you there's one very large identifiable segment, all of whom are likely to benefit and be adherent on SEPHIENCE, yet to get trial on the drug. Those things give us a lot of confidence that we have a long way to go, and everything we're hearing in the community, patient community, prescriber community, is a lot of enthusiasm and a lot of excitement and a lot of pent-up demand that remains not only in the U.S., but obviously outside the U.S. as well. Okay. You've referenced that 70% of patients with PKU have, at one point or another, tried Kuvan. Why do you think it was such a high percent for a rare disease therapy, and ultimately, why did so few of them stay on therapy, and why is SEPHIENCE going to be different? Yeah. I think it's important to understand PKU as a disease, and I think people often underestimate how debilitating a disease it is. The standard of care for folks, it's newborn, diagnosed at birth. From the beginning of life, you're on a highly restrictive diet. If you talk to individuals with PKU, they will tell you how restrictive that diet is in terms of their lifestyle, how you're forced to make a trade-off between trying to have foods you may like or that your friends or family eat, either trying those foods and having debilitating cognitive effects and brain fog or, again, not being able to partake in these foods. There's a high degree of interest in getting on a therapy that can potentially lower your phenylalanine and allow you to liberalize your diet and have the foods that other folks in your family or your friends are having. I think that's why you had a large number of people try Kuvan. Now, unfortunately, it didn't provide those effects, I think, for the vast majority of people, and that's why people didn't stay on it. Because if you have to have this restrictive diet and a therapy, and the restrictive diet doesn't change, or you don't feel better, there's no need to also take a therapy. It's really not the kind of setting where I'll just try it because maybe something will work. No, you want a therapy that's going to change your already very burdensome and restrictive life with the disease. I think the other thing to point out is while that percentage of patients tried the drug, that means that 30% didn't. Who are those 30%? Those are individuals who are believed to have what are known as non-BH4 responsive mutations. That means that they have a genetic mutation that shouldn't respond to Kuvan or BH4. Part of our launch has been trying to get folks who tried and failed previous therapies, those who are on Kuvan, because our data show that 100% of individuals on sapropterin who have a benefit when they switch to SEPHIENCE do better. Do better in terms of Phe lowering and diet liberalization. There's also the 30% who were therapy naive who have these more severe mutations, and we're seeing them come back to care, come back to the clinic, and we're having success with those more severe mutations, which I think is a really important segment that many people didn't expect us to be able to access so soon or even at all in the launch. Now that we've accessed all those segments, we've said that we've gotten prescriptions from 100% of the centers of excellence in the U.S. That's a very broad base for which now, as we move further into launch, we just penetrate deeper and deeper into each of these segments at each of these centers. Okay. Do responses look different across patients, like diet changes, mood impacts, et cetera? What's the minimum benefit a patient would want to see to consider staying on therapy chronically? It's a really good question because one of the things we're learning is that response looks different for different individuals. I think being able to lower phenylalanine alone has benefits. Folks will say that they feel better, they have less brain fog, they have less fatigue, can do more just by having a better control of the phenylalanine. Clearly, folks also would love to be able to liberalize their diet, even if it means just one meal a day. For a kid, being able to sit in the lunchroom and have a similar lunch to other kids. Yeah. That one meal means a lot. We have heard stories time and time again of that being able to happen, or families that can go out to eat and everyone can go out to eat and have food together, and that is really transformative for folks. As you alluded to, we are hearing more and more as well about CNS benefits, improved mood, decreased brain fog, decreased anxiety, and so these benefits come in many different forms. In effect, when we look at payer policies and different payers, they define benefit in these different buckets. There is quantitative benefits such as lower phenylalanine, increased protein intake or diet liberalization, but also general medical benefit, just feeling better, being able to think clearer, decreased anxiety and such. All of these play a really important part, and this is why we are seeing such high levels of adherence and why there is still a very large number of folks with interest in getting on the therapy. What gives you confidence that the discontinuation trends you are reporting will start to stabilize soon? Why is this indication also so different relative to other ones in the rare disease where we often have to wait several months, years Yeah to understand if there is a true benefit? As we shared at Q2 earnings, we're about 20% discontinuation rate, and we believe we're now approaching steady state. We said we expect to ultimately be in that range of 20%-25%. That's what we saw in the clinical studies. What gives us confidence is that is what we're seeing in the numbers and the trends and discontinuations. Also, the fact that, as we alluded to early on, we saw a larger number of patients than expected coming from that bucket of therapy-naive patients, those with more severe disease. To be able to have that high level of adherence in the most severe patients means a lot because, as you said, this is a disease where you know if you're responding or not. Yeah. We've all done work, and we have experience in neurological disorders or neuromuscular disorders where you're not sure if the drug is working because you're slowing progression, and so how would I have progressed if I'm not on the drug? I don't know. Maybe it's helping. It's just hard to tell. In PKU, you can quantify benefit. You can quantify benefit on a blood test relatively quickly. What we've seen and heard from prescribers is, in general, they're giving about a three-month trial of the drug to understand if someone's responding, either in terms of phenylalanine lowering or increased protein intake. When we understand the duration of that trial period and look at the numbers, that's why we sense we're coming to steady state. What's the biggest misconception you've heard from investors about the SEPHIENCE launch, and what are your thoughts as to why it's not true? Well, I think one you raised this morning already, that why didn't all the patients come on in year one? Yeah. I don't know. I've never heard of that in a disease launching in the first year. Look, I think there's been a lot of misconceptions about the launch, and I think we've just been ticking through them as we go along, whether it's the fact that therapy-naive patients are never going to come back to clinic. They are. That you're never going to get adults on drug. We are. I think that people are not appreciating how large the potential is here, and that individuals with PKU want a drug. I think a lot of people thought that since the vast majority of patients weren't on Kuvan Right meant that folks didn't want to be on a drug. Well, that's not true. They'd want to be on a therapy that's going to help them, that's going to make them feel better, be able to enjoy more food and such. We're already at a run rate that it probably exceeded Kuvan peak, and we're not even one full year into the launch. I think that just says that this is different. You need to think about this therapy differently. It's differentiated, and there's great potential to get to where we said. We believe this is a $2 billion plus therapy. Everything we're seeing, we're on that trajectory to get there and even further. We remain confident in that, and with continued growth in the U.S., we think there's a long way to go just given the number of patients. Then, as we said, this being a true global launch, as we open up more and more countries and gain pricing and reimbursement, we're going to see growth outside the U.S. Yeah. How should we be thinking about ex-U.S. opportunities? You already have a pretty substantial footprint even before this product was approved and continues to be approved in other regions. Yeah. As you alluded to, we have a global commercial infrastructure. We have teams that are very experienced in bringing rare disease therapies to patients. We've demonstrated to do that in a number of different disease areas with a number of different therapies. We've said there's about 58,000 patients globally in markets where we commercialize, 17,000 in the U.S., so over 40,000 outside the U.S. and we're already seeing early success. We started first by launching in Germany last summer, taking advantage of the free pricing period there. We're seeing opportunity for continued growth in Germany. We launched in Japan at the end of the first quarter, and we had really a solid uptake in the second quarter and really excited about the opportunity there. While there's only about 1,000 patients in Japan, we have pricing that's on par with the U.S. that's going to be set for 10 years since it's an orphan drug. We're leveraging the in-patient programs in a number of countries in Europe and other regions of the world. We've already begun pricing and reimbursement discussions in a number of countries in Europe. We've got recent approvals in the Middle East and expect to be launching there in the near future. Brazil was approved earlier this year, and our teams are very experienced in navigating the complexities of access and reimbursement in Brazil. We've already gained the highest classification possible as an innovative therapy from CMED, and we're already putting in place what needs to be done to leverage first the judicialization process there that can lead to group purchase orders and a successful commercial opportunity there. We're going to expect to be continuing to growing in markets in Europe, Middle East, Russia, Commonwealth of Independent States, Latin America, Canada, all these different countries we expect to continue to contribute probably as we move into 2027 and beyond. Okay, thanks. Let's switch gears to votoplam for Huntington's disease. I know you and your partner, Novartis, have discussed meeting with the FDA later this year to discuss the recent data. Can you just talk from a high level since the Street saw the data, what new analyses the company has conducted since that time? Has this changed how you think about the profile of votoplam? Yeah, I think we all remain incredibly enthusiastic about the profile of votoplam. This has been a clinical development program that we have talked about when we started it before the licensing deal really followed in the steps of Evrysdi and how to develop an oral splicing molecule for primarily CNS disease. What we have been able to show over the course of the development program is first understanding the dose. It is safe and well-tolerated. The drug is going where it is supposed to go in terms of achieving the necessary levels of CNS exposure to get throughout all the brain regions which are affected by Huntington's disease, as well as evidence of dose-dependent lowering of huntingtin protein. We said all along that we believed we needed to be achieving roughly 30%-50% huntingtin protein reduction in order to achieve long-term efficacy, and that is exactly where we are. We then moved into the phase II study, where we wanted to understand dose exposure, HTT lowering in Huntington's disease patients, be able to understand early effects of clinical benefit, which we have first against placebo and now 24 months against natural history, and again reinforce safety and tolerability and understand the appropriate population whom we can best capture effect over the long term, which we have been able to do with the stage two patients. After we shared the 24-month data showing 52% slowing of disease progression at the higher dose in the stage two patients, we said that we would discuss with Novartis the potential to talk to FDA about the data. We have been very clear that the announcement by uniQure that they are planning on submitting a BLA, which is now submitted based on cUHDRS as an intermediate clinical endpoint, was an important data point for us. We believe that if you look relative to that data package, we believe we have a very strong package. We have evidence of slowing over 24 months of 52%, which is meaningful. We have dose-dependent effects of benefit. We have exposure in a larger number of patients. We have a placebo group against whom we were able to benchmark efficacy. We also have objective measurement of HTT target engagement and lowering. That is something you typically see in a gene or cell therapy. We have that with the oral therapy, given the fact that we can leverage the fact that it has systemic exposure to look at blood cells and confirm that the drug is in fact working the way it should. The potential confirmatory study, phase III study is up and running. We think all the important points there, including the fact that the drug is reversible if need be, make it worthy of having a discussion with the FDA of how they would view the data package for potential accelerated approval. Okay. I know all the details haven't been disclosed publicly yet, but what is the rationale behind the interim for the phase III? Is there a potential to also approach the regulators at that time as well? Absolutely. So look, the Novartis team, they've been really excellent partners for us. We're really proud of the partnership, and they put together a study plan for phase III that's very thoughtful, that was very well powered, and really sets the stage for success in the early symptomatic patients. The idea of the interim analysis is, look, it's a very large trial, a target enrollment of about 770 individuals. The primary endpoint is change in cUHDRS up to 36 months, which means when a certain number reach 24, a certain number reach 36, that study will be over. When you have that large a study that's that well powered, it opens up the possibility of taking an earlier look at an interim analysis with the potential to have success, and that was the whole idea behind the interim analysis. So you're absolutely correct. There's many bites at this apple. There's the potential of discussing accelerated approval based on the PIVOT-HD long-term data from phase II. There's interim analysis of phase III, and then there's the completion of phase III. So there's many different opportunities along the way. Okay. Based on the patients you evaluated in phase II and the ongoing phase III, which patients at this time do you believe are going to be most appropriate for this therapy, and how large is that market? Yeah. I think this is a really important concept in, let's just say neurology at large, which is you have drugs that you believe can be beneficial to the full spectrum of patients. However, in terms of clinical trial and demonstrating efficacy based on endpoints, there could be varying sensitivity to treatment effect based on stage of disease. That is why when we started this program, one of the important questions we wanted to answer is what is the optimum clinical trial population in whom efficacy can be recorded in the relatively short duration, relative to the duration of the disease, of a clinical trial? That is one of the things we wanted to look at, and the hypothesis going in is that the Stage two patients were probably that sweet spot where the disease was not so far progressed that it would be hard to show clinical effect over the course of a trial, especially when you are acting at the etiology of the disease, HTT lowering. Or were not so early that you are not manifesting enough clinical changes over the course of the trial that you can show that you are slowing those changes. So we think this is really about the optimum clinical trial population, but we believe that there is the ability to treat the full spectrum of HD patients, and in particular, the very early stage, and even those that— This is a genetically diagnosed disease. If you can treat individuals early by slowing the production of the causative mutant protein, you would want to start therapy as early as possible. So that is a long way of saying that we think the addressable market is really the full spectrum patients. What we have focused on now in phase III is the population in whom we think we are best able to capture that clinical benefit and gain authorization. Okay, thank you. So maybe touching more on your pipeline, how has the oral small molecule splicing platform gotten better as you have had plenty of years of diligence now between Evrysdi and now votoplam, and how is this going to influence the future pipeline? Yeah, we're incredibly excited about the splicing platform. As we shared at our R&D day last December, one of our priorities for the past couple of years, and as we've been transforming PTC for the future, was to really focus on the splicing platform. It was our view that this had been a bit under-cultivated. If you think about what we have in that platform, it's a very powerful RNA platform of oral molecules that are able to target CNS diseases and achieve biodistribution that you can't necessarily achieve with other approaches of targeting RNA, whether that be siRNA or ASOs. Just biodistribution is a big challenge. With oral therapies, we're able to get full brain biodistribution as well as systemic distribution, and the fact that we can achieve RNA sequence specificity with the oral small molecule is incredibly appealing. What we've really done over the past couple of years is double down our efforts on splicing and leverage a lot of the important learnings we've made. For example, the Evrysdi and votoplam both targeted a single dinucleotide sequence. Other people working in splicing have also only been targeting that sequence. We found that there's over 250 additional sequences we can drug and have started to begin that work of doing that. We've built PTC, which is an innovative engine that leverages our small molecule library, our understanding of target sequences and the biological relevance of those sequences that helps us by both facilitates and accelerates the discovery of molecules and our ability to move them through. The MSH3 program, which we recently announced a development candidate for, is really exciting. PTC-303 can target Huntington's disease, a different aspect of Huntington's disease that's complementary to Huntington lowering and may be particularly relevant in juvenile HD. It can also target DM1 and other triplet repeat expansion disorders. That's really exciting. That program started about 3. 5 years ago. That's warp speed compared to the time it took to get Evrysdi through the lab and to take votoplam through the lab, and we're hoping to do more of this faster development, more therapies that we can get forward for splicing. So we're really excited. We think this is obviously a validated, highly valuable RNA technology platform. Okay. We've actually been seeing a lot more increased interest recently for your acquisition of ST-920, a gene therapy for Fabry disease. Why did the company think this would be a good fit for you, and how are you thinking about its commercial potential early on? Yeah, absolutely. Look, we said we like to be strategic and opportunistic, and I think this ticked both those boxes. We expect that deal to close in the next one to two weeks. This was an opportunity to get a BLA stage asset. We paid $111 million upfront. That is high value. We think this is a potentially very valuable market. We are still doing our work on the commercial opportunity, but looking at previous analyst estimates and some of our early work, we believe this could be a $750 million-plus global peak opportunity. For us, this was about looking at this compound as a potential therapy that could be very meaningful to patients. Enzyme replacement therapy is the standard of care in Fabry disease, so the ability to deliver a one-time administered durable enzyme replacement therapy we felt was really, really meaningful. We have got a number of folks on our team who have worked in Fabry disease in the past, whether that be on Replagal or Fabrazyme, who are very passionate about helping the Fabry community, and together we saw this as a therapy that really can deliver a much needed therapy to the Fabry community. So we are incredibly excited about it. We have said that we expect the BLA submission to be completed before the end of this year. Our team is bringing their experience in getting gene therapies approved. We had one of the first AAV therapies approved with Upstaza, so we know very well what it takes, particularly in the CMC realm, which is very complicated. So we are all rolling up our sleeves, look forward to helping getting this package in, and getting this across the line, and getting to what we think could be a very important and meaningful therapy to the Fabry community. Okay. Pierre, you have quite the robust balance sheet there. How should we be thinking about any BD opportunities, and how are you as an organization going to balance the cost of the internal programs versus out-licensing opportunities? Yes. We are very pleased obviously with our strong cash position. We closed Q2 with over $2 billion. The Sangamo transaction, which is discussed, was $100 million in change up front, less than 1% of our cash balance. We still have significant firepower available to us. We still obviously can develop all our internal programs and have the potential to be cash flow breakeven this year, and then obviously think about profitability, sustainability for the business. It gives us full flexibility, we receive full power on all our internal programs, and we will still look at additional opportunities to complement what we already have in a disciplined manner, which we have always been in the last couple of years. I think the Sangamo transaction highlights how we think about creating value for our shareholders. Okay, thank you. Lots going on at the company. I can only ask so much in 30 minutes, but big picture, what do you think is the most misunderstood or the undervalued component to your valuation right now? I think a few things. Big picture, being a company that has our revenue potential this year, we have talked about already how we have raised our guidance several times as we continue to perform. The potential of SEPHIENCE to be a multibillion-dollar product, a differentiated R&D portfolio, including votoplam, which could be a significant value for which we do not have to incur any more operational expenses. To be able to be cash flow breakeven this year heading towards profitability. You put all that together, that is pretty unique. I think there is obviously significant value in, I think, SEPHIENCE alone that is not appreciated if you think about the true opportunity. When you think about the uniqueness of a company our size, a differentiated rare disease company with strong product portfolio, a strong R&D portfolio, and the ability to be cash flow breakeven and then profitable in the near future, I think that is pretty special. Okay, great. Well, thank you both so much for being here. Really appreciate your time. Wishing you all the best. Thank you very much, Kristen. Thank you.