Good morning, everyone. Thanks for joining Jefferies' Healthcare Conference in London. My name is Clara Dahn, one of the biotech analysts here. Here sitting next to me, we have the team of PTC Therapeutics, Matt Klein, CEO of PTC, and Pierre Gravier, Chief Financial Officer of PTC. Welcome. Thank you, Clara. Great to be here. It has been a really busy year for PTC, from commercial launch to clinical readouts. Just before we go deeper into the pipeline, why do you not give the audience an overview of PTC and tell us what has kept you busy for the past year? Great. Thank you. PTC is a global biopharmaceutical company focused on rare disease therapies. We have a robust commercial portfolio with six marketed products that we ourselves commercialize around the world. We have an innovative R&D pipeline anchored by our validated splicing platform. As you mentioned, it has been a busy year for us, highlighted by the initial global approvals and global launch of SEPHIENCE, our oral therapy for PKU. As we have talked about, given the significant unmet need for patients with PKU, we expect this to be a multi-billion dollar opportunity for PTC. As we shared at our Q3 earnings a couple of weeks ago, the launch is off to a fantastic start. I am sure we will get into a little bit more detail on the launch and what we see coming for SEPHIENCE over the course of the chat. Great. Yeah, definitely, we're going to spend a little bit of time on PKU and SEPHIENCE. Maybe before we talk about the drug, about the launch, I think it's important for the audience to understand the disease itself as well, the background. What's the biggest unmet need in PKU, and especially in the context of patients' dietary lifestyle? What do you see as the most important things patients care about? Yeah, absolutely. Look, there remains, despite there being two approved therapies for PKU, there remains a significant unmet need. This is a population of about 17,000 individuals in the United States. We've said about 58,000 in markets where we intend to commercialize worldwide. Again, while there are two approved therapies, the vast majority of patients are not on these therapies, whether it be due to not having enough efficacy in terms of patients being able to have significant lowering of their phenylalanine levels, or, as important, and in some cases more importantly, the ability to liberalize their diet. Patients with PKU are born with an inability to metabolize phenylalanine, which is an amino acid contained in protein. Therefore, the standard of care is a highly restricted diet. If an individual is not able to feel better in terms of having less brain fog, cognitive impairment, and be able to take more protein, there's no added benefit to being on a therapy because already their basic care or the basic standard of approaching their disease is being on a highly restrictive, burdensome diet. That's one reason why an individual may not be on one of the approved therapies. The other approved therapy for adults only has significant tolerability and safety issues, making it very difficult to get to a dose that's effective and then tolerate a dose that's effective. In a way, this represented a very unique opportunity in rare disease where there's all of the benefits of having therapies been in the market already. That is, centers of excellence identified, well-aggregated patient communities, payers that understand the disease and understand that value can be drawn or tied to phenylalanine lowering. There is also newborn screening, so patients are known at birth. Yet, without any of the disadvantages in that there is a significant unmet need, a significant desire for patients to be on a therapy that can be safe, well-tolerated, and bring the benefits of phenylalanine lowering and diet liberalization. With SEPHIENCE, we have a highly differentiated small molecule oral therapy that is once a day and that has demonstrated significant efficacy in clinical trials, significant added benefit relative to the existing oral therapy and the head-to-head clinical study. Also, importantly, showing the ability to allow individuals to liberalize their diet. In the open label extension of our phase three trial, 97% of patients were able to liberalize their diet. Two-thirds of patients were able to get to levels of protein equivalent to the recommended daily allowance of protein intake for an individual who does not have PKU. This includes these effects in the most severe patients. What we have in SEPHIENCE is a safe, well-tolerated therapy that is able to significantly lower phenylalanine and, for most patients, enable the ability to liberalize their diet. It is really ticking all those essential boxes in meeting the unmet need for kids and adults with PKU. SEPHIENCE was approved in July this year. Maybe let's just talk a little bit more about this product. Fresh out of the gate, it put out a really incredible first partial quarter revenue numbers. Maybe just talk to us a little bit about what you've been hearing from physicians in the field about their experience. How does the narrative have changed for PKU treatment with the arrival of SEPHIENCE? Yeah, absolutely. As I mentioned in my previous comments, we had this backdrop of significant unmet need and a highly differentiated therapy. I'll also add that we have an experienced commercial team that's demonstrated success in marketing rare disease therapies, especially in competitive and generous sized markets. We had time to prepare for this launch. We had mapped out all the Centers of Excellence, had been well integrated with the patient community, a very strong understanding of the decision makers at the specialty centers, whether that be physicians, whether that be nurse practitioners, the importance of building strong relationships with dieticians who are often the point of contact for PKU patients. We were able to set all that up. Once we had approval, we were able to get the launch off the ground quite well. In the first six weeks or so of the third quarter, we reported $19.6 million in revenue, broad penetration in terms of number of prescribers, touching all the Centers of Excellence in the U.S. We also got the launch initiated in Germany as well, again, with close ties to key specialty centers there. What we're hearing from physicians and the patients is a strong desire to get on the therapy. We're getting feedback from a lot of the key physicians that they expect to try all of their PKU patients on SEPHIENCE, regardless of whether they are on existing oral therapy, regardless of their severity. That's exactly what we've seen in the early days of the launch. We shared at our earnings call that we've seen the full spectrum of patients, including patients as young as two months of age being prescribed SEPHIENCE. We have a patient as old as 79 years of age being prescribed SEPHIENCE and also seeing the full range of severity. We're hearing a lot of reports from physicians of them wanting to try their more severe patients on drug first with very good results, classical PKU patients who are seeing, in some cases, 80%-90% reduction in phenylalanine. What this is doing is just driving that desire of the physicians to try all of their patients on PKU. That really supports the notion that SEPHIENCE will become the standard of care for PKU patients. I also want to touch the point you mentioned earlier about the broad clinical specialties prescribing SEPHIENCE. Are you seeing any trends among physicians, nurse practitioners, and dieticians in terms of what the mix looks like? Are their experiences consistent? What we're seeing is that at the specialty centers, and again, I meant there's 104 Centers of Excellence in the U.S., that there's prescriptions coming from physicians. We're seeing more prescriptions actually come from nurse practitioners. Again, being able to also tie in the dieticians who are at the centers. Not surprisingly, if there's individuals who are not on an existing PKU therapy, they're not seeing the doctors frequently because there's very little being offered to them by the physicians at the center. However, since diet is the mainstay of therapy, they are in touch with the dieticians and nutritionists at these centers. This is, again, part of the important work you do prior to a launch, which is understanding the dynamics at each center, who are the decision makers at each center, how are they in touch with individuals at the center, and understanding that on a center-by-center basis so that we can provide direct support. I'll also add an important part of our building out our customer-facing teams for the launch was adding a number of dieticians to the PTC medical field force. The reason for that is we want to be able to provide peer-to-peer support and also understanding that as individuals get on SEPHIENCE, management of diet and the diet liberalization process becomes very, very important because we want to ensure that once an individual starts therapy, there's not this rapid increase in dietary protein, but rather a gradual, measured approach so individuals are set up for success in their diet liberalization process. Do you get a sense of what percentage of the existing PKU patients haven't gone on any therapies or what percentage have tried approved therapies, but ultimately discontinued? I mean, we've done our own survey, and it tells us physicians would like to prescribe SEPHIENCE really across a full spectrum of patients. Just maybe based on what you've seen so far, any patient segment you would think is the lowest hanging fruit in your view? Yeah. There are probably three broad segments of patients: those who are on therapy, which we've said is quite small; those who have tried and failed, which is a bit larger. It is estimated that 70% of patients have tried the oral therapy, but again, very few remained on it. Then there is a bucket of patients or a segment of patients who are "therapy naive." Those are often patients who are a bit more severe, for whom most physicians believe there would be no benefit of going on the oral therapy, so they were never tried. In terms of the "low hanging fruit" in the launch, it is interesting. What we've heard is different things from different Centers of Excellence. I had mentioned before that we've done some head-to-head studies with the existing oral therapy and found in our most recent study, the Amplify study, that we were able to provide on average 70% greater lowering of phenylalanine compared to giving BH4 alone. That really supports what we know based on the mechanism of SEPHIENCE, which is if there is an individual who has had some benefit from taking sepiapterin and a BH4, they will have a much better response to SEPHIENCE. If they have a little bit of lowering of phenylalanine, there should be much greater lowering of phenylalanine and the ability to liberalize diet. We also know that individuals who have mutations that are known as non-BH4 responsive mutations or quite simply ones that are not expected to respond to giving BH4 or sepiapterin, whether that's Kuvan, generic, or branded, they too are able to have benefit from the therapy. What we're seeing is at some centers, the prescribers are prioritizing those who are already on the oral therapy and saying, "This is pretty straightforward. I'm going to switch one once-a-day oral therapy to SEPHIENCE, a much more potent and more effective oral therapy. In other cases, we're seeing physicians want to get those therapy naive patients or more severe patients who currently don't have a therapy and said, "Okay, while I could always switch the patients who are on the oral therapy, why don't I prioritize those who don't have something right now and get those individuals on drug?" Again, that's exactly what we're seeing. The most important point, Clara, is the one that you mentioned, is that what we're hearing time and time again is the desire to try all patients on SEPHIENCE, whether those come at the start of the launch or as we get further into the launch. I also want to talk about the market access. I mean, you've mentioned very positive payer feedback and minimal restrictions. What kind of efforts are you making to make sure this remains consistent moving forward? Maybe just talk to us about what the typical prescription journey looks like for PKU patients as well when their journey to get reimbursement. Absolutely. There are two important factors here. One is, as I mentioned, the fact that there have been previous PKU therapies. Payers are familiar with the disease. They understand that you can tie value to reductions in phenylalanine. Two, we have a lot of experience in commercializing rare disease therapies. We spent a lot of time prior to launch meeting with payers. We have continued to do so after launch. Being able to provide the differentiated characteristics of SEPHIENCE, specifically the phase three data, as well as, as I mentioned, this head-to-head study Amplify, being able to arm with head-to-head data and showing a payer the superiority you have relative to the existing oral therapy goes a long way in not having to have step edits or step threes because you show clear superiority and clear differentiation. Again, that is what we are seeing. We are still in early days. We do have a few payers who have already written their policies, including one very large payer. They are basically wanting just authorization relative to the label, which is quite broad in terms of age and severity. We are not seeing step edits and very reasonable criteria to keep individuals on therapy. That is really a good sign. In the early days of the launch, in terms of the journey, it has really been, if there has been any pushback or requirements, it has really mostly been prior authorizations to the label. Again, the label in the U.S. is one month of age and older, full spectrum of patients. In Europe, it is all age groups, no age restriction. Prior auth to the label is quite inclusive. As we get more and more policies coming on board, we'll, I think, continue to expect to see very few limitations in access. You mentioned about the Europe launch. How are we thinking about the reimbursement dynamic outside of the U.S.? How do you see the revenue opportunities for SEPHIENCE shaping up in those regions? Yeah. We have always talked about, in all of our rare disease launches, the importance of maintaining a narrow pricing corridor. A lot of what we think about in terms of the launch outside of the U.S. is about sequencing the countries and sequencing the launches in a way that we can maintain that rigid pricing corridor. That is something that has always been very important to us and I think is even more important today with all of the discussions of most favored nation pricing. We initiated the European launch in Germany, roughly concomitant with the U.S. launch. As you know, in Germany, we have the six-month free pricing period, and the price is on par with the U.S., so quite consistent. We've also been able to provide drug to countries where there's early access or named patient pathways where, again, we can get the drug to individuals in the country, but also dictate the price and keep the price consistent with the U.S. We've also begun our formal pricing and reimbursement discussions in Europe. It is very, very helpful for these discussions to be able to have head-to-head data against sepiapterin and also have evidence of diet liberalization because in Europe, medical foods and formulas, which are part of the standard of care for PKU patients, are reimbursed. Being able to show that getting on SEPHIENCE will lessen the burden on the payer system to continue to provide medical foods and formulas is important. We've also mentioned that we plan this year to have approvals in Japan and Brazil. We will be initiating launch shortly thereafter in Japan in particular. We expect that launch to be in the first quarter. For the existing PKU products, the pricing in Japan is actually higher than in the U.S. This will be another country where we'll be able to maintain our pricing corridor. Moving forward, what metrics, what launch metrics are you going to provide to the street to help us understand how the launch is going beyond the revenue numbers? Yeah, absolutely. What we said we would provide in the third quarter and at the next update, which will be at JP Morgan, will be total revenue. We'll break that out by U.S. and ex-U.S. As I mentioned, it was $19.6 million for the first six weeks or so in the third quarter. That included $14.2 million in the U.S., $5.4 million outside of the U.S. We also said that we'll be including the total number of patients on therapy, which was over 300 patients at the time of Q3 earnings, as well as patient start forms, which was over 520 at the time of Q3 earnings or through the end of the third quarter, and also payer mix. One of the unique aspects relative to other rare diseases of PKU is that about two-thirds of patients are on commercial insurance. Typically, in rare disease, we see the opposite: about one-third commercial, two-thirds government. This is a bit unique. Of course, in the early days of launch, we expect a slightly larger than two-thirds amount of patients on commercial insurance. When we get to steady state, we expect that to be at two-thirds. It will be total revenue broken out, U.S., ex-U.S., patient starts, patients on commercial therapy, and payer mix in the early days. As we get deeper into the launch and we can speak more definitively on some of the other key elements, perhaps patient segments and things like that, once we're able to do so, we will. Also maybe a question for Pierre. How are you thinking about the profitability with the revenue opportunities with SEPHIENCE? Yeah. We always talked about that when we started to completely transform the company two years ago. We said that profitability was a very important target for us. The timing, we said near term, and we're getting there slowly but surely. You can see this year revenue guidance $750 million-$800 million. OpEx was unchanged, $730 million. We're close. The exact timing will depend on the curve for SEPHIENCE, but we will get there. SEPHIENCE is the product that will get us to profitability and beyond. We think about that product to be multi-billion dollar potential. OpEx will decrease over time. We had a few expensive trials coming to an end this year. It is a very important target for the company, and we're getting there very closely. Great. For the last few minutes, I also want to touch on the rest of the pipeline and maybe on the DMD first. The franchise has been pretty sticky despite generic entry. Maybe talk about kind of your efforts or strategy to maintain that revenue against the competitive dynamic from generic. Yeah, absolutely. This is our Amplify program in the United States where we lost exclusivity in February of 2024 and still are at about 70%+ of peak revenue. I think this is attributable to a few things. First, with rare disease drugs, we do not see the typical cliff that you see with larger drugs. There is not really a race to the bottom because there are just not sufficient patients to be able to have that trade-off of price and volume. While there are still six generic entrants in the market, prices remain pretty much as it was prior. The other part is the brand stickiness that we have been able to cultivate through our work in the Duchenne community. I'll point out in particular our patient services team, PTC Cares, which does a lot of work in providing white-glove service for patients in terms of helping support them, reminding them of time for renewal, helping them navigate the payer system, which is important not only for Amplify but other aspects of DMD care, including durable medical equipment and other factors. There is a lot of loyalty and a lot of benefits that come from staying on branded drug. I'll also point out that this PTC Cares team that provides that white-glove service to our Amplify patients is also at the forefront of our efforts at PKU. Again, this idea that working very closely with patients and their families to navigate the healthcare system breeds a lot of brand loyalty as well as adherence to the drug. For vatiquinone in FA, what might be the possible scenarios after you plan FDA meetings this quarter? Talk about that a little. Yeah, absolutely. We have an FDA meeting planned for later this quarter. This is in follow-up to the CRL received in the summer. We're interested in discussing with the FDA what are potential paths to resubmission. One possibility, of course, is to do another randomized controlled trial. There may be others. This is one of the things we want to discuss with FDA, given the fact that there remains a significant unmet need for pediatric and adolescent patients with Friedreich's ataxia, given that the only approved therapy is for individuals 16 and older. Of course, Vatiquinone has a very strong data package in terms of both benefit and safety in younger Friedreich's ataxia patients. A very similar question for Huntington's disease as well. You have an FDA meeting planned this quarter. What are you planning to discuss there? Yeah, absolutely. We're incredibly excited about the PIVOT plan, PTC518 Huntington's disease program, which we have partnered with Novartis. We read out results from the phase two trial, which were in the summer, which were positive, showing dose-dependent effect in Huntington lowering, as well as signs of early clinical benefit relative to placebo at 12 months and then longer term at 24 months, showing dose-dependent benefits on disease progression. We're expecting to read out results from all patients at the 24-month time point in the spring. We've mentioned that we're having this FDA meeting in the fourth quarter. The purpose there is twofold. One, to align with FDA on the design of the next efficacy trial, which will be important as the confirmatory trial in the context of accelerated approval or the registration trial if the accelerated approval pathway is not available. Second, to gain a high-level understanding of the FDA's thoughts on accelerated approval. Again, this is in the neurology division in Cedar, a division that has leveraged the accelerated approval pathway to get drugs forward for other severe neurodegenerative diseases like ALS, like Alzheimer's disease. The idea there is just to get an understanding of what their thoughts are as we head into a data readout in the spring. We might have 30 seconds left. I just want to quickly touch on your upcoming R&D day. What should we expect there? Yeah, we're really excited to share our progress on our scientific platforms. The company has focused a lot in the past couple of years on showing how we've brought spirit of execution and focus to our later stage programs and our commercial efforts. This will be an opportunity to show that we've been doing a similar approach. We've had a similar approach to our earlier research platform. Being able to show folks the progress we've made on our splicing platform, which has already brought forward Evrysdi, which is the leading therapy for SMA, and PTC518 for Huntington's disease, as well as share some of the programs we have in the preclinical and early clinical space from our inflammation platform. Great. Thank you, everyone, for joining this session. This concludes our discussion here. Thank you, Matt and Pierre. Thank you very much, Clara. Thank you.