for attending Jefferies London Healthcare Conference, and my name is Kelly Shi, one of the senior biotech analysts here. In this fireside chat session, we are very pleased to have Dr. Matthew Klein, CEO of PTC Therapeutics, join us today. Welcome, Matt. Thanks, Kelly. It's great to be here. And so a lot of exciting things happening at PTC, but before we go deeper into the pipeline, why don't you highlight some of the things that you have achieved in 2024, and what should we anticipate for the rest of the year? As we entered 2024, we said this is going to be an exciting year with an ambitious agenda, and I'm excited to report that we have delivered on all of our goals, both in the commercial and the R&D portfolio. We recently had another strong revenue performance in the third quarter. We raised our annual 2024 revenue guidance to $750-$800 million, and we closed the quarter with $1 billion in cash in the bank and said we expect to be at least at that level as we close out 2024. On the R&D front, it's been an incredibly busy year with a lot of execution. We have already submitted three regulatory approval applications to the FDA, all of which have been accepted for review, and one has been approved, and we expect to submit a fourth NDA in December. I can just walk quickly through them. The first application was a BLA for our gene therapy for the ultra-rare disease of AADC deficiency. That was approved last week, and we're very proud of that accomplishment. It is the first-ever gene therapy that is directly administered to the brain ever to be approved in the U.S. It came with a Priority Review Voucher, which we expect to monetize in the very near future. The second approval application was an NDA for our PKU program, which had a very strong phase 3 trial, very strong results that support the product differentiation, and we've talked about how we see this easily as a billion-dollar-plus product globally and perhaps even in the United States. We resubmitted an NDA for our drug Translarna, which was accepted for review, and we expect to submit an NDA for Friedreich ataxia in December of this year. Really, as we look back on 2024 thus far, we've executed on all our plans. We're on schedule to execute on all the remaining milestones for the year and enter a very exciting 2025 with a strong cash balance, a robust commercial revenue, and a number of anticipated product launches globally. Fantastic. I have a long list to go through the pipeline. Maybe let's start with commercial. So for the DMD franchise, specifically for Emflaza, can you walk us through your strategy to maintain the revenue in the competitive landscape, especially like generic entry? Yes. So Emflaza is a corticosteroid that we commercialize in the U.S. It lost exclusivity in February, but we've been able to maintain robust commercial revenue. In fact, in the third quarter, we reported $52 million in revenue, which was actually quarter-over-quarter growth, which is almost unheard of in the context of a genericized market. As we talked about, we really attribute this continued strong performance to two things. First, when we think about rare disease drugs, it's not the typical race to the bottom in a genericized market. There tends to be a lot more stickiness to branded product. And then on the other component of this is our team has worked incredibly hard to ensure we enjoy that brand stickiness. We work very closely with the community. We're very well integrated into the community. We also have our PTC Cares program, which is a group of case managers who provide a tremendous amount of support to patients and their families. So not only are you getting a prescription for Emflaza, but you're also getting a lot of support to help navigate the complexities of the healthcare system. So when you put all of this together, we've been able to enjoy robust revenue still in the context of the genericized market. Okay. Good to know. And Translarna, we have a non-stop news flow in both the U.S. and also in Europe on the regulatory front. Maybe just remind us what to expect for the next steps in both regions. And also importantly, what has been the physician and the patient feedback on Translarna? Yeah. So maybe I'll start there. Translarna remains the only therapy that's been developed specifically for boys and young men with Duchenne muscular dystrophy secondary to a nonsense mutation. We currently commercialize in over 50 countries, and it's a therapy that over the years continues to demonstrate to be safe and well tolerated, and we've accumulated a significant amount of data that shows not only short-term benefit in our clinical studies, but in our long-term STRIDE registry, we've shown the ability of Translarna to delay key morbid milestones of disease, such as loss of ambulation by three and a half years, loss of pulmonary function. And so the feedback continues to be incredibly strong from patients and physicians worldwide. In Europe, as you're aware, we had a recent negative opinion on reexamination that is now under review by the European Commission. We're going to sit back and watch that process. Of course, the last time it went to the European Commission, the opinion was sent back to the CHMP for an ask of the totality of evidence to be reviewed. That didn't necessarily happen, so we'll see what happens in terms of the EC's view. But as we've talked about, we're going to control what we can control. We're ensuring that the drug remains available to patients in Europe for as long as we remain authorized. In the United States, we resubmitted the NDA in the third quarter. That file was accepted for review. Again, that's based on the wide range of data, including the full totality of data from study 41, our most recently completed placebo-controlled trial, as well as that long-term data I alluded to from STRIDE, which confirms that the benefits that were recorded in the trial are manifesting cumulatively over many years as important effects on delay and loss of ambulation and other morbid milestones of disease. Okay. Great. And for Evrysdi, now the dominant SMA drug under the commercialization effort by Roche, how do you see the sales trajectory and also, most importantly, the impact on PTC's top line in the coming years? Yeah, so we're very proud of the success of Evrysdi. That is the first-ever small molecule splicing agent that's been discovered and approved, and that, of course, came from PTC's splicing platform. Roche recently reported now there's over 16,000 patients worldwide on Evrysdi, making it, as you mentioned, the leading SMA therapy globally. It was quite clear from Roche's third quarter presentation and discussion that there's still a lot more ways to go in terms of achieving peak penetrance. So we therefore expect revenue to continue to grow over time, and of course, we enjoy a portion of that revenue in the form of royalty payments, which will continue to contribute to PTC's top line in the coming years. Okay. Great. One key investor focus is the PKU program and so maybe starting with the overview of the supporting data you used for the NDA and how does it compare to the standard of care, and how do you think about the potential of your PKU therapy? Yeah. So we, as the patients and physician community, are very excited about sepiapterin, which is our therapy for PKU. It's an oral small molecule that has a dual mechanism of action, and the clinical studies have provided a very strong, highly differentiated product profile that supports its ability to serve the still significant unmet need of PKU patients globally. It's estimated there's approximately 56,000 patients in addressable markets with PKU. The U.S. may be the largest market of between 17,000 and 20,000 patients, and it's said only about 10% of patients are currently served by available therapies. While there are available therapies, and many of the key pillars for commercial success, such as newborn screening, centers of excellence, a well-aggregated patient and physician community, as well as payers that understand PKU, there's a need for a highly effective and safe therapy, and we believe the data we have for sepiapterin supports that. First, from our phase three trial, the Aphinity trial, we had highly statistically significant and clinically meaningful results. In the overall population, we had an average reduction in phenylalanine levels, which is the key endpoint for PKU, of over 60%. In the subset of patients with classical PKU, that's the more severe patients, we had a mean reduction of 69% in phenylalanine levels. That's saying that even in the most severe patients, we're able to deliver highly transformative results. In the entire population, we had over 80% of patients, 84% of patients achieved phenylalanine levels below target guideline of 360 micromolar per liter. That's important for two reasons. One, it's getting patients to a range that's now acceptable and tolerable of phenylalanine, but critically important, it also brings patients to a level where they can now start liberalizing their diet, and for PKU patients, the ability to liberalize the diet is really the holy grail of any therapy because otherwise, patients are stuck to very burdensome, poor-tasting, stigmatizing diets as a source of protein, and to be able to then have a therapy that lets you now enjoy regular meals is incredibly important for patients. We also had 22% of patients in the trial achieve normalization of phenylalanine levels, which is almost unheard of for a therapy for PKU. We then had the patients who were in the trial roll over to a long-term extension study where we were able to demonstrate thus far that there's durability of these important effects on Phe lowering or phenylalanine lowering, and we enrolled a portion of the patients in something called a Phe tolerance protocol. A Phe tolerance protocol is a way to study how much a patient can liberalize his or her diet and still maintain control of phenylalanine. So in other words, can we make a difference in patients' lives and bring them what they really want, which is the ability to have a more liberal diet and still maintain phenylalanine control? And what we've shown so far in the open label extension is about 60% of patients are able to get to a level of protein beyond the recommended daily allowance for an unaffected individual. In other words, they're able to get beyond what you or I may have in terms of our daily protein intake and still have control over phenylalanine, and that's so, so important for patients. It's important for patient uptake as well as physician uptake, so when you take this totality of data along with a consistent safety and tolerability profile, we have a therapy that we believe is highly differentiated and can fill that significant unmet medical need for PKU patients worldwide. Oh, got it. Super insightful, and so you see a lot of unmet needs, including also the room to improve on the quality of life for patients, so put a number on that. How much of a market share you could actually anticipate for sepiapterin? So as we said, there's roughly 10% of patients that are currently served by therapy, and the feedback we have gotten from a number of KOLs around the world is they believe that this is a therapy that they would try all of their patients on. Now, when we think about the commercialization, there's a number of key patient segments, including those who aren't on any therapy or have never tried any therapy, those who have tried therapy and failed, those who have tried therapy and remain on therapy. And we believe we have data that can support accessing each of those segments. Obviously, as we think about commercial launch, those will be prioritized, but we believe that we can make a significant impact and access a large number of those patients, both those on therapy and those who are not currently served. I see. Now, the PDUFA date set on July 29th of next year. Have you heard anything about the possibility of an adcom meeting? We have not. We don't expect to have one. I think PKU is well understood. This is a point where having previously approved therapies is very helpful because we have an understanding of what the regulatory authorities look for in terms of efficacy and safety to support registration, and we believe we have a package that provides evidence of strong efficacy as well as safety. I see. And the one we think about is the future commercial strategy given we have a Kuvan generic. So how should we think about the pace of launch and what's your strategy? What's the sweet spot to target down first, like all that? Yeah. So we've been working on this. When we initiated the Affinity trial a few years ago, we wanted to make sure that we had centers of excellence all over the world involved in that study. That's a very important first step because that gets the drug in the hands of KOLs and at the leading institutions around the world. Furthermore, when we completed the Affinity phase three trial and initiated the open label extension, we allowed direct enrollment again as a way to get more patients, more KOLs involved. There's a very, let's just say, sepiapterin is very well known in the community around the world. There was a recent seminar at the metabolic meeting in September at the SSIEM. There were over 400 people there, full room. So people know this drug is coming, and I've said they're very excited about it. We've also done a lot of work in the patient community. PTC, as being rare disease focused for so many years, always makes it a priority to partner very closely with the patient communities and help with disease education and disease awareness. So what we're doing is really supplementing those existing commercial pillars that are already there so that we can be ready at the time of approval to quickly launch. We will, of course, look at the segments that we prioritize. We'll look at those therapy naive patients who maybe have never tried before, who now would be able to have a therapy that can be safe and effective for them. We keep hearing from physicians a desire to also look at switches early on because even in the context, for example, in the U.S., if there's a step edit for insurance, this is quite straightforward because it's basically a blood test phenylalanine level that after a week on therapy, you can demonstrate that there is better management of Phe with sepiapterin than, say, generic Kuvan. So I think the fact that it is a genericized market shouldn't have an impact because, again, this is really a story about differentiation and superior efficacy. I see. And do we expect a data update next year for the Phe tolerance trial? Yes. We'll continue as we do data cuts to provide an update to the community. Okay. Fantastic. Maybe moving to the PTC518 in Huntington's disease. This has never been an easy space, but we see the landscape, the sentiment to the landscape actually evolving as a positive sign. So maybe first, what has been the learnings from the 12-month data and what kind of feedback have you heard from physicians first? Yeah. So PTC518 comes from our splicing platform and follows on the heels of the successful discovery and development of Evrysdi for SMA. We were able to take a lot of the key learnings we had in what made Evrysdi successful in developing an oral small splicing agent for whole brain disease to the development of PTC518, including important elements of target selectivity and specificity to make sure that we're really hitting just the Huntington target and not other genes, to ensure that we have excellent brain exposure, incredibly important in Huntington's disease, which is a whole brain disease, and we've been able to demonstrate preclinically that we are affecting the whole brain, and then a lot of important lessons in the development. I think one unique feature of Huntington's disease, as you mentioned. It is a challenging disease as all neurodegenerative diseases are, but it's pretty unique in that it is the one neurodegenerative disease where we know the cause for all patients. It's a genetic mutation in the Huntington gene that results in the production of a mutant Huntington protein that causes cell inflammation, cell stress, cell death, and ultimately neurodegeneration, and what we're able to do with PTC518 is directly target that Huntington gene and turn down the production of that disease-causing protein. So again, we're in a unique situation where we know what causes the disease and we can target it, and so what we've been doing in the PTC518 development program is sequentially tackling the key things that we need to do to be sure we have a drug. And so what we focused early on is assuring that we have appropriate PK/PD relationship, that is, being able to show that the drug gets absorbed, it's getting to adequate levels of exposure in the brain to have its effect, and that it's working the way we intended to do, that is, by inducing splicing and decreasing the production of that disease-causing mutant Huntington protein. And so with our most recent data readout this past June, that was 12-month data on the first 30 or so patients that have come through the PTC518 phase 2 PIVOT-HD trial, and we were able to show durable lowering of blood Huntington protein levels that was dose-dependent and achieving lowering in the range of 20%-50%, which is that identified range of where you're likely to have clinical benefit. We show that the drug is getting excellent exposure in the brain. In fact, we have higher drug concentrations in the CSF fluid than the plasma. We were able to show decreases in mutant Huntington protein in the CSF consistent with the dose-dependent reductions we were seeing peripherally, so a very good sign that we're getting brain activity, and finally, at 12 months, we were able to see dose-dependent effects on a couple of the important clinical scales, including the total motor score and the cUHDRS, so we have a data package at 12 months that's telling us the drug's getting where it needs to go, the drug's doing what it needs to do in lowering Huntington protein, and we're starting to see early signs that it could be having that clinical benefit that can make this an effective disease-modifying therapy. Great. And in the light of this optimal PK/PD data and biomarker data for the next update, what kind of functional metrics we should focus on? Yeah. So the next data readout we expect to be in the second quarter of 2025. We've said that we'll complete the trial or the last patient visit for PIVOT-HD at 12 months in the first quarter, and then it'll be a little bit of time to get the results. And that will be a readout on approximately 140 or so patients who have completed 12 months of PIVOT-HD. That will allow us to have a more robust data set confirming the huntingtin reduction peripherally and centrally, and then also allow us to have data on more patients looking at some of these clinical outcomes, including total motor score, including cUHDRS. So we really look forward to having that data set, and we've also said that we expect to meet with the FDA next month in December to have a discussion on their views of whether huntingtin lowering could serve as a surrogate marker that could support accelerated approval. And we've talked a lot about how the scientific evidence clearly shows that lowering Huntington protein could lead to significant clinical benefit and that huntingtin lowering should be occurring in the 20%-50% range, which is, of course, what we've been achieving in our clinical studies. Okay. And we have gone through a lot, but we only have three minutes left for the rest of four programs. Maybe congrats on the U.S. approval Upstaza. Maybe for the audience not very familiar with that, can you highlight the unmet needs and how do you think this therapy could do commercially and what kind of benefit it brings to patients? Yeah, absolutely. So AADC deficiency is an ultra-rare disease, and children are born without the enzyme that allows them to make dopamine. And dopamine, of course, is the neurotransmitter in the brain responsible for motor function. So these children, in the most severe cases, have no spontaneous motor function. The gene therapy is delivered through a specialized neurosurgical procedure. We always say it's minimally invasive, but people say, "How can you be minimally invasive brain surgery?" But it is. But it's done to basically deliver the gene therapy to a specific location in the brain called the putamen, which is the part of the brain that needs the dopamine. So we put the gene where it needs to work, and we're able to record weeks afterwards that there's now an increase in dopamine production. What we see over the course of months to years is children gradually obtain motor development milestones, first being able to lift their head, then being able to sit up, then crawl, and in some cases, be able to walk. We've even had reports that children ultimately catch up and start achieving all regular milestones. This is an ultra-rare disease, and we said that the patient numbers are quite small, and there's a commercial opportunity. It's modest. We've said that part of this is not only the ability to bring an important therapy to patients. This is obviously also pioneering in that it opens up a whole new concept of drug delivery directly to the brain, but also the PRV, which is going to be important to us from an economic standpoint. I see. And last but not least, vatiquinone, you're actually building a franchise of clinical programs around it. Maybe in the last 30 seconds, highlight what are the indications to pursue and the key catalysts for this therapy? In 30 seconds, I'll focus on our NDA to be submitted in December, which is for the treatment of adults and children with Friedreich ataxia. There's an approved therapy for Friedreich ataxia, but it's for 16 and over. We have, based on our phase 3 MOVE-FA study, evidence of safety and efficacy in pediatric and adolescent patients as well as adults. We've aligned with the FDA on the approval application, which is going to be based on that placebo-controlled study showing benefit not only in slowing functional decline, but improving the symptom of fatigue, as well as confirmatory evidence from long-term studies, which we recently shared in October, including that after three years of treatment, we have a 50% slowing of disease progression. Okay. Fantastic. Well done, and so congrats on all the progress being made in 2024, and looking forward to an event for 2025, and thanks.