All right. Good morning. Thank you for joining William Blair's Growth Stock Conference. I'm Sami Corwin, a research analyst covering PTC at William Blair. I'll refer you to williamblair.com for a full list of disclosures. Kicking us off this morning is Dr. Matt Klein, the CEO of PTC. So without further ado, Matt, welcome. Thank you, Sami, and good morning, everyone. Before I get started, I refer you to our forward-looking statements here. PTC was founded over a quarter century ago with the mission of using pioneering science to deliver therapies to patients with rare diseases who desperately needed them. We've succeeded in this mission and built a global biopharmaceutical company that discovers, develops, and commercializes transformative therapies for patients with rare diseases. Last year, PTC celebrated its 25th anniversary, and that was a perfect time to reflect on our many pioneering accomplishments, including pioneering the field of RNA-directed therapies, pioneering the field of oral splicing molecules, establishing the field of drug development for Duchenne muscular dystrophy, and developing the first-ever direct-to-brain administered gene therapy, Upstaza. But it was also an important time to make changes so that we could position PTC for future success, and we did that. As we began to build the PTC of the future, we emphasized focus. We focused our R&D portfolio on small molecule therapies and focused our R&D efforts on areas of science where we have unique expertise, including ferroptosis and splicing. We performed a portfolio prioritization exercise through the prism of return on investment, making the decision to discontinue programs that either had a low probability of technical success and/or commercial success. We completed reductions in workforce, reducing headcount by approximately 30% while maintaining critical elements of our R&D and commercial teams critical to future success. As a result of the portfolio prioritization and the right sizing of the company, we decreased 2024 projected OpEx by over 25%. This decrease in OpEx was a significant departure from our years of market OpEx growth and fundamentally changed the trajectory of the company, such that for the first time, we can envision being cash flow break even in the not-too-distant future. In addition, we completed a royalty financing that provided us sufficient cash to advance the next wave of PTC products, and it also allowed us to retire a debt facility that significantly limited us from both a financial and an operational standpoint. Our PTC strategy leverages our innovative science, our development expertise, and our robust global commercial infrastructure. Our scientific platforms, as I mentioned, focus on two areas where PTC has unique expertise to discover and market impactful therapies. Those include splicing and ferroptosis and inflammation. Our development efforts are focused in two therapeutic areas, neurology and metabolism, where we have extensive expertise and a track record of success. As we build the PTC of the future, we will also continue to sustain our global commercial infrastructure in bringing important therapies to patients with rare diseases around the globe. Our commercial teams will continue to market therapies that PTC discovers and develops, as well as commercialize therapies that we in-license through business development transactions. We have a robust portfolio that supports our growth and our value creation for years to come. We have six products in our commercial portfolio, five of which we market around the world for patients with rare diseases. Our development portfolio includes a number of highly innovative therapies for neurological and metabolic disorders, including PKU, Huntington's disease, and ALS, which I'll detail later in the presentation. Our research platforms have a number of innovative programs that are at varying stages of preclinical development. As we look back on 2023, our commercial teams again had an outstanding performance, with total revenue of $938 million, including $611 million from our DMD franchise. As we moved into 2024, our commercial teams continued to perform with outstanding revenue performance quarter after quarter. 2024 has also been an incredibly exciting year for a number of regulatory and clinical milestones. We remain on track for all of these milestones that we planned for the year, and in the first quarter, we submitted our BLA in the United States for Upstaza, our gene therapy for AADC deficiency, and submitted our marketing authorization application for our PKU program in Europe. Both of these files have been accepted and are now in the review process in the United States and Europe respectively. We have a number of additional exciting milestones still to go this year. Later this quarter, we plan to share results from our PTC518 Pivot HD trial, which I'll talk a bit more about shortly. We have plans to submit, resubmit our NDA for Translarna to the FDA mid-year. We'll be submitting our NDA for sepiapterin, our PKU program, no later than the third quarter. We expect top-line results from our registration-directed study of utreloxastat in ALS patients in the fourth quarter, and we plan to submit an NDA for vatiquinone for Friedreich ataxia patients by the end of the year. So a number of exciting things still to come this year, and I'm excited to report that we remain on track for all of these important milestones. Now, let me take a deeper walk into some of our key programs, and I'll start with our sepiapterin program for PKU. As I mentioned, we have submitted the marketing authorization application in Europe already in the first quarter. That's been validated, and review is underway. We expect to submit the NDA for sepiapterin no later than the third quarter, and we have a number of additional global submissions planned this year. Last year, we had shared the results from our phase III AFFINITY trial of sepiapterin in pediatric and adult patients, and this trial had incredibly strong results. The primary endpoint was reached in the placebo-controlled portion of the study with a highly statistically significant and clinically meaningful effects. We demonstrated substantial reduction in blood phenylalanine levels. We had over 84% of the patients meet guidelines for phenylalanine control. We had over 20% of the patients have normalization of phenylalanine. That's almost unheard of, and importantly, the drug was safe and well-tolerated. The main results from this study, the primary analysis, is shown here on this slide, and this really highlights how significant the treatment effect for sepiapterin was demonstrated to be in the clinical trial. In purple, we see the mean reduction for all patients in the trial who were treated with sepiapterin of 63% in phenylalanine. That's a very strong result that was not only highly statistically significant, but clearly clinically meaningful. If we look at the light blue bar and we see that we had a 69% mean reduction in phenylalanine in classical PKU patients. Classical PKU patients, that's the more severe subset of PKU patients that are traditionally been very difficult to treat, and as we see here, we're able to deliver a significant reduction of phenylalanine in this important patient population. Following the completion of the placebo-controlled portion, patients were then enrolled in an open-label extension study to capture long-term safety and efficacy data, and a portion of patients were enrolled in a Phe tolerance protocol, results of which are shown here. What we do in the Phe tolerance protocol is we gradually increase the amount of protein each patient can take and then see if the drug can still keep their phenylalanine under control. This is really important for PKU patients who traditionally have highly restrictive diets that significantly impact their quality of life. For patients, the holy grail of a therapy is something that allows them to liberalize their diet. As you see on this graph, first, in purple, you see the gradual increase, the gradual regimented increase in protein intake for patients in this part of the study. As you see, we're increasing protein levels beyond the RDA or the recommended daily allowance of protein for someone without PKU. You then see in orange, the mean phenylalanine levels for these patients as they increase their dietary protein intake. And as you can see, as patients are getting to levels of protein that non-affected people take, they're still maintaining phenylalanine control. So simply stated, these data demonstrate that sepiapterin allows patients with PKU to liberalize their diet in meaningful ways, which again, is incredibly, incredibly important for patients as well as for physician uptake. The AFFINITY data and the Phe tolerance data support that sepiapterin can address the still significant unmet medical need of PKU patients. The data support that we can address three key patient segments. First, therapy-naive patients, including those with classical PKU. Second, patients who have failed on current therapies, and then finally, patients who are not well controlled by current therapies. Last summer, we had a deep dive where Professor Ania Muntau, who's one of the global KOLs for PKU, said that she intends to try all of her PKU patients on sepiapterin, which is a very strong endorsement of the potential for sepiapterin. When one considers that there are 58,000 patients with PKU worldwide, the large number of patients in each one of these segments, and the physician enthusiasm for the drug, we clearly see sepiapterin as being an over $1 billion product. We look forward to continuing through the regulatory process and bringing this drug to patients around the world as soon as possible. I'll now shift to our PTC518 Huntington's disease program, and as I mentioned, this is also going to be an exciting quarter for this program. The PTC518 program comes from our splicing platform and follows on the success of the discovery and development of Evrysdi for spinal muscular atrophy. There's many key attributes of PTC518 that make it a highly differentiated therapy, Huntington lowering therapy. First, it's orally bioavailable. It's highly selective and specific for the HTT target. It gets across the blood-brain barrier and is not effluxed, allowing for full brain exposure. We've demonstrated in preclinical and clinical studies that it reduces Huntington RNA and protein in a dose-dependent fashion, and it is able to achieve lowering uniformly throughout the brain.... It's this combination of characteristics that makes PTC518 one of the most promising, if not the most promising therapy currently in development for Huntington's disease patients. Last year, we shared the 12-week interim data from the first set of patients who completed 12 weeks in our Pivot HD Huntington's disease study, and this interim data readout met all the key objectives. PTC518 was demonstrated to lower Huntington mRNA and protein in peripheral blood cells in Huntington's disease patients in a dose-dependent fashion. We were able to demonstrate excellent CNS exposure with, in fact, higher levels of CSF levels of drug than plasma levels of drug. Importantly, PTC518 was well-tolerated, with no treatment-related serious adverse events and no evidence of NfL spikes. Coming on in the second quarter, we plan to share results from the 12-month readout of that initial cohort of patients on whom we previously reported 12-week data. This 12-month data readout will include data on safety and tolerability, as well as biomarker data, including levels of Huntington CSF protein, NfL in the plasma and CNS, as well as volumetric MRI results, and we'll also be sharing early results from key functional clinical scales, including the Total Motor Score, cUHDRS, as well as total functional capacity. Next, moving to our vatiquinone Friedreich ataxia program. Last summer, we shared results from the placebo-controlled MOVE-FA study of vatiquinone in pediatric and young adult patients with Friedreich's ataxia. There were a number of important findings from this study, including the significant effect on the upright stability subscale of the mFARS disease rating scale. The upright stability scale is the most sensitive and relevant portion of the mFARS for pediatric and young adult ambulatory patients. The upright stability scale has been shown to be predictive of risk of long-term loss of ambulation, and in fact, the treatment effect recorded in MOVE-FA equates to a 9-month preservation of ambulatory function over 72 weeks. That's an incredibly meaningful, clinically meaningful finding for ambulatory patients with Friedreich's ataxia. We also had significance achieved on the bulbar subscale of the MOVE-FA, the, of the mFARS scale. We had significant findings on the fatigue scale, including the functional components of the fatigue scale, which supports that we're having an important functional benefit in pediatric and young adult patients with Friedreich's ataxia. Following discussions with the FDA, we now plan to submit an NDA for vatiquinone for the treatment of Friedreich's ataxia later in 2024. Finally, I'll discuss our utreloxastat ALS program. Utreloxastat targets 15-lipoxygenase, which is a key regulator of the ferroptosis pathway. The recent literature clearly demonstrates the importance of ferroptosis in ALS and other neurodegenerative disease pathology. It's now well understood that targeting ferroptosis is an excellent strategy for trying to affect disease progression in ALS. This is an overview of our CARDINALS-ALS registration-directed study. It's a double-blind, placebo-controlled trial in which patients are first observed for 2 months to record a baseline rate of disease progression on the ALSFRS score. Patients are then randomized 2 to 1 to receive utreloxastat or placebo for 24 weeks, and the primary endpoint is change in that 24 weeks on the ALSFRS score, with other endpoints capturing other relevant aspects of disease, including respiratory function and survival. We completed enrollment in this study in the first quarter and look forward to sharing top-line results in the fourth quarter of this year. As you can see, PTC is well positioned for future growth and success. We have a focused strategy, leveraging R&D and global commercial expertise. We have a strong balance sheet and numerous value-inflecting milestones planned in 2024. We are well positioned to continue our success in delivering transformational therapies to patients with rare diseases. Thank you. ... Yeah, Upstaza, as I mentioned, we've submitted the BLA in the United States. It's already marketed in Europe, and the UK, and recently also approved in Taiwan as well as Israel. And the... The filing has been accepted with priority review, and we expect a PDUFA action date in November. Since we have a couple minutes before the breakout, just start some Q&A? Yeah, please. Wonderful. So Translarna's regulatory activity in Europe has been a bit of a rollercoaster, and most recently, there was an update that the European Commission decided not to adopt the CHMP's negative opinion of Translarna and kind of sent it back to the CHMP. Can you provide an update as to what the current status of Translarna's evaluation is, and what kind of the next steps are, and what the potential outcomes could be? Yeah.... It has been a bit of a rollercoaster. Look, you know, we are excited about the prospect of being able to continue to deliver Translarna to patients in Europe. That's now been afforded by the EC decision. As we've talked about, Sammy, we've continued to commercialize the therapy since the beginning of the year. Nothing has changed. It's been business as usual for us, and we've taken advantage of every day we possibly can to make sure that patients have drug and obviously also preserve the revenue. A lot of what we did, when I talked about the changes we made last year, a lot of that was planning for a future where we didn't necessarily have the European Translarna revenue, and we were very confident that we had built a strong company, a strong balance sheet, that we would be able to succeed with PKU, with HD, with everything else we did without the European revenue. And so now, this is all really just potential upside for us that we, we look forward to continuing to have. In terms of the regulatory next steps, as the CHMP itself posted on its website last week, there are two things at play here. One is the European Commission did not adopt the negative opinion. It sent it back to the CHMP and said: "We would like for you to consider the totality of evidence, including the real-world STRIDE data, in a revised opinion." In addition, there was also the determination that the European Court of Justice ruling in March of this year regarding scientific advisory groups impacted the scientific advisory groups that we had during the initial Translarna procedure, such that we were notified by the European Medicines Agency that everything that happened in the initial procedure from September fifth, the date of the first SAG forward, has been invalidated. It's as if those things never happened. So we are now, from a procedural standpoint, returned to the first initial procedure, where there will be another scientific advisory group. And by the way, this is something they're doing for a number of companies that they have found to be impacted by this court decision. So we will move through the process in dealing with the issue with the SAG, and separately, the CHMP will deal with their mandate from the EC to look again at the totality of data, including STRIDE. They've stated that they expect... CHMP has said they expect to move through these in the next few months. We'll continue to work with the CHMP. Look, we've said all along that the totality of evidence is quite clear, supporting the treatment benefit of Translarna for boys and young men with nonsense mutation DMD, both in the short term, as evidenced in the clinical trials, and importantly, in the long term, in terms of the multi-year delay in loss of ambulation, the preservation of pulmonary function, which we're able to clearly demonstrate in the STRIDE registry. So we look forward again to having this opportunity to review these data with the CHMP, in hopefully what will be a revised opinion that will keep Translarna on the market indefinitely. Great. And I guess in terms of potential outcomes, is it only likely that conditional marketing authorization would be renewed, or is full authorization on the table again? And is it possible you would have to run an additional confirmatory study as a requirement? So, we are in the realm of the unprecedented, so I guess anything is possible. But realistically, look, I think. They were asked to look at maintaining the authorization of Translarna. Whether that's a full approval or conditional, either way, you know, is great. It's all upside, and especially for patients. And also, if it's a conditional, there'll be some additional data collection requirement, whether that's another trial, whether that's more registry work, we don't know. But obviously, we would welcome the opportunity to collect more data in the context of a continued authorization of the product. I guess, could you discuss a little further what data in the STRIDE registry you think supports the efficacy and safety of Translarna for continued approval? Yeah, I think, first of all, the you know, we've had patients on the drug for over a decade, longer, and it continues to have a very strong safety profile. What STRIDE specifically shows is that when we look at the patients on Translarna and compare them to a robustly matched natural history cohort from the CINRG registry, that we delay the loss of ambulation by many years. The most recent report was 3.5 years. That's of unequivocal meaningfulness for ambulatory DMD patients. When you think about it, the goal of a therapy in Duchenne muscular dystrophy is slow the progression, slow the progression to these critical milestones of loss of ambulation, loss of pulmonary function, ultimately loss of cardiac function and death. So by slowing the loss of ambulation by several years, first of all, that in and of itself is incredible, incredible finding. It also delays the achievement of the other negative milestones with therapy. So we have the data. The data clearly show that, and I think one of the things there's been some discussion about is the evidence that we now have, that we can address any potential concerns about this not being a placebo-controlled trial, again, which we can easily do. I think which is why there was such a tremendous outpouring of protests from the patients and physicians all over Europe with the negative opinion because the experts see that we're able to provide patients with Translarna and why that's so important and why that needs to stay on the market. Great. And with the recent European Commission's announcement, PTC also suspended their revenue guidance. Can you provide any insight as to when you might provide new guidance? Yeah. what that might look like will be similar to what you did previously, earlier this year, where it was a bit of a range, depending on the outcome? What are your thoughts there? Yeah, I think a couple things. So as I mentioned, we built this year's revenue guidance on the assumption that we would lose Translarna European revenue at the end of the first quarter, around the time that the adoption of the opinion by EC was expected. So given that we would continue to market the therapy and continue to have revenue, we decided to suspend guidance because it no longer was accurate. We obviously now have upside from Translarna. I think once we have clarity on what the revenue opportunity for 2024 will be, as things play out with Europe and the process, that's when we'll look to reinstate it. We wanna be able to give really an updated guidance for the rest of the year. As soon as we can do that comfortably, we will, and we expect that should be in the near future. Great. And, so it's previously been stated that Translarna's European contribution is about 45% of total Translarna revenue. Can you talk about growth in additional geographies as well, and how you kind of envision that growth over the next couple of years? Yeah. As we talked about, the proportion of total Translarna revenue from Europe has declined over time. We started in Europe, but we've worked very hard, our teams have worked very hard to build a global franchise around Translarna. And not surprisingly, we're seeing growth now in areas outside of Europe, such that the last estimate was roughly 45% contribution to total Translarna revenue from Europe. We fully expect to have continued growth outside of Europe. We've talked a lot about the European decision. We've not seen an impact on the revenue elsewhere. Obviously, the most recent decision from the European Commission not to adopt the opinion further supports the notion that people are not listening to what seemed like a very odd and decision by the CHMP, and that the data really do speak to the evidence of benefit. Then clearly, we have the opportunity in the US as well with the NDA resubmission. That would obviously also be a significant growth to Translarna revenue. Great. Yeah, and with the la- oh. What are your competitors planning to approve for prime number? How is that? Yeah, I think, you know, you can probably go to Vegas and pick your play on what that decision is gonna look like from FDA on the dystrophin gene therapy in the United States. I'm sorry? ... I think the current label for that is for boys four and five years old, which is an extremely limited portion of the overall DMD population. Also important to note that if you look at the label for that therapy, there's not clear evidence of benefit in a number of the specific exons or the specific mutations in DMD, many of which are where nonsense mutation patients are. So from our standpoint, even with a broader label, we don't expect there to be a significant impact on the Translarna revenue opportunity in the United States. Looking at the U.S.'s decision on Translarna, can you talk a little bit about physician excitement in the U.S. and any experience they may have had with it, any anecdotal evidence? We've been developing Translarna for a long time. We have a couple hundred boys in the U.S. who've been on Translarna for over a decade. This is something that physicians and patients in the U.S. have long wanted, the opportunity to have access to Translarna commercially, just like boys with nonsense mutation DMD have all over Europe and the Commonwealth of Independent States and Latin America. There is a strong demand for this drug. I think there's a great deal of excitement that we've been able to work constructively with FDA and agree that we have a package that should be accepted for full review. We believe, again, that with the data we have from the most recent placebo-controlled trial, as well as the real-world evidence from STRIDE, and we know that there's been increasing acknowledgment, particularly at FDA, of the importance of real-world evidence in capturing true treatment effect on long-term aspects of a disease. I think everyone's really excited to finally have this opportunity to have the drug in the U.S. I guess, how are you thinking about the risk of U.S. approval, considering there is outstanding evidence of its long-term benefit and safety, and yet it didn't meet its primary endpoint in its most recent trial? If the NDA is accepted, do you think that an AdCom would be pursued? I'll take the second part first. I don't know on the AdC om. We'll cross that bridge when we get there, and obviously, I think that would provide us a great opportunity to talk about the more relevant aspects of the data. In terms of the endpoint, what's interesting is that Study 41, which included 359 boys with nonsense mutation DMD, didn't meet the primary endpoint in the pre-specified primary analysis population, which was a subgroup of patients. We were in a unique situation, again, with Translarna, that we did achieve statistical significance in the overall enrolled ITT population on six-minute walk distance, North Star, timed function test. So here you are in the overall population, which would most closely mirror a label. You have significant findings and functional benefit across endpoints, which has not been shown for any therapy in gene therapy or small molecule. And, you know, a lot of our discussions with FDA were around that fact, that this was not a post-hoc subgroup, the ITT is all comers, and the fact that we were able to provide a number of different statistical sensitivity analyses that confirm that the findings of benefit are real. Because the concern when you don't hit your primary endpoint is that the findings that you're reporting as significant are occurring by chance. Well, again, first, it's not chance that the overall population hit. It wasn't like we went digging for a subgroup, and we did all the statistical analyses showing that this is a real and reliable finding, which we believe meets the bar of persuasive evidence that the FDA would be looking for to pair with the confirmatory evidence of long-term effect in this drug. Great. Thank you so much, Matt. We're going to head to Burnham A for our breakout session to continue this conversation. Thank you.