We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for joining us today. It's my pleasure to have the Stoke team with me. To my direct left, Ian Smith, CEO, and to his left, Jason Hoitt, Chief Patient Officer. Welcome, both of you. Thank you, Andrew. To get started, would you mind providing a brief introduction about Stoke, zorevunersen, your lead product, where you are, the next milestones, what you're trying to achieve? All that would be very helpful. Sure. I'm looking forward to the Q&A session more. Thanks. Let me give you a quick update. First of all, thank you for joining us this morning here in person and also online. Start with the safe harbor statement. Those things that I'm about to say, please check our filings in terms of safe harbor language, forward-looking statements. Stoke Therapeutics is a company that's focused on genetic medicines. We have a lead medicine to treat genetic epilepsies, specifically Dravet syndrome. We're targeting the root cause of that disease, Dravet syndrome, and we're doing it in a way with an ASO. We administer the medicine. It basically boosts the expression of NaV1.1 via boosting SCN1A, which is the depletion in Dravet syndrome. We do increase the expression of NaV1.1, and that is the root cause of Dravet. What it results in is a reduction in seizures. Dravet, unfortunately, is a disease where these children grow to maybe 18 months old, two years of age, and then have no cognitive or behavioral benefits as growth as they go forward. They stagnate from two years on. What our medicine does is it provides, because you're expressing NaV1.1, it does actually provide benefit in terms of more neurotypical development as a child and an adolescent. It's a remarkable medicine. If I was just to quickly profile, it's one of the few genetic medicines that actually gives back function, and that's really important. Genetic medicines typically stabilize a disease or slow the decline from a disease. Our medicine actually picks these children up effectively and provides cognition and behavioral benefits as long as they continue to take the medicine. We do have four years worth of data of measuring children on our medicine. That four years of data has shown durable reductions of seizures, approximately 75% from their baseline. When I say durable, that is 75%, and that's remained durable over a four-year period now. It's actually five years if you include the phase I/II study. They rolled over from a phase I/II study into the OLE. We've also measured their cognition and behavioral benefits over that four-year period, and we see a continuous addition of cognition and behavioral benefit in each of those four years. In fact, we've done a statistical analysis of those where we show that they have a P value of less than 0.01, for each of those years. The medicine is actually quite remarkable in terms of how it benefits these children. We're in phase III. We're running a phase III study. We're about to complete enrollment in that study. It's a 52-week study, that data would read out in middle of next year. We anticipate doing a rolling filing, which would start in Q1 of 2027, that would initiate with the submission of CMC details. Jason, next to me, is responsible for CMC and manufacturing, and I'm sure he'll talk about that later. The last submission within that NDA would come with clinical data in the middle of next year, and therefore give us the potential for an approval in Q4 of 2027 or Q1 2028. We do have other medicines in the pipeline with a similar approach. We approach haploinsufficient diseases. We have a medicine for a genetic form of progressive loss of eyesight called ADOA. We also have preclinical medicines with the same approach that focus on haploinsufficient diseases, SYNGAP1, which is a neuroscience or a development disorder. We have some earlier stage programs as well. Our balance sheet is very strong. We had over $400 million of cash as of Q1, and our runway is all the way into 2028. We're financed all the way through into launch, and so we're in a very strong position. With that, Andrew, back to you. Okay. Very good. Bottom line, zorevunersen has the potential to give back function. You have four years worth of data, and that in of itself is highly differentiating. Starting as we think about the peak sales opportunity of this drug, maybe starting with price. In phase III, if you are able to confirm cognitive benefits, the neurodevelopmental benefits, what does that mean for pricing power? What kind of bookends or precedents should we think about? I'm going to get Jason, just to introduce Jason Hoitt. He has the unique title of Chief Patient Officer. That is because Jason is responsible for our commercial organization, medical affairs, and manufacturing. I'm going to have Jason answer that question. I would just start with. We've done a lot of payer work already. The reason why we can do this work so early while we're in phase III is because we do have that four years worth of data, where we've been able to measure the patient's benefit in terms of seizure reduction and also cognition and behavioral benefits. We've also had a publication in The New England Journal of Medicine that validates those results. Jason's been taking all of this data and over the last three to six months, I would say, has been spending a lot of time with his team, with the payers, and maybe provide the feedback, Jason. Yeah, absolutely. Thanks for the question. I think it's timely because I think historically there's been an assumption that because there are anti-seizure medicines available for Dravet syndrome, that those are an appropriate analog to compare a disease-modifying drug for Dravet syndrome too. That's not the case. I think we see other genetically targeted disease-modifying treatments as more appropriate analogs for what we're doing with zorevunersen. So to Ian's point, earlier this year we went out and tested with payers and doctors different label scenarios and different elements of the phase III being included or not being included, being statistically significant versus directionally consistent. That relative to the three years at the time when we first tested this of open label extension data from the phase I/II. Across both of those audiences, what we learned is that the phase I/II and OLE data longitudinally are likely to be the most compelling pieces of evidence that we have at the time of a potential approval for both doctors, payers, and ultimately families. When we talk to payers, to directly answer your question, Andrew, payers told us we look at the totality of what's in the public domain when we think about reimbursement policy and how we're going to cover a new medicine. When we asked them this, it was before "The New England Journal" publication. It was in late February when we had this piece of market research done. It predated "The New England Journal" citation. What payers told us then is that from their perspective, the seizure suppression and the durability of the seizure suppression are driving a tremendous amount of value in zorevunersen, knowing that it's being dosed on top of the best standard of care medicines available today. Then the Vineland data, the open label extension data on cognition and behavior to them are the demonstration of disease modification and the demonstration of the fact that zorevunersen is doing something different for their members than anything else that they can offer them today. Our takeaway from that is that irrespective of what the label says on the secondaries for EMPEROR, we will be in a very good place from a reimbursement perspective, given "The New England Journal of Medicine" publication, given the totality of the data. To that point, we're deploying our team of national account directors that will be directly engaging with payers, predominantly medical directors, as this will be a medical benefit, to educate them around Dravet, educate them on the profile of zorevunersen we have to date so that ultimately, in just over a year when we have top-line results from phase III, there's already a foundational level of understanding of the product and a deeper understanding of Dravet syndrome itself. As a result of that, we feel really confident in our ability to secure genetically targeted rare disease modifying pricing potential along the lines of a Spinraza, for example, or the exon skippers from Sarepta. I think those are appropriate analogs to think about when you think about where the pricing could land for zorevunersen. Exon skippers are $1 million. Very good. There's price and then there's the volume side. You've said the prevalence of Dravet in the U.S. alone could be 16,000 patients. When investors try to do their own work, they simply do some kind of incidence math from that to derive prevalence, and they don't get as large of a number. Can you walk us through how you derive 16,000? Jason will. He'll give you those same metrics as well, Andrew. I'm just going to start with the simplicity of we have identified 6,000 patients based on coding for Dravet. Those are 6,000 patients that are 24 years and younger, and they're on Dravet medicines, so they've been coded already. There is an immediately addressable patient population with Dravet. There is a further 10,000 approximately, maybe more, that we need to identify with screening. That's the simplicity of the market. That's just in the U.S. alone. Jason will help you understand how we go beyond that 6,000 and how you get to the 16,000-20,000 in total. I will just also say that given my experience in rare disease, I've worked in rare diseases now for 30 years. I was at Vertex Pharmaceuticals and cystic fibrosis. When you create a disease-modifying medicine, screening prevails and you identify more and more patients. I anticipate that's what will happen here. Those children that unfortunately are having seizures and maybe developmental disorders, they may not be diagnosed, and they may be just being treated with seizure medicines. I think we're going to have the opportunities to identify them and put them on zorevunersen and benefit them in a broader way. Over to you, Jason. To get into how we derive the 16,000, which is a U.S.-specific number, right? Before we started the EMPEROR trial, we wanted to understand, to the best of our ability, the total prevalence of patients both currently and at the time of a potential approval in the seven major geographies where we were running the EMPEROR study. That's the EU4, U.K., Japan, and the U.S. In order to do that, similar to what you were mentioning, Andrew, we scaled incidence to prevalence, but we looked back at live birth rates in each of those geographies for the past 85 years, applied the incidence rate, scaled it to prevalence, obviously included, to your point, the Dravet specific mortality in there, largely driven by SUDEP in the pediatric cohort. Then looked at WHO life tables, because once you get beyond that pediatric period, patients do tend to live relatively normal lifespans. So that's where we ultimately got to the number of 16,000 in the U.S. Then when you break that number down from an epi perspective, 6,000 of those 16,000 are 25 and younger. Why that's important is because we have a dynamic in the U.S. where just given how patients are typically diagnosed by a pediatric epileptologist and then cared for throughout their childhood, there's a really strong bond that's formed between the family and the clinician, and there's a reluctance to transition to adult care. So oftentimes, pediatric providers will care for these patients into their mid-20s. I think it's important to understand that there are about 6,000 patients that are in the care of a pediatric epileptologist, the subspecialty of doctors that are most familiar with Dravet syndrome, that are most commonly diagnosing and treating Dravet syndrome, and therefore are going to be the most current with the most recent advances in the field. Of those 6,000, 4,000 are pure pediatric patients that are 18 and younger. To Ian's point, we've cross-checked a lot of this effort with what's available in claims databases in the U.S. today. To Ian's point, the largest claims database out there has about 6,000 identified Dravet patients coded with the Dravet ICD-10 code. If you do some machine learning and extrapolation based on the known patients, and you can predict patients, we feel really confident that based on claims data and the linked NPI numbers to their caring clinician, that we know where about 70%-80% of the 25 and younger population are being cared for in the U.S. today. I see. The greatest opportunity for enhancement of screening is in the older cohort. Perfect. Thank you. Andrew, can I just add, we're focused on the U.S. market. The reason we're focused on the U.S. market today while we're discussing it is we have a relationship with Biogen where we have licensed territories or commercial territories outside of North America. When you look at the total population in the major seven geographies in the world, the total population is estimated to be close to 40,000 patients. Obviously, we take a royalty return and an economic return from outside of the U.S. with Biogen, and we have a very good partner in Biogen. Got it. Let's talk about the FDA. At one point, starting around second half of last year, you're thinking about going to the FDA to get an expedited approval, all while, rightfully so, signaling to the street it's more of an upside case because at the end of the day, you'll have phase III data anyway. Long story short, earlier this year, it sounded as if expedited approval may not be there based on the phase I/ II data. Instead, what are your FDA discussions like nowadays? What are you guys talking about? I'd use a few words like consistent, constant, ongoing. We continue to submit data to the FDA. I would say it's all under the banner of education. The medicine does have breakthrough designated status. The reason we went to the FDA, frankly, in December 2025, to ask whether we could file on the basis of the phase I/ II data and the OLE data, because that data was so compelling, and this disease is devastating, and there is not another medicine to treat it in the way we believe our medicine is treating these kids. We did do that in December. From then on, it's been a form of education. Education around what the disease is, the plausible mechanistic pathway of our drug to treat the disease, which is very important with a genetic medicine given FDA guidance these days. We continue to provide them data specifically around how we measure cognition and behavioral benefit, which is with the Vineland. Recently, about a month ago, we provided the investment community the four-year OLE data of both seizure reduction and cognition and behavior benefits each year for four years. We're providing that data to the FDA to help them understand how our medicine is working. This is all to help with the pathway of when we ultimately submit the phase III data, that it helps them understand how our medicine is working and the benefits it's providing to these children. Great. Speaking of Vineland, which is the key endpoint here, maybe give us a sense of what you saw actually in phase I/II, the degree of benefit that you saw, and how does that compare to what's clinically meaningful out there? Yeah. You specifically asked about Vineland, Andrew, so maybe I could just help you understand what Vineland is. Vineland is an assessment that's done by a neuropsych with these patients. They actually ask the questions of the patients' families and caregivers. If I was to wave my hand at somebody in the front row here and say, "Hey, can you see my hand?" For those of you that are online, somebody who's sitting in the front row could see my hand and has nodded. That's actually similar to a Vineland question, where I'm asking a question, they're receiving that question, and then they're acknowledging what I'm asking them. There's a receptive and an expressive communication. Those are two of the domains as an example in Vineland, and that's actually an example of how you conduct Vineland. We're using five key domains to measure cognition and behavior of these children. They are expressive communication and receptive communication, motor skills, social abilities, and things like that. That's how it's administered. Obviously, for the phase III study, we take a baseline score of a Vineland, and then we measure the Vineland score at week 52 in the phase III study. Given that our medicine is working in terms of the root cause of the disease, we expect that it will provide a benefit and provide these children a gain of function as measured by Vineland. We've also, in the past medical conferences, provided videos of what our medicine has been able to do. Baseline video of children with the physician, and then one year on and further on in terms of these children with the physician. Those are available. If you come to the company, we're happy to share them. It's not anecdotal. They've been presented at medical conferences. We've had children that, unfortunately, are not functional, and then when they've been on the medicine for a period of time, they've been able to respond to the physician, respond to their name, touch their nose, and just follow actions, ask questions. We have children that unfortunately struggle walking but have been able to now kick a soccer ball and things like that. They may sound incremental, but these are huge to these children's families. As I said, our medicine works in a chronic manner, and the four-year data has suggested that these children get better each year as measured by Vineland. It's quite remarkable. The Vineland benefit that you saw across the subdomains, how much was it in phase I/ II, and then how does that compare to natural history, to be clear? I'm sorry, Andrew. I forgot that part. Thanks for reminding me. Clinically beneficial, defined by caregivers or/and physicians, is two Vineland points. In the four-year data, we have Vineland scores that are out to 15, 16 in most of the domains. If you just measure Vineland over a one-year period, when we look at a dosing schema that's similar to what we're running in phase III, we have Vineland scores that are anywhere between eight and 12. Our phase III study is actually powered to show a difference of two Vineland points. It's powered with a 90% probability confidence level for a P value of 0.01. We feel as though we're very well powered to these endpoints. Obviously, we used all the data that we gathered in the phase I/ II and the OLE to design our phase III study. Great. As for the sham side of things, you do have a natural history study. Talk about what you've seen, what untreated Dravet patients can achieve on Vineland after a year, which is your? Thank you, Andrew. We did a two-year natural history study. It's called BUTTERFLY. We measured the patients, obviously baseline. We followed these patients, or these children, through a 24-month period. What we've effectively found is that their baseline was the same as their endpoint at the end of 24 months. I believe the average age of that study was between seven and 10 years old, somewhere close to there. We do have a natural history study that we have published and presented and given to the FDA, and it was shown in The New England Journal of Medicine. Yeah, it goes to what I said earlier on this call, which was these children grow normally to 18 months, two years of age, and then unfortunately, they stagnate. What we're doing is we're lifting them up off that stagnation line. Yep. In the U.S. side of things, as we dig deeper a little about success here on Vineland. In the U.S. side, my understanding is there is a hierarchy of the five that you mentioned. For this to be statistic and fileable, what does that mean on this hierarchy? Do the first two need to be stat sig, for instance? Remaining three trending? I don't know how it works, basically. No, it's a good question, Andrew. Just to be clear, you're referring to the secondary endpoint. First of all, the drug is approvable if we hit our primary endpoint, which is seizure reductions. The secondary endpoints actually provide additional information in terms of statistical significance of how the medicine is working and understand the medicine. In the U.S., the secondary endpoints does have a kind of a list in terms of priority of secondary endpoints to hit. The number one actually is still seizures. We have a secondary endpoint at week 52 to show the durability of seizure reductions. Number two and three are communication, expressive and receptive communication. We need to show a clinical benefit there that's greater than two Vineland points. As I said, we are powered to a P value of 0.01 and a 90% confidence level in those. The others do follow the order. There is a hierarchical order that in the U.S. you need to, as you get through one, you go to the next. Just while I'm talking about it, in Europe, it's more of a combination of those secondary endpoints that supports approval with the secondary endpoints. Got it. Actually going back to the Vineland benefit that you saw in phase I/ II, can you speak to intra-patient variability, actually. Were there any hyper-responders driving the overall Vineland effect, for instance? Was everyone very consistent on their Vineland benefit? Yeah, it was fairly consistent, the variability. We've shown graphs with the error bars, so you can actually see that it's actually pretty tight. I don't know whether that's a real word in terms of statistical significance. No, there's no super responders that sway the Vineland score. I think the best way that I could provide you the basis of that is we've run statistical analysis on this data. The P values that we've achieved for year one, year two, year three, year four, so four years, individual years, have P values of less than 0.01. If you had variability, you wouldn't get to P value less than 0.01. Yeah. The drug goes to the root cause of the disease. It helps express NaV1.1. Our animal models say we're expressing NaV1.1 maybe to close to wild type. We do anticipate that this provides this kind of benefit. Great. Bigger picture, should you succeed on seizures, which I think you will high probability based on the phase I, and you show this kind of Vineland score benefit, the therapeutic index is very high. I still have to ask, though, in the phase III, would you expect SAEs, for instance, with this drug? And if so, what kind of SAEs? You're asking me to use a crystal ball and say SAEs. All I can point to is the data that we have, to be honest, which is we have five years' worth of safety. Just to give a background, we had approximately 80 patients, maybe a little more, 80 patients that rolled on to the OLE studies from the phase I studies. We have been able to follow those 80 patients, 90% of those 80 patients are still on medicine five years later, or four years later in the OLE, but in total, nearly five years. We've obviously collected a safety database with that, the drug's well-tolerated. We've administered over, I believe it's now 900 doses of this drug in these 80 or so patients. We're about to close enrollment of 150, 160-patient trial, and so we have a large number of patients that have also been on medicine in our phase III. We haven't had any dropouts in the phase III, as we reported about a month ago on our Q1 call. The safety profile from the four-year OLE data shows the medicine is well tolerated. Great. Great to hear. Actually before the phase III reads out in mid-2027, you're already starting with the rolling submission in Q1. Sounded like CMC manufacturing to start. Remind us how many modules there are, and what's next after that, and then it sounds like the gating factor is that phase III dataset ultimately. Yeah. Rather than go through each individual module, I'm going to say that the bookends are we start with a CMC manufacturing module, which we anticipate providing that information to the FDA starting in Q1 2027. The last module is clinical data, which we'd anticipate completing the submission in the middle of 2027. Great. As I said earlier, that because we're doing a rolling submission, we anticipate, based on satisfactory data. Yes. That we have approval in Q4 2027 or Q1 2028. Great. Let's just say this is approved ultimately in the label, what will the front page label say? Will the Vineland-3 data be included in the body of a label, whether it be phase I/ II open label or the phase III data? It's a really important question, Andrew. We actually had a board meeting yesterday. I was talking to our board about this, which is you've got to define what a label is. The label allows you to promote the medicine to what you believe the medicine is doing for these children. We want to promote this medicine in a way that we believe what it's doing for these children is it's significantly reducing the seizures on top of standard of care medicines, and it's providing gain of function, cognition, and behavior, and that's durable, and it's year after year. To get that kind of promotion of what the medicine is doing, we need a successful phase III, and then we also need the OLE data on the label. The OLE data, obviously by the time we file, will be five years in duration. That's why we continue to submit it to the FDA, so they understand it, and it was validated with The New England Journal of Medicine. There is a section within a label just for people's understanding, and this is a detail, but it's important. There is Section 14 in a label, and it requires you to disclose clinical studies results that help you understand how the medicine is effective and safe. It's a requirement. When you have a medicine that's a genetic medicine that treats chronically, and you have data that shows durable reductions in seizures and improvements in cognition and behavior over that period of time, we believe that data will be in the label. Great. It's great to see everything coming together, the pieces coming together. Fingers crossed on the phase III success. Congratulations on the progress. Yeah. Thank you, Andrew, and thanks for taking the time today, all. Thank you.