I think we're ready to get started. Great. All right. Well, it is my pleasure to introduce Ian Smith, CEO, and Jason Hoitt, Chief Patient Officer of Stoke Therapeutics. My name is Kevin Strang. I'm one of the biotech analysts here at Goldman Sachs. Welcome. Thank you. I guess we'll just start getting right into a question for you, Ian. What were your priorities when you took on the CEO role at Stoke? Can you sort of provide a mark-to-market on your progress against those priorities and what you're focusing on from here? Yes. First of all, thank you for everybody joining us on the webcast and those that are in the room with us today. Just as stepping back, I have been on the board of Stoke Therapeutics for three years now. While I was on the board at Stoke, I also was an advisor to the company. About 15, 18 months ago now, or 15 months ago, the board asked me to transition at that time, and I was the interim CEO for six or seven months, and I took the permanent CEO position in October last year. That's the background. How did I think about goals and achievements for the company? Well, first of all, it started with, I wanted to help the company become the greatest advocate it could be for what Dravet was as a disease, the devastation of Dravet. Once you understand that and understand what our medicine is doing for Dravet children, you actually start to become a very strong advocate for your medicine as well. That is kind of the meta-goal, so to speak, for the company today. What that translates into is understanding the audiences that need to understand that. So the physicians. The physicians that treat Dravet or seizures today with medicines that only treat the seizures. Our medicine treats beyond the seizures based on all the data that we've seen so far. We treat beyond the seizures in Dravet. Educate the healthcare environment to what our medicine can do for those children. Also to then understand how to progress the medicine to get it to these children that deserve the medicine, and the families that deserve the medicine, and build a company. Frankly, I worked with Vertex Pharmaceuticals for 20 years and saw medicines for cystic fibrosis over 20 years come from the bench all the way to changing children with CF, changing their lives. You have to build a whole means working, building a development organization to run the studies, having a regulatory group that has the right and appropriate interactions with the FDA, including breakthrough designation, being those accelerated pathways through to these patients, building a medical affairs group that educates market, building more of a business function in terms of manufacturing and commercial, and frankly, understanding Wall Street as well in terms of educating the investment community to the opportunity that Stoke is creating in terms of an investment. I think all those areas needed acceleration and investment of time and people. Then you asked me, Kevin, about mark-to-market. I'm really happy with how the company has progressed over the last 15 months. It really has accelerated the awareness in terms of the advocacy of the medicine, and that means also the advocacy of the disease. I'm very happy. From a stock price, I wish our stock price was a little higher, but who doesn't? The company is building itself out. We've made great progress in the phase III, which I'm sure we're going to talk about, and there's a greater understanding of the medicine and the opportunity today. I'm very happy with it. Great. That's a great place to start. You mentioned the disease itself, Dravet. At a very high level, what is that unmet need that you see today? You mentioned ASMs versus disease modification. How do you view that unmet need? Then we can get into zorevunersen's ability to meet that. Yeah. Just consistent with what I said about being an advocate for the disease first, just a little quick, what is Dravet syndrome? Genetically, Dravet syndrome is a depletion of SCN1A, and therefore you don't express NaV1.1 in the brain. What our medicine does, zorevunersen, it boosts the allele or the gene SCN1A that is functional and to express NaV1.1. What we've seen, what that results in is that it not only reduces seizures in Dravet because you go to the root cause of the disease, but it also provides cognition and behavioral benefits to these kids. In Dravet, they normally 24 months old. Unfortunately, when they get to about that, even when they're 20 years old, neurotypically or neurodevelopment-wise, they're still two years old. What our medicine does by giving back that expression of NaV1.1 is it provides a gain of function while you're on the medicine because you're expressing NaV1.1, and there's still neuroplasticity there. Whether you come onto the medicine as a two-year-old, five-year-old, 10-year-old, 12-year-old, what we're seeing is there is a gain of cognition and behavior as measured in our clinical studies. That is not provided anywhere for these Dravet children. There are very good anti-seizure medicines that are anti-seizure medicines and reduce seizures. Seizures is still one of the unfortunately uncontrollable symptoms of Dravet. All of our data, which shows 75% reduction in seizures, improves in cognition and behavior, is on top of standard of anti-seizure medicines. We're driving that benefit even on the medicines that are available today. That's because we go to the root cause of the disease of expressing NaV1.1. Got it. That's from your phase I/II as well as your recently shared four-year open label extension data. Do you just want to highlight, especially with the four-year data, what that means? That's very recent data that you shared. We're in the unique position where the company has been in development of zorevunersen now for six years, yet it is a truly breakthrough genetic medicine. Typically with medicines like that, my history, you move quicker in the clinic. We've been in the clinic now for six years, and by the time that we file an NDA, we will have been in the clinic for seven years. What that has allowed us to do, though, is for that first patient that came in the phase I/II study six years ago or five years ago, they went through the phase I/II dose escalating study, but then rolled over into an OLE. That OLE we now have captured. A rare position where we have that gives back function, we're able to measure how much function it's giving back over a four-year period now, while also seeing the durability of seizure reduction over a four-year period. All that data, what it shows is we're seeing seizure reductions of approximately 75% on top of standard of care medicines that is durable out to four years now. In terms of cognition behavior, we've even run a statistical analysis that shows for each of the key domains of Vineland, which is how you measure cognition behavioral improvements. All the five key domains, year one, two, three, and four were statistically significant in terms of improvements each year in cognition and behavior of five key Vineland domains. Great. Moving on from that data to your currently running phase III EMPEROR study. I believe you're guiding to completing the randomization of that study this month. That would enable a readout middle of next year. Can you talk about how that study was designed to capture both the seizure benefit and the neurodevelopmental outcomes, the Vineland-3 secondary endpoints? It is a 52-week study, anticipated to be 150-160 patients. We're anticipating completing enrollment this month, the month of June. The primary endpoint is week 28, measuring seizure reduction. Secondary endpoints are Vineland-3, which is a measurement tool of cognition and behavior, that's run at week 52. That's the design of the study. Patients go through the study ultimately can roll over to an OLE study if they're in sham they continue on the study, they have the option. As far as the study and the progression of the study, I can't give an update today on webcast, a month ago, we had recruited or enrolled 130 patients at 150 or 60. Of those 130, approximately 90 were through the first two doses of 70 mg, we had 0 dropouts, which is quite remarkable. That might be driven by the intent to get to an OLE, it also shows that the drug is being well-tolerated in the phase III. Great. You mentioned the sham control arm. I guess, how did you approach powering for that sham control arm? You've done some natural history work as well, and you've also looked at natural history work. Talk to us in terms of that data and what you expect or what you expected when you designed the trial on that 52-week endpoint. I believe you presented last year some 18-month data as well. I guess if you could go over that. Yeah, it's a good question. This may be something that is a little different of our phase III program is we've powered the study based on the secondary endpoints, not the primary. The primary endpoint of seizure reduction, the seizure reduction is so demonstrative as what we've seen in all our data, that we actually moved to the secondary endpoints and powered the study off the secondary endpoints. The powering in the study of the secondary endpoints is powered to a P value of 0.01 with a confidence level of 90%. It's conservatively powered, and that brought us to 150 patients. We anticipated that there could be a 15% dropout, and we anticipated 150 patients to come into the study. So far, we don't have a dropout, and I anticipate that the study could be as high as 160 patients. We're very well powered. Now, the data that led to that powering calculation was data we provided to the investment community and at a medical conference in August of last year. That showed that when you take a dosing schema or regimen, complete dosing regimen, that's similar to the phase III dosing of 230 mg over a 12-month period, we actually showed Vineland improvements of around 8 to 12 points, I believe. I think or 8 to 11 points. The study is powered to show two points improvement. We're very well powered. We're in good shape. We've also provided a statistical analysis of that regimen rather than just showing the absolute Vineland scores. We compared that to natural history study, and we showed that we hit statistical significance at certain time points, and that was with an N of 8. Great. For how these secondary endpoints are being looked at in the U.S. versus Europe, can you just remind investors what those differences are and whether they should think of any hierarchy for these sub-domains? Even in the patient community or the physician community, are there certain sub-domains that are more important than others? The sub-domains that we're looking at for the NDA versus the European filing are the same sub-domains. It's the same study in terms of the endpoints. To your question in terms of are there higher priority endpoints, if you talk to families and caregivers and physicians, you will find that there is a kind of a priority, and they tend to focus on receptive and expressive communication. The one difference between the two filing strategies is in the U.S., it is a hierarchical assessment of the secondary endpoints, whereas in Europe it's a composite. The trial design is very similar. There is a slight difference in four European countries where we're doing a lumbar puncture cohort. Sorry, a needle prick cohort in terms of sham, whereas the U.S., U.K., and Japan is lumbar puncture. Got it. As you move past the data and towards regulatory outlook for zorevunersen, what does it need to achieve to be viewed as a disease-modifying therapy and by regulators, physicians, payers, et cetera? I want to jump all the way to, I think it's already being recognized as a disease-modifying therapy because of the totality of the data. Yeah. When you look at the four-year OLE data and this durable reduction of seizures on top of standard care medicines, 75% reduction of seizures, you're seeing these cognition and behavioral benefits in year one, year two, year three, year four, that each year they're statistically significant. That totality of data is already being recognized in the medical community and the payer community as a disease-modifying medicine. I think you're asking more about what's the regulatory environment and how they look at it. Again, I think it's very similar, whereas you've got to hit a primary endpoint to get the medicine approved. We're very confident with that. With the secondaries, we're very confident there as well, I don't think that you have to go and have five out of five secondary endpoints hit at each one. You've also got the OLE data, which would be in the label. The label has a part of the label where you've got to show your data from other clinical studies if it helps a physician understand the benefits and risks of a medicine. It's actually in the FDA guidance, and it's called Section 14. Your clinical studies are required to be in there. This is a chronic medicine. When you have five-year data, you should put that in the medicine to help people understand how the medicine is affecting these children. You mentioned Section 14. What are good analogs for investors to look to? Yeah. The best analog I could give you is probably SPINRAZA. Why is it the best? It's also an ASO. The SPINRAZA looked at their primary endpoint at six months. They actually missed their secondaries, but the OLE data was on the label because they followed these children. If you're familiar with SMA, unfortunately these children, they don't sit up, roll over. They die at very young ages. Biogen, like ourselves, actually continued these patients into an OLE study and measured them, and it helped to understand what the medicine did chronically. These children lived longer and also had greater movement and function. All that data went on the label because it helped people understand how the medicine affected these babies in SMA. We see it exactly the same in terms of being an analog that you're asking for. There are others as well. Jason's been involved with some of them. Coincidentally, SKYCLARYS and QALSODY, also from Biogen, are good examples of observed data being added to the Section 14 of their labels. Yeah. Great. I guess, on the topic of analogs, and I have a feeling it could be similar for this question as well, but how are you thinking about pricing? Yeah. I'm glad you asked the question, Kevin, because I think historically there had been a misconception that because we're launching in Dravet and the only approved medicine so far in Dravet have treated just some of the symptoms, namely the seizures of Dravet, that we would kind of be pigeonholed or ballparked to that price range. The reality is that what we're doing is addressing the underlying genetic cause of the disease. What we're doing is affecting the syndrome itself by doing so. Therefore, I think more appropriate analogs are genetically targeted disease-modifying medicines for rare disease. The analogs we've been talking about most recently are obviously SPINRAZA, as you mentioned. The exon skippers from Sarepta, I think, are also appropriate analogs, debut medicines like that are changing the paradigm in addition to addressing the underlying genetic cause. Got it. For filing, you've mentioned rolling submission is the plan as soon as first quarter of next year, potentially allowing for a launch maybe early 2028, around that timeframe. Any gating factors to getting that initial submission started? What are the advantages that you have with breakthrough and using that rolling submission as the phase III data comes in? We'll start with the advantage of breakthrough designation affords us the rolling submission. We anticipate starting the rolling submission in Q1 2027. The first section of that rolling submission will be CMC. Jason can update you as where we are there, but we're right on schedule, no problems, including inspection and quality. The rolling submission would take us through to the last clinical submission. That would be after the week 52 clinical data. That would be in the middle of next year. At that point, when you complete your rolling submission, you get a PDUFA date that would be eight months after the last submission. That would put you in Q1 2027 for launch, or PDUFA date Q1 2027. If you look at the history of rolling submissions, breakthrough designation, approval generally comes anywhere between four and six months after last clinical submission, which could potentially put us into Q4 2027. We're right on track in terms of what we're preparing for in terms of CMC, preclinical. Obviously, we're ongoing with the clinical data in the phase III study. Got it. Potential approval launch later next year, early 2028. Correct. Moving to the commercial opportunity, I feel like you've recently talked about your estimation of the patients available at launch, around 6,000. Can you talk about what goes into that number, be it claims data, literature prevalence, et cetera? Yeah. I think that the number 6,000 comes from two different ways of looking at it, right? You can look at it from an epi perspective, where going back a couple of years ago, before we initiated the EMPEROR study, we wanted to understand overall prevalence in the geographies where we were running the study. We initially looked at the core seven geographies around the world, U.S., EU4, U.K., and Japan. We took 85 years of live birth rates and scaled incidence to prevalence, applying Dravet specific mortality, which largely is due to sudden unexpected death in epilepsy. That ultimately got us to a total population for the U.S. of 16,000 patients approximately. When you break that down by specific ages, about 4,000 of those 16,000 are purely pediatric patients under 18. In Dravet syndrome, there's this dynamic of patients predominantly being cared for by pediatric neurologists, pediatric epileptologists, that are initially the ones that diagnose the patient and care for them throughout their life, up until they need to transition to adult care. As you can imagine, patients, families, they develop a strong bond with the clinician that's been caring for them over time, and there's a reluctance to transition to adult care. Oftentimes, the pediatric providers are caring for these patients into their mid-20s. The patients that are cared for by that group of specialists that are the most familiar and the most up to date with what's going on in Dravet are particularly relevant. 6,000 is the number of patients from an epi perspective that are 25 and younger in the U.S. Now pivoting to patients that are already identified today with an ICD-10 code for Dravet from claims data, there are also coincidentally 6,000 identified patients in the most robust claims database in the U.S. today. That's across all ages, but coincidentally, it also happens to be 6,000. We've brought several pieces of claims data in-house so that we can mine and analyze the data, and we've applied some machine learning principles to the already diagnosed patients, looking at other CPT codes, treatment codes that are consistent with a Dravet diagnosis and then applied that algorithm to the total claims universe. In doing so, we feel really confident that we know where about 70%-80% of the 25 and younger patients are being cared for today. As we launched the disease awareness campaign last year, for example, we have the ability now, because there are linked NPI numbers for clinicians in there, to hyper target specific messaging to specific segments of clinicians based on the behavior that we are seeing from them from a diagnostic and a treatment perspective in an effort to change the behaviors that we would like to change and educate on the areas where they specifically need education. Got it. It seems pretty concentrated. Is there anything in terms of launch execution that you are planning for field force design- Yeah specific barriers you are looking for based on your work? Yeah. Obviously this is contributing to how we think about field force design. To your point, Kevin, this is a highly concentrated market, right? In this market, 50% of patients, based on claims data, are in eight states. There are 1,200 clinicians that are caring for about 70% of the total Dravet opportunity. Then if you also look at the claims based on centers, sites, or practices that are caring for patients, it is also 124 sites represent 70% of the opportunity. That could be group practices, hospitals, et cetera. With a concentrated opportunity like that, we are looking at a very lean commercial infrastructure that will allow us to completely maximize this opportunity. You are talking 20 to 25 salespeople total, matrix field organization, but a commercial team that is well less than 100 people to maximize the U.S. opportunity. What does the timeline look like for that? Our medical affairs team is nearly fully built at this point. Obviously, the medical affairs team needs to be out and engaging with clinicians, and they have been for the last couple of years. We have an amazing team of regional medical directors that are engaging with KOLs today. From a commercial perspective, the leadership team is in place, the entire commercial leadership team. All folks that have done this before, gone from a clinical stage company to a commercial stage company, launched the first medicine in rare disease, and the majority of us have done this together before. It's a strong foundation to start from. The vast majority of our hiring for, in particular, field-based personnel, will start after phase III data. We'll be gating some of our spend and some of our hiring to that. Leadership will be in place before then, and obviously all of the work to prepare for the onboarding of those teams will be done before then as well. Got it. How are you thinking about, we talked about different age segments. There's the 18 to 25 segment that's often treated by pediatric specialists still. There's the above 25 segment. How are you sort of approaching that, and do you need additional studies for the adult population when it comes to payer access and things like that? Yeah. Maybe I'll take the first part of that first. Yeah, as you can imagine, just based on how genetic testing has evolved over the last couple of decades, the claims universe that exists today is disproportionately representative of the younger cohorts of patients, the 25 and younger. There's more work to be done from a diagnostic perspective to identify those additional 10,000 patients that are largely adult patients. The focus of our screening efforts will be on that adult segment, on the adult providers, while we also want to move diagnosis as early as possible for patients. To your point, payers may limit reimbursement to trial inclusion criteria. We anticipate having data for patients that have aged into adulthood from our phase I, II, and OLE studies that we will specifically look at. In addition to that, later this year, we're going to be starting a small adult study, looking primarily at safety, we're also going to look at seizures, we're going to look at neurocognition, and we're going to look at some endpoints that are specific to adults. Great. I wanted to talk about durability of therapy and sort of how you think about that. I know you obviously have long-term data at this point. In addition to that, what other assumptions are going into how you view the persistence of therapy in the real world? Yeah. We've now got four years of OLE data, and the retention in the OLE study has been remarkable. The fact that we're also now well into the phase III, we've seen zero dropouts to date, I think the family seeing the benefit is the greatest motivator to stay on treatment. To your point, we're already starting to build our patient services offering. Obviously, with a rare genetic disease, we'll have a team of in-house folks that are interacting with families, interacting with offices, helping with everything that we can compliantly help with to get a patient on treatment and ultimately help them stay on treatment. Great. Can I just give you a statistic? The OLE, the patients that rolled over into the OLE, 90% of them are still in the OLE four years later. That's in an OLE. It's a remarkable retention. Great. I wanted to move on to a competitive standpoint. Is there anything that you're looking at in the disease-modifying landscape? I know obviously that's sort of how you think about your therapy in the disease-modifying category versus an ASM. When you look at that disease-modifying landscape, is there anything? In terms of gene therapies, could those potentially be? Are those what you look at as complementary, competitive? How do you see that when you look at other rare diseases? We don't see anything that's the same as what we've got. We don't see somebody that's maybe trying to make a beta-sarcoglycan. Frankly, we don't see it, we've got a very strong IP portfolio, we also have five years worth of data. In terms of gene therapy, we do see some interesting approaches. There's a company out there that's doing gene therapy, we look at that as somewhat validating. That's putting the SCN1A gene back in. That's an interesting approach. It's very early. They've been trying to figure out their dosing, they put out some data recently. It's interesting, I think. I kind of look at Zolgensma and SPINRAZA, and if you look at the history of an ASO and gene therapy, the gene therapy was interesting, but most patients roll on to SPINRAZA because of the durability, the point you were just making, actually, Kevin. The durability and the consistent response because you're continuously dosing. I think there's a lot of questions that remain about gene therapy in terms of its true one-time dosing and durability of benefit, as well as there's got to be questions on safety, because the administration has got to bore a hole in the skull and inject into the brain. It's AAV therapy still, and so it must come with some safety concerns as well. We'll see how the landscape evolves, but there's nothing right now that we look at and say, "Yeah Makes sense. I wanted to ask briefly on your partnership with Biogen, since we haven't really spoken about that yet. How has that partnership evolved over time? Obviously, there's a lot of overlap with the ASO space and the rare disease space. What's been most valuable? I'll go all the way back to before the partnership existed and say I was on the board company with its business development opportunity. The number one question was: do we have the global capabilities to get this medicine approved and launched into patient populations and into single-payer markets? The answer two years ago was no, so we started the competitive process. Even when we started the competitive process, Stoke would like to have had Biogen as a partner because of SPINRAZA, because of its manufacturing capability, because of its global reach and its capability, and SPINRAZA in SMA. We closed with Biogen, I believe it was February 2025, so just over a year ago. The relationship with Biogen has been excellent. It's been everything we hoped it might be in terms of how they're helping us outside of the North American territories. They bring a lot of capability to the table. We're running the studies. We're responsible for the design, the progression of the studies, and we keep Biogen updated, but we have a whole governance structure in terms of joint steering committees, joint development committees, joint commercial committees, joint manufacturing committees. There is daily conversation and exchange of information between the two companies. It's working really nicely. I see we're essentially at time. I wanted to briefly ask about your program in ADOA, STK-002. What should we be looking for in that program on the horizon? Finally, just in terms of your cash position, where are you at today and what sort of milestones does that get you to? Yeah. Quickly, ADOA is a genetic progressive loss of eyesight. We are in a phase I/II single-dose escalating study. We're in our first cohort of dosing. We anticipate four cohorts, with Cohort 3 and 4 potentially giving you an efficacy readout towards the end of this year or early 2027. We're pretty excited about that. We think OPA-1 is the right target to increase mitochondrial function. To your second question on cash, we're very well capitalized. We've got over $400 million of cash as of the end of Q1, and that cash supports us all the way through to 2028. We're also supported by Biogen paying 30% of the development costs for zorevunersen, we're in very good shape. Great. Well, thank you, Ian, Jason, and the team at Stoke. Appreciate it. Yeah. Thank you. Thank you for listening.