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Hello, and thank you for standing by. My name is Bella, and I will be your conference operator today. At this time, I would like to welcome everyone to Stoke Therapeutics' first quarter 2026 business and financial update conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. We do request for today's session that you please limit to 2 questions only. If you would like to ask a question during this time, simply press star, then the number 1 on your telephone keypad. To withdraw your question, press star 1 again. I would now like to turn the conference over to Thomas Leggett, Chief Financial Officer. You may begin.

Good afternoon, and welcome to Stoke Therapeutics' first-quarter 2026 business update conference call. I'm Thomas Leggett, Chief Financial Officer of Stoke Therapeutics. Joining me on today's call are Ian Smith, our Chief Executive Officer, Dr. Barry Ticho, Chief Medical Officer, and Jason Hoitt, Chief Patient Officer. As a reminder, today's webcast presentation is available in the Investors section of our website. This webcast is being recorded and will be available for replay later this evening. Before we begin, please note that today's discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially. Please refer to our filings with the SEC for additional information. With that, I'll turn the call over to Ian.

Welcome, everyone, and thank you for joining us this evening. On today's call, we will review recent progress with our business. In a few minutes, Barry will review new top-line 4-year longitudinal data from our ongoing phase I/II open-label extension studies, also known as the OLEs. Barry will also provide an update on progress with enrollment into the phase III EMPEROR study. Jason will speak to how these data support our commercial planning, starting with labeling through to patient access as we prepare for potential U.S. launch in late 2027, early 2028. Before we go to the details, I want to briefly summarize how Stoke has progressed over the past 12 to 18 months. I think it may be helpful to understand where we were, where we are today, and how we are positioning ourselves for the future.

Over the last year, we have experienced an increase in awareness of the company, which can be attributed in large part to greater advocacy and education related to both Dravet syndrome, a severe and debilitating disease, and how zorevunersen may treat the root cause of this disease to change the course of the lives of these patients and their families. This effort has included continuous sharing of clinical data, specifically with greater presence at medical congresses, supported by an expansion of our medical team that has developed close and trusted relationships with physicians around the world. We have echoed this education with many stakeholders, including regulatory agencies and the investment community. One example of this is the recent publication of our phase I, II, and 3-year OLE data in the New England Journal of Medicine that has enhanced the awareness and understanding of Dravet syndrome and the potential of zorevunersen.

The manuscript has shown that zorevunersen is a potential first-in-class medicine that may lead to more neurotypical development while reducing seizure burden, even when patients currently taking standard care ASMs. Last year, we showed durable reductions in seizures and continuing improvements in cognition and behavior and safety out to 3 years. Today, we are sharing an additional year of data, now out to 4 years, where we see continued durability in seizure reductions and additional improvements in cognition and behavior. These data increase our confidence in the potential long-term benefits and safety of zorevunersen for those living with Dravet syndrome, including the potential to narrow the development gap between them and their neurotypical peers.

The OLE data factor prominently into our labeling plans for zorevunersen to support patient access and how we may promote our medicine, as well as reimbursement to support early patient uptake and will be shared with the FDA as part of our ongoing interactions and educational efforts. Our phase III EMPEROR study, once expected to take 18 to 24 months to enroll, is on track to complete enrollment in the U.S., U.K., and Japan in June, just 10 months after the first patient was randomized. This rapid enrollment underscores the severity of Dravet syndrome, alongside substantial awareness of zorevunersen and its potential to treat the disease in a way no other medicine currently can. Going forward, we remain focused on EMPEROR and seeing this study through to completion and data readouts in mid-2027.

As soon as the final patient is randomized, we will be approximately 1 year away from a data readout. These data are expected to complete our rolling NDA submission, which is anticipated to start in Q1 2027. With more than $400 million on our balance sheet, we are funded well beyond the phase III readout and through to potential U.S. launch of zorevunersen. In addition to this strong financial position, over the last year, we have transformed our shareholder base, including recent sales to several select long-term fundamental investors, another sign of growing awareness and conviction in zorevunersen. In summary, Stoke has transformed itself over the last year and has emerged as a stronger, more capable organization with growing awareness for the unique opportunity in front of us. We are well-positioned to enter our next phase of growth as we prepare to launch zorevunersen in the U.S.

With that, I will turn the call over to Barry.

Thank you, Ian. I'll start by reviewing the new four-year safety and efficacy data from the phase I/II OLE study before providing an update on the phase III EMPEROR progress. Before I begin, I want to thank the team here at Stoke who has worked to generate these data, and also the investigators and their staff, and then most importantly, the families who have participated in these studies. These data are from the first 75 people to continue treatment with zorevunersen after completing treatment in the phase I/II studies. At the time of the four-year data cut, approximately 77% of the patients remained in the studies, which demonstrates a commitment and belief in zorevunersen. With that, I will review the latest data. Zorevunersen is an investigational antisense oligonucleotide.

Of the 81 patients who received at least one dose of zorevunersen in the phase I/II studies, 93%, or 75 of them, continued treatment in the OLEs, receiving zorevunersen on top of their standard anti-seizure medicines. As a reminder, there was a 6- or 7-month gap between their last dose in the phase I/II study and their first dose in the OLE study. The phase I/II studies were dose-finding studies, as such, patients came into the OLEs having received various dose levels of zorevunersen. Dose levels for individual patients in the OLEs varied between 20 milligrams and 45 milligrams, depending on when they entered the study. The top blue line represents all patients treated with less than 70 milligram loading doses in the phase I/II studies before continuing treatment in the OLEs.

By month 29, all patients in the blue line were receiving 45 milligrams every 4 months, consistent with our Phase III maintenance dosing regimen. At the time of this analysis, 11 of these patients had reached month 48. The orange line represents patients initially treated with 1, 2, or 3 doses of 70 milligrams before continuing on in the OLEs. At the time of the analysis, 14 of 17 patients had reached month 28 in the OLEs, and all had been on a maintenance dosing regimen of 45 milligrams for at least 1 year. Here you see median reductions in major motor seizure frequency of 59%-91% for these patients through month 28 compared to patients' Phase I/II baseline. I will remind you that these seizure reductions were demonstrated in patients who are continuing to be treated with standard of care anti-seizure medicine.

Our phase III EMPEROR study is evaluating 2 loading doses of 70 milligrams followed by 2 maintenance doses of 45 milligrams. Here we show the same data, but in 16-week intervals instead of the 4-week intervals shown on the previous slide. This more clearly shows the ongoing trend of reductions in seizure frequency over time. Reductions in seizures remain the primary goal of treatment, which is one reason there are so many antiseizure medications in use today. However, there is a growing awareness of the severe neurodevelopmental consequences of Dravet syndrome. Here you see a simple graphic that illustrates the widening gap in development between neurotypical children and those with Dravet syndrome, whose development starts fairly normally and then plateaus around the age of 2.

zorevunersen is designed to address the underlying pathophysiology of the syndrome by upregulating NaV1.1 protein expression, which is the root cause of the disease. Vineland-3 is a standardized assessment of behavioral outcomes that is widely used in both clinical practice and research to evaluate cognition and behavior over time. The respondent is typically a parent or caregiver, and the assessment is conducted by trained raters, which reduces the potential for bias. Vineland evaluates four domains: communication, motor skills, socialization, and daily living, each composed of multiple sub-domains. The assessment has been used throughout the clinical development of zorevunersen, starting with the BUTTERFLY natural history study. A published survey of caregivers and clinicians indicated that most of them generally consider a 2- to 3-point change in Vineland score to be clinically meaningful.

On the next slide, you see the results of the Vineland-3 assessments for each of the 4 years of the Phase I/II OLE studies. The first five sub-domains shown on the top of this chart highlight five key sub-domains in which statistically significant improvements were demonstrated at 1, 2, 3, and now again at 4 years of treatment compared to OLE baseline. Comparison of these Vineland sub-domains to baseline was pre-specified in the OLE protocols. These five key sub-domains are being assessed in the Phase III EMPEROR study. The latest 4-year data shown are particularly notable, demonstrating additional improvements beyond what was observed in prior years. This is a modeled analysis in which changes are compared to the patient's baseline score at entry into the OLE. We cannot measure the effects going back to the phase I/II study baseline since only one of the studies included blind assessments.

Therefore, these results do not account for any potential improvements experienced in the phase I/II treatment period. These data are striking and provide substantial support for the disease-modifying potential of zorevunersen by targeting the underlying genetic cause of Dravet syndrome and restoring protein function to the brains of these children. These data suggest that zorevunersen may durably reduce seizure frequency and lead to improvements in cognition and behavior in patients whose neurodevelopment generally stagnates around the age of 2. I will now review the latest safety findings. We have more than 5 years of clinical data from the phase I/II, and early studies. Across these studies, more than 850 doses have been administered. Overall, no new safety findings have emerged, and zorevunersen continues to be generally well-tolerated.

Elevated CSF protein lab values occurred in approximately 94% of patients, of which 59% have been classified as a treatment-emergent adverse event. No serious or severe clinical manifestations have been associated with CSF protein elevations. There have been no reports of hydrocephalus. We are very encouraged by these long-term data that continue to demonstrate that zorevunersen is generally well-tolerated with effects across multiple measures of disease when administered to patients who are already taking the best available antiseizure medications. These effects are consistent with disease modification and give us confidence that zorevunersen may change the neurodevelopmental trajectory of people living with Dravet syndrome. We look forward to the results of EMPEROR for confirmation. I will now share our latest progress with EMPEROR. EMPEROR is a global, double-blind, sham-controlled phase III study of zorevunersen.

Approximately 150 patients are planned for enrollment in the U.S., U.K., and Japan, where sham is administered via lumbar puncture. Data from these patients will be used for our U.S. NDA submission and are expected to be the final data necessary to complete our rolling submission. New patient entry and screening for this cohort is now closed. Patients currently in screening will continue through the 8-week screening period. Following successful completion of screening, these patients will be randomized to zorevunersen or sham administered via LP. As of May 5, approximately 130 patients have been randomized to zorevunersen or to sham. In addition, approximately 18 have completed their week 28 visit, which is an important milestone given the study's primary endpoint of change in seizure frequency, which will be assessed at week 28.

The study will remain blinded for the entire 52-week treatment period, given the secondary endpoints measuring cognition and behavior will be assessed at week 52. I will also note that to date, no patients have discontinued treatment in EMPEROR, while approximately 91 patients have already received the two loading doses of 70 milligrams of zorevunersen or sham and will continue treatment with two doses of 45 milligrams or sham. We expect the final patient to be randomized to zorevunersen or LP sham in June, putting us on track for our phase III readout in mid 2027. At least 20 patients are planned for enrollment in Europe, where sham will be administered via needle prick.

Although not planned for our NDA submission, it was important for us and for our partner, Biogen, to ensure experience with zorevunersen in Europe and to provide an opportunity for patients to participate in this study. Patient screening in Europe is underway, with 15 of 16 sites now active. We anticipate completing enrollment in Europe in Q3. As Ian mentioned, the study has enrolled quite rapidly, which speaks to the need and enthusiasm for a disease-modifying treatment. We look forward to seeing this study through to completion while turning more of our attention to preparations for potential U.S. approval and launch. With that, I will turn the call over to Jason.

Thank you, Barry. As you just heard, EMPEROR is nearly fully enrolled, which puts us into a roughly 18-month window for the earliest potential U.S. approval and launch. Today, I'll share how we're preparing to deliver zorevunersen to all patients who could potentially benefit in the U.S. I'll start with the patient population. There are an estimated 38,000 patients with Dravet syndrome across the seven major markets where we're running the EMPEROR study, the U.S., U.K., EU 4, and Japan, including approximately 16,000 in the U.S. alone. These estimates were derived by scaling annual incidence to prevalence using country-specific live birth rates over the past 85 years and adjusted for Dravet-specific mortality.

Despite the many antiseizure medications in use today, persistent seizure burden remains for most patients, and these medications do not address the underlying genetic cause of the disease, resulting in a widening gap in neurodevelopment as patients with Dravet syndrome fall further and further behind their neurotypical peers as they age. The U.S. Dravet patient population is highly concentrated, with approximately 70% of patients being seen by roughly 1,200 healthcare providers. From a clinical practice perspective, our research indicates that there are approximately 124 sites of care where about 70% of patients are seen. There are 26 Dravet syndrome comprehensive care centers across the U.S., and most of them are participating in at least one zorevunersen clinical trial. Turning now to the patient population. We estimate there to be 16,000 patients in the U.S. across all ages.

Of those, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider. Pediatric neurologists are typically more familiar with Dravet syndrome and tend to follow patients into early adulthood. Data from claims analyses also give us insight into the immediately addressable population and the providers who care for them. Together, these analyses give us confidence there will be approximately 6,000 addressable patients at the time of a potential launch. As genetically targeted medicines continue to emerge, the role of genetic testing becomes increasingly relevant. We're encouraged by our market research that suggests that clinicians anticipate screening will significantly increase with a disease-modifying treatment that addresses the underlying cause of Dravet syndrome.

Treatment guidelines published in 2022 highlight the importance of a genetic diagnosis of Dravet syndrome to guide treatment decisions, including avoidance of contraindicated medicines like sodium channel blockers. These guidelines are increasingly relevant as the treatment landscape shifts toward disease modification with potential treatments like zorevunersen. We will continue to expand and enhance the unseen disease awareness campaign launched last year to emphasize the importance of genetic testing and the diagnosis of all patients, irrespective of age. This omni-channel campaign will incorporate targeted and specific messaging to providers based on their diagnostic and treatment behaviors ascertained from claims analyses. Consistent with a rare genetic disease with a concentrated market and the entry of a high science genetically targeted treatment, we anticipate being able to maximize this opportunity with a lean commercial infrastructure.

On the medical affairs side, our team is now fully deployed across the country, with regional medical directors highly experienced in rare neurological diseases who are engaging directly with clinicians to enhance medical and scientific education. What we consistently hear is that clinician conviction in a medicine like zorevunersen increases the more they understand the data. Longitudinal data and recent publication of our data in New England Journal of Medicine are contributing significantly to the awareness, understanding, and enthusiasm for zorevunersen. Phase III EMPEROR study, long-term longitudinal data from the phase I, II, and OLEs, and recent New England Journal of Medicine publication provide an unusually deep data set, particularly for an investigational medicine that's in phase III. Taken together, these elements support the overall value proposition of zorevunersen as a potential disease-modifying therapy.

From a commercial standpoint, we feel very confident in where we are today as we await phase III data from EMPEROR. As Barry shared, we have a high degree of conviction in our EMPEROR phase III study. The study design, including dosing regimen, endpoint selection, and powering, were informed by a robust data set from the phase I, II and the first two years of the OLEs. As those data have matured, our confidence has only increased. We now have five years of clinical safety and efficacy data to support zorevunersen. By the time of our anticipated phase III readout in mid-2027, we expect to have an additional year of OLE data for inclusion in a potential label.

Given that zorevunersen is intended to be a chronic, lifelong treatment, the long-term data from the phase I, II, and OLE studies are the most comprehensive set of efficacy and safety data we've generated to date to inform clinical use. In market research with healthcare providers and payers, they told us that the longitudinal data are the most compelling piece of evidence that we may have at the time of a potential approval. We also know that payers will review and assess the totality of the data, not just what's in the label. The recent New England Journal of Medicine publication will further support our educational and access efforts. We plan to deploy a team of national account directors in the second half of this year to begin engaging more directly to educate payers through pre-approval information exchange presentations on Dravet syndrome and the data supporting zorevunersen.

There's no question that the label is critically important. If approved, the label will be the basis for all promotional communications and healthcare provider education, supporting their understanding of how to appropriately prescribe zorevunersen throughout a patient's life. A comprehensive label is particularly important for community providers who are more likely to be general neurologists that may not have as much experience with Dravet syndrome as epileptologists do. Importantly, FDA guidance supports inclusion of data from clinical studies that provide other important information about a drug's effectiveness that may not be furnished by the pivotal studies and that practitioners would consider important to clinical decision-making. In summary, our well-designed phase III study, robust longitudinal data that will continue to mature ahead of a potential launch, and feedback from payers, providers, and caregivers give us confidence in the value of zorevunersen as a disease-modifying treatment for Dravet syndrome.

With that, let me turn the call over to Thomas to discuss our financials.

Thank you, Jason. I will now provide the financial results for the first quarter of 2026 as reported in our business update today. Full financial results can be found in our 10-Q. We ended the quarter with $411 million cash equivalents, and marketable securities, which we expect will fund operations through a potential U.S. launch in late 2027 or early 2028. During the first quarter, we raised $80.7 million in net proceeds through our ATM program, selling approximately 2.6 million shares of common stock to high-quality fundamental investors. Overall, we continue to invest in advancing our phase II study and preparing the organization for potential commercialization while advancing our pipeline and maintaining a strong financial position. Our projected path runway into 2028 supports phase III execution and commercial readiness and launch.

As Jason described, we expect a lean commercial infrastructure given the concentrated nature of the Dravet syndrome market. I will now turn the call back to Ian for closing remarks.

Thank you, Thomas. 2026 is off to a strong start with rapid enrollment of our Phase III study, an additional year of longitudinal data from our OLEs that further support our confidence in and a growing awareness of zorevunersen as a potential disease-modifying treatment. With that, operator, please open the line for questions.

At this time, I would like to remind everyone, in order to ask a question, press star then the number one on your telephone keypad. We do request for today's session that you please limit to two questions only. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Pete Stavropoulos with Cantor. Your line is now open. Please go ahead.

Hello, Ian and team. Thanks for taking our questions. Congrats on the 4-year data and heading to enrollment completion in less than 1 year. A great accomplishment. For the 4-year data, how do these outcomes for both seizure reduction and the Vineland align with your expectations for the 4-year marker? Can you share how you think these data add to what we've already seen for zorevunersen? As a follow-up, you know, I did notice, you know, some variability in the subdomains and some changes in the scores since the 3-year readout last August. How should we be thinking about that variability?

Pete, thank you for those comments and questions. I'm gonna start with how we felt when we, you know, frankly opened up the envelope and saw the data from the four years studying these patients in the OLE. Yeah, we were frankly thrilled. What the data shows you is that we are going to the root cause of this disease with zorevunersen. The continuous reduction in seizures over this, what is now a five-year period, and also the gains each year in cognition of behavior show that you're going at the root cause of this disease. Before I push it over to Barry, I wanna just pause for a moment and cause everybody just to think.

When is the last time that you may have seen four years worth of OLE data for a medicine that treats a root cause of a disease, so you therefore you can collect over four years longitudinal data? It is very unique. What that is allowing us to do is to truly understand how this medicine is helping patients. You know, encourages us as well as increasing our confidence of what we may expect in our Phase III, also going to how we feel about this medicine should be promoted to the patient community and the physician community. Truly outstanding data from this study. This study started before I joined the company.

I wanna congratulate the company on the thoughts of running this study to collect this data to inform the treating community and the patient community. Barry, your thoughts?

Yeah. Thanks for the question, Pete. This is Barry. Again, the goal in developing a disease-modifying therapy would be to demonstrate a meaningful effect across multiple different aspects of the disease. That's really what we're seeing here. This is exactly what we were hoping for in terms of results, especially over the four-year period that these patients have now been followed. The consistency and the durability of the results that we're seeing is really encouraging and gives us more confidence in zorevunersen as a treatment with a disease-modifying effect for patients with Dravet syndrome.

Barry.

Barry, there was a second-

Yep

-question in terms of, uh-

The follow-up was in terms of the difference in the subdomains. First of all, again, just to remind you, these 4-year data occurred after patients were enrolled in and followed in the Phase I/II study. The results are compared to the baseline after they enrolled in the open-label extension study. We're really encouraged by the consistency of the results that we're seeing here across all 5 subdomains. In addition to what we saw in terms of durability and the seizure reductions, we said, as we mentioned, that we're seeing now statistically significant improvements across these 5 subdomains from year 1, 2, 3, and 4 compared to the open-label extension baseline. That's really a remarkable effect to see that level of rigor in terms of results.

The modeling that we do is dynamic. We do include additional patients as they reach milestones within the open label extension study. We add those patients into the database. That's why there is some variability that you're seeing, Pete, in terms of the actual scores that were achieved.

Thanks, Pete.

Your next question comes from the line of Sumant Kulkarni with Canaccord Genuity. Please go ahead.

Thanks for taking our questions. I have two. The first one is a pretty simple one, but it's important, I think. Barry, you reviewed a lot of numbers today. I want to make sure that we get them straight. Could you please walk us through or underscore those key numbers again? That's the first question.

Sure. Thanks, Sumant, for the question. I'll go through it again. We have 130 patients who have been randomized in the study, either to zorevunersen or to the sham in the lumbar puncture group. 91 patients have received either 2 doses of the loading dose of 70 milligrams or the sham group. 18 have completed that important week 28 visit that is the primary endpoint for the study. I'll remind you that there have been no discontinuations from the EMPEROR study to date.

Thanks. Secondly, for Ian or for Jason, what are your latest thoughts on whether the market is adequately appreciating the immense value that zorevunersen might bring to the table for patients with Dravet syndrome in terms of the price that investors might be using in their financial models?

Thanks for the question, Sumant. You know, there's a lot of different answers to your question, frankly. I'm going to ask Jason to go straight to work that we've been doing recently with payers to establish our own expectations and expectations with payers in terms of the value behind this medicine. Maybe Jason, you give. This research that we've been doing has been ongoing for a year or so, but we've also done some very recent research given the data that we have in-hand. Jason.

Yeah. Thanks for the question, Sumant. I think it's particularly timely that you ask because, you know, historically we've noticed there's been a desire to compare what we're doing with zorevunersen to the other approved medicines to treat a form of Dravet syndrome or a symptom of Dravet syndrome, and that's the anti-seizure medicines, right? They're indicated for the treatment of seizures associated with Dravet syndrome and not the syndrome itself. To date, they're the only thing that's been approved for the syndrome. It's natural that you would gravitate there initially. I don't think those are really appropriate comparisons or do justice to the value that zorevunersen has the potential to bring to the market. As such, as you can imagine, we've been talking to payers for some time now.

The most recent piece of research we did with payers was an advisory board, just a couple of months ago. You know, this was obviously before we had the four-year data that we disclosed today in hand, and it preceded the New England Journal Manuscript. What I can tell you is that these payers are telling us that they're looking at the totality of the data when they're thinking about a medicine like zorevunersen. I think the most appropriate analogs are other genetically targeted disease-modifying medicines that go after the root cause of the disease and have an effect beyond just one symptom of the disease, as you're seeing with zorevunersen in the Vineland results, in the quality of life measures, and obviously the seizure data.

We think that the more appropriate analogs are products like Spinraza, you know, another intrathecally administered ASO, like the exon skippers from Sarepta or even Daybue from Acadia, I think are probably more in the window that we're talking about for potential value. You know, given these 4-year data, we're incredibly encouraged with what we've got and look forward to continuing to engage payers. You know, at this ad board, one of the interesting nuggets they shared with us was they encouraged us to go out and start educating them around Dravet syndrome and zorevunersen as soon as possible. That's advice that we're heeding, as you heard in the prepared remarks. We're gonna be deploying our national account director team to really start one-on-one educating payers in the second half of this year.

I might just follow on from Jason and say, you know, it's connected to my opening remarks, which is we are in a unique position where today we have 4 years of longitudinal data of safety and efficacy, and we've shared that with you all, and we will be sharing it with the FDA. When we look into the future and potential filing and approval, we anticipate also supplementing and supporting our filing with this OLE data. At that time, it will be 5 years worth of data. What we're hearing, as Jason said, from the payer community, is that this longitudinal data helps establish the value of this medicine to the patient. Very, very, very important, this data.

Thank you for that question, Mr. Kulkarni. Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead.

Hey, good afternoon. This is John on for Andrew. Congrats on the 4-year data. What a great milestone. Given that the EMPEROR study is a 52-week study, maybe just talk about your confidence in hitting those key secondaries. Then as you explain that, could you also perhaps elaborate on the U.S. stats analysis and sort of provide the exact hierarchy to support the completion of your rolling BLA or NDA? Do each of the 5 sub-domains need to hit stat sig in the U.S.A. or does maybe only 1 need to hit stat sig? Thanks.

John, thanks for the question. I'll actually lead off, and then Barry can talk about the other parts of your question. This data really, when you take the totality of the data, helps you understand when you understand the kind of the pathophysiology of this disease, which is unfortunately a lack of NaV1.1 protein, expression of NaV1.1 protein. When you understand the pathophysiology of this disease, it also helps you understand how our medicine is getting to the root cause to help express NaV1.1, and therefore that plausible mechanistic pathway truly is established with this data. Remember, this data is treating patients on top of standard of care medicines.

The mechanistic pathway to address this disease must be going around those other medicines and right to the root cause of this disease. That provides us with the overall confidence of how this medicine is working, and therefore the play through to actually the phase III and how we think about the phase III that as we've referred to in the past, we continue to dose on top of standard care medicines, but we continue to see this reduction in seizures and also this improvement of cognition and behavior. Maybe Barry can talk about why we have the confidence in the phase III and go back to when we designed it and based on the data.

Yeah. Thanks, Ian. Thanks, John. Again, when we designed the phase III study to look at the 1-year secondary endpoint, those were powered based on substantial amount of data from our phase I/II OLE studies from 81 patients. That is a very meaningful amount of data for us to work with and gives us confidence that we will be able to show the statistically significant results at 52 weeks. We've also done some additional analyses of our phase I/2a study, and we showed some of those data first in last July at the European Paediatric Neurology Society meeting, where we showed a comparison looking at the 1-year data. There we again showed substantial and significant changes for the Vineland subdomains compared to natural history.

We went a step further and did what's called a propensity-weighted scoring, which is a very rigorous way to compare 2 different databases. Those were shown at the American Epilepsy Society meeting at the end of last year. There again, where we took the patients who were getting a dose level that was similar to what we are using in our phase III study, compared that to the 18-month time point, which is essentially the same as the 52-week data point, because again, we had that 6-month gap before. When we looked at those phase I/2s data compared to natural history, we showed statistical significance there again with comparison to the different subdomains. We have a high degree of confidence that we will be able to show statistical significance with those subdomains.

As far as whether those need to be shown, to FDA, we've had those discussions. We know FDA will look both at a composite as well as the individual ones. We've ranked those, but we have a high degree of confidence that we will be able to meet those in the phase III study.

Thank you guys so much, and congrats again.

Thank you.

Your next question comes from the line of Laura Chico with Wedbush. Please go ahead.

Good afternoon. Thanks for taking the question. Two for me. Ian, Jason, Barry, you've all highlighted the significance here of getting the OLE data on the label. I'd love to hear a little bit more about how that actually happens, what does that actually look like, and your confidence there. The follow-up would be, I just wanted to clarify on some earlier comments, could you point to some specific examples where long-term data were included on a label? Thanks very much.

Laura, it's a great question, and frankly, it's a question we receive frequently. I'm gonna start by, you know, what is the purpose of a label for a medicine? Frankly, it is for physicians. It's to help understand the safety and efficacy of the medicine. I'm telling you things that you already know, but there may be some things that people are not aware of. Yes, the label is for understanding safety and efficacy. That's what people primarily focus on. What you do need to understand is that the label is broad and there are sections of the label, particularly the one that's called clinical studies.

It's where you have supplementary clinical studies that support the understanding of the safety and efficacy of the medicine and how it may benefit a patient or how it may benefit a prescribing physician understanding of the medicine and the safety and benefits to that patient. There are specific industry guidance that I'm happy to point people towards. Given that I am on the call and you asked the question, it really is important. In October 2022, there is industry guidance that talks about multiple endpoints in clinical trials, and you can research that, and you will find that it talks about supplementary data from clinical trials should be included in a label to help understand safety and efficacy of the medicine.

It was also, as far back as 2006 in other industry guidance that talked about section 14 and the use of clinical studies that support the understanding of the medicine. It is very clear. There are many analogs, and I'll ask Jason to talk about those, because Jason's been out in the field talking to payers, as well as, you know, educating physicians through medical affairs. It is a path that is used. The unusual position that we're in, as I mentioned at the beginning of the call, is that we will have 5-year data that helps you understand the chronic dosing in Dravet of our medicine.

That supplements what would be pivotal information with the primary endpoint being most important to, 'cause that gets you approval of the medicine. Expanding the label to include this supplementary information, and it's only following the industry guidance. So we're in a unique position where we have this long-term OLE data. This supports the chronic use of our medicine, providing safety and efficacy. There are other analogs to this to your question, and Jason, maybe you should talk about those 'cause we do look at them, and we do discuss them with payers and other physicians. Jason.

Yeah, absolutely. I think, Laura, it's a great question, and I think I'll give you a few examples that you can use. You know, once again, an appropriate analog here, I think, is SPINRAZA. At the time of approval, you know, SPINRAZA, you know, was approved at the six-month interim. The observed data from the NURTURE study were really important to have in section 14 of SPINRAZA. Another good example would be SKYCLARYS for Friedreich's ataxia or QALSODY for ALS. All three of those products have observed open label data in section 14 of their labels. I think they're all very appropriate to look at.

You know, to that point, you know, payers and healthcare providers are looking to this data, but I think more so for healthcare providers than for payers. Because healthcare providers, in particular the community ones, are reliant on the label for how to prescribe the drug. When we talk to them, you know, they and payers alike tell us that the 4-year data or the longitudinal data will probably be the most compelling piece of evidence that we have at the time of a potential approval. I think, you know, for the purpose of having them understand, you know, as the guidance states, right, that practitioners would consider important to clinical decision-making.

We've heard from market research that these types of data are critically important and the most compelling thing that we could potentially have in the label for healthcare providers. For payers, they'll look at the totality of all the evidence. Given what we heard from them earlier this year, even before a New England Journal publication, I think we're in really good shape with respect to how payers are thinking about zorevunersen.

Laura, or maybe Barry, do you want?

Yeah, I'll just add on.

On a statistical significance and how you approach this as a clinician.

Yeah. I'll certainly add, especially to what Jason said, the importance of having information in the label. As a practicing physician, I turn to the label for information as to how to use the medicine and to know what to expect both for myself and to explain to the patients and their families what to expect. It's just so rare to have this long-term data in the label, especially at a time of launch. This will be very useful in order to be able to share expectations for what the potential benefit and risk of the medicine are. The safety data are equally important.

Laura, I'll just add one more thing to kind of the credibility of the OLE data that we will be sharing with the FDA, cause we only just recently received it. Is that we made comment that year one, two, three, and four in the five key subdomains were all statistically significant compared to OLE baseline. That endpoint of the five key domains compared to baseline was a predetermined endpoint. That's very important that it was a predetermined endpoint. We've not gone in here and retrospectively calculated that. It was a predetermined endpoint, and we'll be sharing this data with the FDA.

The statistical significance of it was on one of the slides, but each of the five key domains is less than 0.01.

That's super helpful. Thank you. If I can sneak one in just for Barry, a housekeeping question. How many patients were in the pre-screening? I think I missed that when you went through the numbers. Thank you very much, and congrats.

Initially in the pre-screen, there were over 200 patients initially.

I think what Laura's referring to is how many is in the pre-screen now to close out enrollment at approximately 150. Laura, the key numbers, and as you can probably tell, I follow these on a daily basis. I talk to Barry's office is right next to mine. We expect to end up randomizing and dosing with Sham or drug, approximately 150 patients by in June. The remaining patients, you know, to bridge the gap from the 130 that we're at today to 150 in June, is significant in terms of our expectation of how many will transfer to randomization and dosing. You know, we continue to look at a screen fail rate.

That screen fail rate has played out, and that's why we're confident to now reiterate. We have closed screening. That's how confident we are that we will attain at least 150 patients, by June.

Thank you for that question, Laura Chico. Your next question comes from the line of Marc Goodman with Leerink Partners. Please go ahead.

Yeah. Hi. Two questions. One, you mentioned the pricing discussion with the advisory group and the payers last quarter. Curious if you discussed if you didn't have positive secondary endpoints and it was just a epilepsy, so to speak, drug, right? I mean, if it's a seizure reduction drug, which is very strong data on top of standard of care. The second question is on the 16,000 prevalence. You mentioned 6,000 were addressable at launch. How did you come up with the 6,000 were addressable? Do we know how many of those 6,000, like, are they actually on, you know, FINTEPLA or are they taking EPIDIOLEX or something like that? Like, were you able to find out, like, patients that are actually Dravet patients that are, you know, have taken a drug? Thanks.

Yeah, great questions, Marc. Let me take, maybe the first one, around the payer interaction. We did ask that question, and I think what we heard back from payers was that they will look at the totality of the evidence, and from their perspective, the longitudinal data are incredibly compelling. You know, I think first it's important to reiterate we have a high degree of conviction in how we've designed EMPEROR and what we, you know, think we're gonna see at the end of the EMPEROR study when we get the data card in the middle of next year.

We did ask payers that question just in case, and they told us the longitudinal data are incredibly compelling and that they won't exclusively rely on the label, that they will look to all of the evidence that's in the public domain. You know, knowing that this was before the New England Journal publication came out in March that we spoke to them, I think it was January, February was when we were having our payer interactions. Between the New England Journal and now with the four years of data, we feel really confident that we're gonna have a very robust package to bring to payers at the time of a potential approval. Those educational efforts for payers on what we have today and just Dravet as a, as a whole are gonna start in the second half of this year.

We're well out in front of it when it comes to payer education. Specifically on the second question around the 6,000 addressable at launch. It's a great question because you can really come at it from two ways, Marc Goodman. The first way is when you look at just the epi analysis that I had mentioned, where we looked at the last 85 years of live birth rates on a country-by-country basis and then applied Dravet-specific mortality to come to what we anticipate to be the prevalent population at the time of a potential approval. That gets you to the 16,000 patients in the U.S. that we've talked about. The 6,000 is in reference to those patients from that epi analysis that are 25 or younger.

The reason why 25 matters is because, as you can imagine, pediatric epileptologists, pediatric neurologists are the subspecialty that are most often diagnosing and caring for patients with Dravet syndrome. You know, as patients are diagnosed, you know, oftentimes as infants, but certainly as toddlers, they grow up with the pediatric provider. There's a strong loyalty to those providers. Those providers are typically the most well-educated around Dravet syndrome and most familiar with how to treat it. Naturally, there's a bit of a reluctance to transition to adult care. What we've heard from pediatric epileptologists is that they're most commonly caring for patients into their mid-20s. That's why that mid-20s number of 6,000 matters to us. I think another way that you can potentially come at this is looking at claims data.

When you look at claims data, there are multiple claims databases out there. All of them have different levels of capture. When you look specifically at, for example, the claims database that has the most diagnosed Dravet patients in it, that has 6,000 patients with a confirmed ICD-10 code for Dravet syndrome. When you look at it from a claims analysis, you also see 6,000 patients. When we further break down that claims analysis and we look at ways that we can predict where patients are based on that peri-diagnosis period for, you know, confirmed patients, we can determine where likely and predicted patients are as well. Through those analyses, we feel pretty confident that we know where about 70%-80% of the 25 and younger patients are being cared for today.

Thank you for that question, Mr. Goodman. Your next question comes from the line of Yaron Werber with TD Cowen. Please go ahead.

Great. Thanks so much and congrats on the data. Really nice to see it. A couple of questions. Number one, it sounds like you're gonna start the rolling submission sort of in the first half of next year or have data, you know, after kind of starting mid-year or so and then finish the rolling. I believe there's an extra 40 patients that you're gonna be enrolling in Europe. Do you need to wait for that data, or can you file on the rest of the data without those patients? Thank you.

Yeah. Thank you, Yaron. Nice to hear from you. Let's just go to what we stated in our prepared remarks that we are committed to and anticipate, which is we anticipate to start our rolling submission in Q1 2027. You know, I just wanna emphasize why that's important because if we start that rolling submission in Q1 of 2027, it allows the last submission within our NDA submission to be the clinical data from week 52, which would be around the middle of the year. When you look back in the kind of the somewhat recent history of breakthrough medicines and rolling submissions, what you actually find is that the timeline then to approval is generally around 6 months or less.

That's why we've referred to our timeline for potential approval of Q4 2027 or maybe early 2028. I just wanna kind of reiterate that and why the rolling submission is so important. You asked about the, you stated it as 40 patients. We actually think it's gonna be between 20 and 30 patients in those European countries. That cohort of patients is actually needle prick placebo or sham controlled. We will not wait for that data to be clear. You know, all is pending timelines. At this point in time We see our data completing and submitting from the lumbar puncture part of the study that is being run in the U.S., U.K., and Japan as being our basis for filing.

Thank you for that question, Mr. Werber. Your next question comes from the line of Tom Shrader with BTIG. Please go ahead.

good afternoon. Thanks for all the update. back to the 6K, I think it is interesting. Of the 16K, those older people, do they not have seizures anymore? I just point out that Biogen has feasted with SPINRAZA on older patients that don't have that much to gain, but nonetheless do gain something. Jason, as I'm sure you've done a ton of work. From your 6K, if you look across the landscape of ultra-orphan drugs or orphan drugs like this, what percentage would you expect to get treated? Do you expect 6K is your peak penetration, or is there another cut for what you would actually expect to get on drug? I appreciate it's kind of a guess, but thank you.

maybe with the first question, Tom, with seizures in adults, and maybe Barry wants to add to this. you know, as patients age, the disease does evolve, and the seizures move from predominantly daytime seizures to predominantly nocturnal seizures, and the seizure types do change. Adult patients do have seizures. They have other manifestations, but I think in adult patients, quality of life is what we hear from caregivers is the number one objective in treatment. obviously we're gonna look to study in a small open-label study we're gonna plan to start later this year in some adult patients to predominantly look at safety, but also to look at some of the adult-specific endpoints.

With respect to your second question around the 6K, you know, we really haven't guided to peak penetration, but what I can tell you is that when you look at the demand for the EMPEROR study, the response that we're hearing from healthcare providers to, you know, even the 3-year data. Obviously, the 4-year data are new and haven't been shared publicly until an hour ago. You know, continuing on those trends is obviously incredibly compelling to clinicians. They consistently tell us that the durability of the seizure suppression and then, you know, the continuous improvement in Vineland over time give them a lot of confidence in how they could be able to prescribe this drug for their patients and just specifically what to expect.

that's why we're hearing from them that the four-year data and the longitudinal data are probably gonna be the most compelling piece of evidence that we'll have at the time of approval. I think, you know, what I can say is that over the last couple of years, the level of enthusiasm has increased dramatically with additional data, with additional engagements, with an enhanced presence at scientific meetings, with the deployment of our regional medical directors to directly work to educate clinicians around this, the Dravet syndrome as a whole and around zonisamide. we're seeing just robust enthusiasm, and that has continued, as you can imagine, and even further been solidified with a publication in The New England Journal of Medicine.

you know, I would say that we have really strong conviction that there is incredibly robust demand that we will see at the time of a potential approval.

Perfect. Thanks.

I'll just add. Sorry, Tom, I'll just add. In our open-label extension studies, we do have adult patients who are continuing to be treated, and we see that those patients continue to have substantial reductions in seizures and have improvements in their cognition and behavior. That to us is already a very good sign of what to expect.

I agree. Okay, thank you.

Thanks, Tom.

Your next question comes from the line of Edward Marks. Your line is now open. Please go ahead.

Hey, Ed, you may be on mute.

Mr. Marks of the inheritance.

Hi, thanks for taking our question. This is Joey. Would you anticipate payers would require patients first fail a certain number of anti-seizure medications before being considered eligible to receive zonisamide? Would you expect that the drug would be used immediately upon a confirmed genetic diagnosis?

Yeah, I think it's a great question, Joey. I think, just maybe taking a step back, I think, you know, mechanistically, I don't necessarily know that it will matter all that much just based on how patients present, how they're diagnosed, and how they're initially treated. you know, if you think about the patient journey, right? A patient will typically present to the healthcare system, oftentimes in an emergency room, in the middle of a febrile seizure. that febrile seizure is the first symptoms that families often experience. obviously, that's a pretty scary event. they go to the hospital, they get treated for febrile seizure. A lot of times they're told the febrile seizure is common in infants, and they treat the seizure, and then the patient gets discharged. Well, that patient is obviously getting treated with anti-seizure meds.

It, you know, as they make their way to a neurologist, you know, obviously, if they make their way to a neurologist right away, they're gonna get that confirmation earlier. By the time they get to a neurologist and the neurologist orders a genetic test, they're obviously treating the seizures before that. They will be put on an anti-seizure medicine as soon as they present to the healthcare system. With the rapidity with which anti-seizure meds are added and switched based on either, you know, side effects or waning efficacy, oftentimes patients will have failed, you know, two anti-seizure meds before they would even get the result of a genetic test. I think they could. I think some payers could mandate a failure of some ASMs.

In the grand scheme of our ability to get this drug into the hands of patients who could potentially benefit, I don't see it as a roadblock or a hindrance.

Great. Thank you so much for taking our question.

Your next question comes from the line of Jessica Fye with JPMorgan. Please go ahead. </edited_transcript

Hello, this is Adam on for Jess. Thank you for taking our call. Question. Just a few. How should we think about the SGN-A trajectory as you're ready for launch? When could we see data on STK-002 from the OSPREY study? One more, if I could. Will you publish baseline demographics for the EMPEROR trial once enrollment is complete?

I'll take the first two questions, and Barry, maybe you can take that last one. Adam, I don't think we know each other, but I've spent a long time working within the rare genetic disease space. I see a lot of similarities to my former life here where I was working with Vertex in cystic fibrosis. To be very clear, in terms of SG&A, our first of all, in a medicine like this, it is an education of the science of how the medicine works. It is not a sales and marketing effort, just to be clear. I saw this with the cystic fibrosis medicines, and I see it exactly here as well. That education is done through medical affairs.

I wanna be clear, we are fully built out in our medical affairs group today because that medical affairs group has been focused on enhancing understanding of ceriponorsene to enhance the well, let's say accelerate the recruitment of patients into our phase III study. The commercial build is small. We may actually end up with less than 100 people in total in sales and marketing. It is a minimal cost in terms of supporting this medicine commercially. As far as the A in SG&A, that's going to be lean as well. This is, if you wanted to take a look at financials and, you know, the Vertex financials are a good one to look at without the R&D investment because obviously Vertex has a broad pipeline as well.

That's a good model for you to look at. As far as ADOA is concerned, it's in a phase I/II dose escalation study. We are in the first low-dose cohort. We anticipate doing four cohorts and anticipate we may start to see efficacy data in the third or fourth dose cohort, the higher dose cohorts, and that would be towards the end of this year or early 2027. Obviously, the primary endpoint of that study is for safety, and that's why it's a dose escalation study. We will be looking at efficacy specifically in those third and fourth cohorts later this year and early 2027. Barry, do you wanna talk about the analysis of data?

We've been so focused right now on getting the patients into our phase III study. We hadn't really talked about what data we're gonna divulge later on. I'll tell you that we have designed the study very carefully so that the sham and the active arms are going to be as closely as possible equal in terms of their age, gender, and seizure baseline numbers. That's really what we've been focused on in terms of the demographics.

Thank you. I appreciate it.

Yeah. Thanks, Adam.

Your next question comes from the line of Yatin Suneja with Guggenheim. Please go ahead.

Hey, guys. Thank you for all the details. Very helpful call. Maybe just like a follow-up on question that Adam asked. For the I mean now that the enrollment is gonna close hopefully soon, right, in the next couple weeks, could you maybe characterize the baseline that you have enrolled so far? Like, what type of the CC severity? How should we think about the phase III mix relative to the phase I/II cohort that any notable difference or similarities?

First of all, we have already closed enrollment into screening, Yatin. To be clear, we have closed enrollment into screening. The patients are now going through that 8-week screen period and will flow through into randomization for dosing. For that clarity. In terms of the demographics, I mean, we don't actually have visibility of those exact demographics. We can tell you how we screen patients, but even there, we don't really want to go into kind of the specifics of the screening other than to say that they're absolutely consistent with how we've screened patients in the past of what we've brought into our studies.

To be very clear, the reason we don't talk about the specifics of the screening is, we want to have an integrity to that screening process without people understanding what they're exactly being screened for in terms of the cutoffs.

Thank you for that question.

Thank you.

Mr. Suneja. Your last question comes from the line of Rudy Li with Wolfe Research. Please go ahead.

Hey, thanks for taking my question. I have a follow-up for the key secondary endpoints in the phase III. If you miss some of them, would this still be possible to include certain secondary outcomes in the label? How would that potentially impact the eventual label language? In this scenario, can maybe provide more color, how do you plan to use natural history data to support payer discussion? Thank you.

Rudy, maybe I'll take that question. I appreciate the question. You know, frankly, when I look back at this last hour of the call, we've had a lot of discussion around this and the secondaries. The secondaries are important, but to be, you know, frank with you in terms of understanding how the medicine works, it will be about hitting the primary endpoint, which allows you to get approval of the medicine. It will be a combination of the secondaries and the section 14 other clinical supplementary studies that we talked about earlier on this call. The most important supplementary study or supplementary evidence of how this medicine is utilized and the efficacy and safety of the medicine will come from our OLE study.

That is why Jason has been out discussing with payers and healthcare providers in terms of, you know, what is most important to them. That feedback, as you heard from Jason earlier today, it is this four-year data at this point, which will be five-year data by the time that we file. As far as hitting P-values and secondaries, we remain confident. Barry gave you the rationale for why. I've talked about it a number of times in prior calls. Look to the data we've provided in the past on a dosing schema that is similar to that of the phase III. We've also done, you know, propensity-weighted analysis to compare natural history, as you refer to dosing.

Those analysis gave us a lot of confidence of what we would anticipate in terms of the secondaries that we'd hit. We're most encouraged by this 4-year OLE data and how it supports and therefore should be in the label and how it supports the understanding of the efficacy and safety of zorevunersen.

Right. Makes sense. Congrats on the data, and thank you.

Thank you, Rudy.

That concludes our Q&A session. I will now turn the call back over to Ian Smith, Chief Executive Officer, for closing remarks.

Thank you, Bella. I don't really have any closing remarks other than to say thank you. Given Rudy's question at the end there, I think it actually allowed us to summarize the call. I wanna thank everybody for their time today and let them know that we are available in our office, as we hang up here, and we're happy to take further questions and look forward to keeping you updated as we progress with our EMPEROR study and continue to dose in the OLE studies. Thank you very much.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Stoke Therapeutics third quarter 2025 business and financial update. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you need to press Star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press Star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Thomas Leggett, Chief Financial Officer. Please go ahead.

Good afternoon, and welcome to Stoke Therapeutics' Third Quarter 2025 conference call. I am Thomas Leggett, Chief Financial Officer at Stoke Therapeutics. Joining me are Ian Smith, our Chief Executive Officer, and Dr. Barry Ticho, Chief Medical Officer. Jason Hoitt, Chief Patient Officer, will join us for the Q&A portion. Today's webcast presentation is available in the Investor News section of our website. It is being recorded and will be available for replay later today. Before we begin, please note that today's discussion includes forward-looking statements. These are subject to risks and uncertainties, and actual results may differ materially. Please refer to our filings with the SEC for additional information. With that, I will turn the call over to Ian.

Welcome, everyone, and thank you for joining us today. I'm honored to have been asked to serve as the CEO of Stoke Therapeutics. This is an incredible company with significant opportunity ahead of it. I could not be more excited to be part of the team as we advance zorevunersen through phase III and build the company to deliver long-term value to Patients, our Employees, and Shareholders. On today's call, we will review our third-quarter progress. I'll start by summarizing where the company has come from and how that has brought us to today. I will talk about what priorities are next for us. Stoke's Progress in 2025 has put us in an important growth trajectory. There are several drivers of our momentum.

With four years of zorevunersen Clinical Experience and two years of Natural History Data, we have compiled a wealth of data to support our understanding of Dravet Syndrome and the potential for zorevunersen to treat this devastating disease. In addition, to support the phase III study, our long-term longitudinal data give us a clearer picture of the Disease Modifying Potential of zorevunersen and the benefits it could provide for people living with Dravet Syndrome and the families and caregivers who support these people. One of our priorities for 2025 has been to bring broader and more consistent understanding of zorevunersen to Clinicians, the Patient Community, and the Investment Community. We have done so primarily through Scientific and Medical Communications and our interactions at Medical Congresses. These activities, along with increasing awareness of the severity of Dravet Syndrome, are contributing to significant interest in our phase III study.

Back in August, we told you 150 patients had been identified through the investigator Pre-Screening Process. That number has now grown to more than 200 patients. In a few minutes, Barry will share an update on progression of those patients through the Formal Screening Process and into Enrollment and Study Randomization. As we continue to move forward with EMPEROR, we are preparing to meet with the FDA to discuss potential expedited regulatory pathways to bring zorevunersen to patients as soon as possible. This Multi-Disciplinary Meeting is part of the standard process for Investigational Medicines granted breakthrough therapy designation. Although zorevunersen was granted breakthrough designation last December, we did not request the meeting until we had phase III OLE Longitudinal Data. This now allows us to bring a comprehensive and current safety and efficacy data set to the discussion.

The breakthrough process was created to expedite the development and review of drugs that are intended to treat serious conditions. As part of that, the FDA commits to the involvement of senior FDA Managers. The meeting will be guided by a briefing book that is submitted in advance by the company. We have submitted our briefing book, which includes data and a series of questions, one of which relates to the potential for an expedited regulatory pathway for zorevunersen. With the growing awareness of Dravet Syndrome and the data to support the Disease Modifying potential for zorevunersen, the market opportunity is taking shape. As we move through our phase III and prepare to potentially launch zorevunersen in the U.S., we are investing in foundational efforts that will enable us to rapidly scale our business to reach as many patients as quickly as possible.

Through 2025, we have prioritized leadership in our core areas of our business, namely Medical Affairs and Commercial, as well as the Executive Team. The Medical Affairs build has increased the level and quality of our interactions with the Clinical Community. Our Commercial Leadership Team is now in place with experienced leaders in Market Access, Pricing, Marketing, Commercial Operations, and New Product Planning. TMC and Supply Activities remain on schedule to support the phase III and potential launch. We're in the initial stage of market-shaping activities starting with Unseen, a Disease Awareness Campaign to increase Awareness of Diagnosis of Dravet Syndrome through Genetic Testing. You'll be hearing more about this effort, which is designed to confront the gap in disease diagnosis. zorevunersen demonstrates the potential of our platform. We see a broad opportunity to develop additional Disease Modifying Medicines, particularly in Haploinsufficient Disease Areas of CNS, Eye, and Heart.

In terms of the eye, we recently presented data from our two-year ADOA natural history study that offer insights into underlying biology of Disease Progression and Clinical Assessments that support Clinical Development of STK-002. Recruitment has begun for our phase I dose-escalating study of STK-002 as a potential treatment for autosomal dominant optic atrophy. Sites are active in the U.K., and European sites are expected to initiate in early 2026. While moving through this dose-escalating study, the earliest we would anticipate potential efficacy data from Osprey would be toward the end of 2026 or early 2027. Next in the pipeline is our SYNGAP1 Program. Similar to Dravet, SYNGAP1 is a Neurodevelopmental Disorder that is primarily caused by a Haploinsufficiency. Preclinical work continues as we work towards the potential nomination of a Clinical Development Candidate in 2026.

Our experience with zorevunersen and relationships with treating physicians and patient advocates have been helpful in our early planning for a potential SYNGAP1 Clinical Development Program. In addition to these programs, we continue to invest in our early-stage pipeline across Multiple Therapeutic Areas. We look forward to providing updates as our Pipeline Programs Advance. I will now turn the discussion over to Barry for a brief review of key data and an update on progress of EMPEROR.

Thank you, Ian. I will focus my presentation today on a few of our more recent analyses that support our phase III study and the long-term Disease Modifying Potential of zorevunersen. These data will be central to our discussion with the FDA later this year. Here on slide seven, you see the reductions in seizure frequency observed among patients who were treated with zorevunersen for up to three years in the OLEs following an initial nine months of treatment in the phase I/II studies. As a reminder, all of these patients were taking standard-of-care anti-seizure medicines. The orange line shows patients who were initially treated with 70 mg Loading Doses followed by Maintenance Dosing in the OLEs. Our phase III Regimen is two loading doses of 70 mg followed by Maintenance Doses of 45 mg.

Also notable, however, are the continuing reductions in seizures for patients in blue who were treated with Loading Doses of less than 70 mg. These patients were treated with different maintenance dose levels in the OLEs until approximately month 28, by which time all of them had transitioned to 45 mg. Of the 80 eligible patients who completed phase I/II, 94%, or 75 patients, entered the OLEs. Today, approximately 58 patients continue on treatment, providing important long-term longitudinal safety and efficacy data. It's important to remember that Dravet Syndrome is more than seizures. It is a complex, lifelong condition with devastating impacts on cognition, behavior, and quality of life for patients and families. What you see in the illustration on slide eight is a representation of the anticipated trajectory for Neurotypical Development in green and for people living with Dravet Syndrome in orange.

Data from natural history studies tells us that neurodevelopment plateaus within the first few years of life for people living with Dravet Syndrome. As time goes by, they fall further and further behind their neurotypical peers. Understanding the effects of Dravet Syndrome beyond seizures is fundamental to the design and interpretation of data from studies of potential Disease Modifying Medicines. Our natural history study and phase I/II studies provide early insight into which clinical assessments would be most effective in the evaluation of neurodevelopment. Vineland-III emerges as a highly effective assessment for patients with Dravet Syndrome because it evaluates key aspects of cognition and behavior that are impacted by the disease, including communication, motor skills, socialization, and daily living. These four domains are supported by a number of subdomains that are scored on a standardized scale. Vineland is conducted by a trained central rater, which reduces the potential for bias.

To help understand the scoring and what it means in real life, we conducted and published a study of caregivers and clinicians that helped define thresholds for clinical meaningfulness. At least half of respondents said that a one to three-point change per subdomain per year was considered to be clinically meaningful. Suggesting that even a small change can have a substantial impact. Turning to slide 10, you see the most recent line number data from patients treated with zorevunersen in our OLE studies. These are the same patients included in the Seizure Analysis I showed you earlier. As you can see, there are dramatic improvements in Cognition and Behavior within the first year, which continue through years two and three. These improvements are in addition to any improvements that may have been experienced within the first nine months of treatment in the phase I/IIa studies.

As we designed our phase III EMPEROR study, we went back to our data. Using Clinical Data from patients in our phase I/IIa study and its corresponding OLE study, we conducted an analysis to guide our selection of dose regimen and key secondary endpoints. On the left, you see marked improvements across five key measures of Behavior and Cognition. These measures are now included in the key secondary endpoints of our phase III study. On the right, you see an analysis that shows minimal changes among patients followed in our Natural History Study and whose covariates such as age and baseline seizure frequency match the patients on the left. Four years of data from our clinical studies of zorevunersen have provided a robust safety data set summarized on slide 12. Zorevunersen has been generally well tolerated across our phase I/IIa and OLE studies.

The most common treatment-emergent adverse event was CSF Protein Elevations, which occurred in 14% of patients in the phase I/IIa studies and 45% of patients in the OLE studies. Overall, 86% of patients in the OLE studies experienced CSF Protein Elevations. No clinical manifestations have been associated with these Elevations. One patient discontinued due to elevated CSF Protein. Treatment-emergent serious adverse events were reported in 22% of patients in the phase I/IIa studies and 29% of patients in the OLEs. Across all studies, one patient experienced suicide. Overall, 81 patients have received at least one dose of zorevunersen. Some OLE Patients have now been treated for more than four years with up to 15 doses. These data provide support for the phase III EMPEROR study, which is off to a great start. 30 sites are now actively recruiting patients in the U.S., U.K., and Japan.

The first patient was randomized to zorevunersen in August. More than 20 patients have been randomized, and approximately 35 additional patients have entered the formal eight-week screening period that immediately precedes randomization. In total, more than 200 patients have now been identified by investigators as part of a pre-screening process. We anticipate similar demand for EMPEROR in Europe, where we expect sites to initiate in the first half of 2026. We are on track to complete enrollment in the second half of 2026. Since June, we have received nearly 400 medical information requests, which is an average of nearly three per day. Half of these requests were related to site locations and eligibility criteria from interested caregivers.

The volume of inquiries and the length caregivers are willing to go to for an opportunity to participate in EMPEROR are remarkable and support the significant and urgent need for Disease Modifying medicine to treat Dravet Syndrome. The impacts of this disease go beyond the Individual Patient. Dravet Syndrome impacts all aspects of life for entire families. By addressing the underlying cause of the disease, we believe zorevunersen has the potential to change the course of the disease and the lives of patients and their families. The team and I look forward to taking our substantial data package to the FDA and to working with them to explore potential expedited pathways that would bring zorevunersen to patients faster. I will now turn it back over to Tommy.

Thank you, Barry. I'll now provide the financial highlights from our third quarter. Stoke has maintained our strong financial position. We ended the third quarter with $328.6 million in cash, cash equivalents, and marketable securities. Subsequent to quarter end, we raised $48.7 million in net proceeds from our ATM via Single-Block Trade. We expect our cash runway to fund operations to mid-2028. Moving to the income statement, total revenue for the quarter was $10.6 million versus $4.9 million in Q3 2024. This increase in revenue was largely driven by a $6.7 million increase in revenue recognized as part of our collaboration on zorevunersen with Biogen. This was partially offset by $1.1 million lower revenues from Acadia. Net loss for the third quarter was $38.3 million, or $0.65 per share, compared with $26.4 million, or $0.47 per share, for the prior year. This was driven by an increase in operating expenses.

More specifically, R&D expense was $37.7 million versus $22.2 million a year ago. This is driven by spend associated with our phase III EMPEROR study, advancement of our early-stage pipeline, and hiring across the R&D organization. SG&A for the quarter was $16 million versus $12.7 million a year ago. This reflects increased investment in the growth of our commercial capabilities and team. I'll now turn the call back to Ian for closing remarks.

Thank you, Thomas. 2025 is shaping up to be a defining year for Stoke, and we are amid a significant transition of our company. zorevunersen is an incredible opportunity, firstly for patients, but for our company as well. The data Barry just summarized made clear the severity of Dravet Syndrome and the dramatic impact zorevunersen could have for patients and their families. Given that, we see it as our duty to get zorevunersen to patients as quickly as possible. The primary way we intend to do that is to continue to activate more sites and enroll more patients into EMPEROR. We will also continue our educational efforts to bring greater awareness of Dravet Syndrome and the understanding of the data that support the Disease Modifying Potential of zorevunersen.

Our team will be present and active at the upcoming American Epilepsy Society meeting in early December, where we anticipate sharing additional Clinical Data. In parallel, we are continuing our preparations for our meeting with FDA to discuss potential expedited regulatory pathways for zorevunersen in the U.S. Our Balance Sheet is in great shape with a cash runway that takes us into mid-2028. I want to thank everyone at Stoke for their hard work toward our mission. I also want to acknowledge the courage of patients, their families, and caregivers who are participating in our clinical trials. I look forward to a busy and productive Q4. Operator, would you please open the line for questions?

Thank you. At this time, we will conduct a question-and-answer session. As a reminder, to ask a question, you need to press Star one one on your telephone and wait for your name to be announced. To withdraw your question, please press Star one one again. Please stand by while I compile the Q&A roster. Our first question comes from Pete Stavropoulos from Cantor. Please go ahead.

Hi, Ian and team. Congrats on the progress, and thank you for taking my questions. First is, you presented three-year OLE Data at an international epilepsy congress in August, and additional data in October, I guess, Seizure Data and Cognitive and Behavioral Data. And I assume it's in the briefing book for the PDD Meeting. My question is, with that data in hand, what are some of the potential scenarios we might anticipate based on the PDD Meeting with the FDA? And importantly, should we read anything across from the uniQure experience?

So thanks for that question, Pete. And maybe I'll take the second question first. First of all, yes, I saw that we all saw the uniQure information yesterday. I want to, first of all, say there's something there that's disappointing, firstly. And what I mean by that is disappointing for Huntington's patients and their families. I'm sure hope was rising there, and so disappointing. We at Stoke, obviously, in a very different disease area. We're in a different division. And we're in a different process. And so that's why I wanted to just take the second question first. But the overall question in terms of our process with the FDA, yes, we are taking all of our data, which is now four-year data when you include the phase I/II data and the three-year OLE Data to the FDA, and it is in our briefing book. It is extensive.

It goes down to patient-level data. And I would say one of the most important things in the briefing book is actually the Safety Data that gives you confidence over a four-year period for some patients. And with over 800 doses now in all those patients, I do also want to take a moment to describe our process that we're going through with the FDA. In my prepared remarks today, I did comment that we received breakthrough designation for zorevunersen in December 2024. We chose to wait to get our three-year OLE Data. And also, we had the phase I/II data, both safety and efficacy, and take that to the FDA, to your question, Pete, and take that to the FDA. This meeting that we have is actually a perfunctory meeting under the breakthrough designated class of medicines. It's called a Multi-Disciplinary Meeting. So it's standard in the process.

And part of that is to go down to the FDA and educate around the Pathophysiology of the disease itself, educate around the mechanism of action of the drug and how that addresses the Pathophysiology of the disease, and share safety and efficacy data with the FDA and discuss with the FDA how you may expedite regulatory pathways. Now, one thing that is different than the usual Multi-Disciplinary Meeting is that we have four-year data. These meetings normally take place around early data. And so we're excited, as I mentioned in the prepared remarks. We're going down there before the end of the year. We're actually going down in December. We've already submitted our briefing book, and we're looking forward to that discussion with the FDA.

What are some of the potential scenarios, like outcomes?

Yeah, another good question, Pete. As you've heard a number of times now when I've spoken to you, I call it bookends. There is one bookend, which is you get on the most expedited path through to filing an NDA. And that outcome would be defined as the FDA saying everything is a review issue based on our questions in that briefing book. When the FDA says it's a review issue, that means that you can file your NDA, and everything would be a discussion and a review issue in your NDA. The other end of the outcome with those discussions with the FDA could be, "Please proceed. Perform your phase III." And again, as I just mentioned, one of the differences in other companies going to the FDA with the Multi-Disciplinary Meeting is they don't usually have an ongoing recruiting phase III program. We do.

And as Barry mentioned on his remarks, we've already randomized over 20 patients into that study. And so the other bookend to the outcomes is actually run the phase III, which is progressing very nicely. There are iterations in between. For those of you that are listening today, you've probably heard me say the iterations in between will be a process of discussion with the FDA about how you may amend the trial, cut the data, use other types of data, but basically use the data you have and use the ongoing phase III in a different way, potentially cutting data earlier at different endpoints with different powerings in agreement with the FDA. And if we go down that pathway, obviously, we'll communicate that at the time.

All right. Thank you. Very helpful. Just one additional question, Tom. Just the data presented at the recent medical conferences, can you just help us understand the magnitude of the cognitive and behavioral improvements on the Vineland-III data? And just I know you touched that on slide nine, but just help us better understand how clinically meaningful these changes are and how has it been received by physicians and KOLs that treat these patients.

Yeah. So. I'll take the initial part of that question, then Barry will follow up. I think the key piece of data for investors to focus on, because what I hear in your question, Pete, is you're asking, "How can we get comfortable that you'll hit your key secondary endpoint with Vineland?" And is there data you've presented at conferences that could correlate to that possibility or probability of hitting the endpoints? And the data we provided at CNS is probably the most appropriate data. The CNS data that Barry was referring to in his slides is based on a dosing that's similar and consistent to that we're using in the phase III. And with that data, we did see significant responses in the five key domains in Vineland.

Maybe, Barry, you want to talk about the context of those data and what those actually mean when you start to score a nine and a 10?

Yeah, Pete. So the question you're asking is a question we asked ourselves as well. And so we went out and asked clinicians and caregivers directly and said, "What point change on this scale would be meaningful as a change to the child with Dravet Syndrome?" And we published these data in a peer-reviewed journal that said that a change of one to three points would be meaningful. And especially when we talked to the families, they said changes in communication were especially important. And these families have actually gone to the FDA and told the FDA directly that changes in communication would be important.

And notably, that's where we're seeing some of the largest changes, not just after one year, but as Ian said, after two years, after three years, we continue to see improvements in these subdomains that are important to the families as well as to the clinicians.

All right. Thank you very much for taking our questions, and congratulations on the progress.

Thank you, Pete.

Thank you. Our next question comes from Laura Chico from Wedbush. Please go ahead.

Good afternoon. Thanks for taking the question. I actually just have two, so one that we've fielded from investors centers on the EMPEROR design and whether you could pursue an early approval solely based on the primary endpoint of seizure reduction alone. I guess I'm curious, would that be an option? I'm trying to understand the impact on secondary measures like Vineland. Obviously, that's carrying a lot of weight there, and then I have a follow-up.

So, I mean, the answer to your question, Laura, is yes, we could seek an approval based on seizure reduction. And we could cut the data for week 28 primary endpoint. But the broader answer is we will not do that. We believe the medicine is a Disease Modifying Therapy for Dravet Syndrome. The underlying pathophysiology of this disease is there is a we need to increase expression of NaV1.1. The way that our medicine works is that it increases expression of NaV1.1 and therefore affects the whole Syndrome. And so for the sake of an expedited process that might save six months because you're talking about a week 28 primary endpoint versus a week 52 endpoint, we would not go for an approval for reductions in seizures in Dravet Syndrome.

This is a Disease Modifying Therapy, and we will be looking for a label to treat Dravet Syndrome based on the data that we have so far and we expect to receive from our phase III study.

Understood. That makes sense. My follow-up then, you're guiding to enrollment completion by the second half of 2026. If you were to leverage a rolling submission, when would you be in a position to initiate that process? Thank you.

The timeline broadly at this point in time is to complete enrollment of 170 patients in the phase III in the second half of 2026, which means on a 52-week study that we would have data in the second half of 2027. Probably within late 2027, early 2028, we would be filing an NDA.

Thanks very much.

Thank you. Our next question comes from Andrew Tsai from Jefferies. Please go ahead.

Hey, guys. Congrats on the progress. This is John, Oz for Andrew. Thanks for taking our questions. Two from us, if we can. First, just a little bit of a follow-up on the prior question. Based on your progress with EMPEROR for enrollment, it seems like it could actually be tracking ahead. Is there a potential earlier outcome at which you think you could fully enroll the study? And then. Maybe for the second one, to get a better sense of what kind of % improvement zorevunersen is showing on Vineland when you're seeing such strong 8-14 point benefits, would you be able to share or do you have plans to share at AES, for example, the baseline Vineland scores from the phase I/II for the five domains you're going to be assessing?

And then maybe any color around if the phase III baseline scores are expected to look similar. Thanks.

So, the number of questions there. So if we miss them, please ask them again. But, firstly, you're correct that the trial is proceeding ahead of our expectations, both with trial sites opening and the recruiting of patients, the screening and recruiting of patients, and we anticipate that it will continue that way. This has been a wonderful effort by the Stoke team in terms of medical affairs and communication and the clinical team, and to help with awareness of the medicine and also the disease, and I think that is all helping accelerate that phase III recruitment timeline. At this stage, we're not moving our guidance. I think we're still at the beginning stage. As we said, we've randomized over 20 patients into a study for 170 patients, and as we move through it and we have a better visibility of the recruitment timeline, we'll update at that time.

And Barry, do you have a comment on the vigilance data regarding the phase I/II? I think what you're referring to is the, "Do we have the vigilance data from the phase I/II data that was a nine-month study? And have we disclosed that?" Was that the question?

Just more about the baseline Vigilant scores for that study.

So, the answers there are, first of all, in the phase one two, again, only in the U.K. study were we measuring the baseline data. In the U.S. study, we did not look at Vineland at the baseline. So most of the baseline data come for all patients from the open-label extension study. And that's where we're showing the changes, again, these dramatic changes and improvements in the scores over time. As a reminder, as we mentioned, for the natural history, those patients, their scores hardly change at all over time, over one or two years. So this is a dramatic difference from that. But in terms of overall baseline data, we're not going to be showing those data at AES for the actual scores, no.

Maybe I'll pick up from Barry, but a key part of our briefing book and data to the FDA is actually our natural history study that was run over 24 months. And we have disclosed that. In fact, I think it was recently published as well. And so that'll be a key piece of the comparison to the phase I/II and the three-year OLE Data. And then also to your question in terms of AES, yes, we'll continue to provide you data as we go through these medical conferences with AES being a very important conference for us.

Thanks so much, and congrats again.

Thank you.

Thank you. Our next question comes from Tom Shrader from BTIG. Please go ahead.

Good afternoon. Thanks for taking the question. Good luck with the big meeting. I wanted to ask a little bit about patient-level data. If you look at slide seven, even far out, the seizure reductions seem fairly noisy. And I'm just wondering, do you see is that patients that get benefit for a while and then revert? Do you see any evidence that the treatment is transient or does an individual patient sort of better behave and it's kind of monotonically down? And then I have a pipeline follow-up.

So I'll answer. Maybe Barry will follow up. But part of the, I'm going to say, noise in those error bars is as you go further out, it's a low number of patients. Whereas what's interesting, Tom, is when you take a look at on slide seven, and that is the OLE Data, which is after the nine-month phase I/II. And if you think about these patients now moving through into the OLE Data, when you look at the earlier data, both on the seizure reductions, whether it's the lower dose group or the higher dose group, it becomes tighter because you've got more patients. And so that data actually is not noisy when you have a lot more patients.

When you get further out to the far right of that slide with the one you're referring to, yeah, there's a couple of wide error bars, but that's where you have the least number of patients. And then I would just say that even where you do see the error bars, and I would focus on the left-hand side of that slide, you still see, even with the low dose, you still see if the median is around 75 or 70, you still see 60-85, if not bigger, reductions in seizures. All of that is a dramatic benefit to these patients that, remember, are taking three, four, and sometimes five standard-of-care anti-seizure medicines.

And I'll just add, again, Tom, that the natural history, that zero line that you see there, that's where the change that we would see on these same anti-seizure medications the patients are on, we're seeing almost no change in their seizures. So that's a dramatic difference from what would be patients who are just on the anti-seizure medications alone.

Okay. And if I can follow up, as you start to think about a pipeline, as you head into a program, is the odds that you'll find a lead candidate? I remember you had something like 200 candidates early on. Is the odds you'll find success high, or is it low? And maybe you can comment on what you learned from Rett, which is an important one that I guess didn't work out. So as you go into the pipeline, is SYNGAP1 just the best disease, or do you have data that it's one that's likely to work?

So thanks for that question, Tom. I'll just rewind the clock maybe six or seven months when I started in the position of CEO, and I asked the team pretty much that question, and I wanted us to do a full strategic review of certain disease areas, and what I mean by a strategic review, start with the market, start with can you develop the medicine in terms of its endpoints and potential accelerated pathways, and then preclinical safety and efficacy models and models that are more human-like in the proof of concept in animal, but also causing the company to really focus on haploinsufficiency, and we came away, I can tell you, with a number of new disease areas that are touched on in our slides, and that's cardiac and a couple of other areas, and so we are working; those are the earliest stages.

Now, if I go to the mid parts of our pipeline, which is SYNGAP1 and ADOA, those are both haploinsufficient diseases. Rett is not. Rett is a little different, and we may have learned a lot from Rett in terms of maybe creating kind of more functional protein, but it's still mutated, and so there were some challenges in Rett. But as far as SYNGAP1 is concerned, ADOA is concerned, and then in cardiac and a couple of other disease areas that we're looking at, those are all haploinsufficient areas, which is our platform to focus on those disease areas.

Perfect. Thank you. Useful answer.

Thank you. Our next question comes from Marc Goodman from Leerink Partners. Please go ahead.

Hi. Hi. Good afternoon. This is Basma Ong for Marc. Thank you for taking our questions. Our first question is on the BUTTERFLY study. Could you please remind us whether the company has received alignment from the FDA on the study design and on the goals of the study? Just to make sure that the study is robust enough, and also, we have a follow-up question.

I'm sorry, but I couldn't quite understand the slide you were referring to. If you're asking about.

Yeah. The BUTTERFLY Natural History Study. The BUTTERFLY.

Barry, do you want to? So I'll take the first part of that question, and maybe Barry will follow up. When in discussion with the FDA, I can tell you how they focus on natural history studies and how they're utilized. I'll tell you what the FDA does not like. The FDA does not like a Retrospective Analysis of real-world data or natural history studies to try and realign with what your primary and secondary endpoints are in your study. So they like endpoints to be pre-specified and consistent with the studies that you're running. That is exactly what we've done with BUTTERFLY. BUTTERFLY looked at seizure reductions as well as the Vineland. And that is consistent with how we've run all our studies. And that's most important. And I'll refer to it. It's called RDEP. It's Real-World Evidentiary Principles that the FDA put guidance out on.

And that specifically talks about being aligned and not being retrospective analysis, being more predetermined analysis as you go into these studies if you want to use them as comparisons or control arms.

Okay. Great. We have one quick clarifying question regarding the EMPEROR study. Could you remind us again whether the patients are required to stay on stable dose for the background ASM throughout the 52 weeks or after the 26th week? I'm sorry, the 26th or 28th week primary endpoint, they can actually change the dosing of their background ASM?

Yeah. This is Barry again. So the study requires that for the first 28 weeks, the patients do not change their background Anti-Seizure Medications. After that, because of some of the variability of the disease, we do allow some changes. But for that primary key endpoint there, there are no changes allowed.

Okay. Thank you.

Thank you. Our next question comes from Yaron Werber from TD Securities. Please go ahead.

Hi. This is Jana Ong for Yaron. Congrats on the quarter, and thanks for taking our question. For us, your phase I/II studies and your phase III have slightly different dosing schedules. So I was wondering how that was going to factor into how you design a label for zorevunersen if you do pursue this kind of accelerated pathway. Also, just to follow up on one of the earlier questions, you said that one of the potential aspects of your discussions with the FDA are how you can iterate on how to amend your trial, cut the data, use other cuts of data from your phase III trial to also accelerate approval. What do you think are the most kind of promising possibilities among those scenarios? Thanks.

So good questions. First one, in terms of the dosing. Absolutely correct. It is a fact that there is not a patient that is dosed on the exact schedule that we're using in the phase III. And just to be clear on that. There are patients that did receive two doses of 70 mg of zorevunersen but then had a six-month gap. Before they went into the OLE study and then received 45 mg every four months in the OLE. That dosing in terms of 70s and then 45 mg maintenance dose is consistent with what's in the phase III. What the piece that's inconsistent is a six-month gap instead of a four-month gap. And so yes, we understand the point that you're making. It is something that could be a discussion with the FDA.

However, we would point to the data from the phase I/II and the OLE in terms of its consistency and durability from the phase I/II, the six-month gap in dosing, and then into the OLE where those seizure reductions are durable and are maintained. Plus, you see the same with Vineland where you get an improvement in cognition and behavior, as mentioned by the Vineland scores. And that continues into the OLE study as well. And we presented that data to you over three years in terms of looking at it from a longitudinal basis where you see an improvement in year one and then year two and then year three in the OLE in most of the domains. And so that is the data that we'll be using to support the dosing regimen that is in the phase III design that we would be seeking approval for.

Thank you. Our next question comes from Jessica Fye from JPMorgan. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking my questions. And a few here kind of long questions, but maybe short answers. So first, you talked about the FDA meeting scheduled in December. When would we know the outcome of that meeting? Would you plan to wait for the minutes before communicating to the street on the path forward? Or are there scenarios where you think the feedback would be clear enough to communicate before receiving the minutes? Second one is, I think you had 130 patients in pre-screening this summer, and then that grew and grew, and now I think you mentioned 200. But of the 130 from August. How many of those folks are still in pre-screening versus screening versus screened out for some reason? Trying to tie that 20 patients randomized. Back to kind of these large pre-screening numbers. Third, to the extent you're able to see blinded safety data from phase III, anything you can say about the patients treated so far? Is the safety consistent there? And lastly, it looks like you raised about $50 million via the ATM this quarter. Can you just refresh our understanding of the balance sheet? Thank you.

Okay. Jess, I think I got all those down. Number three, blinded safety data from our phase III. No commentary. It's a blinded study, and it's an ongoing phase III study. The other three questions, you asked about disclosure coming out of the December meeting with the FDA. Disclosure will be driven by when we believe that we are moving the timeline that we're currently communicating to you this evening. And that is to complete enrollment in the second half of 2026 and then with data coming in the second half of 2027. The moment that we're confident that we are moving off that timeline, whether it's an expedited pathway, an accelerated recruitment, we will then provide a communication. You asked specifically about minutes. I believe you should always wait for the minutes.

My experience over years now is that you can have good and bad meetings with the FDA, but you should always wait for the minutes to see exactly how they recorded it. It is your document of record and allows you further discussion with the FDA. And so we will be waiting for those minutes, and we will then understand those minutes to allow us to communicate and update if necessary to you all. In terms of the pre-screen, think of it as in kind of an upside-down triangle where you've got 200 patients or 150 patients in pre-screen. They then flow into the screening part of the study. And to reference what that means, there is a six-week pre-screen period in front of dosing or randomization in the EMPEROR study. So 60 of those pre-screen patients, so approximately 60, have gone into screening.

Once they go through screening and they're acceptable patients for our study because there are certain criteria that are consistent to the phase I/II and the OLE patient recruitment, then you move through to randomization in the EMPEROR study. And there is over 20 of those 60 that have moved through screening that have moved into randomization. And just so you can continue to do the math or kind of like the equation of how many patients you could expect in the near term to move into the study, we expect probably about an 80% success rate in screening patients. So there are patients that do fail screening for certain criteria, but we anticipate an 80% screening success rate. And so 80% of those 60 should move into randomization of the trial very shortly.

And the last question you had was regarding, can you remind you of the strength of the balance sheet?

Yes. So Jess, I'll take that. Thanks, Ian. So we ended the quarter with $328.6 million in cash, Jess. So we have a very, very strong financial position. And as you mentioned, we raised $487.4 million by a single block trade through our ATM. These funds not only push us further into mid-2028, but they also support the continued investment in our organizational capabilities and, importantly, our earlier stage programs. So at this time, we're not providing any changes to our runway, but we will update on our guidance once it does change.

Thank you.

Thank you. Our next question goes from Joseph Stringer from Needham & Co. Please go ahead.

Hi. Thanks for taking our questions. Just as a follow-up, what are some of the most common reasons for screen failure? And then secondly, for the Vineland-III, I think you said that European regulators will consider the composite score. That's different from FDA. So can you just walk us through the details of that particular analysis? Are the same five subdomains being used or being analyzed as part of the composite, and are they equally weighted? Thanks.

Hi, Joseph. This is Barry. Thanks for the call. So, in terms of the screen fail reasons, there are a few. One is that there is a minimum number of seizures that the patients have to have before they enroll in the trial. The primary endpoint is seizures, so we want to make sure that we can measure a change from baseline in those patients.

Some of the patients, if they get sick for whatever reason in that period of time, then they may not be able to enroll right away, and we have to wait until they recover, and sometimes it's just for family reasons that once they're in the trial and they realize that, for whatever reason they're not going to be able to meet all the commitments, then they may not do, so those are the primary reasons, but again, as Ian said, the screen fail rate is actually quite low and very gratifying for us. In terms of the endpoints for Vigilant, yes, those five key endpoints that we measured, again, those are the ones that we heard from investigators, from families. Those are the ones that are most important to see a change.

Those are part of the composite and also would be individual endpoints that we would measure as part of the study. And there was a question on composite versus hierarchical.

Thank you.

So the composite, well, those endpoints will be assessed both as part of the composite as well as separately individually for the study.

Thank you. Our next question comes from Sumant Kulkarni from Canaccord Genuity. Please go ahead.

Good afternoon. It's nice to see all the progress, and thanks for taking our questions. I have three. First, what specific aspects of the data that you have generated already for zorevunersen do you think would be the key for FDA to allow an earlier filing?

Sumant, it's a good question, and I often use the phrase in our industry, "I love all my children the same," and what I mean by that is there's not really a key part of the data. It is actually the totality of the data, and I actually think about it as in what is most important within this data set because obviously it's seizure reductions and then this continuous improvement in Vineland scores over a period of nearly four years now. It's actually the magnitude and the longevity of the responses that are so different than baseline and natural history. That's what I would point to as being one of the most compelling aspects of this data set. Yes, it is up to 90 patients' data. Not all of those 90 are still on medicine in the OLE, but a lot of them are.

But it's the fact that that data set goes for four years and has that durability of response that you've seen, whether it is the reduction in seizures or whether it is the improvement in cognition and behavior for these patients that unfortunately plateau after two years of age, so.

I'll ask the second and third questions in one shot here. So could Biogen's expertise with the FDA or experience with the FDA on antisense oligonucleotides help you with your interactions with the agency? And second, given you have some launch readiness efforts already underway, could you share your latest thoughts around potential pricing for a product that is currently uniquely positioned to modify the progression of the disease?

Yes. So firstly, to clarify our relationship with Biogen. Biogen is a wonderful partner. They were the partner of choice before they became the partner of choice because of their capabilities outside of North America. We retain rights. Commercial rights in North America. However, we've retained worldwide development rights. So Biogen is a wonderful partner because of their experience outside North America, particularly commercialization, and they have capabilities such as manufacturing, and they've got SPINRAZA, which is also an SMA, and they have treatment centers. So they've worked with treatment centers around the globe. And so that is highly beneficial to us as a company. As far as the regulatory processes are concerned, both in the U.S. and Europe and Japan, we work collaboratively with Biogen. We are the lead. I'll just say that. We are the lead.

But we have a whole governance structure set up between the two companies where you have employees and leaders and executives on those governance committees that share the execution of the plans and how we go to the agencies. And the relationship between ourselves and Biogen has been very good for the nine months that we've been together now, and I anticipate it will continue.

Yeah, and on the pricing question, Suman, I think, first, it's important to note that we're pretty far away from setting a price here. We haven't done a formal pricing project yet, but I think even just the way you asked the question is right on target in the sense that we anticipate bringing a rare Disease Modifying Treatment to the market, and we want to make sure that we're, number one, maximizing patient access to treatment, and number two, maximizing the value of the asset and reflecting the value that it's bringing to the Dravet treatment landscape, and so I think other rare genetically targeted Disease Modifying Treatments are the appropriate analogs.

I think things like SPINRAZA, the CF treatments from Vertex, and other disease Modifying Treatments looking at rare Genetic Diseases are probably the right place to focus if you're looking for a place to anchor to before we actually set a price. Got it. Thank you.

Thank you. Our next question comes from Ananda Ghosh from H.C. Wainwright. Please go ahead.

Yeah. Hi, thanks, guys. Congrats on the quarter. I have three questions. Maybe the first one, given the durability of the seizure reduction and plus the cognitive and behavioral improvement seen in the 36-month Wiley, how confident are you in meeting the EMPEROR phase III endpoint for major motor seizure frequency, given that it's just sham-controlled? And a follow-up question on the same aspect is that, let's say, if the secondary endpoint, such as Vineland-III score, kind of gets shy of achieving statistical significance, what are the plans existing for regulatory strategy and positioning of the label?

Just so you understand, I have Barry, our Chief Medical Officer, sitting right next to me here. And I cannot tell you that I've dug into the phase III design and the powering and the data and worked closely with our clinical team. And. So our confidence is high. This is an exquisitely designed phase III study with a. Powering to a P-value of 0.01, a 90% confidence level, with a P-value of 0.01. The seizure reduction primary endpoint, which is what approval will be based upon in terms of a result from the phase III, obviously, you can see that we reduce seizures with this regimen that's similar to this. To the extent of 80% on top of standard care medicines. And so our confidence in seizure reductions is very high. In terms of the secondary endpoints, I think the data to look to.

To understand the confidence in hitting the key secondary endpoints is actually the CNS data that we showed in August. I can't remember the number of the slide it's on, but it's in the deck, and you can take a look at that. But on that slide, you do see Vineland scores over. A period of, I believe, 68 weeks of. Scores between 8 and 11 points. And so you can compare that to how the study is powered. The study is powered for a. Two-point improvement in Vineland to, again, a 90% confidence level of 0.01 for a two-point. Improvement compared to the sham control. And so when you compare that to the CNS data that is on slide and Barry's going to read it to me because I'm in slide 11, so I don't have my glasses on. So.

But yes, our confidence is high based on that data. And. So. Yeah.

I'm sorry. Did you?

Did I get all your questions?

Yes, for the first part. I have two follow-up questions, if I may. The second question is on safety. With the elevated CSF Protein, which has been consistently observed and you have reported, one question is, are there any data suggesting long-term impact of the elevated CSF Protein across any patient population? And a follow-up on that would be. What additional safety data or mitigation strategies will you present to the regulators?

I'll quickly give you a summary, and then Barry can go into more detail. But what we present to the regulators is the detail that is behind the summary that is in a slide in the deck again. And somebody's going to give me the number of the slide while I keep talking to you. That's slide 12 in the deck. So, but we share the patient-level data with them in the briefing book. And it's that patient-level data over this four-year period that we share and over 800 doses. And that's what we're sharing with the FDA. And the summary of that is the drug is well tolerated. I think it's one of the strengths in terms of the briefing book and the package, is the safety profile over a four-year period that we can take to the FDA and then potentially focus the discussions on efficacy measures.

And Barry, do you have anything to add in regards to CSF?

I'll just mention again that we do see the elevated CSF Protein levels in the open-label extension study at various time points. What we have not seen are any clinical manifestations associated with it, specifically looking at things like hydrocephalus that might be associated with that. So we track that very carefully. And regardless of how long the patients have been on treatment, and as we said, we have patients now who have gotten more than 15 doses, we have not seen any of those manifestations in the patients who had elevated CSF Protein.

Got it. Thanks. Maybe the last question on the OPA1 program, OPA1 program. You showed us some encouraging Falcon Natural History study recently. And the question, but then one aspect of it is that the slow progression of the disease in itself. So. How does it kind of. How do you kind of mitigate that slow progression aspect of the disease as you kind of plan your trials, like the human clinical trials?

Yeah. It's a really good question. Earlier on this call, I mentioned that when I started as the CEO eight months ago, I asked the team to go through a kind of a strategic assessment of different disease areas that we may take drugs forward in. One of the questions I posed to the team is, how do you develop drugs in the area? And it's exactly for the reason that you're mentioning, which is sometimes the endpoint in a slowly progressing or deteriorating disease, such as losing eyesight over a long period of time. It's very difficult to run studies with them unless you actually improve eyesight. And so ADOA was a great example where the team did extensive work in animal models. And I referred to human-like animal models for safety and efficacy earlier in this call as well.

And what the team did, which was incredible, they ran a non-human primate model with a control. And what we found, and it's a non-human primate model that has actually ADOA. It's not actually a created model. It's actually a non-human primate with ADOA. And in that data, we found that the eye that was injected actually improved eyesight as measured by neurofilament measure, fluorescent filament measure. And that showed kind of more activity in the eye. And we compared that to the control arm, which showed deterioration of control eye in another monkey. And that showed deterioration. And that was actually the data that pushed us forward into the clinic. And I've mentioned it now in a couple of calls and also at conferences.

But that data gave us the confidence that as we go through Clinical Development, we will be looking for an improvement in vision, not a slowing of progression of eyesight. And recently, there was a company that put out some data that validated the OPA1 target. So it's a very interesting area. And Barry, do you have further comments?

Yeah. Well, I could just say that the measures that we had in the monkey study were functional measures of the nerve function, the optic nerve function, and also measures of mitochondrial function. So that's something called flavoprotein fluorescence. And we showed that. We know that in our natural history study, that's elevated in patients with ADOA. It's above normal. And in the Monkey Study, we showed that those levels were reduced. So that would go along with the potential for improving vision in patients.

Great. Thank you, guys.

This concludes the question and answer session. I will now turn it over to Ian Smith. For closing remarks.

Yeah. Thank you. I just want to say thank you for you all taking time out to listen to us. We appreciate the questions and our opportunity to respond to those questions and help you more understand Stoke Therapeutics, and I look forward to keeping you updated as we progress along. Thank you for your time this evening.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.