Stoke Therapeutics, Inc.

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 SOAP 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 two questions only. If you would like to ask a question during this time, simply press star, then the number one or telephone keypad. To withdraw your question, press star one 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 Tico, Chief Medical Officer, and Jason Hoyt, 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 of 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 four-year longitudinal data from our ongoing Phase 1-2 Open Label Extension Studies, also known as the OLEs. Barry will also provide an update on progress with enrollment into the Phase 3 Emperor Study. Jason will then speak to how these data support our commercial planning starting with labeling through to patient access as we prepare for potential US 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 Zariva-Nursen 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 1, 2, 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 cerebrinosis. The manuscript, has shown that cerebinosin 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 anti-seizure medicines. Last year, we showed durable reductions in seizures and continuing improvements in cognition and behavior and safety out to three years. Today, we are sharing an additional year of data, now out to four 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 cerebronursome 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 cerebronursome to support patient access and how we may promote our medicines. 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 cerebronursin 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 readout in mid-2027. As soon as the final patient is randomized, we will be approximately a year away from a data readout. These data are expected to complete a 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 Zariva-Nurson. 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 Zoriva Nursen. 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 Zoriva Nursen in the U.S. With that, I will turn the call over to Barry.

Thank you, Liam. I'll start by reviewing the new four-year safety and efficacy data from the Phase 1-2 OLE study before providing an update on the Phase 3 EMPEROR progress. Before I begin, I want to thank the team here at Stokes who has worked to generate these data, and also the investigators and their staff, and most importantly, the families who have participated in these studies. These data are from the first 75 people to continue treatment of cerebronursin after completing treatment in the Phase I-II studies. At the time of the four-year data cut, approximately 77% of the patients remain in the studies, which demonstrates a commitment and belief in cerebronursin. With that, I will review the latest data. Cerebronursin is an investigational antisense oligonucleotide. Of the 81 patients who received at least one dose of Zoriva Nersen in the Phase I-II studies, 93%, or 75 of them, continued treatment in the OLEs, receiving Zoriva Nersen on top of their standard anti-seizure medicines. As a reminder, there was a six- or seven-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, and as such, patients came into the OLEs having received various dose levels of zarivinersin. 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 four months, consistent with our phase three 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 one, two, or three 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 one year. Here you see median reductions in major motor seizure frequency of 59% to 91% for these patients through month 28 compared to patients phase 1-2 baseline. Again, 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 3 EMPEROR study is evaluating two loading doses of 70 milligrams, followed by two maintenance doses of 45 milligrams. Here, we show the same data, but in 16-week intervals instead of the four-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 anti-seizure medicines in use today. However, there was a growing awareness of the severe neurodevelopmental consequences of Gervais syndrome. Here you see a simple graphic It illustrates the widening gap in development between neurotypical children and those with Brevet syndrome. The development starts fairly normally and then plateaus around the age of two. BrevaNersen is designed to address the underlying pathophysiology of the syndrome by up-regulating NAV1.1 protein expression, which is the root cause of the disease. Blindman 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 subdomains. The assessment has been used throughout the clinical development of Zeriva nursing, starting with the butterfly natural history study. A published survey of caregivers and clinicians indicated that most of them generally consider a two- to three-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 four years of the Phase 1-2 OLE study. The first five subdomains shown on the top of this chart highlight five key subdomains in which statistically significant improvements were demonstrated at one, two, three, and now again at four years of treatment compared to OLE baseline. Comparison of these violent subdomains to baseline was pre-specified in the OLE protocols. These five key subdomains are being assessed in the phase three emperor study. The latest four-year data shown are particularly notable, demonstrating additional improvements beyond what was observed in prior years. This is a model 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 one-two study baseline, since only one of the studies included Bind-On 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 Zoriva-Nersen. By targeting the underlying genetic cause of Dravet syndrome and restoring protein function to the brains of these children, these data suggest that Zoriva-Nersen may durably reduce seizure frequency and reduce lead to improvements in cognition and behavior in patients whose neurodevelopment generally stagnates around the age of two. I will now review the latest safety findings. We had more than five years of clinical data in the Phase I, II, and OLE studies. Across these studies, more than 850 doses have been administered. Overall, no new safety findings have emerged. and Zoriva nursing 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. Importantly, no serious or severe clinical manifestations have been associated with CSF protein elevations. There have been no reports of hydrocephalus. In summary, we are very encouraged by these long-term data that continue to demonstrate that Zoriva-Nersen is generally well-tolerated with effects across multiple measures of disease when administered to patients who are already taking the best available anti-seizure medicines. These effects are consistent with disease modification and give us confidence that Zoriva-Nersen may change the neurodevelopmental trajectory of people living with Travay syndrome. We look forward to the results of EMPEROR for confirmation. To that end, I will now share our latest progress with EMPEROR. EMPEROR is a global, double-blind, sham-controlled phase three study of Zeriva nursing. Approximately 150 patients are planned for enrollment in the US, UK, and Japan, where sham is administered via lumbar puncture. Data from these patients will be used for our US NDA submission and are expected to be the final data necessary to complete our rolling submission. New patient entry into screening for this cohort is now closed. Patients currently in screening will continue through the eight-week screening period. Following successful completion of screening, these patients will be randomized to zarivinersen or sham administered via LP. As of May 5, approximately 130 patients have been randomized to Zoliva Nursing, or to SAM. 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 emperor, while approximately 91 patients have already received the two loading doses of 70 milligrams of Zoriva Nurcin or sham, and will continue treatment with two doses of 45 milligrams or sham. We expect the final patient to be randomized to Zoriva Nurcin or LP sham in June, putting us on track for our phase three 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 Cerebral Nursing 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 Zivinersen 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., EU4, 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 anti-seizure medicines in use today, persistent seizure burden remains for most patients, and these medicines 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 Zoriva-Nursen 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 the disease-modifying treatment that addresses the underlying cause of Dravet syndrome. In addition, 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 Serebrenersen. 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 omnichannel campaign will incorporate targeted and specific messaging to providers based on their diagnostic and treatment behaviors ascertained from claims analysis. 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 Zeriva-Nursen increases the more they understand the data. Longitudinal data and recent publication of our data in the New England Journal of Medicine are contributing significantly to the awareness, understanding, and enthusiasm for Zeriva-Nursen. Phase III Emperor Study, long-term longitudinal data from the Phase I, II, and OLEs recent New England Journal of Medicine publication, provide an unusually deep data set, particularly for an investigational medicine that's in Phase 3. Taken together, these elements support the overall value proposition of Zoriva-Nursen as a potential disease-modifying therapy. From a commercial standpoint, we feel very confident where we are today as we await Phase 3 data from EMPER. As Barry shared, we have a high degree of conviction in our EMPER Phase 3 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 Cerevanursin. 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 Cerevanursin 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 labels. So 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 Zeriva-Nurson. 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 Zareva-Nersen 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 Xeriva-Nersen as a disease-modifying treatment for Xeriva 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, cash equivalent to 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 to 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 two study and preparing the organization for potential commercialization. while advancing our pipeline and maintaining a strong financial position. Our projected cash runway into 2028 supports phase three 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'll now send 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 and additional year of longitudinal data from our OLEs that further support our confidence in and a growing awareness of cerebronursome 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 Stravropoulos with Kantor Fitzgerald. Your line is now open. Please go ahead.

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

So, Pete, thank you for those comments and questions. I'm going to start with how we felt when we, you know, frankly opened up the envelope and saw the data from the four years with studying these patients in the OLE. You know, we were, frankly, thrilled. What the data shows you is that we are going to the root cause of this disease with zurbanersen. 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. And before I push it over to Barry, I want to 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 therefore you can collect over four years longitudinal data. And it is very unique. And what that is allowing us to do is to truly understand how this medicine is helping patients and encourages us as well as increases our confidence of what we may expect in our phase three, but then also going to how we feel about this medicine should be promoted to the patient community and the physician community. So truly outstanding data from this study. And this study started before I joined the company. I want to congratulate the company on the thoughts of running this study to collect this data to inform the treating community and the patient community. And Barry, your thoughts?

Yeah, thanks for the question, Pete. This is Barry. So again, the goal in developing a disease-modifying therapy would be to demonstrate a meaningful effect across multiple different aspects of the disease. And that's really what we're seeing here. So 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. And the consistency and the durability of the results that we're seeing is really encouraging and gives us more confidence in Zoriva-Nurcin as a treatment with a disease-modifying effect for patients with Dravet syndrome. Sorry, there was a second question in terms of... So the follow-up was in terms of the difference in the subdomains. So first of all, again, just to remind you, these four-year data are occurred after patients were enrolled and followed in the Phase I-II study, and then the results are compared to the baseline after they enrolled in the open-label extension study. And we're really encouraged by the consistency of the results that we're seeing here across all five 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 five subdomains from year one, two, three, and four compared to the open-label extension baseline. And that's really a remarkable effect to see that level of rigor in terms of results. The modeling that we do is dynamic, so we do include additional patients as they reach milestones within the open-label extension study. We add those patients into the database. And so 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, so could you please walk us through or underscore those key numbers again? That's the first question.

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

Thanks. And secondly, for Ian or for Jason, what are your latest thoughts on whether the market is adequately appreciating the immense value that Zeromanersen 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, Saman. Yeah, 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. So maybe, Jason, you give. And 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. So, Jason.

Yeah, thanks for the question, Samant. So I think it's particularly timely that you ask because, you know, historically we've noticed there's been a a desire to compare what we're doing with zarivinersen 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. But to date, they're the only thing that's been approved for the syndrome. So it's natural that you would gravitate there initially. But I don't think those are really appropriate comparisons or do justice to the value that zarivinersen 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. And, 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. But 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 xerevinersin. And 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 xerevinersin in the Vineland results, in the quality of life measures, and obviously the seizure data. So we think that the more appropriate analogs are products like Spinraza, you know, another intrinsically administered ASO, like the Exxon Skippers from Sarepta or even Debut from Acadia, I think are probably more in the window that we're talking about for potential value. But, you know, given these four-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 through a syndrome and zuriva nurse and as soon as possible and that's advice that we're heating as you heard in the prepared remarks we're going to be deploying our national account director team to really start one-on-one educating payers in the second half of this year so 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 we today we have four years of longitudinal data and

of safety and efficacy. And we've shared that with you all, and we will be sharing it with the FDA. And when we look into the future, the potential filing and approval, we anticipate also supplementing and supporting our filing with this OLE data. And at that time, it will be five years worth of data. And 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. So very, very important, this data.

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

Hey, good afternoon. This is John on for Andrew. Congrats on the four-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. And then maybe as you explain that, uh, could you also perhaps elaborate on the U S stats analysis and sort of provide the exact hierarchy to support the completion of your, uh, rolling DLA or NDA, um, do each of the five sub domains need to hit stat SIG in the USA, or, um, just maybe only one need to hit stat SIG. Thanks.

So 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, well, when you understand 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. So the mechanistic pathway to address this disease must be going around those other medicines and right to the root cause of this disease. And so that provides us with the overall confidence of how this medicine is working and therefore the play through to actually the phase three and how we think about the phase three 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. And maybe Barry can talk about why we have the confidence in the phase three and go back to when we designed it and based on the data.

Thanks, Ian. Thanks, John. So, again, when we designed the phase three study to look at the one-year secondary endpoint, those were powered based on substantial amount of data from our phase one to early studies from 81 patients. So that is a very meaningful amount of data for us to work with. It 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 Pediatric Neurology Society meeting, where we showed a comparison looking at the one-year data. And there we, again, showed substantial and significant changes for the Vineland subdomains compared to natural history. And then we went a step further and did what's called propensity weighted scoring, which is a very rigorous way to compare to two different databases. And those were shown at the American Epilepsy Society meeting at the end of last year. And there, again, where we took the patients who were getting a dose level that was similar to what we are using in our Phase 3 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 six-month gap before. But when we looked at those Phase 1, 2 data compared to natural history, we showed statistical significance there again with... with comparison to the different subdomains. So 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.

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? And then 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 the label? Thanks very much.

Laura, it's a great question, and frankly, it's a question we receive frequently. I'm going to start by, you know, what is the purpose of a label for a medicine? And 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. And so, yes, the label is for understanding safety and efficacy. And that's what people primarily focus on. But what you need to understand is that the label is broad. And there are sections of the label, particularly the one that's called clinical studies. And 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, but 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 that 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. So it is very clear, and 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. But it is... 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 five-year data that helps you understand the chronic dosing in dravet of our medicine. And that supplements what would be pivotal information with the primary endpoint being most important because that gets you approval of the medicine. but then expanding the label to include this supplementary information. And it's only following the industry guidance. And so we're in a unique position where we have this long-term OLE data that supports the chronic use of our medicine to provide the safety and efficacy. And there are other analogs to this, to your question. And Jason, maybe you should talk about those. Because we do look at them, and we do discuss them with payers and other physicians. So 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. And, 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. And so, the observed data from the NURTURE study were really important to have in Section 14 of Spinraza. Another good example would be Skyclaris for Friedrich's Ataxia or Kalsodi for ALS. All three of those products have observed open label data in section 14 of their labels. So, I think they're all very appropriate to look at. And, 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. And when we talk to them, you know, they and payers alike tell us that the four-year data or longitudinal data will probably be the most compelling piece of evidence that we have at the time of a potential approval. And so 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 health care providers. But for payers, they'll look at the totality of all the evidence. And 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 serivinersen.

And Laura, or maybe Barry, do you want to? Yeah, I'll just add on. Statistical significance and how you approach this as a clinician?

Yeah, so 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 the time of launch. And so this will be very useful in order to be able to expect to show share expectations for what the potential benefit and risk of the medicine are. And 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, because 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. So that's very important that it was a predetermined endpoint. We've not gone in here and kind of retrospectively calculated that. It was a predetermined endpoint, and we'll be sharing this data with the FDA. And the statistical significance of it was on one of the slides, but each of the five key domains is less than .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-screening, there were over 200 patients initially.

I think what Laura is referring to is how many is in the pre-screen now to close out enrollment at approximately 150. So, Laura, the key numbers, and as you can probably tell, I follow these on a daily basis. I talk to various offices right next to mine. And we expect to end up randomizing and dosing with sham or a 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, and I'll 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, Michiko. Your next question comes from the line of Mark Goodman with Lee Rink. 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 an 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. And 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? And do we know how many of those 6,000? Like, are they actually online? you know, Fentepla, 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, Mark. So let me take... maybe the first one around the payer interaction. So, 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. So, 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 think we're going to see at the end of the Emperor study when we get the data card in the middle of next year. But 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. And so, 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 going to have a very robust package to bring to payers at the time of a potential approval. But those educational efforts for payers on what we have today and just Dravet as a whole are going to start in the second half of this year. So we're well out in front of it when it comes to payer education. And then 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, Mark. 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. And 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. And, you know, as patients are diagnosed, you know, oftentimes as infants, but certainly as toddlers, they grow up with... pediatric provider. And so 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. And so naturally, there's a bit of a reluctance to transition to adult care. And so what we've heard from pediatric epileptologists is that they're most commonly caring for patients into their mid-20s. And so 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. And so when you look at claims data, there are multiple claims databases out there. All of them have different levels of capture. But 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. So when you look at it from a claims analysis, you also see 6,000 patients. And then 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. And through those analyses, we feel pretty confident that we know where about 70 to 80 percent of the 25 and younger patients are being cared for today.

Thank you for the question, Mr. Goodman. Your next question comes from the line of Garen Werber with TD Cowan. 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 going to 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. Do you plan to, I believe there's an extra 40 patients that you're going to 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.

Yes, thank you, Jeroen. Nice to hear from you. Firstly, 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 want to emphasize why that's important because 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 six months or less. And that's why we referred to our timeline for potential approval of Q4 2027 or maybe early 2028. So I just want to 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 going to be between 20 and 30 patients in those European countries. That cohort of patients is actually needle prick, placebo or sham control. And we will not wait for that data to be clear. You know, all these pending timelines, but 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 US, UK, and Japan as being our basis for filing.

Thank you for that question, Mr. Werber. Your next question comes from the line of Tom Schrader with the 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? And I just point out that Biogen is feasted with Spinraza on older patients that don't have that much to gain but nonetheless do gain something. And then Jason says, 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? And I appreciate it's kind of a guess, but thank you.

Yeah, so maybe with the first question, Tom, with seizures in adults, and maybe Barry wants to add to this, but, 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, but 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. And so, obviously, we're going to look to study in a small open-label study we're going to 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. And then 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 three-year data, obviously the four-year data are new and haven't been shared publicly until an hour ago. But, 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. And that's why we're hearing from them that the four-year data and the longitudinal data are probably going to be the most compelling piece of evidence that we'll have at the time of approval. So 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 the Dravet syndrome as a whole and around Zareva-Nersen. 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. So, 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. 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.

Okay, thank you. Thanks, Tom.

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

Mr. Marks?

Hi, thanks for taking our question. This is Joey. Our question is on the, would you anticipate payers would require patients first fail a certain number of anti-seizure medications before being considered eligible to receive Zorevinircin, or 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 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. And that febrile seizure is the first symptoms that families often experience. And obviously, that's a pretty scary event. But 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. So as they make their way to a neurologist, obviously if they make their way to a neurologist right away, they're going to get that confirmation earlier. But by the time they get to a neurologist and the neurologist orders a genetic test, they're obviously treating the seizures before that. And so they will be put on an anti-seizure medicine as soon as they present to the healthcare system. And with the rapidity with which anti-seizure meds are added and switched based on either side effects or waning efficacy, oftentimes patients will have failed two anti-seizure meds before they would even get the result of a genetic test. And so I think they could, I think some payers could mandate a failure of some ASMs, but 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. Thanks so much for taking our question.

Your next question comes from the line of Jess Phai with JP Morgan. Please go ahead.

Hello, this is Adam. Thank you for taking our call question. Just a few. How should we think about the SG&A trajectory as you're ready for launch? And when could we see data on Stoke 002 from the OSPRI study? And one more, if I could, will you publish baseline demographics for the emperor trial once enrollment is complete?

So I'll take the first two questions, and Barry, maybe you can take that last one. So Adam, I don't think we know each other, but I've spent a long time working within the rare genetic disease space, and I see a lot of similarities to my former life here where I was working with vertex and cystic fibrosis. And so to be very clear in terms of SG&A, 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. And that education is done through medical affairs. And I want to 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 Zareba nursing to enhance the, well, let's say accelerate the recruitment of patients into our phase three study. The commercial build is small. We may actually end up with less than 100 people in total in sales and marketing. And so it is a minimal increase. cost in terms of supporting this medicine commercially. And as far as the A in SG&A, that's going to be lean as well. So 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. But that's a good model for you to look at. As far as ADOA is concerned, We have a, it's a, it's in a phase one, two study, 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 cohort. And that would be towards the end of this year or early 2027. And obviously it is a, it is the primary endpoint to that study. is for safety, and that's why it's a dose escalation study, but we will be looking at efficacy, specifically in those third and fourth cohorts late this year in early 2027. And Barry, do you want to talk about the analysis of data?

Yeah, so we've been so focused right now on getting the patients into our face-to-face study, we haven't really talked about what data we're going to holds later on. But 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 the age, gender, and seizure baseline numbers. So that's really what we've been focused on in terms of the demographics.

Thank you. I appreciate it. Thanks, Adam.

Your next question comes from the line of Yarin Zonia with Guggenheim. Please go ahead.

Hey guys, thank you for all the details. Very helpful call. Maybe just one, maybe just like a follow-up on the question that Adam asked. So for the, I mean, now that the enrollment is going to close hopefully soon, right, in the next couple of weeks, could you maybe characterize the baseline that you have enrolled so far? What type of disease severity? How should we think about the phase three mix? relative to the phase one slash two cohort that any notable difference or similarities?

So first of all, we have already closed enrollment into screening yet. And so to be clear, we have closed enrollment into screening. And so the patients are now going through that eight-week screen period and will flow through into randomization for dosing. And so 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 screen patients in the past of what we brought into our studies. And so, and 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, Mr. Suneha. Your last question comes from the line of Rudy Lee with Wolf Research. Please go ahead.

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

So Rudy, maybe I'll take that question. I appreciate the question. 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 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, and then it will be a combination of the secondaries and the Section 14 other clinical supplementary studies that we talked about earlier on this call. And 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. And that is why Jason has been out discussing with payers and healthcare providers in terms of what is most important to them. And 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, but look to the data we've provided in the past. on a dosing schema that is similar to that of the phase three. And we've also done, you know, propensity-weighted analysis to compare natural history, as you referred to, to dosing. And those analysis gave us a lot of confidence of what we would anticipate in terms of the secondaries that would hit. But we're most encouraged by this four-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 Zobreep and Nerson.

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. So I want to 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.