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.