Stoke Therapeutics Inc Aktie

Hello, and welcome to the Stoke Therapeutics Second Quarter 2026 Business and Financial Update. [Operator Instructions] Be advised that today's conference is being recorded. It is now my pleasure to introduce CFO, Thomas Leggett.

Good evening, and welcome to Stoke Therapeutics Second Quarter 2026 Business Update Conference Call. I'm Thomas Leggett, the 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.

On today's call, we will review recent progress across the breadth of our business. Ian will start with an overview and share an update on the ongoing Phase III EMPEROR study. This study is progressing nicely toward a data readout in the third quarter of 2027. Barry will then provide additional detail on EMPEROR and our longitudinal data set from our ongoing open-label extension studies, also known as our OLEs.

He will also review the advancement of other pipeline opportunities that we are progressing, including our investigational medicine for autosomal dominant optic atrophy, or ADOA. We'll then hear from Jason on our commercial planning activities to deliver zorevunersen to all patients who may benefit in the U.S. following a potential FDA approval by early 2028. I will review our financials and specifically the strength of our balance sheet, and then we will open for Q&A. I will now hand the call over to Ian.

Thank you, Tommy, and thank you to those joining us on the call tonight. Starting with our Phase III EMPEROR study, the recent completion of enrollment of 162 patients in just 10 months speaks to the awareness and enthusiasm of zorevunersen and its potential to change the course of Dravet syndrome by addressing the underlying genetic cause of this disease. Patients in the study are advancing through key study milestones, and importantly, there have been no treatment discontinuations.

We are now within 1 year of our Phase III readout to data that would support the completion of our NDA. We continue our discussions with the FDA and have scheduled a pre-NDA meeting later this year as we prepare to initiate our rolling NDA submission in the first quarter of 2027. The meeting will focus on further educating the agency on the long-term safety and efficacy of zorevunersen using prior and ongoing analyses from our Phase I/II and OLE studies. We'll also cover the details of our NDA submission, including the data to be included, the statistical analysis plan, and the timing of each module.

Beyond Dravet, we have a unique opportunity with our platform in additional disease areas. We continue to advance STK-002, our investigational medicine for ADOA. Our Phase I study recently completed dosing of the first cohort of patients, and we have moved into a higher dose in a second cohort of patients. We'll continue our work in SYNGAP1-related disorders. We are also expanding our early research efforts with new targets in haploinsufficient diseases, mainly focused in CNS, given our expertise in the field.

Consistent with our investment in other pipeline opportunities, in July, we strengthened our leadership team with the addition of Tom McCauley, our Chief Scientific Officer, who will help guide the next phase of platform expansion and translational research. And from a financial perspective, our business investment is well supported by our pro forma cash position of approximately $420 million, providing a runway through to potential U.S. launch of zorevunersen by early 2028.

We've entered a period where execution is increasingly important. We remain focused on delivering the data and completing the regulatory and commercial readiness activities necessary to bring zorevunersen to patients as quickly as possible. With that, I now pass you to Barry, who can provide more detail as to our progress.

Thank you, Ian. Tonight, I will start with an update on the progress with the EMPEROR study. EMPEROR is a global, double-blind, sham-controlled Phase III study of zorevunersen in patients with Dravet syndrome. In June, we announced completion of enrollment of 162 patients into EMPEROR. This puts us on track for our Phase III readout in the third quarter of 2027. Data from these patients are expected to be the final data necessary to complete our rolling U.S. NDA submissions, which we expect to submit in the second half of next year. As Ian mentioned, the study is progressing well. To date, more than 140 patients are through week 8 of the study and therefore have received either the 2 loading doses of 70 milligrams of zorevunersen or sham.

More than half of patients have only 1 dose left in the 52-week treatment period. Approximately 60 of these patients have also completed their week 28 visit, the time point at which the primary endpoint of percent change in major motor seizure frequency is measured. The study will remain blinded through 52 weeks, given the key secondary endpoints measuring cognition and behavior will be assessed at that point in time. In a couple of weeks, the first patients in the study will reach that milestone and have the opportunity to progress into treatment extension beyond week 52.

Thus far, no patients have discontinued treatment in EMPEROR. When we designed EMPEROR, we made several assumptions that are relevant when evaluating the study's statistical powering. First, EMPEROR was powered to detect statistically significant effects on the secondary endpoint, measuring improvements in cognition and behavior. This resulted in substantial powering for the primary endpoint.

Second, the study design assumed a certain percentage of patient discontinuation. And as previously mentioned, we have had 0 discontinuations to date. Finally, our enrollment target was at least 150 patients, and we ultimately enrolled 162 in our primary analysis population. All of this reinforces our confidence in the study powering and overall likelihood of demonstrating statistically significant effects on the primary and key secondary endpoints.

Beyond the 162 patients intended to support our NDA, an additional cohort of approximately 30 patients in Europe is expected to complete enrollment this month. Planning is also underway for a new study of zorevunersen in infants and toddlers under 24 months of age. We expect that study to initiate later this year to support our goal of enabling early intervention with this potentially disease-modifying therapy.

Earlier this year, we presented data out to 4 years from our OLE study, which I'll briefly review this evening. I'll begin with our data on seizure frequency reduction. Here we see 4 years of data in which all patients received treatment with zorevunersen. These effects are demonstrated on top of the standard of care anti-seizure medicine patients were already taking. These data include all patients across dose levels, including various levels of loading doses evaluated in the first year of treatment in the Phase I/II studies, as well as various levels of maintenance doses used in the OLE studies.

The orange line most closely reflects our Phase III dose regimen. The blue line is patients who received a variety of doses during the Phase I/II and OLE. By month 29, all of them had transitioned to receiving 45 milligrams every 4 months, which is consistent with the anticipated commercial regimen pending the results of EMPEROR.

While durable seizure control is the most immediate and obvious clinical need, we know that Dravet syndrome is not only a seizure disorder. It is a severe neurodevelopmental disease in which children develop normally till approximately 24 months of age, when they begin to stagnate in development, with minimal improvements in skills and activities such as communication, interpersonal skills, and mobility.

This means that regardless of chronological age, gains in cognition, behavior, and daily function are meaningful. To evaluate potential gains in cognition and behavior, we use Vineland-3, a standardized assessment of adaptive functioning. Here are the 4-year Vineland data from our ongoing OLE studies. These data demonstrate statistically significant improvements in cognition and behavior each year through 4 years of treatment compared to the OLE baseline.

Similar to the seizure data I just showed, these OLE data include patients across all dosing regimens evaluated in our Phase I/II studies, including loading doses that were lower than the 2 70 milligram doses we are evaluating in our Phase III studies. Importantly, all improvements in Vineland scores shown here are measured against patient baseline scores when they entered the OLE study, and therefore do not capture any benefit that may have been observed during the earlier Phase I/II treatment period.

Alongside these efficacy findings, we continue to build a long-term safety dataset for zorevunersen. Of the 81 patients enrolled in our Phase I/IIa studies, 93% or 75 patients continued treatment in the OLE studies. Of those, 57 patients remain in these studies. More than 930 doses of zorevunersen have been administered to date, with some patients receiving treatment for more than 5 years. Overall, no new safety findings have emerged and zorevunersen continues to be generally well tolerated.

The Phase I/II and OLE safety and efficacy data provide a substantial data set that supports the design of our Phase III EMPEROR study and also a detailed understanding of the benefits to patients and how this potential medicine could change the course of Dravet syndrome for patients and their families. These long-term longitudinal data, which include patients who have received up to 16 doses over a 5-year period, offer insight into the ongoing benefits with chronic dosing.

Analyses from this clinical dataset have been well received at major medical conferences and were published earlier this year in the New England Journal of Medicine. Our educational efforts will continue throughout the rest of 2026 and into 2027 with new analyses including effects on seizure severity, improvements in seizure freedom, and quality of life. We'll also continue to share these insights with the FDA.

The data generated to date and successful advancement of zorevunersen in EMPEROR reinforce our belief in the potential of our platform to address the underlying cause of a number of severe genetic diseases. We are particularly focused on diseases caused by haploinsufficiency, where we believe we have a unique opportunity to use our proprietary scientific approach to restore protein expression from the healthy copy of a gene.

In the near term, we are advancing STK-002, our investigational medicine for ADOA. ADOA is a progressive genetic disease that leads to degeneration of the optic nerve and loss of vision starting in the first decade of life. It is the most common inherited optic nerve disorder. The majority of cases are caused by mutations in one allele of the OPA1 gene, resulting in haploinsufficiency, or 50% of the OPA1 protein. There are currently no approved treatments for ADOA.

STK-002 is designed to increase OPA1 protein expression with the aim to improve vision in people with ADOA. Phase I dose escalation study is ongoing in the U.K. and Europe and recently completed dosing of the first cohort of 3 patients. Dosing for our second cohort is scheduled to begin this week, with the third and fourth dose cohorts to follow, subject to ongoing safety assessments. We anticipate early safety and efficacy results in the first half of next year to guide our next steps for development. We are encouraged by our preclinical data, as well as emerging data from the field, demonstrating that upregulation of OPA1 proteins has disease-modifying potential. We look forward to sharing additional updates as the program advances. With that, I will turn the call over to Jason.

Thank you, Barry. Today, I'll focus on 3 areas: the market opportunity in Dravet syndrome, how we think about label and access, and the progress we're making toward a potential U.S. launch. I'll start with the patient population. There are an estimated 38,000 patients with Dravet syndrome across the 7 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. Our estimates are based on an epidemiology analysis that scaled annual incidence to prevalence using country-specific live birth rates over the past 85 years that was then adjusted for Dravet specific mortality.

In the U.S. the Dravet population highly concentrated around centers of excellence and other key treatment centers. Approximately 50% of identified U.S. patients are cared for by the top 50 sites that are experienced in administering intrathecal medicines. Half of them are already participating in a zorevunersen trial.

This provides a strong foundation for early adoption and allows us the ability to maximize this opportunity with a lean commercial infrastructure, including approximately 25 sales representatives who will build upon our longstanding relationships with treating physicians established by our medical affairs teams. We're confident we know where 70% to 80% of the patients 25 and younger are being cared for today.

Out of the estimated 16,000 total U.S. patients, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider. These are patients who would be immediately addressable at the time of potential U.S. launch. Pediatric neurologists and epileptologists tend to develop strong and lasting relationships with patients and families and therefore continue to care for them well into early adulthood. As such, this group of clinicians follow the field closely and are typically the most well-informed about the disease and current treatment options.

In addition, an ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses. This data provides support for our assumptions as well as insight into where patients are in their diagnosis and treatment journey, along with the providers who care for them. We believe diagnosis rates will increase over time as zorevunersen and other genetically targeted treatments continue to advance.

We will continue to invest in targeted disease awareness and educational efforts to emphasize the importance of genetic testing to confirm a Dravet diagnosis. Looking ahead to our NDA submission, product labeling and patient access, we continue to believe that the totality of evidence generated for zorevunersen supports a differentiated value proposition in Dravet syndrome.

At the time of our NDA submission, we expect to have approximately 6 years of safety and efficacy data available from our Phase I/II and OLE studies, providing insight into the durability of treatment effects and the potential for disease modification over time. We intend to incorporate these data into our NDA submission for inclusion in the label.

The FDA guidance is clear that in addition to pivotal study data, clinical study data that provide important information about a drug's effectiveness and that would be useful to practitioners in their clinical decision making should be included in the label. We believe that the longitudinal data from our OLEs are relevant within that framework, and we know from market research that payers and healthcare providers already consider these data to be the most compelling evidence that we may have at the time of potential approval.

As Ian mentioned, we have a pre-NDA meeting with the FDA later this year. We plan to initiate the NDA in the first quarter of 2027, beginning with our chemistry, manufacturing and controls module. We recently completed commercial scale manufacturing validation for both drug substance and drug product and are currently finalizing product specifications.

We continue to expect that if approved, zorevunersen would be granted a broad label for the treatment of Dravet syndrome consistent with our breakthrough therapy designation. This broad label, combined with the existing concentration of Dravet providers and well-established infrastructure for administering intrathecal therapies, positions us for a smooth and efficient adoption with a lean commercial infrastructure at the time of launch.

While we remain focused on accelerating access in our commercial territories in North America, our partners at Biogen are focused on expediting access in countries around the rest of the world. In addition, we plan to initiate a study of zorevunersen in the adult population by the end of this year. This study is intended to expand clinician conviction for zorevunersen in adults and support access among adults living with Dravet. Taken together, the strength of the clinical package, the continued positive feedback from payers and providers, and the progress we're making across commercial readiness activities give us confidence in our preparations for a potential U.S. launch in early 2028.

With that, I'll turn the call over to Thomas.

Thank you, Jason. I will remind you that full financial results can be found in our 10-Q. Today, I'll focus on the strength of our balance sheet position. We ended the quarter with $354.3 million in cash, cash equivalents and marketable securities. Shortly after the close of the quarter, we raised an additional $65.7 million in net proceeds through our ATM program, selling approximately 2.1 million shares of common stock to a high-quality, long-only fundamental investor. This resulted in a pro forma cash position of approximately $420 million.

Along with the reimbursement we received from Biogen for zorevunersen-related expenses and a potential development milestone payment, we expect our cash position to fund our operations through a potential U.S. launch in early 2028.

In terms of our priorities, we continue to invest in advancing our Phase III study and preparing the organization for potential U.S. commercialization while progressing our pipeline and maintaining a strong financial position. Thank you, and I will now ask for the line to be open for Q&A.

[Operator Instructions] One moment, please. Our first question comes from the line of Andrew Tsai with Jefferies.

The first one is, you guys have provided a lot of nice numbers this quarter where patients are exactly in the EMPEROR study. So, maybe bigger picture, what should we be taking away on these various data points as we track study progress and await the Phase III timelines? And then secondly, it sounds like you have this pre-NDA meeting with the FDA in the second half, in part to talk about the SAP plan for EMPEROR. So, may I ask what you guys are hoping to get alignment on? Is it kind of confirming the hierarchy of the 5 subdomains of Vineland-3, maybe confirming which ones need to stat sig for you to file? Just a little bit more color would be helpful.

Andrew, this is Ian, and thanks for the question. It's good to chat to you again. We did provide a lot of, as you put it, nice numbers on the call. I'm going to ask Barry to reiterate those. There were a lot of them, but there are metrics internally of how we measure the trial every single week. And they're very important to us in terms of measuring the progress of the trial. So, Barry, why don't you provide those numbers again, and then I'll take the discussion on the NDA.

Sure, thanks, Ian and thanks, Andrew, for the question. So the study is progressing quite well, and patients are going through trial milestones. Again, as we said, enrollment is complete and we enrolled 162 patients in the study. Of those, 145 patients are through their week 8, which means they've received 2 loading doses of the 70-milligram or sham treatment. About half of the patients have gone through week 24, and so they have only 1 dose left in their 52-week treatment period. Importantly, 60 patients have completed their week 28 visit, and that means that they have hit the time point of the primary endpoint, which is seizure frequency. And we're also very pleased that very soon, patients will start to be reaching their week 52 endpoint, which is the important part of the treatment period study.

Again, no patients dropped out of the study, which is important. And this progress gives us a lot of confidence in EMPEROR to date and is consistent with the data that we've had from the OLE studies as well as our Phase I/II data.

Thank you for that, Barry. Yes, I'll just reiterate the data that we're seeing in terms of no discontinuations with -- given the large number of progress of these patients through the study, continues to emphasize that this medicine is generally well tolerated. That's also consistent with the 5-year data we have in Phase I/II and the OLE, where we've dosed between 70 and 80 patients and continue to show that the medicine is generally well tolerated.

To your second question, Andrew, about the pre-NDA meeting, I'll kind of answer it in a bigger way and tell you all about the meeting. So firstly, the meeting will occur in early fall, so not too far away. This is an ordinary course when you're at the stage of Phase III development, when you're in registration studies. And -- so we're going down to the FDA with 3 objectives or 3 topics. The first being to discuss the sequence of submission of data for our rolling submission.

We anticipate initiating a rolling submission in Q1 of 2027, and that would start with the CMC package followed by the preclinical data, and then closing out that rolling submission in the third quarter of 2027 with the clinical data. So that's the first piece. Second, as you point out it is the SAP, the statistical analysis plan. Again, this is normal practice. Before you get to the end of your Phase III and certainly during your Phase III, you don't want to leave it too late. You need to go down the line on the details of the SAP. The way that our protocol has currently been constructed is that our primary endpoint is not in discussion in terms of the detail, but we will talk about the secondary endpoints.

And the way that the study protocol has been described so far is that we will look at the secondary endpoints in either a hierarchical analysis, and that means taking individual Vineland domains in a hierarchical manner, or we will look at it on a composite basis where you combine those individual Vineland domains. The study is designed, and we've communicated that it is designed in terms of collecting both sets of data.

What we want to do is we want to go to the FDA and discuss exactly how they would like us to present that data. I will just point out that the first, in terms of the hierarchical secondary endpoints is actually continued seizure reduction, I'll just point that out. And then it goes into the Vineland domains.

And then the third topic is the OLE data. As you know, each year we’ve gone down to the FDA and discussed the OLE data. Last year we were discussing with the FDA in the latter part of 2025. This year we have the access to the 4-year OLE data being updated from last year's 3-year. And we're going to discuss that again. Why are we doing that? Because it's the importance of that data to show this is a drug that is a chronically administered drug, and this data has now been administered in patients for up to a period of 5 years.

And we've been able to measure both durable seizure reduction and the continued improvement each year of Vineland scores, which is just a measure of skill and task acquisition of these children that unfortunately have a, you could call it, a Dravet age of approximately 24 months, but we're potentially providing them task acquisition and skill acquisition that then is more typical, more neurotypical of the children that have a greater age and are healthy.

And so the importance of that data, obviously we just discussed before, is it does help us understand the effectiveness of the medicine as Jason has described in his remarks, and we continue to be part of the NDA submission when we file our clinical data around the middle of next year.

Our next question comes from the line of Alyssa Larios with Leerink Partners.

This is Alyssa on for Marc Goodman. I was just wondering if you could walk us through what parts of the NDA you expect to submit starting in Q1 and what will still be left once the EMPEROR data come in.

Alyssa, sorry, you didn't come through. So you're asking about the sequence of the NDA submission?

You just didn't come through, Alyssa, there's some background noise. So as I just mentioned, we anticipate starting our rolling submission in Q1 of 2027. That will initiate with the filing of our CMC package. Jason had a number of comments in his prepared remarks where we are -- we've made great progress in that area, including quality, and so that would be the initiation of the submission in Q1 of 2027.

And the final part of the submission will be clinical data, which will occur in Q3 of 2027, and that data will conclude with the week 52 secondary endpoint measurements to complete that submission in Q3 of 2027.

Our next question comes from the line of Pete Stavropoulos with Cantor Fitzgerald.

First question that I have is, going back to the Vineland-3 subdomains for the Phase III readout, what gives you confidence that 1-year time point is sufficient to sort of see separation between the active arm and sham for the secondaries?

And the second question I have is, one point of discussion has been potential pricing of zorevunersen if approved, specifically around data, what data may be needed to translate to a label that suggests or states disease modification that will ultimately impact pricing. And so can you just provide your thoughts and plan and possible scenarios for getting disease-modifying outcomes into the label? And if achieved, how should we be thinking about pricing?

Thanks, Pete. Number of questions there. Maybe start with asking Barry to help you understand the powering of the study. I'll then talk about the data we have that informed us and support our confidence that achieving both primary and secondary endpoints. And I'll ask Jason to comment on the work we've been doing, which is extensive, to understand the value of the medicine, aka pricing.

Yes, thanks. So, the powering of the study was based on our Phase I/II and OLE data. And the confidence that we have in showing a difference from sham based on the fact that the secondary endpoints, the Vineland endpoints, are powered at 90% or greater, greater than 90% to show a 0.01 or less p-value. And so those results were based on 150 patients enrolling in the study. And as we mentioned, we now have 162. So that increases our confidence that we'll be able to show a significant difference from sham in the study.

Yes. Thanks, Barry. I'll just pick up from where Barry mentioned. And so -- and I would say increasing confidence with 162 versus the initial powering calculations of 150. What I would also add is, in that 150 that was the initial powering assumption, it did also assume a 15% discontinuation rate in that Phase III. As Barry mentioned in his prepared remarks, we have seen 0 discontinuations to date in the study. So if you work the analysis back it was powered, as Barry says, to a 90% confidence level for a p-value of 0.01 to the secondary endpoints from approximately 125 to 130 evaluable patients.

At this point in time, we have 162 enrolled still in the study and 0 discontinuations. Then the data that we used to power the study, frankly, was data from the Phase I/II and the OLE data. But notably, you asked about the confidence, Pete, and this time last year, we provided data to help understand the impact of a regimen that had similar dosing to that in our Phase III study. That data was provided at EPNS last year.

I believe we showed it on our Q2 conference call. If not, there was a disclosure that was very close to August of 2025. And that data showed that in Vineland scores for the 5 key domains that we've been discussing, showed Vineland scores of between 8 and 11 in terms of Vineland scores of each of those domains. And I would just point out that our Phase III study secondaries are powered for a 2 to 3 point delta in Vineland scores.

So we have high confidence of hitting these secondary endpoints, given the data that we have, both from the Phase I/II and the OLEs, and in particular, that dosing regimen that is consistent with the Phase III dosing regimen of 2 70-milligram doses and 2 45-milligram doses, which accumulates to approximately 230-milligrams of dosing.

Yes, and then on your last question, Pete, around pricing and the implications around pricing, it's timely that you asked the question because just earlier this year, we conducted some pretty extensive market research across our constituent audiences, including healthcare providers, payers, caregivers, et cetera.

Specific to the healthcare providers and payers, we wanted to understand the potential implications of different label scenarios and how those audiences think about the data that are included in the label versus other data that may be available in the public domain, published, presented at scientific conferences, et cetera. And I think the long and short of it is that the data to be included in the label are going to be most important for promotional purposes, right? So how our commercial teams are able to educate healthcare providers on the efficacy and safety of zorevunersen at the time of approval.

And when we asked those 2 audiences, both payers and healthcare providers, talking about the different potential scenarios, what could be and would be the most compelling pieces of evidence that they would have at their disposal to drive, in the case of healthcare providers, prescribing for their patients, and in the case of payers, medical policies that support reimbursement for a broad population of patients with Dravet syndrome.

Across the board, the 5-year open-label extension data and Phase I/II data that we anticipate having at the time of approval were the most compelling piece of evidence. So when you think about payers, it's less important that it's included in the label and more important that the data are disclosed and peer-reviewed. So payers are going to look at the totality of the evidence. They'll look at published manuscripts, data presented at scientific congresses, the Phase I/II and OLE data that we've generated to date, right? 4 years of OLE data plus the Phase I/II.

And I think it's not all anchored to the secondary endpoints. One of the things payers told us loud and clear is that the additional seizure reductions that you're seeing on top of the best standard of care medicine will drive significant value. But with that being said, they will look at the totality of the evidence. They'll look at the data that are published in, for example, the New England Journal, right? That comes with a significant amount of credibility, and so we're feeling really confident in how we think about the value proposition and value story for zorevunersen, and that it really should command rare genetically targeted disease-modifying pricing potential consistent with what we've been talking about over the last few months. So hopefully that answers your question a little bit, Pete.

Our next question comes from the line of Yaron Werber with TD Securities.

Congrats on really terrific progress. Maybe I have a couple of questions. The first one is, given that you're going to have 6-year data from the OLE, which potentially can be label-enabling, how does that sort of jibe with the Phase III data? Can they be sort of synergistic? Do you need to hit all the same points in the Phase III that you showed in the Phase I/II? I mean, you noted to us obviously that the delta that you're looking for is a lot smaller and you're obviously very overpowered. And then secondly, I know you don't know exactly how you're going to rank order hierarchically yet in the SAP, the secondary endpoint, but maybe from you, based on your data, what is sort of your wishlist? Which endpoints are the most important?

Yaron, thank you for the question. As I mentioned in my earlier comments, we're heading to the FDA to discuss the pre-NDA, and to have a pre-NDA discussion, one of those topics is the -- will be the 6-year data or the 5-year OLE data. You asked whether it's synergistic. Absolutely, yes, it is synergistic. It is also additive. The importance of that data is that it demonstrates how the medicine is benefiting these patients as well as safety, but is benefiting these patients over a chronic period.

This is a chronic disease and our medicine is a chronically dosed medicine. And so the OLE data allows us to understand the benefits these patients are gathering with seizure reductions being durable through a 5-year period and also to see these cognition behavioral gains that they're having over a 5-year period.

So it is absolutely consistent and additive and synergistic to how we think about the Phase III and will be supplementing the Phase III data in our submission. That's why we continue to discuss it with the FDA. So it's really important, and as Jason says, the OLE data is also important in terms of how we want educate payers, they look at the totality of the data. But I'll also say prescribing physicians, a really important piece upon approval of this medicine, will be having physicians understand how to use the medicine but what benefits it provides to patients beyond the 1-year registration trial and those clinical endpoints. So we're in great shape with that data and as you said, Yaron, we'll have 6 years of data by the time that we start our NDA submission of that clinical data package.

You asked about the importance of the secondaries and the hierarchy. We have, at this point in time, we look at the hierarchy of endpoints, number one, in terms of the primary secondary endpoint is actually continued seizure reduction. But once you get beyond there, you get into the Vineland points. But we've included communication, receptive and expressive communication as being the key measures in terms of the hierarchy.

That's on the basis of physician and caregiver feedback, and we're fortunate that that's where we're seeing benefit through our OLE data as well. And just to give you an idea, because when we talk about Vineland as a measurement tool of cognition and behavioral benefits, what that actually means is these children that unfortunately stagnate at the age of approximately 24 months don't acquire other skills while they chronologically age.

But we appear to be providing benefit where we're giving them function and giving them skill. And in the communication area, for example, we appear to be helping these young children who can barely talk and have a minimal number of words they can use; we're providing the ability to many more words, to actually use sentences, and that's a progression they wouldn't otherwise see. We're also seeing them receiving communication, which allows them to respond and respond to their parents as a real-world example.

And then when you go on further and look at some of the motor skill acquisition, you're seeing children that improve their motor skills and that includes non-ambulatory, becoming more ambulatory, frankly. And this is data that's been collected from our OLE study. And we've shared that, well, it's been shared with videos that are in the New England Journal of Medicine, so have that validation and credibility.

So that's what Vineland means. And it is for us now to turn these Vineland scores into what real-world skill and task acquisition is for a Dravet child that otherwise would stagnate at the unfortunate age of 24 months. And we want to provide them skill and acquisition based on the use of our medicine.

I might just add, Yaron. This is Barry. So despite the wishlist that we have, the powering of the study for the key secondary endpoint is for each of the individual Vineland subdomains. So we power to the one that we think may even be the least likely to achieve, but each one of those have their own high degree of power.

Our next question comes from the line of Laura Chico with Wedbush.

Maybe just one for Jason on commercial. You previously indicated most U.S. Dravet cases are managed at centers of excellence. How should we be thinking about site capacity to treat this intrathecal ASO program? And I guess I'm thinking a little bit more about logistical constraints like procedure slots and imaging. How do you think about site capacity and the impact on a commercial zorevunersen launch? We obviously saw this was important for drugs like SPINRAZA. I'm just kind of trying to understand how things might have changed in the landscape.

It's a great question, Laura. I think, we provided some additional details here this afternoon around specifics for the top 50 sites, for example. So, if you think about those top 50 sites, all of them have 20 or more patients that are under their care, but all 50 of those sites also have experience administering intrathecal therapies, most of them SPINRAZA. And so, given the efficiency that they've developed administering other intrathecal products and their familiarity with the procedures and process that goes into it, we feel like they are really set up incredibly well to handle the capacity that comes through at the time of the potential approval, which we expect to be robust, if based on nothing else, based on the speed with which we recruited the EMPEROR study, but it's also consistent with what we hear in market research.

So we still have more work to do around site readiness and site qualification over the course of the next year or so, but going in, we're definitely benefiting from the fact that there are other intrathecally administered antisense oligonucleotides available in the commercial context and that institutions have protocols already in place with how they're administering those therapies, which gives us a huge advantage going into a launch like this.

Our next question comes from the line of Sumant Kulkarni with Canaccord Genuity.

Nice to see the progress. On slide 11 in your presentation accompanying this update, you mentioned that HCPs and payers indicate that OLE data may be the most compelling data at the time of approval. You alluded to this a little bit and we understand reduction in seizure frequency over and top of standard of care and totality of evidence matters, but what specific components of the OLE data resonate most and does the relative importance of the components of the OLE data vary for HCPs and payers or are those factions looking at them largely in the same way?

Sumant, thanks for that question. Obviously, Jason's going to take this question, but I just want to reiterate what Jason's about to tell you about the importance of that data is, yes, it's our belief, but this is feedback from prescribers and payers. It's what they're telling us. It's not what we are telling you. It's actually what the payers and the prescribers are telling us because we've gone out and as you appropriately should be doing at this stage of drugs development is you should be doing diligence with your payers and your prescribers and helping them understand the medicine. But Jason?

Yes. It's a great question, Sumant. Thank you for it. You know, when we, and I'll take those 2 audiences in sequential order there. So starting with the healthcare providers, I think it goes back to when you ask healthcare providers and caregivers specifically, what are the greatest unmet needs that exist in Dravet today. First and foremost, the number one that you hear is persistent seizure burden. The fact that very few patients ever reach seizure freedom is number one. And I think that from a caregiver perspective, relates back to, watching your child undergo a seizure, for example, right? But not far behind the persistent seizure burden is the lack of efficacy across the non-seizure manifestations of the syndrome and the lack of any targeted medicines that address the underlying genetic cause.

And so when we talk to healthcare providers and they talk about what's most compelling to them, obviously the long-term data are the most compelling because as a clinician, they're sitting across from a patient where they're thinking about prescribing a chronic lifelong treatment, they want to understand what the implications are of administering this medicine to these patients over a long period of time. And so I think they're reassured by the long-term safety profile now going out 4 years of OLE plus the Phase I/II, they're reassured by the persistent reductions in seizures that they're seeing, the durability of that seizure response. And they're certainly reassured by the fact that you see the consistent gains in adaptive behavior and the neurocognitive endpoints as measured by the Vineland Adaptive Behavior Scale.

And then in addition to that, it's quality of life matters, right? As you think about what matters to families, the ability for a child to continue to -- or a child to be able to communicate with their family, the ability to, for example, feed themselves, all of those little activities of daily living and acquired skills, as Ian mentioned, really matter a lot. And then when you think from a payer perspective, payers matter less -- payers care less about, for example, the nomenclature associated with disease modification. What they care about more is, is this new treatment offering something that what I currently have at my disposal for my members isn't?

And so it's what we're doing in the non-seizure manifestations of Dravet syndrome above and beyond the seizure suppression. So they're seeing the additional seizure suppression on top of the best standard of care as being a real value driver. But above and beyond that, the fact that we're affecting other elements or other manifestations of the syndrome really go a long way with payers in driving that value proposition associated.

Our next question comes from the line of Kevin Strang with Goldman Sachs.

Just a quick one on, you mentioned a study for infants and toddlers under 24 months of age as well as generating new data in adults. I just wanted to ask about those 2 bookends, anything on trial design, potential timelines for both of those, and then for adults specifically, is there any data that you can leverage from your OLE in terms of patients that have crossed over into adulthood?

Yes, thanks, Kevin, and appreciate the recent initiation and also the data you sent to us this week about some analysis you've done at the market. So, first of all, the infant-toddler study is part of the requirement for a PIP in Europe, so we're running that study there. It really is as straightforward as that, although the data will help us potentially expand the label and treat even younger patients.

And obviously with the genetic medicine, the earlier you can treat a patient, the more potential you have to put them back on a more neurotypical pathway as well as prevent those seizures. So it is a very important study to get to these Dravet children as early as possible. For the adults, it's a different rationale. The adults, we anticipate that on successful data and approval that our label would be for 2 years and older, and therefore we will have access to be able to have prescriptions to adults.

What the adult study will do, though, it will help us understand the benefit for adults and help provide access and reimbursement for those adult patients. And you are correct. Our studies have been run so far for ages 2 through 18 years of age. And the OLE does have patients that have progressed, that started in their late teens and have progressed into their early 20s now. And we continue to track that data, and that data continues to show seizure reduction, a durable seizure reduction, and cognition and benefit from the first start of dosing when measured to their baseline when they were in their teens.

And our own principle on this is, given that the root cause of Dravet is the lack of normal expression of NaV1.1, whereas we upregulate NaV1.1 protein, and therefore there should be no difference in providing benefit to a, let's say a 15-year-old versus a 21-year-old. And so we'll use all that data. But we will also run an adult study that begins later this year.

You also asked as far as the design of those studies, they'll initiate later this year. As they initiate, we'll provide you study design at that time.

Our next question comes from the line of Joseph Stringer with Needham & Company.

Just a follow-up on the market opportunity in Dravet syndrome. You estimate the prevalence in the U.S. is around 16,000. What do you estimate the current diagnosis rate is in the U.S.? And if there is a disease-modifying therapy available, such as zorevunersen, how significantly do you think the diagnosis rates could improve in the U.S.?

And maybe as a follow-up question, I guess, what are the most appropriate drug comps that we should think about that have a similar setup to what there is for Dravet syndrome now, just multiple approved drugs on the market for several years but no disease-modifying therapy available.

Yes, so thanks for that, Joey. So maybe taking the first part of your question of the 16,000. When we look at claims data, we have a pretty good idea where about up to 80% of the 25 and younger patients are being cared for today. I would say that the diagnostic -- the genetic testing status in the U.S. has really grown dramatically over the course of the last 5 to 10 years. And so I would say that pediatric epileptologists, pediatric neurologists are doing a really nice job at diagnosing pediatric patients even earlier. But the gap -- there is a gap that still remains for the older patients.

And so the disproportionate, I would say majority of the diagnosed patients today are the diagnosed patients that are 25 and younger, of whom we expect there are about 6,000 that will be immediately addressable at the time of a potential approval. That's based on both epi and what we're seeing in claims data, so if you look at total unique claims across all ages, you get pretty close to that 6,000 number in the U.S.

But then when you break it down and you apply machine learning where you're looking at that peri-diagnostic period, looking at concomitant meds, concomitant procedures, CPT codes that are commonly used for Dravet patients and apply that to the total claims universe, that's how we get to knowing where approximately 80% of the patients are being cared for. But not surprisingly, one of our focal points right now is enhancing and increasing genetic confirmation of diagnoses in that, young adult into adult cohort of patients.

With that being said, we feel like the DMT introduction with the potential approval of zorevunersen will dramatically increase the volume of genetic testing in the U.S. And we've actually asked that question to healthcare providers and healthcare providers themselves anticipate that genetic testing will increase 85% to 90% compared to today with the introduction of the disease-modifying treatment.

So, the foundation is there. Our hope is to be able to drive those earlier diagnoses and in the case of the adult patients intervention before approval with additional diagnoses and genetic testing. And then from a comps perspective in terms of -- Joey, from a comps perspective with I think, SPINRAZA is a, the SMA market is a good comp. I think potentially the CF market is a good comp where you had symptomatic treatments available before the introduction of the first disease modifiers.

Our next question comes from the line of Jessica Fye with JPMorgan.

This is Adam on for Jess. I really just want to talk about the SYNGAP program and just curious on timelines here. When can we expect a candidate to maybe enter the clinic?

Adam, thank you for joining the call. So I'll start with, SYNGAP remains a very important disease area for us. Just why? Because there's a lot of closeness of SYNGAP to Dravet in terms of being a neurodevelopment disease. Our platform that upregulates the effective gene to create protein in these patients is applicable to Dravet, as we talked about today. But it also goes to SYNGAP, and so SYNGAP becomes a very important area that we are focused on.

We currently have 5 potential drug candidates that we're studying pre-clinically. We're working through our animal models. And in 2027, we hope that we will pick a development candidate to move then towards the clinic. But I want to reiterate that it's a really important disease area for us to continue our efforts. Now we have success and using Dravet as a proof of principle that our platform can work in these kind of disease areas. And so we will continue our efforts there to do the best for the patients.

Our next question comes from the line of Delma Caiati, with Guggenheim.

So on the ADOA program, the Sentinel cohort dosing is now complete. Can you give us any color on how many patients were dosed and at what dose level? And what did the Sentinel safety review show that supported the decision to escalate? And then for the readout in the first half of '27, what magnitude of change would you consider as proof of concept threshold?

So Delma, I'm going to have Barry summarize the program more holistically to help you understand the decision we made to go into the clinic, which was based on pre-clinical data, obviously. But then where we are in advancing a dose-escalating study where we are already into the increased doses. So Barry, please.

Yes, thanks. And thanks for the question, Delma. So, just as a reminder, ADOA is due to a haploinsufficiency for half the normal amount of OPA1 protein, which is required for mitochondrial function. And we do have preclinical data in an NHP that has a genetic mutation that's similar to what patients have and has a similar phenotype to patients. And there when we administered 002 to those animals, they showed an improvement in their mitochondrial function, as well as an improvement in the function of the optic nerve.

So that gave us a high degree of confidence moving forward into the clinic as well as other data that has come in the field. So the study is a typical dose escalation study, a single ascending dose study. And the first cohort had 3 patients in it. The Safety Monitoring Committee reviewed those data and are approving the escalation to the next dosing level.

We have right now 4 dosing levels that are planned. And each of those are being reviewed for safety on a variety of levels after the injection. And we'll also be looking for potential improvement in vision because since we are improving the mitochondrial function in the patients, we expect that the retinal ganglion cells that are important for vision will be improving in their function as well, and that will allow for better visual acuity as well as improvement in the measure of mitochondrial function, which is what we call the FPF. Those data we anticipate being able to discuss next year.

Delma, I would just point out that as we progress through these 4 cohorts of increased dosing, we anticipate, based on our preclinical work, that we may start to see efficacy in cohort 3 or 4, and that's why Barry is referring to readouts, data readouts that would be in the first half of 2027.

And our next question and last question comes from the line of Rudy Li with Wolfe Research.

As we finish enrollment of the Phase III trial, can you maybe provide more color on the patient population, baseline characteristics as expected, any notable difference versus the Phase I/II trial?

So the patient population for the EMPEROR Phase III study is consistent with the patients that came into the Phase I/II and progressed into the OLE study. And just to ensure that we had an 8-week screen period that required certain baseline characteristics to be tested through that 8-week screen period before they were allowed into the Phase III EMPEROR study. Characteristics, obviously, age, had to be screened for the SCN1A depletion gene and also a certain number of seizures, and so there is a similarity and a consistency between the Phase I/II OLE patients and those that are in our Phase III.

I'll now hand the call back over to CEO, Ian Smith, for closing remarks.

Yes, thank you. I just want to say thank you for taking the time out to join us this evening. We look forward to talking to many of you throughout this week and probably next week and continue to update on the progress of the company. Thank you for your time this evening.

Ladies and gentlemen, thank you for participating. This does conclude today's program, and you may now disconnect.

All right. So I think we're ready to get started.

Great. All right. Well, it is my pleasure to introduce Ian Smith, CEO; and Jason Hoitt, Chief Patient Officer of Stoke Therapeutics. My name is Kevin Strang, I'm one of the biotech analysts here at Goldman Sachs. Welcome.

Thank you, Kevin.

And -- I guess we'll just start getting right into a question for you, Ian. What were your priorities when you took on the CEO role at Stoke? And can you sort of provide a mark-to-market on your progress against those priorities and what you're focusing on from here?

Yes. So -- first of all, thank you for everybody joining us on the webcast and for those that are in the room with us today. Just as stepping back, I have been on the Board of Stoke Therapeutics for 3 years now. And while I was on the Board -- I also was an adviser to the company. And about 15, 18 months ago now -- 15 months ago, the Board asked me to transition -- at that time, and I was the interim CEO for -- 6 or 7 months, and I took the permanent CEO position in October last year. So that's the background.

How did I think about goals and achievements for the company? Well, first of all, it started with -- I wanted to help the company become the greatest advocate it could be for what Dravet was as a disease, the devastation of Dravet. And once you understand that and understand what our medicine is doing for Dravet children you actually start to become a very strong advocate for your medicine as well. That is kind of the meta goal, so to speak, for the company today. But what that translates into is understanding the audiences that need to understand that, so the physicians.

The physicians that treat Dravet or seizures today with medicines that only treat the seizures. Our medicine treats beyond the seizures based on all the data we've seen so far, we treat beyond the seizures in Dravet. And so educate the health care environment to what our medicine can do for those children.

Also to then understand how to progress the medicine to get it to these children that deserve the medicine, the families that deserve the medicine and build a company. Frankly, I worked with Vertex Pharmaceuticals for 20 years and saw medicines for cystic fibrosis over 20 years, come from the bench all the way to changing -- children with CF, changing their lives. And you have to build a whole -- means working -- building a development organization to run the studies, having a regulatory group that has the right and appropriate interactions with the FDA, including breakthrough designation -- accelerated pathways through to these patients. Building a medical affairs group that educates the market, building a more of a business function in terms of manufacturing and commercial.

And frankly, understanding Wall Street as well in terms of educating the investment community to the opportunity that Stoke is creating in terms of an investment. And I think all those areas needed acceleration and investment of time and people. And then you asked me, Kevin, about market to market.

I'm really happy with how the company has progressed over the last 15 months. It really has accelerated the awareness in terms of the advocacy of the medicine, and that means also the advocacy of the disease. And I'm very happy. I wish from a stock price, I wish our stock price was a little higher, but who doesn't. But the company is building itself out. We've made great progress in the Phase III, which I'm sure we're going to talk about. And there's a greater understanding of the medicine and the opportunity today. I'm very happy with it.

Great. That's a great place to start. You mentioned the disease itself, Dravet. At a very high level, what is that unmet need that you see today? You mentioned ASMs versus disease modification. How do you view that need and then we can get into zorevunersen's ability to meet that?

Yes. So just -- consistent with what I said about being advocate for the disease first, just a little quick, what is Dravet syndrome. And genetically Dravet syndrome is a depletion of SCN1A. And therefore, you don't express Nav1.1 in the brain. What our medicine does, zorevunersen, it boosts the [indiscernible] that the gene SCN1A that is functional and to express Nav1.1. What we've seen, what that results in is that it not only reduces seizures in Dravet because you go to the root cause of the disease, but it also provides cognition and behavioral benefits to these kids. In Dravet, they [indiscernible] 24 months old. Unfortunately, when they get to about that [indiscernible] so even when they're 20 years old neuro -- typically or neuro development-wise, they're still 2 years old.

What our medicine does by giving back that expression of Nav1.1 is it provides a gain of function while you're on the medicine because you're expressing Nav1.1, and there's still neuroplasticity there. So whether you come on to the medicine as a 2-year-old, 5-year-old, 10-year-old, 12-year-old what we're seeing is there is a gain of cognition and behavior as measured in our clinical studies. And so that is not provided anywhere for these Dravet children. There are very good anti-seizure medicines that are anti-seizure medicines and reduce seizures. But seizures is still one of the, unfortunately, uncontrollable symptoms of Dravet. And all of our data, which shows 75% reduction in seizures, improves the cognition and behavior is on top of standard of anti-care -- sorry, anti-seizure medicines. So we're driving that benefit even on the medicines that are available today. And that's because we go to the root cause of the disease of expressing Nav1.1.

Got it. And that's -- so that's from your Phase I/II as well as your recently 4-year open-label extension data. Do you just want to highlight, especially with the 4-year data, what that means? And that's very recent data that you shared, so maybe just...

So we're in a unique position where the company has been in development zorevunersen now 6 years, yet it is a truly breakthrough genetic medicine. And typically, with medicines like that -- my history of CF, you move quicker in the clinic. But we've been in the clinic now for 6 years. And by the time that we file an NDA we will have been in the clinic for 7 years.

What that has allowed us to do though is, for that first patient that came in the Phase I/II study 6 years ago or 5 years ago, they went through the Phase I/II dose-escalating study, but then rolled over into an OLE. That OLE, we now have captured [indiscernible] rare position where we have -- that gives back function, and we're able to measure how much function is given -- giving back over a 4-year period now, while also seeing the durability of seizure reduction over a 4-year period. And all that data, what it shows is we're seeing seizure reductions of 75 -- approximately 75% on top of standard of care medicines that is durable out to 4 years now.

And in terms of the cognition behavior, we've even run a statistical analysis that shows for each of the key domains of Vineland, which is how you measure cognition behavioral improvements. All the 5 key domains, year 1, 2, 3 and 4 were statistically significant in terms of improvements each year in cognition and behavior of 5 key Vineland domains.

Great. So moving on from that data to your currently running Phase III EMPEROR study. I believe you're guiding to completing the randomization of that study this month that would enable a readout middle of next year. Can you talk about how that study was designed to capture both the seizure benefit and then the neurodevelopmental outcomes, the Vineland-3 secondary endpoints?

So it is a 52-week study, anticipated to be 150 to 160 patients. We're anticipating completing enrollment this month, month of June. The primary endpoint is week 28, measuring seizure reduction. Secondary endpoints are Vineland-3, which is a measurement tool of cognition and behavior, and that's run at week 52. So that's the design of the study. Patients go through the study and ultimately can roll over to an OLE study. Once they can -- if they're in sham and they continue on the study, they have the option.

As far as the study and the progression of the study, I can't give an update today on webcast but a month ago, we had recruited or enrolled 130 patients -- 150 or 160. Of those 130, approximately 90 were through the first 2 doses of 70 milligrams, and we had zero dropouts, which is quite remarkable. And that might be driven by the intent to get to an OLE but it also shows that the drug has been well tolerated in the Phase III.

Great. So you mentioned the sham-controlled arm. I guess how do you sort of approach -- how did you approach powering for that sham-controlled arm? And you've done some natural history work as well, and you've also looked at natural history work. Talk to us in terms of that data and what you expect or what you expected when you designed the trial on that 52-week endpoint. And I believe you presented last year some 18-month data as well. And so -- I guess if you could go over that.

Yes, it's a good question. This maybe something that is a little difference of our Phase III program is we've powered the study based on the secondary endpoints, not the primary. The primary endpoint of seizure reduction, the seizure reduction is so demonstrative as what we've seen in all our data that we actually moved to the secondary endpoints and powered the study of the secondary endpoints. The powering in the study of the secondary endpoints is powered to a p-value of 0.01 with a confidence level of 90%. So it's conservatively powered and that brought us to 150 patients. We anticipated that there could be a 15% dropout, and we anticipated 150 patients to come into the study. So far, we don't have a dropout and I anticipate that the study could be as high as 160 patients. So we're very well powered.

Now the data that led to that powering calculation was data we provided to the investment community and at a the medical conference in August of last year. And that showed that when you take a dosing schema or regimen, complete dosing regimen that's similar to the Phase III dosing of 230 milligrams over a 12-month period, we actually showed Vineland improvements of around 8 to 12 points, I believe, I think, or 8 to 11 points. The study is powered to show 2 points improvement. So we're very well powered. We're in good shape.

We've also provided a statistical analysis of that regimen rather than just showing the absolute Vineland scores. And we compared that to a natural history study, and we showed that we hit statistical significance at certain time points, and that was with an [ N of 8 ].

Great. And for how these secondary endpoints are being looked at in the U.S. versus Europe, can you just remind investors what those differences are? And whether they should think of any hierarchy for these subdomains? And even in the patient community or the physician community, are there certain subdomains that are more important than others?

Yes. So the subdomains that we're looking at for the NDA versus European filing are the same subdomains. It's the same study in terms of the endpoints.

To your question in terms of are there higher priority endpoints, if you talk to families and caregivers and physicians, you will find that there is kind of a priority, and they tend to focus on receptive and expressive communication. And then the one difference between the two filing strategies is in the U.S., it is a hierarchical assessment of the secondary endpoints, whereas in Europe, it's a composite. But the trial design is very similar. There is a slight difference in 4 European countries where we're doing a lumbar puncture cohort -- sorry, a needle prick cohort in terms of sham, whereas the U.S., U.K. and Japan is lumbar puncture.

Got it. And as you move past the data and towards regulatory outlook for zorevunersen. What does it need to be -- what does it need to achieve to be viewed as a disease-modifying therapy and by regulators, physicians, payers, et cetera?

Yes. I want to jump all the way to -- I think it's already being recognized as a disease-modifying therapy because of the totality of the data. When you look at the 4-year OLE data and this durable reduction of seizures on top of standard of care medicines, 75% reduction of seizures. And then you'll see these cognition and behavioral benefits in year 1, year 2, year 3, year 4 and that each year, they're statistically significant, that totality of data is already being recognized in the medical community and the payer community as a disease-modifying medicine.

I think you're asking more about what's the regulatory environment and how they look at it. Again, I think it's very similar, whereas you've got to hit a primary endpoint to get the medicine approved. So we're very confident with that. With the secondaries, we're very confident there as well. But I don't think that you have to go and have 5 out of 5 secondary endpoints hit at each one because you've also got the OLE data, which would be in the label. The label has a part of the label where you've got to show your data from other clinical studies if it helps a physician understand the benefits and risk of the medicine. It's actually in the FDA guidance and it's called Section 14, but your clinical studies are required to be in there. And this is a chronic medicine. So when you have 5-year data, then you should put that in the medicine to help people understand how the medicine is affecting these children.

Are there -- you mentioned Section 14, what are good analogs for investors to look to?

Yes. I mean the best analog I could give you is probably SPINRAZA. SPINRAZA is -- why is it the best? Because it's also an ASO. The SPINRAZA looked at the primary endpoint at 6 months. They actually missed their secondaries. But the OLE data was on the label because they followed these children. And if you're familiar with SMA, unfortunately, these children, they don't sit up, roll over. They die at very young ages. But Biogen, like ourselves, actually continued these patients into an OLE study and measured them, and it helped to understand what the medicine did chronically. And these children lived longer and also had greater movement and function. And all that data went on the label because it helped people understand how the medicine affected these babies in SMA. We see it exactly the same in terms of being an analog that you're asking for. There are others as well. Jason has been involved with some of them.

Coincidentally, SKYCLARYS and QALSODY also from Biogen are good examples of observed data being added to the Section 14 of their labels.

Yes.

Great. And I guess on the topic of analogs and I have a feeling it could be similar for this question as well. But how are you thinking about pricing?

Yes. So I think -- and I'm glad you asked the question, Kevin, because I think historically, there had been a misconception that because we're launching in Dravet and the only approved medicines so far in Dravet have treated just some of the symptoms, namely the seizures of Dravet that we would kind of be pigeonholed or ballpark to that price range. But the reality is, is that what we're doing is addressing the underlying genetic cause of the disease. What we're doing is affecting the syndrome itself by doing so. And therefore, I think more appropriate analogs are genetically targeted disease-modifying medicines for rare disease. And so the analogs we've been talking about most recently are obviously SPINRAZA, as you mentioned, the exon skippers from Sarepta, I think are also appropriate analogs, DAYBUE, medicines like that, that are changing the paradigm in addition to addressing the underlying genetic cause.

Got it. And then for filing, you've mentioned rolling submission. Is the plan as soon as first quarter of next year, potentially allowing for a launch maybe early '28, around that time frame. Any gating factors to getting that initial submission started? And then what are the advantages that you have with breakthrough and using that rolling submission as the Phase III data comes in?

We'll start with the advantage of breakthrough designation allows us -- affords us the rolling submission. We anticipate starting the rolling submission in Q1 2027. The first section of that rolling submission will be CMC. Jason can update you with where we are there, but we're right on schedule, no problems, including inspection and quality.

Then the rolling submission would take us through to the last clinical submission that would be after the week 52 clinical data that would be in the middle of next year. At that point, when you complete your rolling submission, you get a PDUFA date that would be 8 months after the last submission that would put you in Q1 of 2027 for launch or PDUFA date of -- Q1 2027. However, if you look at the kind of the history of rolling submissions, breakthrough designation, approval generally comes anywhere between 4 and 6 months after last clinical submission, which could potentially put us into Q4 of 2027. And we're right on track in terms of what we're preparing for in terms of CMC, preclinical. Obviously, we're ongoing with the clinical data in the Phase III study.

Got it. So potential approval launch later next year, early '28.

Right.

Moving to the commercial opportunity. I feel like -- you've recently talked about your estimation of the patients available at launch around 6,000. Can you talk about what goes into that number, be it claims data, literature prevalence, et cetera?

Yes. So I think the number 6,000 comes from two different ways of looking at it, right? And so you can look at it from an Epi perspective where going back a couple of years ago, before we initiated the EMPEROR study, we wanted to understand overall prevalence in the geographies where we were running the study. And so we initially looked at the core 7 geographies around the world, U.S., EU4, U.K. and Japan.

And we took 85 years of live birth rates and scaled incidents to prevalence, applying Dravet-specific mortality, which largely is due to sudden unexpected death in epilepsy. And that ultimately got us to a total population for the U.S. of 16,000 patients approximately. When you break that down by specific ages, about 4,000 of those 16,000 are purely pediatric patients under 18. But in Dravet syndrome, there's this dynamic of patients predominantly being cared for by pediatric neurologists, pediatric epileptologists that are initially the ones that diagnose the patient and care for them throughout their life up until they need to transition to adult care. And as you can imagine, patients, families, they develop a strong bond with the clinician that's been caring for them over time, and there's a reluctance to transition to adult care. So oftentimes, the pediatric providers are caring for these patients into their mid-20s.

And so the patients that are cared for by that group of specialists that are the most familiar and the most up to date with what's going on in Dravet are particularly relevant. And so 6,000 is the number of patients from an epi perspective that are 25 and younger in the U.S.

Now pivoting to patients that are already identified today with an ICD-10 code for Dravet from claims data, there are also coincidentally 6,000 identified patients in the most robust claims database in the U.S. today. That's across all ages, but coincidentally, it also happens to be 6,000. We've brought several pieces of claims data in-house so that we can mine and analyze the data. And we've applied some machine learning principles to the already diagnosed patients looking at other CPT codes, treatment codes that are consistent with the Dravet diagnosis and then applied that algorithm to the total claims universe. And in doing so, we feel really confident that we know where about 70% to 80% of the 25 and younger patients are being cared for today.

And as we launched the disease awareness campaign last year, for example, we have the ability now because there are linked NPI numbers for clinicians in there to hyper-target specific messaging to specific segments of clinicians based on the behavior that we're seeing from them from a diagnostic and a treatment perspective in an effort to change the behaviors that we would like to change and educate on the areas where they specifically need education.

Got it. So it seems pretty concentrated. Is there anything in terms of launch execution that you're planning for field force design, specific barriers you're looking for based on your work?

Yes. So obviously, this is contributing to how we think about field force design. And to your point, Kevin, this is a highly concentrated market, right? In this market, 50% of patients based on claims data are in 8 states. There are 1,200 clinicians that are caring for about 70% of the total Dravet opportunity. And then if you also look at the claims based on center sites or practices that are caring for patients, it's also 124 sites represent 70% of the opportunity. That could be group practices, hospitals, et cetera.

So with a concentrated opportunity like that, we're looking at a very lean commercial infrastructure that will allow us to completely maximize this opportunity. You're talking 20 to 25 salespeople total, matrix field organization, but a commercial team that's well less than 100 people to maximize the U.S. opportunity.

And what does the time line look for that?

SP-30 So our commercial leadership -- so our medical affairs team is nearly fully built at this point. Obviously, the medical affairs team needs to be out and engaging with clinicians and they have been for the last couple of years. We have an amazing team of regional medical directors that are engaging with KOLs today.

From a commercial perspective, the leadership team is in place, the entire commercial leadership team. All folks that have done this before, gone from a clinical stage company to a commercial stage company launched the first medicine in rare disease, and the majority of us have done this together before. So it's a strong foundation to start from. The vast majority of our hiring for, in particular, field-based personnel will start after Phase III data. We'll be gating some of our spend and some of our hiring to that. But leadership will be in place before then. And obviously, all of the work to prepare for the onboarding of those teams will be done before then as well.

Got it. And how are you thinking about -- we talked about different age segments. There's 18 -- like the 18 to 25 segment that's often treated by pediatric specialists still, there's the above 25 segment. How are you sort of approaching that? And do you need additional studies for the adult population when it comes to payer access and things like that?

Yes. So let me take -- maybe I'll take the first part of that first. And yes, so as you can imagine, just based on how genetic testing has evolved over the last couple of decades, the claims universe that exists today is disproportionately representative of the younger cohorts of patients, the 25 and younger. So there's more work to be done from a diagnostic perspective to identify those additional 10,000 patients that are largely adult patients.

And so the focus of our screening efforts will be on that adult segment on the adult providers. while we also want to move diagnosis as early as possible for patients. But to your point, payers may limit reimbursement to trial inclusion criteria. And so we anticipate having data for patients that have aged into adulthood from our Phase I/II and OLE studies that we will specifically look at. But in addition to that, later this year, we're going to be starting a small adult study looking primarily at safety, but we're also going to look at seizures. We're going to look at neurocognition, and we're going to look at some endpoints that are specific to adults.

Great. And I wanted to talk about durability of therapy and sort of how you think about that. I know you obviously have long-term data at this point. In addition to that, what other assumptions are going into, how you view the persistence of therapy in the real world?

Yes. I mean -- we've now got 4 years of OLE data and the retention in the OLE study has been remarkable. The fact that we're also now well into the Phase III, and we've seen zero dropouts to date. I think the family seeing the benefit is the greatest motivator to stay on treatment. But to your point, we're already starting to build our patient services offering. And so obviously, with a rare genetic disease, we'll have a team of in-house folks that are interacting with families, interacting with offices, helping with everything that we can compliantly help with to get a patient on treatment and ultimately help them stay on treatment.

Just a statistic, the OLE, the patients that rolled over into the OLE, 90% of them are still in the OLE 4 years later. And that's in an OLE. It's a remarkable retention.

Great. From a -- I wanted to move on to a competitive standpoint. Is there anything that you're looking at in the disease-modifying landscape? I know, obviously, that's sort of how you think about your therapy in the disease modifying category versus an ASM. So when you look at that disease modifying landscape, is there anything? And then in terms of gene therapies, could those potentially be -- are those -- what you look as complementary, competitive? How do you see that when you look at other rare diseases?

We don't see anything that's the same as what we've got. We don't see somebody that's maybe trying to make [ better ] zorevunersen. And frankly, we don't see it, and we've got a very strong IP portfolio. And we're also have 5 years' worth of data.

In terms of gene therapy, we do see some interesting approaches. There's a company out there that's doing gene therapy. And we look at that as somewhat validating and putting the SCN1A gene back in. And so that's an interesting approach. It's very early trying to figure out their dosing and they put out some data recently. It's interesting, I think. But I kind of look at [indiscernible] and SPINRAZA. And if you look at the history of an ASO and gene therapy, gene therapy was interesting, but most patients roll on to SPINRAZA because of the durability, the point you were just making, actually, Kevin, the durability and the consistent response because you're continuously dosing. I think there's a lot of questions that remain about gene therapy in terms of its true onetime dosing and durability of benefit as well as there's kind of questions on safety because the administration is going to bore a hole in the skull and inject into the brain [indiscernible] therapy still. And so it comes with -- must come with some safety concerns as well. So we'll see how the landscape evolves. But there's nothing right now that we look at and say we're concerned about.

Makes sense. And I wanted to ask briefly on your partnership with Biogen since we haven't really spoken about that yet. How has that partnership evolved over time? Obviously, there's a lot of overlap with the ASO space and the rare disease space. What's been most valuable [indiscernible]

Well, I'll go back to before the partnership existed and say, I was on the Board of the company with this business development opportunity. But the number one question was, do we have the global capabilities to approve -- get this medicine approved and launched into patient populations in single-payer markets? And the answer 2 years ago was no. So we started a process competitive process.

Even when we started the competitive process, Stoke would like to have had Biogen as a partner because of SPINRAZA, because of its manufacturing capability, because of its global reach and its capability and SPINRAZA in SMA. We closed with Biogen, and -- we closed with Biogen, I believe it was February 2025, so just over a year ago. And the relationship with Biogen has been excellent.

It's been everything we hoped it might be in terms of how they've helping us outside of the North American territories, and they bring a lot of capability to the table. We're running the studies. We're responsible for the design, the progression of the studies, and we keep Biogen updated, but we have a whole governance structure in terms of joint steering committees, joint development committees, a joint commercial committees, joint manufacturing committees. And there is daily conversation and exchange of information between the two companies, but it's working really nicely.

Great. And I see we're essentially at time. I wanted to briefly ask about your program in ODOA (sic) [ ADOA ], STK-002. What should we be looking for in that program on the horizon? And then finally, just in terms of your cash position, where are you at today? And what is that -- what sort of milestones does that get you to?

Yes. So quickly, ADOA is a progressive -- genetic progressive loss of eyesight. We are in a Phase I/II dose, single dose escalating study. We're in our first cohort of dosing. We anticipate 4 cohorts with Cohort 3 and 4, potentially giving you an efficacy readout towards the end of this year or early 2027. And so we're pretty excited about that. We think it's -- we think OPA1 is the right target to increase mitochondrial function.

And then to your second question on cash, we've got -- we're very well capitalized. We've got over $400 million of cash as of the end of Q1, and that cash supports us all the way through to 2028, but we're also supported by Biogen paying 30% of the development costs for zorevunersen. So we're in very good shape.

Great. Well, thank you, Ian, Jason and the team at Stoke. Appreciate it.

Yes. Thank you. Thank you for listening.

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. [Operator Instructions]

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 will 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 then speak to how these data support our commercial planning, starting with labeling through to patient access as we prepare for a 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 of care antiseizure medicines.

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 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 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 4-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 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 4-year data cut, approximately 77% of the patients remain in the studies, which demonstrates the 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 1 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 antiseizure medicines. As a reminder, there was a 6- or 7-month gap between their last dose in the Phase I/II study and the 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 zorevunersen. Dose levels for individual patients in the OLEs vary 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 milligram 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 reduction in major motor seizure frequency of 59% to 91% for these patients through month 28 compared to patients Phase I/II baseline.

Again, I will remind you that these seizure reductions were demonstrated in patients who are continuing to be treated with standard of care antiseizure 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 medicines 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. Respondent is typically a parent or caregiver and the assessment is conducted by trained raters, which reduces the potential for bias. Vineland evaluates 4 domains: communication, motor skills, socialization and daily living, each composed of multiple subdomains. The assessment has been used throughout the clinical development of zorevunersen, starting with the BUTTERFLY natural history study. Our 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 assessment for each of the 4 years of the Phase I/II OLE studies. The first 5 subdomains shown on the top of this chart highlights 5 key subdomains 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 subdomains to baseline was prespecified in the OLE protocols. These 5 key subdomains 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 and entry into the OLE. We cannot measure the effect going back to the Phase I/II study baseline since only one of the studies included bind 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 had more than 5 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 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. 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 zorevunersen is generally well tolerated with effects across multiple measures of disease when administered to patients who are already taking the best available antiseizure medicines. 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. To that end, 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 function. 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 into 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 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 2 loading doses of 70 milligrams of zorevunersen or sham and will continue treatment with 2 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 a 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 7 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 incidents to prevalence using country-specific live birth rates over the past 85 years and adjusted for Dravet-specific mortality.

Despite the many antiseizure 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 health care 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. 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 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 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 zorevunersen 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 zorevunersen.

Phase III EMPEROR study, long-term longitudinal data from the Phase I/II and OLE 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 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 2 years of the OLE. As those data have matured, our confidence has only increased. We now have 5 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 health care 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. 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 zorevunersen. There's no question that the label is critically important. If approved, the label will be the basis for all promotional communications and health care 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 of cash, 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 cash runway into 2028 supports Phase III execution and commercial readiness for launch. As Jason described, we expect a lean commercial infrastructure given the concentrated nature of the Dravet syndrome market.

I'll 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 and 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.

[Operator Instructions] Your first question comes from the line of Pete Stavropoulos with Cantor Fitzgerald.

Congrats on the 4-year data and heading to enrollment completion in less than a 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? And can you share how you think these data adds to what we've already seen for zorevunersen? And as a follow-up, I did notice 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?

So Pete, thank you for those comments and questions. I'm going to start with how we felt when we frankly, opened up the envelope and saw the data from the 4 years of studying these patients in the OLE. 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 5-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 4 years' worth of OLE data in a -- for a medicine that treats a root cause of a disease. So therefore, you can collect over 4 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 III, 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?

Yes. 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 4-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 it gives us more confidence in zorevunersen 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 4-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 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. And that's really a remarkable effect to see that level of rigor in terms of results. Our 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.

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

I have 2. 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, Sam, for the question. I'll go through it again. So 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. 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.

And 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. 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?

Yes. Thanks for the question, Sumant. So I think it's particularly timely that you asked because 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 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 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. And this was obviously before we had the 4-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 zorevunersen. 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 zorevunersen in the Vineland results and the quality of life measures and obviously, the seizure data.

So we think that the more appropriate analogs are products like SPINRAZA, 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. But given these 4-year data, we're incredibly encouraged with what we've got and look forward to continuing to engage payers. 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. And that's device 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.

I might just follow on from Jason and say -- and it's connected to my opening remarks, which is we are in a unique position where we -- 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. And when we look into the future potential filing and approval, we anticipate also supplementing and supporting our filing with this OLE data. And at that time, it will be 5 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.

Your next question comes from the line of Andrew Tsai with Jefferies.

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. And then maybe 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 subdomains need to hit stat sig in the U.S.A.? Or does maybe only one need to hit stat sig?

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 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. 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 III and how we think about the Phase III. But as we've referred to in the past, we continue to dose on top of standard of 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 III and go back to when we designed it and based on the data.

Thanks, John. So 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. So 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/IIa 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 1-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 2 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 I -- Phase III study, compare 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. But when we looked at those Phase I/II data compared to natural history, we showed statistical significance there again 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 the 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.

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

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?

Laura, it's a great question. And frankly, it's a question we receive frequently. I'm going to start by what is the purpose of a label for a medicine? And frankly, it is for physicians is 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 that 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 the label to help understand safety and efficacy of the medicine. It was also as far as back to 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 has been out in the field talking to payers as well as educating physicians through medical affairs. But 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. 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 the 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 providing 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?

Yes, absolutely. I think, Laura, it's a great question. I think I'll give you a few examples that you can use. And once again, an appropriate analog here, I think, is SPINRAZA. At the time of approval, SPINRAZA was approved at the 6-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 SKYCLARYS for Friedreich's ataxia or QALSODY for ALS. All 3 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 to that point, payers and health care providers are looking to this data, but I think more so for health care providers than for payers because health care providers, in particular, the community ones are reliant on the label for how to prescribe the drug. And when we talk to them, they and payers alike tell us that the 4-year data are the 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 for the purpose of having them understand 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 zorevunersen.

And Laura or maybe, Barry, do you want to add on statistical significance and how you approach this as a clinician.

Yes. 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 you expect both for myself and to explain to the patients and their families what you 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 really very useful in order to be able to expect -- to 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 a comment that year 1, 2, 3 and 4 in the 5 key subdomains were all statistically significant compared to OLE baseline. That endpoint of the 5 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 it's -- each of the 5 key domains is less than 0.01.

That's super helpful. If I can sneak one in, just for Barry, a housekeeping question. How many patients were in the prescreening? I think I missed that when you went through the numbers. Congrats.

Initially in the prescreening, there were over 200 patients initially.

I think what Laura is referring to is how many is in the prescreen 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 -- Barry's office is 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 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. We continue to look at the 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.

Your next question comes from the line of Marc Goodman with Leerink.

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 on 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 -- have taken a drug?

Yes. Great questions, Marc. 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 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 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 4 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 2 ways, Marc. 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 apply 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 as patients are diagnosed oftentimes as infants, but certainly as toddlers, they grow up with the 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 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% of the 25 and younger patients are being cared for today.

Your next question comes from the line of Yaron Werber with TD Cowen.

Congrats on the data. Really nice to see it. A couple of questions. Number one, the -- it sounds like you're going to start the rolling submission sort of in the first half of next year, have data after kind of starting midyear 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?

Yes. Thank you, Yaron. 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. 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 time line then to approval is generally around 6 months or less. So -- and that's why we referred to our time line for potential approval of 2027 or maybe early 2028. So I just want to kind of reiterate that and where -- 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 controlled. And we will not wait for that data to be clear. All is pending time lines. 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 U.S., U.K. and Japan as being our basis for filing.

Your next question comes from the line of Tom Shrader with BTIG.

Back to the 6,000, I think it is interesting. Of the 16,000, those older people, do they not have seizures anymore? And I'd 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, as I'm sure you've done a ton of work from your 6,000, 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 6,000 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.

Yes. So maybe with the first question, Tom, with seizures in adults, and maybe Barry wants to add to this. But 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 #1 objective in treatment. And so obviously, we're going to look to study in an open -- 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 6,000 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 health care providers to even the 3-year data. Obviously, the 4-year data are new and haven't been shared publicly until an hour ago. But continuing on those trends is obviously incredibly compelling to clinicians. They consistently tell us that the durability of the seizure suppression and then 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 4-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 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 zorevunersen, 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 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.

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 behavior. That to us is already a very good sign of what to expect.

Your next question comes from the line of Edward Marks.

This is Joey. Our question is on the -- would you anticipate payers would require patients first fail a certain number of antiseizure medications before being considered eligible to receive zorevunersen? Or would you expect that the drug would be used immediately upon a confirmed genetic diagnosis?

Yes. 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. So if you think about the patient journey, right, a patient will typically present to the health care 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 antiseizure 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, the neurologist orders a genetic test, they're obviously treating the seizures before that.

And so they will be put on an antiseizure medicine as soon as they present to the health care system. And with the rapidity with which antiseizure meds are added and switched based on either side effects or waning efficacy, oftentimes, patients will have failed 2 antiseizure 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.

Your next question comes from the line of Jess Fye with JPMorgan.

This is Adam on for Jess. 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 STK-002 from the OSPREY 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 2 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 in cystic fibrosis. And so 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. 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 zorevunersen 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. And so it is a minimal 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 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 -- it's in a Phase I/II study, dose escalation study. We are in the first low-dose cohort. We anticipate doing 4 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 -- the primary endpoint of 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 later this year and early 2027. And Barry, do you want to talk about the analysis of data?

Yes. So we've been so focused right now on getting the patients into our Phase III study. We haven't really talked about what data we're going to bodes 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.

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

Maybe just one -- maybe just like a follow-up on 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? And what type of disease severity? How should we think about the Phase III mix relative to the Phase I/II cohort that any notable difference or similarities?

So first of all, we have already closed enrollment into screening, Yatin. So to be clear, we have closed enrollment into screening. And so the patients are now going through that 8-week screening 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.

Your last question comes from the line of Rudy Li with Wolfe Research.

I have a follow-up for the key secondary endpoints in the Phase III. If we 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 you maybe provide more color how do you plan to use NURTURE history data to support payer discussion?

So Rudy, maybe I'll take that question, and 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 health care providers in terms of what is most important to them. And that feedback, as you heard from Jason earlier today, it is this 4-year data at this point, which will be 5-year data by the time that we file.

As far as hitting p-values in 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 at the data we've provided in the past on a dosing schema that is similar to that of the Phase III. And we've also done 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 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.

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, and you may now disconnect.