Stoke Therapeutics Inc Aktie

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.

Good afternoon, and welcome to Stoke Therapeutics Second Quarter 2025 Conference Call.

I'm Tommy Leggett, Chief Financial Officer at Stoke. Joining me for prepared remarks are Ian Smith, our Interim Chief Executive Officer; Dr. Barry Ticho, Chief Medical Officer; and Dr. Kimberly Parkerson, Head of Neurology Clinical Development. In addition, Jason Hoitt, our Chief Patient Officer, will participate in Q&A.

As a reminder, today's webcast slides are available in the Investors section of our website. This webcast is being recorded and will be available for replay later today. Before we begin, please note that today's discussion includes forward-looking statements. These are subject to risks and uncertainties, and actual results may differ materially. Please refer to the filings with the SEC for additional information.

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

Welcome, everyone, and thank you for joining us today. I've been working with Stoke Therapeutics for two years as a Director and adviser, more recently as the CEO. There's been a great opportunity to get to know the team, the medicines and the disease areas and to support the company through this growth period.

The key priority is obviously Dravet syndrome and zorevunersen as we work to deliver a disease-modifying medicine to patients. What we're seeing with zorevunersen may be new to the field of epilepsy, but I'm struck with the familiarity of the feeling of being part of something very special, again, which is creating a new first-in-class disease-modifying medicine for patients who desperately need it, potentially changing the lives of these children suffering from Dravet syndrome.

Let me start by saying that Stoke is in a strong growth position, defined by a late-stage registrational medicine, well-capitalized balance sheet, expanding pipeline of potential medicines and a very strong partner in Biogen with expansive capabilities to support zorevunersen outside of North America.

Our Phase III EMPEROR study in patients with Dravet syndrome is off to a strong start with sites initiated in the U.S., U.K. and Japan and Europe expected to initiate in early 2026. The first patient is now dosed, and we anticipate rapid enrollment based on the high level of awareness of the study, competitive participation among the study sites and importantly, the urgent patient need.

We continue to generate data that support our understanding of zorevunersen from our Phase I/II and OLE studies. We have prioritized sharing this information broadly as the field begins to transition from a symptomatic treatment to a potentially disease-modifying medicine for Dravet syndrome. We continue to educate around the seizure reductions with our medicine, and those reductions are on top of standard of care antiseizure medicines. More recently, we shared data that was used to inform the assessments of behavior and cognition and the powering of our Phase III study, specifically the substantial improvements in cognition and behavior indicated with a dosing level that is similar to and consistent with the one we are using in our Phase III study. And today, we are sharing with you top line results from the third year of our open-label extension studies.

These data support the long-term potential of zorevunersen to modify the course of Dravet syndrome as indicated by durable seizure reductions on top of what can be achieved with antiseizure regimens as well as continuing improvements in cognition and behavior. Importantly, these long-term follow-up data continued to demonstrate a favorable safety profile. Beyond Dravet, we see significant potential to develop disease-modifying medicines for additional genetic diseases. We have advanced STK-002 into Phase I clinical development for Autosomal Dominant Optic Atrophy. Like Dravet, ADOA is a haploinsufficient disease, and we are uniquely positioned to treat by restoring naturally occurring OPA1 protein expression using our antisense oligonucleotide approach toward the goal of preventing further loss of eyesights and possibly improving vision.

Now to our collaboration with Biogen. Signed in February. This brings global expertise commercializing high-value disease-modifying medicines for rare genetic diseases and strengthens our balance sheet. The terms of the collaboration retains significant value to Stoke while enhancing our ability to deliver zorevunersen to patients globally. We have a strong balance sheet and are well funded through Phase III readout, which is anticipated in the second half of 2027. And our balance sheet and projected investment support a cash runway through to mid-2028.

We continue to build Stoke's internal capabilities by enhancing our leadership team and strengthening key functions, including regulatory, medical affairs and commercial, all fundamentally important functions at our stage of growth. In short, we are establishing a clear trajectory for value creation for patients, for employees and for our investors.

With that, I'll turn the call over to Barry, who will discuss our Phase III study design and progress.

Thank you, Ian. This is a very exciting time here at Stoke as we take zorevunersen into this next phase of clinical development and potential registration and approval. Dravet syndrome is a severe lifelong developmental and epileptic encephalopathy that becomes symptomatic around one year of age. For the vast majority of patients, the cause is insufficient levels of the MAb1.1 protein in the brain. There are many medicines available to treat the seizures associated with Dravet syndrome. These medicines have undoubtedly made a difference for patients, but they just aren't enough. Most patients continue to suffer from seizures and few achieve seizure freedom. Furthermore, side effects of the antiseizure regimen also present their own challenges for patients and their caregivers.

While Dravet syndrome may be best known for its seizure burden, the effects go far beyond seizures. Nearly all patients suffer from one or more behavioral and cognitive effects. The antiseizure medicines were not intended to address these effects. We intend to change that.

Zorevunersen is an antisense oligonucleotide designed to restore naturally occurring Nav1.1 protein levels. As such, it has the potential to be the first disease-modifying therapy for Dravet syndrome. As we designed our Phase III study, we were fortunate to have a large data set available to inform key decisions related to dose level, dose frequency, study endpoint assessments and powering.

Here on Slide 8, you see the dramatic reductions in seizures demonstrated in our Phase I/II studies among patients treated with initial doses of 70 milligrams of zorevunersen on top of standard antiseizure medicines. The most substantial reductions were observed among patients who received either two or three doses of 70 milligrams. Based on these data and additional modeling analysis, we selected a two-dose loading regimen Phase III, with seizures as our primary endpoint for the trial. After receiving their last Phase I/II dose, patients were followed for at least six months before restarting treatment in the open-label extension study.

When designing our Phase III program, we used the initial eight months of data from the OLE that showed substantial and durable reductions in seizures and a favorable safety profile to inform our maintenance dose. We now have an additional year of data on these patients, which are shown here and support the long-term durable reductions in seizures. Kim will discuss these data later in the call. These new long-term data give us confidence in our loading and maintenance dosing as well as the durability of effects.

On Slide 10, you see one of the key analyses that informed our thinking on the Phase III design, which Ian referenced earlier and was presented at EPNS in Munich last month. The analysis shown on the left was performed to assess potential effects on cognition behavior using data from patients treated with dose levels that were similar to and consistent with our Phase III dose regimen.

The effects are striking, particularly in the context of the results from a matched cohort of patients followed in our natural history study. Little to no change was detected in the natural history that patients treated with zorevunersen show cognition and behavioral benefits in the five key subdomains that comprise our key secondary endpoints in EMPEROR.

On this slide, you can see the phase III design. Patients who enroll in EMPEROR will be randomized 1:1 to zorevunersen or to sham. In both study arms, patients will continue to receive standard of care antiseizure medicines. Consistent with the data I just reviewed, patients in the zorevunersen arm will receive two loading doses of 70 milligrams, followed by two maintenance doses of 45 milligrams. An open-label extension treatment period will allow all patients the opportunity to receive treatment with zorevunersen following 52 weeks of treatment in the study.

I will now review the EMPEROR study design and conduct in more detail on Slide 12. Primary endpoint is change from baseline in major motor seizure frequency at week 28. Durability of effect on seizures will be measured as a secondary endpoint at week 52. Zorevunersen is a potential first-in-class disease-modifying medicine. So EMPEROR will also measure effects on behavior and cognition.

Powering for these secondary endpoints is robust and designed with the intent to show statistical significance on both individual subdomain and composite assessments. We were pleased with the level of interaction and input from global regulatory agencies and our advisers as we work together to design the EMPEROR trial. Through these discussions, we aligned around a double-blind sham-controlled study with lumbar puncture for all patients.

As individual European countries got involved later in the process, they required a modification to the sham arm to proceed. In order to ensure our commitment to patients in Europe, we now plan to add a cohort of at least 20 patients in Europe where sham will be administered via needle press. This cohort of patients will be in addition to and complement the originally planned group of approximately 150 patients who will be randomized to receive zorevunersen or sham with lumbar puncture in the U.S., U.K. and Japan. We expect to activate at least half of the 70 study sites by year-end and European sites to initiate by early 2026.

We see significant and growing global interest in EMPEROR, which supports our expectation to complete enrollment in the second half of 2026 with a Phase III data readout in the second half of 2027. EMPEROR is off to a great start. We have had a high degree of confidence in the study design based on a large data set and the ongoing patient need. Our natural history study has proven invaluable in understanding the effects that Dravet syndrome has on patients over time as well as the limitations of the current standard of care medicine. Our experience with zorevunersen in Phase I/II and the ongoing OLEs has helped us understand the initial and ongoing effects of zorevunersen and has demonstrated an encouraging long-term safety profile.

Our assessments of behavior and cognition have been validated and our endpoints and powering are informed by our years of experience and data. As announced yesterday, the first patient was dosed in EMPEROR. Study investigators have identified approximately 130 potential participants, and that number continues to increase. More than 10 clinical sites have initiated across the U.S., U.K. and Japan with more coming online weekly. This is exactly the kind of start we were hoping for, and it positions us well for continued enrollment success.

With that, I would like to turn the call over to Kim for a review of the new three-year open-label extension date.

Thanks, Barry. Before I share the new data, I want to express my gratitude to the patients, caregivers, advocates, clinicians and stoke employees who have brought zorevunersen to where it is today.

Having treated patients with drug-resistant epilepsies for many years in my clinical practice, I can tell you that these data are profound and meaningful. The community has been waiting a long time for something that would address the syndrome, not just the seizures. We remain confident that we may very well see a significant advance in treatment for patients, which would have impacts for them and also for their families.

With that, it's my honor to share the new 36-month data. More than 90% or 75 eligible patients who completed treatment in the Phase I/II studies continued treatment with zorevunersen in the open-label extension studies. The high 77% retention to date in the OLEs has provided us with a robust data set to assess the long-term effects of zorevunersen in these patients.

Here on Slide 15, you see the three-year effect on seizures observed across patients treated with zorevunersen in our OLE studies following treatment in the Phase I/II studies. I'd like to call your attention to the top blue line, which shows patients treated with less than 70-milligram loading doses in the Phase I/II studies before continuing treatment in the OLE. As patients transition to more stable 45-milligram dosing, you begin to see on the right side of the graph, a trend toward further reductions in seizures.

Turning our attention to the orange line, you see the substantial and durable effect for the patients treated with loading doses of 70 milligrams, followed by continued dosing of 30 milligrams or 45 milligrams every four months in the OLEs. For these patients, we observed a median reduction of 59% to 91% in major motor seizure frequency across each time point through month 20. The durability of effect is consistent with what we would expect for a disease-modifying medicine and supports our EMPEROR Phase III registrational study.

But we know Dravet syndrome is more than just a seizure disorder. Dravet syndrome is a complex disease that presents daily and life-altering challenges for patients, their families and their caregivers. On the left, you see the impact on patient health and well-being. For most, seizures remain the primary comorbidity. However, Dravet impacts all aspects of life for patients and their families, some of which are shown on the right.

On Slide 17, you see a graph that illustrates expectations for the development of a neurotypical child shown with the top line and a child with Dravet syndrome shown with the bottom line. Consistent with findings from natural history data, including results from our two-year BUTTERFLY study, patients with Dravet syndrome experienced minimal improvements in cognition and behavior. Overall, patient development begins to plateau within the first several years of their life. And over time, they fall further and further behind their neurotypical peers and their ability to achieve developmental milestones. The Vineland-3 assessment is helping us measure changes in cognition and behavior in patients with Dravet syndrome.

I'll now review what the assessment is and how it works. As summarized on Slide 18, Vineland-3 is a clinically validated and widely used tool for assessing neurodevelopment over time. It is typically administered through a semi-structured interview with the patient's caregiver that is conducted by neuropsychologists or other trained raters. There are four domains evaluated with Vineland-3: communication, motor skills, socialization and daily living. These domains are broken down into a series of subdomains, which are evaluated on a point system scale. We use the Vineland-3 across multiple of our clinical studies, and it is now being used to evaluate key secondary endpoints in our Phase III EMPEROR study. Our natural history study also helped in the selection of Vineland-3 as an assessment for our clinical studies.

So now today, we are showing data on Slide 19, which are quite remarkable and striking. What you see here is the progression of Vineland-3 results for patients treated in the OLE studies with zorevunersen over one, two, and three years following treatment in the Phase I/II studies. For this analysis, patients were measured against their own baseline scores at entry into the OLE and demonstrated improvements through year 1 of the OLEs and continuing improvements in year two and year three. The improvements you see here are in addition to any improvements the patients may have experienced during the nine-month Phase I/II treatment period.

Notably, some patients received doses as low as 10 milligrams upon entering the OLEs. As a reminder, small changes on the Vineland-3 are considered meaningful to clinicians and caregivers of patients with Dravet syndrome.

To give you context, our published survey indicated raw score improvements ranging from 1 to 3 points over a year across individual subdomains would be considered clinically meaningful to at least half of caregivers. The 36-month data show profound changes, addressing the underlying protein deficiency appears to restore function and help patients achieve more of their developmental milestones. In effect, zorevunersen appears to be narrowing the gap between the normal course of disease and neurotypical development that I showed you earlier.

While these graphs get clinicians like me really excited, hearing caregivers and clinicians talk about what these data mean in real life only increases the sense of urgency we feel here at Stoke to advance zorevunersen to patients. In addition to compelling efficacy data, we are highly encouraged by the safety profile observed across our studies to date. This safety summary represents over four years of clinical data, including the first year of treatment in the Phase I/II studies, followed by over three years of treatment in the OLE.

Over this time period, zorevunersen has been generally well tolerated. 81 patients received at least one dose of zorevunersen. In the Phase I/IIa studies, 30% of patients experienced a treatment-emergent adverse event related to the study drug. The most common were CSF protein elevations, which we continue to observe in the OLEs. Approximately 86% of patients have developed elevated CSF protein levels, of which 45% have been classified as a treatment-emergent adverse event due to the laboratory values. Importantly, no clinical manifestations have been associated with CSF protein elevations. Only one patient has discontinued treatment due to elevated CSF protein levels. Treatment-emergent serious adverse events have been reported in 29% of patients in the OLEs, and none have been attributed to study drug. Across all studies, only one patient experienced SUSARs.

To date, more than 700 doses of zorevunersen have been administered across the studies. Patients have received up to 15 doses of zorevunersen with 41 patients having received 10 or more doses. This is highly encouraging as we think about the Phase III design and ongoing treatment.

I will now turn the call back over to Barry.

Thank you, Kim. Stoke has long believed in the potential of its platform. And today, I'm pleased to share that we have initiated a Phase I study of STK-002 for Autosomal Dominant Optic Atrophy, the most common inherited optic nerve disorder. From a genetic and mechanistic perspective, ADOA shares a lot of similarity with Dravet. The majority of cases of ADOA are caused by mutation in the OPA1 gene, which leads to diminished protein function or haluinsufficiency related to OPA1 protein deficiency.

In a healthy eye, the OPA1 protein plays a key role in maintaining mitochondrial structure and function. Patients with ADOA reduced levels or function of the OPA1 protein, pairs mitochondrial function and results in decreased energy production. Without sufficient OPA1 protein, the retinal ganglion cells cannot meet the metabolic demands and gradually degenerate. The result is optic nerve atrophy and progressive vision loss.

Approximately 80% of patients are symptomatic by age 10 and about half of all patients are legally blind. About 1 out of every 30,000 people around the world are estimated to have ADOA with a higher incidence of approximately 1 out of 10,000 in Denmark due to a founder effect. We estimate that approximately 13,000 patients are currently living with ADOA across seven key geographies, including the U.S., EU5 and Denmark.

As described on Slide 23, we have generated compelling preclinical findings that support advancement of STK-002 into the clinic. We have observed increased OPA1 protein levels and improved mitochondrial function in ADOA patient fibroblasts treated with STK-002. Increases in OPA1 protein have been demonstrated with STK-002 in vitro and in vivo, including dose-related increases in OPA1 protein expression in nonhuman primate retinal ganglion cells following intravitreal injection. STK-002 has been found to be well tolerated across multiple species.

In addition, today, we are sharing new efficacy and safety data from a study of STK-002 conducted in a nonhuman primate model of ADOA that has a mutation in the OPA1 gene, resulting in insufficient protein in the mitochondria. These NHPs have disease characteristics similar to humans with ADOA and therefore, represent a unique opportunity to evaluate STK-002.

The new data we are sharing today on Slide 24 show improvement in mitochondrial and retinal function three and five months after treatment with STK-002 in an NHP model of ADOA. Intravitreal injections of single doses of STK-002 were well tolerated in diseased NHPIs. These data suggest the potential for STK-002 stabilize or perhaps even improve vision by restoring functional protein levels.

Based on these data, we have initiated a Phase I study of STK-002 in ADOA patients. OSPREY is an open-label single ascending dose study designed primarily to evaluate safe, but which will include assessments of clinical activities. Study initiated in the U.K. last week, and we expect sites in Europe to initiate later this year. There are currently no treatments approved for ADOA. We believe our approach represents a unique opportunity to address the underlying cause of ADOA by restoring naturally occurring protein function.

I will now hand the call over to Tommy to discuss our financial summary.

Thank you, Barry. For those following along, I'll be speaking to Stoke's financial results as provided in the 10-Q and earnings release.

Stoke is in a strong financial position as we enter Phase III and expand our platform into new disease areas, starting with ADOA. We ended the second quarter with $355 million in cash, cash equivalents and marketable securities, which we continue to expect will fund operations beyond the Phase III readout and into launch readiness to mid-2028. Total revenue for the quarter was $13.8 million, which is driven by revenue from our Arcadia and Biogen collaborations of $10.6 million and $3.2 million, respectively. We expect revenue from Biogen to increase going forward as we continue to execute on EMPEROR and our other zorevunersen related activities.

Our net loss for the quarter was $23.5 million or $0.40 per share, slightly improved from the prior year period despite a $6.9 million year-over-year increase in operating expenses. Operating expenses during the second quarter were comprised of R&D expense of $25.9 million, which reflects continued investment in our Dravet program in key areas of our business, namely medical affairs, while also expanding our pipeline. G&A expenses of $15.3 million were largely driven by the continued expansion of our commercial team and capabilities. In summary, our strong balance sheet enabled us to invest in zorevunersen, our pipeline, including ADOA and capabilities while maintaining our cash runway to mid-2028.

I'll now turn the call back over to Ian for closing remarks.

Thanks, Tommy. Our recent progress and overwhelmingly positive response to the start of EMPEROR underscore the unique potential of zorevunersen. The era of disease modification is upon us. There is a palpable feeling within Stoke as we work together to create something truly special, a medicine that will transform the lives of patients and their families and realize the potential of our platform. We have the unique opportunity to build a company around the technology, which can create even more medicines to help even more patients. I am energized and committed to doing everything I can to support the team as they embark on this journey.

Thank you, and I will now open the call for questions.

[Operator Instructions] Your first question comes from the line of Laura Chico from Wedbush.

I wanted to start with a regulatory question for zorevunersen. Ian, first, you've got three-year OLE data now in hand along with natural history data. Second, if I'm understanding this correctly, you've got 130 patients already in prescreening for a Phase III study that's got a target enrollment of 170 patients. And then third, you've got breakthrough therapy designation.

So I guess my question is, looking at the guidance documents for accelerated approval for serious conditions, I'm wondering if you could help us understand how could you explore a faster path to market for zorevunersen?

Laura, thank you for the call. I want to, first of all, start by reminding everybody that zorevunersen has a breakthrough designated class. We applied for breakthrough designation last year in 2024, and we were granted it towards the end of 2024. We were granted breakthrough designation for Dravet syndrome. What that means is the FDA reviewed our safety and efficacy data as of last year and saw the safety efficacy data and efficacy, specifically for seizures as well as cognition and behavioral benefits. That's really important to understand. So the FDA has already seen a lot of data.

We chose to wait under the normal process of breakthrough designation to collect further data and the key piece of data being this extension of the OLE being into 36 months now with the hope that the seizures continue to be reduced and durable and durably reduced as well as the cognition and behavioral benefits continue to extend. We were very -- we were thrilled that that's how it played out.

We will take all of this data to the FDA. We have a responsibility to the FDA to discuss all of our data to discuss the disease itself and how our medicine may address this disease, and that will all be part of a discussion with the FDA in the second half of this year. We have a responsibility to see whether we can get this medicine to patients as fast as possible given the data that we've seen.

We have begun the Phase III study, not changing time lines in terms of recruitment and getting the medicine to patients through a validated Phase III study. And if things change, we'll let you know at that time. But yes, we are very excited about this data. And under the breakthrough designation, we'll have all kinds of discussions with the FDA.

And maybe one quick follow-up, if I could. In terms of what is the range of outcomes then, I guess, in terms of the second half following the meeting, would this be a potential earlier-than-expected filing? Or I guess maybe if you could walk through that, that would be helpful. And I'll hop back in queue.

Yes, it's difficult to answer that question, Laura. Somebody actually asked me a very similar question just the other day internally. And there is no answer because the answer is actually so broad because the way it works with the process is we create a briefing book, we go down to the FDA and we share all data as well as the magnitude of benefits and also safety that we're having in these patients. And you ask a number of different questions to the FDA. And sometimes you get support and sometimes you get pushback and sometimes you get amendments and changes and you continue the process forward.

So it's very difficult for me to say what is the potential outcome of those discussions. It is all really backwards and forwards with the FDA. And if anything changes from our current time lines, we'll advise you at that time.

Our next question comes from the line of Marc Goodman from Leerink.

Can you help us understand the magnitude of the cognition and behavior improvements in the Vineland-3 data in this OLE data that you're showing? Just talk about the clinically meaningfulness of the changes. I don't know, context of what these changes mean in real life for the patients, please, and the caregivers.

Thanks, Marc, for the question. I'll try to address that. So really, as regards, I think, cognitive and behavioral outcomes, I think first, it's really important to recognize that patients with Dravet, really, there's not one size fits all for all these patients. I think that they all come in a bit heterogeneous at baseline.

I think, that being said, I would say that we're all beginning to learn more about what these changes look like. And I think that's through a few things. One is we certainly have anecdotes from investigators of how these patients have changed over time. And then I think that we had one of our investigators present videos of one patient in December last year. This certainly was something I think that was really emotional for all of us. And I think a lot of that on my mind, I've certainly seen patients in clinic with Dravet syndrome. And really, this change, I think, that we saw, at least in that patient was something that is not something we would expect in a normal course of disease with Dravet.

So I know that certainly, this won't help you at the moment. But I think that over the course of our Phase III study, I think we're going to get a good handle on what these patients look like and what they do over time. And I really think that's going to be informative for the community as a whole across a lot of different DEEs and neurodevelopmental disorders.

I think if we really focus on the numbers, in particular, the numbers from the data across the three years, in particular for those five key subdomains, but certainly across even others that we didn't see early change in, these points are really 8 to 10-ish points of change. And if we think about the data that caregivers have really given us through the survey we did with them, they identified even 1 to 3 points as something clinically meaningful.

So, I think in short, I can't paint a perfect picture, I think, of what before and after looks like. But I think the magnitude of change across these Vineland subdomains will be things that families can see in the daily life of these patients across multiple developmental areas. And I think that with time, hopefully, they'll have significant impact and really the quality of life of patients and their families both.

I mean were you surprised just at the changes from 24 months to 36 months? I mean on some of these domains, it was pretty amazing.

Yes. I think we all looked at it. And I have to say, I think several people internally had almost tears come to their eyes to say, hey, we're really continuing to see improvements here. So I think it was really remarkable for all of us. And I certainly am looking forward to replicating this in a larger group of patients as we really get this Phase III done.

Marc, this is Barry. I'll just add in addition to the cognition and behavior effects that we saw over the three years, what we were seeing is that as the patients were on the maintenance dose of 45 milligrams, those patients started to move more and more towards a greater degree of seizure reduction, a trend towards reduction.

And so that tells us also that, first of all, the medicine is working according to the mechanism of action of the medicine to reduce seizures as well as the effects of the Nav1.1 deficiency, but also that as we continue patients for long enough and observe them for long enough, they're seeing a benefit as we get to the higher dose.

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

Thanks for sharing the data. So in the past, you've mentioned how you've done various analyses to help you design the Phase III EMPEROR study. So can you explain what data you've used exactly and give us a sense of how those data help inform your powering assumptions on Vineland specifically?

Barry, why don't you take the question? I mean, focus on seizures and cognition and behavior.

Yes. Thanks, Andrew, for the question. So the data that we used to determine the power calculations for the Phase III partially came from an analysis that we presented earlier this year at the European Paediatric Neurology Society, where we looked at a response in a group of patients who had a dosing regimen that was similar to and consistent with the Phase III study. And when we looked at those responses on the Vineland, we saw that when we modeled it out for one year, those patients had all had substantial improvements in the cognition and behavior based on the Vineland score. That was especially in contrast to a match group of patients in the -- from our natural history study, we showed very little change at all in that score. So that was a substantial contrast and shows the effect. And we then powered the study based on that response, and we did give a change in the point score based on what we expected to be a potential placebo response. So we reduced it by 20% and use that to power. That's where we came up with the 150 patient score.

I'll note that we also have long-term data from open-label extension studies, which gives us very much confidence on the safety long term. We have now patients who've been dosed for over four years. We've given almost 800 doses of zorevunersen in our studies. And we have patients who've gotten multiple doses over 15 -- some of them up to 15 doses of the drug. So that safety profile is also helping us with the design of the study.

And then finally, for the seizure endpoints, we also looked at the response based on the two-dose loading regimen as well as the 45-milligram dosing. And we also powered that very conservatively with a 0.01 p-value and a 90% power and a generous placebo effect as well. So we're very confident in the powering of the study.

Yes. And let's just say, come second half 2027 when the data arrives. Can you describe what constitutes stat sig in Vineland? How many of the five individual subdomains need to hit stat sig? And for each subdomain, what kind of placebo-adjusted delta do you need to see to be stat sig?

Yes. We've powered the study based on what we think is a clinically meaningful change. So that power is based on response that we had from a survey that we mentioned was a 2 to 3 point -- or sorry, 1- to 3-point change in the raw score of the Vineland. And so statistically significant would be a change in that range. But we think that based on our data that we have, we will potentially have greater changes than that. So, again, this was a conservative assessment with a powering that was used to allow for a generous potential placebo effect.

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

Tommy and team, congrats on the progress and the data for the OLE. First question is, are there any trends in terms of degree of seizure reduction and benefit measured by the neurodevelopmental scale Vineland-3. And I'm curious to know if younger patients are driving improvements on the subdomains versus older patients.

Maybe I'll take the first part of that question, Barry, Kim, and then ask you guys to kind of talk about kind of the subsets and individual -- not individual but groups of patients' reactions.

One of the striking results from the 36-month data from the OLE study was actually month 24 to month 36, where our low-dose patients, it's on the Slide #15, where the lower dose patients continued to see a reduction in seizures. And what I mean by continue to see a reduction in seizures, they continue to go lower. So they came into the study with reduced seizures, but the seizure reduction for those low-dose patients was not as significant. But as they continued through the one-year, two-year and three-year on a consistent dose of 45 milligrams every four months, we saw those seizures actually further reduce. It's on the slide, as you can see, but it was one of the more striking responses that we see that goes to the mechanism of action of this drug and restoring Nav1.1 in the brain and therefore, causing these children to respond better to our drug over a longer duration of time. That is one of the trends that we were very excited about.

As for trends with different patient demographics, Barry, Kim, do you?

Yes. So I think you had a couple of other kind of points in that question. One, I think, had to do with kind of the seizure reduction and the Vineland responses. And I think that's a really difficult kind of correlation, I think, to do, particularly with the overall kind of small sample size in total kind of for a Phase I study across different doses. If you really look at the 70-milligram patients, the vast majority of those patients had over 50% seizure reduction. So then when you try to go to some of the lower doses, there's a lot more variability in their seizure response. And so really being able to correlate seizure responses and viand are really tough right now. I think that's something we can try to do more with certainly Phase III.

I think with respect to the younger and older patients, for the Phase III, we've elected to put in patients 2 to 18 years of age because we've seen changes across the spectrum of ages in our Phase I/II study. And so I think that certainly looking across the different sub domains, some do have appear, at least by kind of a covariate to have some preference towards younger and older versus older than younger. But I think that we're confident that we can really move the bar, I think, across all of these patients from young to older.

I think that from the mechanism of action of the drug, we're upregulating the fundamental problem of this disease. And there's really no reason to think that maybe it's going to take more time. We don't know. There may be changes in the neural networks, those sorts of things, but there's really no fundamental reason why upregulating Nav1.1 even in a later age cannot produce benefits in these patients. And so that's why we're studying 2 to 18 at least right now. And certainly, the Phase III is going to give us more insights, I think, into that.

All right. Yes. I mean I definitely agree that you may see benefit across all ages, but my assumption is and many investors are assuming that the younger you go, the more sort of dramatic outcome you may have on these neurodevelopmental sort of outcomes. So curious, out of the 150 plus 20 patients that you're enrolling in the Phase III, are you sort of capping the number of older patients or enrolling a certain -- a minimum number of younger patients in the study?

So, Pete, maybe I'll take the kind of the front end of your second question, which is what we're seeing here in the data is definitely a rush to treat patients as young as possible. If you treat a two-year-old, for example, you may have the possibility of changing the course of their lives. Treating a 15-year-old that may have more advanced disease, whether you can recover them may be challenging.

I mentioned in my prepared remarks that I have a familiarity in terms of feeling for zorevunersen for my prior role in cystic fibrosis. And we always try to get the medicine to the children at the earliest a as possible because if you can correct the fundamental causal biology of Dravet, then you may put these kids on a more normal path of development and prevent their seizures. And so it is a goal of the program.

But as far as saying do patients respond differently at different ages, the fundamental mechanism of action, we should have responses. They may have different responses at different ages. But the way that clinical trial has been designed is in the type group of 2 through 18. There is a slight loading of patients 7 through 10, I believe it is, but it should be beneficial for the patients in the age group 2 through 18.

Our next question comes from the line of Rudy Li from Chardan.

Congrats on the Phase III progress. So I have a question regarding the OLE data. So can you talk about the higher incidence of CSF protein elevations in the OLE part? Any specific concern, especially for the 45% of patients classified as treatment-emergent AEs. Just curious what can be attributed to the higher levels in the OLE study?

Rudy, good to hear from you. Thanks for the question. As far as the CSF protein levels go, first of all, as a reminder, that is a laboratory finding, and it occurs as a standard measure every time a child has or one of the patients has a CSF lumbar puncture done, we do that as a routine test. Most importantly, we've looked specifically for any effects, clinical effects of the elevated CSF protein, and we have not seen any in the patients -- in the 81 patients that we've dosed so far.

The elevated CSF protein, those are a class effect. So they're known to occur in other intrathecally administered oligonucleotides, approved ones as well. And so the reason that we see it now later with additional dosing, it may be more of a procedure-related effect. And again, the point is that we now have long-term data with patients dosed for some of them for over four years. And the safety profile continues to support moving into Phase III. And again, we have, from the CSF protein perspective, not seen any reason that, that should prevent us from moving into the study.

Our next question comes from the line of [ Jeanie Kim ] for Tom from BTIG.

I wanted to ask a little bit more about the decision to explore STK-002 in Autosomal Dominant Optic Atrophy. What prompted this decision to pursue this now in this condition? And any comments on the most key data outcomes from your nonhuman primate study that contributed to the rationale would be super helpful.

Jeanie, I'll take the front end of that question, and then maybe Barry can tell you about the data we collected. But over the last six months, when asked by investors and analysts, I've talked about a process that the company went through. And that was a process where you effectively do an evaluation of the opportunity in ADOA. What that means is understanding patients that you may treat and provide benefit to. It's how you may run the clinical studies and what your preclinical safety efficacy package is. And it's a complete assessment of the disease area. And following that assessment and frankly, the data that we received relating to the nonhuman primates, that gave us the confidence and frankly, excitement to go into study ADOA with STK-002.

I will just point out that in these genetic diseases where you have a slowly progressing disease and with ADOA, you have a slowly progressing loss of eyesight, you really want to have significant efficacy to be able to run the clinical trial because you're trying to separate from natural history. And so when we saw the nonhuman primate data where we potentially improved vision, it gave us the confidence to move into clinical development, knowing that we can study these patients with STK-002.

And maybe, Barry, if you want to specifically talk to that nonhuman primate data, which really was the trigger.

Yes, Jeanie, thanks again for the question. And we are very excited about these data. We're very excited about the opportunity to treat this disease. I'll tell you both my father is an ophthalmologist, my brother is an ophthalmologist. And when I told them that we were treating patients or trying to find a treatment for patients with ADOA, he said to me, wow, that's great because I have several families I follow, and we cannot do anything for them. And since I mentioned it to him, he keeps every few weeks, he calls me and says, I found another patient. So this is a large group of patients that are undiagnosed and have no treatment options at all. It's a very exciting time for us here at the company.

And what made us even more exciting with the data from this monkey model, this monkey model was a spontaneously occurring naturally occurring monkey that had a family of monkey that had the same mutation in the OPA1 gene that we find in some patients with ADOA. And they had a very similar profile in terms of some of the testing that we did in our natural history study of patients with ADOA, we found those very similar ones in monkeys with ADOA.

So when we looked at a few specific tests, one of them being something called the flavoprotein fluorescence, which measures mitochondrial function, we found that just as we found in people with ADOA, we found in the monkeys that they had high levels of this FPF because the mitochondria were not functioning well. And when we injected 002 into the monkeys, we saw that the FPF levels either stabilized or actually improved within a short time within less than half a year. That gave us a lot of encouragement that we might be able to see this as a biomarker in a clinical trial.

And then we also looked at using something called the electroretinogram at the functioning of the nerve because this is an optic nerve disease. And when we looked at the patients we see, we know that those patients have abnormal ERGs. And now when we looked in the monkeys after they were dosed with 002, we saw that the ERG pattern improved. The nerve function was improving. So these are the best measures that we could have in an animal model since we can't actually measure vision, but it gives us a high degree of confidence that when we start treatment in people that we may be able to see actual visual improvement after treatment with 002.

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

I was curious, with 130 patients identified in prescreening and the 170 target enrollment for your Phase III trial in Dravet, can you talk about how you're going to be communicating enrollment updates? Should we expect sort of quarterly progress updates? And how do you think about the possibility of delivering Phase III data prior to the back half of '27, just given how many patients are in prescreening?

Thanks, Jess. I'll take your question. If you don't mind, I'll broaden it in terms of really, you're asking about time lines and disclosures. So we are very excited. The demand from the patients' families to push their children into the trial and the speed that they want to go through screening. And -- but the rate-limiting feature is actually opening of the clinical trial sites. And so we're going through that process, and we're making good progress. As of now, it's still early in the trial. Everything is pointing positively. But at the point that we do see a change in what we've communicated as being recruitment will complete in the second half of 2026.

When we see a change from that, we will actually communicate that at the time in an appropriate forum. That same goes for the data. Obviously, it's a one-year trial. So if we've got a one-year recruitment period, that means it's one year from ending of recruitment. So we're still maintaining the delivery of the top line data in the second half of 2027.

The other thing I want to refer to in terms of disclosure is, as you're seeing, the company is taking the opportunity, whether it's a medical conference, it's a quarterly conference call here, and we're providing data to you to understand the medicine. We think it's our responsibility to help our investors and the analyst community understand the medicine that the company has created. And so we're taking the opportunity to provide data as we move along, including the 36-month OLE data today, which is striking.

And we have medical conferences coming up. We've got a medical conference coming in Labor Day weekend, and we have one later in the year that we will be present at and we'll be providing further data. And so please expect us to continue to communicate the benefits and safety around this drug as we progress. And as far as time lines are concerned, if they do move, we will communicate at that time.

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

I got two. Maybe the first one, Barry, for the Phase III for EMPEROR, the 20 patients in Europe specifically, I imagine you can lump them right into the overall study and treat them sort of indistinctly. And do you need to enroll 1:1 in the EU just given the requirements of the way the sham injection is going to be? Is it going to be 1:1 drug versus placebo?

And then for the ADOA, so it's a single injection out to 48 weeks. So clearly, you're expecting from your nonhuman primates, very stable sort of protein expression. Do you think it's going to last longer than 48 weeks overall long term? And how many patients would you enroll in that Phase I?

So, Yaron, I'll take the first question in terms of the regulatory authorities and ask Barry to respond to you on ADOA, and it's good to hear from you again.

Maybe if I give you the kind of the broader picture, this was a study that was agreed and aligned with the major regulatory authorities globally. And what I mean by that is the U.S., Europe, Japan and U.K. And it's a long arduous process that includes getting clinical trial designs approved in individual countries as well.

Later on in the process, we actually had feedback from certain European countries that required a needle prick sham control to be part of the study as opposed to a lumbar puncture sham control. And so what we simply did is we added 20 patients in a separate cohort in those four European countries. and we just increased the number for lumbar puncture and maintained our 150 patients.

What we're doing overall is kind of maintaining the integrity of the study in the event that there is a separate analysis that is required, but we want to maintain that powering of 150 with lumbar puncture and patients being blinded through a lumbar puncture sham control. And so simply put, we added 20 patients, at least 20 patients in Europe. It doesn't change our time line, and it doesn't change our regulatory filings nor the powering of the study.

And I'll just add. So, Yaron, your question about 1:1. So yes, it is 1:1 balance, so 1:1 for sham and for active. And that applies to the number of patients in Europe as well.

Sorry, there was one other question -- you had one other question about the 002. And as you know, Yaron, these oligonucleotides have -- do have long half-lives, and we have already some data from our animal model showing that the oligonucleotide can have a half-life of nine months or longer. So a single injection could have an effect over that full 12 months of the clinical trial. And so that's why we're going to be following these patients and observing them that entire period of time.

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

This is Eddie on for Joey. Congrats on starting enrollment in EMPEROR. Just a couple from us. When do you anticipate beginning some of the North America commercial build-out? And what do you expect the sales force composition and cost to be at peak?

And then elaborating a little bit more on the ADOA I -- Phase I program. Is there any requirement for OPA1 genetic screening? And what might be the cadence of some of this data after you have a 48-week duration for the primary endpoint, but when might see some interim data or final data and then progression into Phase II?

Yes. Thanks for the question, Eddie. This is Jason. On the commercial front, right now, we're a relatively small team. We have expertise in marketing, market access and new product planning. We intend to slowly build the team over time as we start engaging in efforts like a disease awareness campaign later this year, starting to educate the market and better understand the market through insight generation.

At peak, we anticipate somewhere in the neighborhood of about 20 salespeople with additional kind of cross-functional support functions in the field to support reimbursement, patient education and site activation for the intrathecal administration on the commercial front. So a relatively modest overall field-based infrastructure for this rare disease.

I'll just add to Jason's comment in terms of being involved with medicines, disease-modifying genetic medicines like zorevunersen and other CF medicines. You don't sell a medicine. You actually help with access and reimbursement for patients and families. The medicine by the time it's approved is usually very well understood and known because as you conduct your trial, you're actually utilizing most of the treatment centers globally for your major geographies. And so the commercial build is focused on access and reimbursement and understanding the market. And it's why I made a comment in my own remarks that medical affairs is fundamentally important for the stage of the company right now where we educate both families and advocacy groups and also the physicians as terms of the medicine. And so it's more of a science education than it is a commercial cell. So, I just want to reiterate that. And that's why Jason refers to the kind of the low build.

As far as the ADOA study is concerned, it's a Phase I study, which is dose escalating and it goes through multiple doses. And so I always view those studies as no news is good news because primary endpoint is actually safety as you escalate the dose. But at the point that we may see data that causes us to act beyond just the study we're running, then we'll inform you. That could be over the next year. It could be over a longer period. It all depends on what dose we get to that we start having safety -- maintaining safety and start having efficacious outcomes. And so we'll let you know when we see that.

And I'll just add on the -- your question about the genetic testing. So OPA1 gene is included in many panels for inherited retinal disease and other vision issues. So it does not require a separate test. The issue is that many of these patients either never get tested or even if they do get tested, there's nothing available, so they get lost to follow-up. So we're hoping to do an extensive education campaign, and Jason is going to be part of that and also encourage genetic testing for children who have vision problems when they're young.

I will now turn the call back over to Ian Smith for closing remarks.

Yes. Thank you. And thank you for all that participated in the call today. Thank you for the questions, and thank you for those people that were on the line and listening. We're very happy to provide this update to you all, and we will be available in our offices post call to answer any further follow-up questions. Thank you for attending the call today.

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