All right. Well, welcome once again to the forty-sixth Annual TD Cowen Healthcare Conference. I'm Yaron Werber, from the Biotech team, it's a great pleasure to moderate the next fireside chat with Stoke Therapeutics. To my right, needs no introduction, Ian Smith, CEO. To his right, Jason Hoitt, Chief Patient Officer, who joined the company about two years ago.
Two years ago. Yep.
Excellent. Thank you. I think you did the panel with us last year too.
I did, yep.
Fantastic.
Thanks for having us back.
Ian, I think it's our first fireside chat.
Yes, it is.
in capacity at Stoke.
Yeah.
Really a lot to talk about, in terms of FDA interactions, enrollment, long-term follow-up from the phase one, two, and ultimately how that can play into label, enrollment in the phase three, data in phase three, and then labeling, pricing, and market size. We have 29 minutes.
Anything else?
Yeah. And the meaning of life. Maybe, Ian, let me turn it over to you maybe first to give us maybe a little bit overview and kind of what are you focusing on right now?
I think the easiest way for me to answer that question would be to help you understand what the questions we're receiving and the focus we're receiving from the investment community, I'd say over the last couple of months. We came through 2025 by using the data that we'd gathered from studies, specifically phase I, II studies and an open-label study that had been run for three years, and utilizing that data to help the investment community understand the profile of a medicine that could potentially change the direction of Dravet syndrome in these young children. Both, one, reduction in seizures, but two, also improvements of cognition and behavior. 2025 was a focus on helping people understand the medicine and helping people understand the disease itself.
I do think there was a learning that had to go on. As we transition into 2026, with people having a better understanding of the medicine and what the medicine can do for these kids, people are now turning their attention to potential success in the phase III study. What is the market opportunity? Drilling down on market opportunity, including not just access to patients, but how we think about pricing of the medicine, which then leads to a discussion about label, 'cause the type of label that you get drives the pricing of the medicine. We're starting to move into that period of education in the Dravet community to how our medicine may have uptake in the commercial setting.
That's been the focus, and we're having a great day. We made a long list of good investors today, and happy to be here to chat with you.
Excellent. That's great having you. Let's talk about the updated phase I, II OLE that you updated AES continue to show robust seizure reduction in patients who are heavily pretreated on as much as almost six previous seizure meds. That level of data is, you know, unprecedented and ongoing improvement in cognition and behavior. Maybe a couple of things. Number one, obviously, the phase III is gonna look at seizures at 26 weeks and at 52 weeks, and it's gonna look at cognition at 52 weeks, the EMPEROR study. Excuse me. You can use all that OLE data to help drive what's on the label on the clinical section.
Can you talk about that, especially on cognition, and behavior and why it's important, and as a part of the Breakthrough designation, how much flexibility FDA is using?
Okay. A lot in that, Yaron. I'm gonna narrow the question to how do you get to your preferred label that leads to pricing and promotion of the medicine for what is coming out of the clinical studies? Often people think about the label of a medicine being the primary endpoint and the secondary endpoint, but there is also another aspect to the label which is called Section 14, CLINICAL STUDIES. This is really important to understand that, you know, ultimately, if we want to be able to promote the medicine or price the medicine, what is gonna be most important here is the reduction in seizures, 'cause that's the primary endpoint, and that will provide approval of the medicine.
It's going to be the observed data over a longitudinal period that already is three years, but by the time we file, could be five years data, 'cause we're coming up on four-year OLE data. By the time we file, it'll probably be close to five-year data. If we can show longitudinal data of neurocognition and behavioral benefit over a five-year continuous period, that's what's going to really drive the profile of this medicine along with the seizure reductions, which allows then Jason, frankly, Jason Hoitt, who's our Chief Patient Officer, to work with the payers to be able to price the medicine for the benefit it's providing to the patient, but then also to promote it as a medicine that reduces seizures but also adds back to these patients the improvement in cognition and behavior.
This is not a medicine that stabilizes cognition behavior. Unfortunately, in Dravet syndrome, you develop more normally through an 18-month to a 24-month period, you unfortunately flatline from there. When you're 10 years old, 15 years old, 20 years old, you're still unfortunately like a two-year-old. What our medicine does is it provides more years of neurotypical development as shown by the OLE data that we've measured now over three years.
Got it. Then that data gets incorporated on top of what you see in the phase III?
That is correct. The way the label will work is that, you get your primary endpoint, and it'll, the primary endpoint will be on the label, so will the secondary endpoints. There's, as I said, Section 14 observed data. The principle of that section is clinical data that you've gathered from clinical studies, that helps a caregiver understand the medicine and the benefit it provides to a patient can be provided in that section of the label. There are many precedents for it, especially with disease-modifying therapies. You know, the best example, and probably the closest example for us would be that of SPINRAZA.
Can you maybe just remind us the Vineland is obviously an important tool and what did it show using the phase III dose scheme? What did it show on the phase I, II?
Yeah. We actually did show an analysis at AES in December 2025, where we did a propensity score matching of natural history study compared to patients that were on a dosing schema that was consistent to that in the phase III. When we ran that study, we showed statistical improvement on Vineland in a number of different measures, at month, let's see, which it was month 18 and month 24. We had to use month 18 because it had to be the accumulation of dosing that was consistent to what we're dosing in phase III. We showed that there was statistical significance. The importance of hat was that that was with an N of seven.
Mm.
When you propensity match, you've got to find the patients in the drug arm that are consistent with those that are in the natural history study. There was 20 or so patients in the natural history study, but we could only match patient criteria to approximately seven patients from the drug arm. When we ran the analysis, compared the Vineland with the various different domains, the five different domains, we show statistical improvement of certain domains.
Okay. Let's talk maybe about EMPEROR. EMPEROR is enrolling really well. It's about 160 patients US and Europe, another 20 in Japan. It sounds like between the current enrollment plus the patients already in screening, you're gonna get there pretty quickly, we're expecting you'll finish enrollment sometimes this quarter, then you'll sort of enroll the last 20 or so, right, in Japan. 52 weeks, we're looking at data mid-next year, so to speak.
Your last point is correct. We'd anticipate because of completion of enrollment data in the middle of mid-2027. Just to kind of parse out the study, we have two parts to this EMPEROR phase III study. First cohort of patients are lumbar puncture sham control patients, that's about 150-160 patients. That the completion of that cohort of patients of the 150-160 lumbar puncture sham control patients should be in Q2.
Mm-hmm
... of this year. There is a further 20-30 patients that are in the EU IV, so the main EU countries, Those would probably read out, you know, a few months later or complete enrollment a few months later, still to be decided on that timeline. Those patients would be added to the lumbar puncture patients for a total of 170-180 patients. That would then be the filing in Europe.
Got it. Those patients are, they get a placebo.
They get a needle prick.
A needle prick.
It's a needle prick sham. By this time, roughly this time last year, maybe in the spring of last year, as we were proceeding ahead with the phase III, couple of the European, ethics committees pushed back on a lumbar puncture for sham control. They asked us to do a needle prick. We wanted to maintain the integrity of the core part of the study, so we increased the size of the lumbar puncture sham control study to 150-160. We added this cohort of patients to get needle prick.
Got it.
It's gonna be really useful though for reimbursement as well in Europe. It's not just.
Mm
running the phase III study. Reimbursement, will depend on that as well.
These are all control patients then?
No. No.
They're one to one also.
Yeah, to one as well, randomized-
Then there's another 20 in Japan.
nope. That's part of the.
That's a part of.
... 150.
Yep. That's a part of the 150.
Yeah.
Okay. Is the 20 capped? It's still going to be 20 in Japan, or it's a part of the overall study?
There are certain regulations about how many patients you need in each country to gain reimbursement. You know, roughly, it's gonna be around 15 or so patients in Japan. Europe, it's 20-30. The U.S. is the majority of the study.
Okay. Got it. It looks like Biogen will file after you, after you file in the U.S.
Yeah.
Maybe just remind us the powering for the primary endpoint on seizures at 26 weeks?
Well, it's easier for me to answer the question as being what is the powering of the study. The powering of the study is a 90% confidence level for a p-value of 0.01 for our secondary endpoints. That helps you understand that the powering for the primary is robust. For the secondaries, it's still, it's robust because we've got a 90% confidence level, but p-value of 0.01. It's actually measured to the receptive and communication endpoints of Vineland.
Okay. That was actually... I mean, to level set for the audience, you're starting with an 80% seizure reduction roughly in the phase I, II on the primary. Even if there's gonna be some decrement for phase III, the control historically does, I mean, this is fourth, fifth line, 20%?
Yep. That's a good number.
you know. Even if you're going down to 50, which will be a huge decrement, probably unlikely to go down, you're
Yeah
fairly highly powered.
That's correct. We also When powering the study and doing our statistics to power the study, we also assumed a 20% response rate, both in seizure reduction and also in the Vineland. We anticipated there could be a placebo benefit, so to speak, in primary and secondaries.
Okay, great. What we're getting to is the important question, which is on the secondary endpoints, I think you're measuring even five different subdomains.
Mm-hmm.
You mentioned, receptive communication and cognition. Are those all hierarchically delineated in the secondaries? You have to go through each one sequentially? Do you do them in parallel? Do you do two of them in parallel and the rest sequentially? How does that work?
The primary, secondary endpoint is still seizures, just to be clear. The primary is week 28 seizure reduction. The first secondary endpoint is week 52 continuous seizure reduction. In the U.S., there is a hierarchical assessment of each domain of Vineland. You proceed through those as whether you hit statistical significance or not. In Europe, it's a little different. The Vineland is a composite score, which means you add them together and do an average.
Mm-hmm. Of all five domains at that point?
Correct, yes.
You do an average. Okay.
Yeah.
Any two domains can drive that average too, and that's okay?
Yes. Yeah.
Yep. In your case, receptive communication is the secondary and then cognition. That's the order. Then you have the other three.
It's receptive, expressive communication. Receptive is the first one. Second one is expressive-
Expressive
... communication.
Cognition. Yeah.
Just to give people an example of what this is like 'cause it's, you know, it's technical language. It's Vineland-3, and it's expressive and receptive communication. I just wanna help people understand what it means. If I look at Michael Partridge out there in the audience and say, "Hey, Michael, can you hold your hand up? Can you see my hand?" You nod. I'll do it again. "Michael, can you see my hand? Can you hold your hand up? Can you nod?" Michael did it each time I asked him, and that would score you a two. A Dravet child, unfortunately, wouldn't respond, and that's shown by our natural history study. When you do it each time asked, and this is literally a test within the Vineland, then you score a two.
two is described as being clinically meaningful by caregivers. There are a list of questions. You can actually, Within a domain, you could score 15. What we've been seeing after 12 months of therapy on a dose level that's similar to our own in phase III is scores of nine, 10 and 11. It helps you understand what, you know, clinically meaningful is two, but we're actually achieving nine, 10s and 11s in a dosing schema that's consistent with our phase III. Going back to the powering, as you asked before, Yaron, we're powered for 0.001. 0.01, sorry.
Yeah.
Yeah.
Any questions from the audience? You know, we cover a lot of the other companies in Angelman. We spend a lot of times on these endpoints.
Yeah.
Um-
We're, we're doing, I mean, people should spend a lot of time on these endpoints. They define the medicine for it to be in a differentiator from being an anti-seizure medicine, and it is more than that. We've been spending a lot of time with the FDA explaining that as well. Recently we were there for a multidisciplinary meeting. When you get Breakthrough designation, you have the opportunity to go meet with the FDA to, you know, go through a list of topics that the FDA needs to understand. One of those is the pathophysiology of the disease. Dravet is created by a lack of expression of NaV1.1. We can then show them how our medicine mechanistically improves the expression of NaV1.1 by targeting a certain gene.
Why is that so important? If you think about what the FDA has written recently talked about plausible mechanistic pathways, if they understand the pathophysiology of the disease, how our drug actually works by expressing NaV1.1, they understand that you get to the root cause of the disease. If you're getting to the root cause of the disease, not only are you reducing seizures, but you have the opportunity to actually give these children a chance to develop more normally. That's what our medicine is, that's the importance of this frequent interaction with the FDA.
Yeah. Mark?
Yeah. Is the Vineland adjudicated or scored centrally? Just to kind of... I know there's probably not gonna be able to see a response, but just for that robustness.
Yes. I mean, you actually answered your own question perfectly. We have central raters. They're neuropsychologists, and they do the assessment of the child. Yeah.
They go into the sites to do that?
Yes.
Yeah.
Yeah. It allows for consistency, a measure. They see the same patient. They go to the sites. There's four of them. Yeah.
Can we talk about, maybe, Jason, even, to you a little bit.
Yeah.
Help us understand the market a little bit, market dynamic. One of the things we hear sometimes is if you look at, you know, some of the other drugs out there, they haven't done as well in Dravet, the anti-seizure meds.
Mm-hmm.
Talking about whether it's GW or Zogenix.
Yeah.
Zogenix particularly. Some people feel that as a result, the market's not a big market.
Yeah.
Secondly, perhaps, what's the latest on pricing for disease-modifying ASOs?
Yeah, it's a great question. When you look at the market as it exists today, from an epi perspective, you got about 35,000-40,000 patients in the core, excuse me, seven geographies where we're running the EMPEROR study, the U.S., Japan, U.K., and the EU 4. The U.S. is about 16,000, somewhere between 15,000 and 20,000 in the U.S. It's about the same in the EU 4. Now, if you further break that down, there are about 6,000 patients that are immediately addressable upon launch. You can look at that from two different perspectives. If you look at it from the epi perspective, there are about 4,000 patients that are 18 and younger, pure pediatric patients.
There's a dynamic in Dravet syndrome where these patients are diagnosed by a pediatric epileptologist. They're cared for by a pediatric epileptologist their entire life up until the point where they become an adult. Naturally, there's a bond that's developed there, and there's a reluctance to transition to adult care. Oftentimes we hear from pediatric epileptologists that they're caring for patients into their mid-twenties. If you look at patients that are 25 and younger in the US, it's about 6,000. You could also come at this from a different perspective, from a claims analysis perspective, and look at patients that are confirmed with an ICD-10 code for Dravet.
Mm-hmm.
An ICD-10 code that's only existed since 2020. In the most robust claims and claims, capture database, there are 6,000 patients that have been identified. Of the 16,000, there are 6,000 identified. We know that the genetic testing, the genetic testing has improved, access to genetic testing has improved, and the utilization of genetic testing in the pediatric setting is very robust right now. I think there are opportunities for improvement in identification of adult patients, and in large part, that's because they were unfortunately born before the ICD-10 code existed, before genetic testing was more widespread or as widespread as it is today, and/or in some cases, they were born before the gene was identified.
In a lot of cases, they may be in the care of a neurologist, an adult neurologist, but they're likely coded as intractable epilepsy.
Mm-hmm
... putting some effort forward now to enhance genetic testing, enhance awareness of genetic testing.
It's also there was no real medicine to give them. you're gonna give them-
Yeah
... the same bunch of drugs anyway.
Exactly.
What's the point?
Right.
I like to think about it very simply. Jason mentioned all the numbers, but, upon approval, or I should say upon potential approval, there are 6,000 readily addressable, identifiable patients to be treated for Dravet syndrome. That's where you start. The other patients, you've got to screen, you've got to identify. They tend to be older and, but they will come into the system once you start screening.
In terms of the age for your label, what are you anticipating?
The label should be two and older. We have Breakthrough designation to treat Dravet syndrome for children two and older. We've already got a designation for Breakthrough designation to treat Dravet syndrome for two and older, so that it should follow that.
Where do you think this is gonna fit in? Is this gonna be the first medicine the patients or the caregivers reach for, or is this gonna be an add-on?
I think there are a couple of elements here, right? There's just the mechanistic elements of diagnosing and treating Dravet, and then there's the healthcare provider and KOL enthusiasm for a disease-modifying treatment. I'll start with the latter first. If you look at the consensus paper that was published in 2022 for the diagnosis and treatment of Dravet, the KOL experts that were involved in that paper, even in advance of the initial phase I, II data for ZOREVUNERSEN being available, suggested that if a disease modifier was approved and proven safe and efficacious, they would wanna move it as early as possible in the treatment armamentarium for Dravet, which naturally makes sense.
When you think about how a patient with Dravet syndrome presents today, most often they're showing up to a hospital in an ambulance because they're having that first seizure. It's usually a febrile seizure. Naturally, the emergency room docs and the neurology consult, if a neurology consult is called in, wanna control the seizure first. Even if you have a really astute provider, right? There are some institutions in the U.S. that have febrile seizure clinics that immediately upon that first febrile seizure are ordering a genetic test to see if there's an underlying genetic cause for the seizure that they're seeing. They're not gonna wait for the result of that genetic test to treat the seizure that's happening in front of them. They're gonna use rescue meds, and then they're gonna prescribe an anti-seizure medication.
Naturally, all patients that are starting on ZOREVUNERSEN will start with a foundation of anti-seizure drugs consistent with how we're studying it in the phase three.
Right. At that point, it's just a question, are they gonna start on one or two? When they're refractory, Does a quick add-on?
Yep.
Do they really move it on quickly? Whether they're seen in an academic center, in a children's hospital.
Correct
... or misdiagnosed or add on later on. The broad list of the label and then access is critical. How do you think about access and price?
Yeah. I think, you know, obviously our access strategy is to ensure that this medicine is available to all patients that can potentially benefit from it. The way we're designing our patient services offering and our market access approach will be based on that. Obviously, from a pricing perspective, we want this to reflect the value that ZOREVUNERSEN is bringing to this market. You know, I'm glad you asked the question because I think over the past couple of years, there have been some misconceptions around how we may be able to price a drug like ZOREVUNERSEN . I think historically it's been more anchored to even the best anti-seizure meds. I don't think that in any way is doing justice to the profile of this medicine that we hope to bring to market.
I think it's more appropriate to think of it in the context of other genetically targeted disease-modifying treatments that...
Mm-hmm
... that have already been approved. Medicines like SPINRAZA from our partner in Biogen, another intrathecally administered ASO. Something like the exon skippers from Sarepta, the CF medicines from Vertex, I think are far more appropriate analogs than the anti-seizure meds.
The two most recent ASOs are, you know, SPINRAZA. Well, there's pimavanserin, but that doesn't really count 'cause that's gonna go into a broad market. That was $595-
Yeah
... for HAE.
Yeah
... it's ranging between $680 and $800.
Yep
... depending on the dose.
I think the other ones that we talked about are in that same ballpark.
Yes. Yep. SPINRAZA, I think is one of the originals-
It is.
of the deal.
Yeah.
It's about half of that.
SPINRAZA currently is about $600 for every two.
Oh, with the price increases?
Yeah.
Oh, okay.
Yeah. You know, we'll see what the pricing is of SPINRAZA high dose, which should be coming through shortly. They're good analogs for how we think about our medicine. I'll just bring it all the way back to Jason Hoitt's talking about the profile of the pricing of a medicine and range of the pricing of the medicine, but that's only based off the label that we anticipate getting. Again, I'll bring us back to it's really important to ensure that we have the observed data from, the observed longitudinal data over that three, four, five-year period showing this cognition and behavioral improvements.
Maybe another question from the audience. In terms of manufacturing, maybe help us understand what it is that you're responsible for versus what's Biogen doing?
Yeah. Per the terms of the contract, we each have responsibility for manufacturing for our own territories. On our side, we're progressing well with our CMC activities. We've completed our drug substance PPQ runs, our drug product PPQ runs are upcoming in the next few months. We should have everything we need to write module three of the NDA this year.
You're using a C.A., a contract manufacturer?
We are. Yep.
Biogen will start with your capacity and then transition to their manufacturing facility?
Biogen's looking to ramp up their manufacturing for ZOREVUNERSEN as we speak.
Does it make sense for you to source it for them or for them to at least be a backup?
We're actively talking to them about ways that we can work together on the manufacturing side. I think we're evaluating second source manufacturing for drug substance and drug product. Naturally, Biogen's our partner rest of world. They have significant experience and expertise in manufacturing ASOs. We're looking at the whole landscape before we make a decision.
'Cause in many ways you can argue putting it into their facility with a fixed cost already accounted for and the volume, the extra cost could be fairly attractive in many ways.
It could be.
Okay. Let's maybe move to Autosomal Dominant Optic Atrophy and which is now in phase I, STK-002. This is the phase 1 OSPREY study. It's a dose escalation study that is ongoing. Maybe help us a little bit of understand the natural history of these patients and what we can expect. This is only a single dose, and that maybe what the durability could be based on preclinical data.
Yeah. ADOA is a genetic disease that leads to the progression or loss of eyesight over time, and many patients see presentation in the first decade of life. Over, you know, half of patients ultimately progress to the point of legal blindness, and there are no interventions currently today for ADOA. There are about 13,000 patients in the U.S. and Europe. It's about one in 30,000-35,000 in most of the world with founder effect in Denmark, where the incidence is about one in 12,000. It's a dose escalating study that we dosed the first patient in last month, and we're eagerly looking to see what those results look like.
It's a very similar approach in terms of ADOA is a haploinsufficient disease where one of the genes does work, the other doesn't. We cause an overexpression of the OPA1 and that, you know, based on our preclinical non-human primate models, and measuring flavin-based fluorescent protein, that we actually see an improvement in eyesight. We go into the clinic hoping that we'll get to levels of being able to improve eyesight in these patients that were once having a deterioration of eyesight. We're in the phase 1 dose escalating study. 4 doses anticipated. We've already dosed patients in the low dose group, and we'll continue through this year and probably into early 2027.
The anticipation is we may start to see efficacy later this year and early 2027 when we get to those two high dose groups that the 0.5 milligrams and 0.7 milligrams.
it's a 0.0... That's a fixed dose?
Correct.
Yeah.
It's a single dose.
Mm-hmm.
The efficacy is measured by the usual, Best-Corrected Visual Acuity, you know, how many numbers do you improve.
How many patients per arm?
it's three to five.
Yeah.
3x to 5x 4x. We're talking about 12 to 20 patients.
Yep.
All right. Well, I think we're a little bit over. Team, thanks so much for joining. We appreciate it.