Session of the Morgan Stanley Global Healthcare Conference. I'm Judah Frommer, one of the SMid Biotech analysts here. Let me just get through a quick disclosure before welcoming Stoke Management to the stage. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, we have Ian Smith, Interim CEO and Director of Stoke Therapeutics with us. We appreciate you being here. Ian, maybe we can start off with an introduction. Can you give a brief description of the company for those not completely up to speed and briefly tell us why you're excited about the opportunity ahead for Stoke?
Sure. So thank you for those people who are joining us online and those people that are here in the room with us today. I'll refer you all to our safe harbor statements that's more fully disclosed in our SEC filings. So yeah, thank you for the introduction, Judah. I'm Ian Smith. I'm the Interim CEO of Stoke Therapeutics. Stoke is a company that's focused on haploinsufficient diseases. And our primary focus at this point in time is in a disease area called Dravet syndrome. Dravet syndrome is a genetic epilepsy where there is a mutation in a gene that results in a lack of expression of NaV1.1 protein. What we do treating the disease with an ASO is we upregulate NaV1.1.
That'll go to the root cause of this somewhat horrific disease. The disease is defined as being severe seizures from early on in life, six months to 12 months, that progress throughout life and also is typified by a lack of neurodevelopment. Unfortunately, these children may develop towards 18 months, two years of age, but from that age onwards don't develop neurotypically. Because we're addressing the disease to the root cause, what we are seeing with our clinical data is that we actually significantly reduce seizures in these children, even on top of standard of care medicines, and we also are starting to see providing some more neurotypical behavior and cognition benefits to these children when they're being dosed with our drug.
We're in phase III at this point in time. We initiated that study about a month ago, and we're opening trial sites, recruiting patients. We have a large number of patients in pre-screen already. The company is in wonderfully healthy financial position to support the clinical trial all the way through to approval and beyond. I'm looking forward to answering your questions today, Judah.
Yeah. Great. Maybe we could just dig a little bit further into Dravet, kind of the underlying pathobiology, drivers of disease, and maybe just highlight for us kind of standard of care and where that leaves the unmet need for zorevunersen.
Yeah. So as I just mentioned, kind of the pathophysiology of the disease is actually a lack of expression of NaV1.1 protein. What we're doing is we're correcting a mutation in a gene that causes that gene to express NaV1.1 more normally. And so that's the root cause of the disease, and that's how we're treating this disease, our mechanism of action with our medicine and ASO. In terms of how we're progressing, the data that we've seen so far is it hasn't been seen before in this disease area.
And what I mean by that is there are standard of care medicines out there to treat seizures, but there is no medicine that treats Dravet syndrome. In fact, the company received breakthrough designation from the FDA about a year ago now. And that breakthrough designation was for the treatment of Dravet syndrome. Other medicines are labeled for the treatment of seizures in Dravet syndrome, but not the whole syndrome.
And that's important to understand the differentiation because that's the FDA recognizing the benefits that we're providing in terms of neurocognition and behavior. And so we're going down a pathway with the phase III to establish a disease-modifying medicine for the treatment of Dravet syndrome, which obviously includes seizures and neurodevelopment.
Okay. Great. And like you said, you're in phase III. But maybe we'll spend a little bit of time talking about the four years of clinical activity that came from the phase I/II OLE studies to date. What would you say are the key efficacy outcomes regarding anti-seizure activity and also effects on cognition and behavior that you'd highlight from those data sets?
So Judah, you're referring to our long-term data is a combination of the phase I/II studies that we ran, and those patients rolled over into an OLE study, open label extension study. That has now been going on for three years. And so we actually have effectively four-year data of how our medicine is treating this disease. We recently announced the year four, so to speak, or the third year in the OLE data to show how we're affecting this disease and helping these children. Number one, the reduction in seizures is approximately 85% in terms of median reduction of seizures on top of standard of care.
Those patients rolled over into the OLE study, and when you follow them out through three years, that seizure reduction is durable in terms of it stays down at the 80%, 85% level. It's really important to understand why that is such a profound long-term durable response because, again, it is on top of standard of care medicines, yet we continue that durability of seizure reduction because we're going at the root cause of the disease. It's effectively a proof point, maybe even viewed as a clinical biomarker that you are getting to the root cause of the disease. And if you are getting to the root cause of the disease, that's why you're also seeing these cognition and behavioral benefits.
The other piece of the long-term data is the cognition and behavioral benefits that we're seeing. So that's measured by an assessment called Vineland-3. Vineland-3 has multiple domains in terms of communication, daily living skills, societal activities, motor skills. It's multiple domains. And then there's questions within each one of those domains that you assess the patient's cognition and behavior. And we've now administered that assessment over, first of all, the phase I/II period that was nine months and then into the OLE study, which may have been at one year and two-year. And what we've seen there is this consistent improvement in cognition and behavior.
And if I could just describe what that means, if you heard what I said at the beginning of my discussion here, that these children, unfortunately, don't develop beyond a two-year-old kind of cognition and behavior. Yet what we're seeing is when you dose these children, they actually do improve their cognition and behavior. And some of the results that we've seen in certain domains are dramatic. We recently put out data on a dosing level that's consistent with our phase III, similar and consistent to our phase III dosing level that showed Vineland-3 scores that were in the range of eight, nine, 10, and 11.
And clinically meaningful is measured as a two. And so these scores and the durability and this consistent improvement, even when you look at quality of life, year two is better than year one, and year three is better than year two. So there is this trend of consistency of cognition and behavioral improvements in these children. So they're dramatic in terms of how this drug is putting protein back into the place where it needs to be to help these children.
Can you just remind us what dosing looks like in the OLE versus what you have in the phase III and how you were able to do kind of that subset analysis to compare to the phase III?
Yeah. So the phase I/II study, it was a dose escalation study, 30 mg, 45 mg, 70 mg. The data that we actually went forward with was the 70 milligram dose. We did see an increasing or a significant reduction in seizures continued to get larger and larger. And so we went with the 70 milligram dose. Those patients then rolled over into the OLE. The OLE is dosed at 45 mg every four months. And so when we saw that the reduction in seizures at 70 mg for two doses or three doses, we actually chose two doses because the results were, there wasn't a big difference between the two results.
But then they continued that durability of seizure reduction and improvements in cognition and behavior. That told us that the dosing schedule here in phase III should be two loading doses, two doses of 45 mg four months apart. Not dissimilar to another very, very important medicine, which is Spinraza, which is another ASO where that treatment paradigm is one of loading dose and maintenance dose, which is how we've designed our treatment.
Okay. Great. And one aspect of the story is, I guess, for the OLE patients, there were many patients that were on multiple anti-seizure meds and still experienced significant reduction in seizures. So when you talk to KOLs and caregivers, what's the perspective on the seizure reduction?
It's funny. That question has been asked in nearly every one-on-one that I've done today, and sometimes it's a little bit of a lean towards what the answer is expected, that this is more important to have the neurocognition and behavior benefits. What my answer is, is exactly what we found out when talking to families, talking to the physician. You find that seizures is just as important. I used to work at a company, Vertex, which many of you probably know, but I draw in a lot of similarities to Vertex's CF medicines where pulmonary exacerbations was a really scary acute event for these children, could result in hospitalizations.
Their lungs were basically flooding, and they needed to be pumped out. It's very similar to what a seizure is in Dravet. These children, one out of five of them will die before the age of 18 years old. It's not a well-known fact, but they die one out of five before they're 18 years old, and it's usually a complication with a seizure. And so these seizure events are horrific for families. Obviously, the child is aware they're going through them but doesn't know any different. And so you do find that this seizure reduction is fundamentally important to this kind of medicine, as well as the cognition and behavioral benefits.
And the physician will actually respond to both these benefits from the medicine is that they're astounded at the reduction in seizures because they are on top of the standard of care medicine. And our explanation to that is, well, we're expressing NaV1.1, which therefore has a very different mechanism of action than other anti-seizure medicines. That's why it's a significant improvement on top of the standard of care seizure medicines.
Maybe just delving a little deeper into the Vineland-3 scale, which, like you said, is a scale for the phase III. What can you tell us about outcomes on that scale from your BUTTERFLY natural history study that's helping you as a competitor here?
So I'll first of all talk about kind of how you calibrate the scale. I mentioned earlier that it's got different domains that you're measuring in terms of cognition and behavior, but it's got multiple questions in those domains. And if I was to just say, "Hey, Judah, you just looked up at me and nodded." Okay, that's receptive communication. If you do that every time, I ask your name and you look up and you nod, you're receiving my communication and you score what's called a two because you would score a two. That's neurotypical.
And unfortunately, these children generally score a zero. And if you did it occasionally, you'd score a one. That's how the assessment is. It is a list of questions, but that is how the assessment is done. What we're seeing is when you dose at a level consistent with our phase III over a period of 68 weeks, we're seeing scores of nine and 10 and eight and 11. We also ran a natural history study, which basically there was zero or one. That difference in clinical outcome and response from our medicine is what we're measuring in our phase III study, key secondary endpoints.
I also feel as though I want to talk about the practicalities as well of Vineland-3 in that it can sound so academic. Even when I use your name and you look at me and I give you a score of two, it still makes it sound academic. What is translating with these scores of 10 has been shown in videos by physicians at medical conferences. Specifically, there is a medical conference back in December of 2024 when one of our lead physicians showed videos of him interacting with a patient before they were on a medicine and after.
Well, not after, but after the phase I/II study as they were moving into the OLE. You see results such as, and these were presented, as I said. You see results such as a young lady. She could not write. It wasn't legible. She's on the medicine for a year or so, and she's writing nice lists, one through 10, and the words. There's a video showing actually what I just did with you where the physician is asking the child her name. She doesn't look up. He's asking her to touch his finger. She doesn't look up.
They then show a video. I don't know, 12 months or so later. And it's the same young lady. And he asks her name. She looks up. She's smiling. She's giggling. And he's putting his finger up in the end. She's touching his finger. These are the kind of results that manifest themselves into that Vineland-3 score of eight, nine, 10, 11. I just wanted to kind of give the practicalities of what that is as opposed to just saying, "Well done, Judy. You got a two."
Right. And I think you did mention a level of clinical meaningfulness between those on-drug versus matched natural history. So what are you looking for between active and sham control in the phase III?
Yeah, it's a good question. So we have a phase III study that is powered for a 0.1 p-value, 0.01 p-value, sorry, 0.01 p-value for a Vineland-3 score of two as an example. And if you were to compare that to what the results have been in dosing level, it's similar to the phase III. We're actually seeing 10s and 9s and 8s. And so it is a well-powered sham-controlled study where we expect we have high confidence of achieving endpoints. So we have the appropriate kind of definition and label of this medicine.
Okay. And you've seen Zorevunersen working kind of across a relatively broad age range, including teens. I think that's a surprise versus where the program started out and what expectations were at that point. The expectation was younger patients would likely benefit from this. So what does that suggest about the window to see a therapeutic effect on cognitive and behavioral outcomes?
I would translate that into because our medicine goes to the root cause of the disease and increases expression of NaV1.1, it should help all ages. I think the idea or the principle that it helps younger patients, I think that's just more a function of it puts the younger patient on a pathway from when they may be one or two years old on a pathway to a more neurotypical development. And they don't suffer the seizures from when they're very young.
That's the importance of treating a young child because you put them on a more normal path overall of health. The idea of treating pick an age, but the idea of treating a 15-year-old, there is still significant neuroplasticity in the brain. And so the fact that we're expressing NaV1.1, you should still have clinical benefit. And it creeps up. Whether you're an 18-year-old or a 25-year-old, you should still see benefit. The question is that there is that period of time that you didn't take drugs, so you weren't able to be put on that more neurotypical curve of upward development.
If we double-click on the phase III EMPEROR trial, you did just dose or recently dosed your first patient. Can you just walk us through trial design and the key endpoints here? I know you mentioned the Vineland-3 score, but primary versus key secondary outcomes that you're looking for.
Yeah. I'll describe the phase III overall, which is it's a 52-week study of 170 patients. It is sham-controlled, and so it's one-for-one randomization. And the primary endpoint is week 28, which is seizure reductions. Secondary endpoint is seizure reductions at week 52 to show seizures went down, stayed down, so therefore the durability. And then the Vineland-3 scores is the other key secondary endpoint. The study is being run in the U.K., sorry, the U.S., U.K., Japan, and also in four countries in Europe.
First patient was enrolled and dosed a month ago or so. And we've been opening sites in rapid succession now and bringing patients in. We have more than 150 patients that are in pre-screening. There's 170-patient study. And so we anticipate enrollment to complete of 170 patients in the second half of 2026. Because it's a 12-month study, we should read out in the second half of 2027.
Okay. Great. And you touched on the Vineland-3 powering assumptions, but I guess on seizure reduction, what are you thinking about powering for there versus sham?
The study is mainly powered on the key secondary endpoints, so we're still looking for a 0.01 p-value of seizure reductions compared to sham control.
Okay.
That's because of the dramatic drop of 85%, that should be extremely achievable.
Got it. And how do you think about the 52-week duration of the trial and its importance in managing placebo for cognitive and behavioral outcomes?
It's a blinded or sham-controlled study, but that means blinded controlled study. And because the sham control is actually a lumbar puncture, unfortunately, then the patient and the physician, frankly, doesn't know whether they're receiving active drug or not. So we thought that was really important to the integrity of the study. Some people have asked whether we should have done something less invasive for the sham control, maybe a needle prick, or there's been questions of whether we should have even considered natural history comparison. But we designed the study in a very thorough, comprehensive, and conservative way so that we achieve the label for treatment of Dravet syndrome.
Okay. Great. And I think you've said that the phase III should fairly closely replicate the phase I/II. What elements would you describe as precisely the same and other refinements you'd call out from the earlier or the later stage?
There's no real refinements other than it's two loading doses and then a maintenance dose, which is all in one study now as opposed to putting two studies together. But I think the really important point of replication of the phase I/II in the OLE is the type of patient we're recruiting for. They do have to have a mutation in a single copy of SCN1A. They have to have a certain number of seizures in an eight-week leading period to the study. And they also need to be on a stable background of standard of care medicines.
The patients we've treated are on anywhere between three and four anti-seizure medicines. And they need to be on a stable basis of those when they come and start in our study. So that is absolutely consistent with the phase I/II studies, hence why we expect replication of results into the phase III.
Okay. And how would you characterize demand for enrollment in the trial, I guess, from the investigator and patient or caregiver side of things?
In the last—which month are we in now?
September...
In the last eight and a half months, it's been logarithmic in terms of the awareness of the medicine and what the medicine may do for these kids. And therefore, the families and the advocacy groups pushing the kids towards their physician and the physician wanting to bring them into the study. And therefore, the physician working with their IRB to review protocols and open up the clinical trial site. It really has been logarithmical, the rate of awareness and acceleration of demand into these studies. And so for us, it's really rewarding that we might be giving these kids a chance, even if it's in a clinical trial, but then the opportunity to get this medicine to the kids.
Okay. Great. And I think the possibility of an accelerated pathway to approval is kind of an important aspect of the story. You have 36-month OLE data. You have the BUTTERFLY natural history data. You have breakthrough designation and FDA commentary around development for rare diseases with high levels of unmet need. I guess, how would you characterize potential to pursue that?
It's a nice summary, Judah, so what you just said there is we have a lot of data and momentum to go to the FDA and have a discussion, which is what we're going to do. I want to be very clear that maybe if I step back and give you a little bit of where the company has come from and where it is today, but the company does have, as I said earlier, Breakthrough Therapy Designation for this medicine to treat the syndrome. Once you're in that class of medicines, one of the requirements is to actually go meet with the FDA. It's an FDA requirement in a meeting which is known as a multidisciplinary meeting.
In that meeting, you get the opportunity to provide a briefing book and have an education session with the FDA, but also a question-and-answer session with the FDA. Part of the education is the pathophysiology of the disease, the mechanism of action of the drug, and how it addresses the pathobiology of the disease, and then you show safety and efficacy, and usually it's early safety and efficacy. What we have is four-year safety and efficacy, so we've got very mature late-stage type data, and so we'll educate all around our medicine and what Dravet syndrome is, and we'll help the FDA understand that one out of five children don't pass beyond 18 years of age, and we have an opportunity that if we reduce seizures specifically, there's a good chance that we help that.
What that meeting also allows us to do is to ask questions in terms of pathways to bring the medicine to the patients as fast as possible. And we will ask those questions in terms of whether there are expedited pathways while we have an ongoing phase III. So you could look at the phase III as being a confirmatory type trial. And we will ask questions whether we can get a label to treat Dravet syndrome earlier than the readout of the phase III and use the phase III as a confirmatory trial. What I'm trying to explain is this is actually the natural process when you get breakthrough designated.
What is unique about this process, we believe, is the mature data that now can be you could view it as much as four years on treatment. It is also dramatic in terms of the seizure reductions on top of standard of care, as well as seeing these cognition and behavior benefits, which haven't been seen before when treating Dravet. And so we're looking forward to having those discussions. And as things change, we'll update as we go.
Okay. Great. And speaking of label, I guess, how are you thinking about the potential for label, I guess, specifically if you're accepted on those secondary endpoints, specifically the Vineland-3 subdomains and pricing, I guess, label and pricing if everything goes as planned?
Maybe to give you kind of the spread of pricing, which is just a function of the importance of the medicine. The anti-seizure medicines can be $150,000 a year. Yet if you go all the way to genetic disease-modifying therapies, pick Spinraza as a good example. It's another ASO. It treats, as you know, SMA. But Spinraza is probably $700,000 a year in its first year of treatment. So that is a wide spectrum, which depends on the label. But the label is only a reflection on what the drug can provide benefit.
And so the importance of reducing seizures is still primarily there. But actually getting to show that you improve cognition and behavior and maybe potentially putting a child on a better neurotypical development pathway is a medicine that has much greater value to that family and that child. That's when you afford yourselves a higher price because you're providing higher value in terms of treating the disease.
And then maybe as we think about the next 12 months in terms of value-creating events or catalysts that you'd point out, what would be kind of the top ones for investors to focus on?
I think the top one, frankly, would be exactly where we're focused right now, which is discussions that we have a responsibility to see how we can bring this medicine to the patient as soon as possible. Then beyond that one, I think it's also how is our phase III recruiting because that goes to timeline again and filing. So how is that recruiting and how are we executing on that timeline with the phase III study? Other things would be more about continuous kind of cuts and looks at data from the OLE study.
I mean, it's going to be a very rich data source. 90% of the patients that were in the phase I/II rolled over into the OLE. Approximately 80% of those 90% are still in that phase at that OLE study. And so we can look at that and have cuts of different types of data that help you understand how our medicine may be benefiting these children.
Okay. Great. And then just rounding it out with cash runway and what it covers, you have a little over $350 million in cash, Biogen covering 30% of the reimbursing costs. I think you said you're funded into mid-2028. So does that funding fully support your pipeline plans? And I think you said at the top that this is a haploinsufficiency platform. So where else could we go from here?
Yeah, the company is very well capitalized, as well as we have a wonderful partner in Biogen for the ex-North American commercial rights. They support 30% of the costs of the development of zorevunersen. And so when you combine that R&D funding of zorevunersen and also the upfront money that they pay us and the money that we have in the balance sheet, we are in a very good position in terms of capitalization, which supports the company for all its growth prospects that go beyond Dravet syndrome.
We just recently announced that we're in the clinic in another haploinsufficient disease, which is called ADOA, which is autosomal dominant optic atrophy. That study should be underway shortly. We're working on other haploinsufficient neuro diseases. SYNGAP1 is another example. But the balance sheet supports all of that and protects us all the way into kind of launch-ready mode for zorevunersen and Dravet.
Okay. Great. I think we'll cap it there, and we appreciate the attendance again.
Okay. Thank you, Judah. Thank you.