Conference Transcript - STOK 2026-08-12

Samanth Kulkarni, Analyst — CounterContinuity

Good morning, everyone. I'm Samanth Kulkarni, a Senior Biotechnology Analyst at CounterContinuity, and I'm really pleased to have Stoke Therapeutics with us here today. Thankfully, you didn't have to travel too far, but I'm still thankful that you made it to the event. We're really happy to have you, and thanks to everyone for attending and for tuning into the webcast. Stoke is, again, at a very interesting time in its evolution. They have a Phase 3 study for a product called Zarevonersen for Dravet syndrome. this is going to be one of the few products that potentially treats the entire syndrome and not just symptoms with that i'll turn it over to ian smith the ceo we also have chief patient officer jason height that's a really important role because this is a different kind of paradigm for the for the treatment of travey and in the audience we have don kalmar who is the chief of corporate affairs as well so with that ian please uh we can actually launch into a direct q a if that's the way to do it and thank you we also have a mic going around so please feel free to raise your hands. Don't be shy. We'll get to your questions if any in the audience have that. So I'll start first. You know, Zareva Nersin, as I mentioned, very different. It's probably going to change the treatment paradigm if and when it's approved, hopefully when. So you have an Emperor phase three trial now.

Speaker 3

What can you say about how the trial is going that gives you confidence in achieving what you would need to achieve to get the product approved? thanks for the question and good morning everybody I do have to provide my safe harbor statement so you'd see our SEC filings for all the forward-looking statements are covered in the in our SEC filings just last week we had the opportunity to have our second quarter call and we did provide an update at that point on the phase three study and just to kind of broadly It's a phase three study, sham-controlled, 162 patients study with a primary endpoint at week 28 and a secondary endpoint at week 52. As far as the progress of the study, we couldn't be happier. First of all, 162 patients enrolled. We did target 150. We ended at 162. Of those 162, 145 are already through week eight. Why is that an important time point? Because at week eight, you've taken two doses of 70 milligrams, and it also means that all you have to take now is two doses of 45 milligrams over that 52-week period. Also, in terms of the progress of the study, we have approximately 80 patients that are through week 24. Week 24 is important because you've now received three of the four doses you'll receive over the 52-week period. And then lastly, as a mark of the progress of the study, we have 60 patients that are already through the primary endpoint at week 28. So 60 of the 162 patients are through the primary endpoint. And progress so far, which I think is also reflective of a well-tolerated drug, is we have zero dropouts. So zero dropouts at this point. And so the drug clearly is well tolerated, which is also supported by the totality of the data that we have gained from an OLE study that is now extended dosing through a four-year period, a five-year period in total if you include the phase one, twos. And so all is proceeding very well with our phase three study. And we look forward to give you another update probably towards the end of the third quarter.

Samanth Kulkarni, Analyst — CounterContinuity

Yes, Emperor March is on. So, in terms of discontinuations, you said zero patients. That is a remarkable statistic. Could you explain why that might be?

Speaker 3

Well, it is a remarkable statistic in terms of a phase three. Just again to reiterate, it's a phase three and we have a lumbar puncture sham control. um and so you know you we we did plan for uh discontinuations uh as you might expect with a sham control lumbar puncture um and we planned for a 15 discontinuation rate and uh so and that was in the powering of the study of 150 patients 15 discontinuation so approximately 125 to 130 of valuable patients to hit our primary and secondary endpoints. Why is it that we have no dropouts? Well, first of all, I think it's a well-run study. Our team, our field team, our medical directors are working well with the sites, and the sites are well-educated to what our drug can potentially do for these patients based on the data we've provided at medical conferences. One is a statement of fact. The drug must be well-tolerated to date. Otherwise, we would have seen dropouts related to the drug, but we have no dropouts, so that must be a kind of a mark to the well-tolerated profile of the drug. And then secondarily, at this point, no dropouts from the study could also point to, we have an OLE that these, or a second treatment period that all these patients can roll into. And so if you're in the sham control and you're not sure whether you're on drug or on sham, because of the education we've provided around this drug, you're probably hoping that you can move into that post-week 52 treatment period where you're guaranteed drug. The second part to what I'm saying is obviously a little bit of speculation because we're blinded to all the data. But the trial's going very well, and the education around this drug, because of the five-year data set that we have in terms of safety and efficacy, I think it's also educating the physician who is managing the patient as well.

Samanth Kulkarni, Analyst — CounterContinuity

So as I mentioned in the PM, zirubinocin is a product that could treat the syndrome, not just symptoms. And most of the standards of care today is based off of reduction of seizure frequency, which is a symptom. So what are the features in the Emperor Phase 3 trial that lend itself to tease out these differences well on targeting syndrome versus symptoms?

Speaker 3

Yeah, so first of all, I'll start with we have breakthrough designation to treat Dravet syndrome, not to treat seizures, to treat Dravet syndrome. That breakthrough designation was provided on the submission of data for both seizure reductions and our Vineland scores after two years of patients being on drug. And so we submitted the OLE data and the phase one data where we showed seizure reductions but also showed cognition and behavioral gains, and we submitted that to the FDA to request breakthrough designation. They gave us the breakthrough designation because they recognized in the behavioral and cognition gains that the patients were receiving within that phase 1, 2, and the OLE data set. We then designed a phase 3 trial that, one, as a primary endpoint, does measure seizure reductions at week 28, as I mentioned, but also at week 52, we're measuring the cognition and behavioral gains through an assessment called Vineland 3. And it's got multiple domains, such as receptive communication, expressive communication, motor skills, interpersonal skills, social skills, things like that. And it's a questionnaire within each one of these domains that a neuropsych provides to the caregiver. And the caregiver can see whether the child responds to the caregiver's voice, to their name, whether the child was nonverbal and is now using words. And that's what's within the Vineland domains, whether it's receptive for expressive communication and motor skills. And so we've designed the secondary endpoints to measure those behavioral and cognition gains. And that's consistent with what we've seen in our four-year OLE data. So the patients have been on medicine now for five years, but we've measured after the first nine months, they've had the opportunity to roll into the OLE data. And we've measured each year within that four-year period of the the gains in cognition and behavior in those domains I just mentioned, and that data we've provided to the investment community, but we've also had it presented at medical conferences. It's also in a New England Journal of Medicine, and we've also provided videos as well, and so it's all validated. It's credible, and what we're seeing is there's children that are going from non-verbal to verbal to non-ambulatory to more ambulatory, and that data is there If you look up Vineland 3 in terms of the domains and the types of questions that are asked, you'll see that it says, does the child recognize the child's own name? And they'll get a zero if they don't look when asked their name, and if they do it occasionally, they'll get a score of one. And if they do it all the time, they'll score a two. And we're getting scores now when children have been on the medicine for a four-year period that are in the teens, as in 15, 16, and 14. And so the longitudinal data after being on this medicine chronically is truly giving gain of function, gain of task. And it's quite unique given the disease. these children grow normally, somewhat normally, other than the seizures to about the age of 24 months, but then effectively plateau. And so if you can provide a medicine that gives a gain of function on a chronic basis, you know, year one on the medicine, year two on the medicine, year three on the medicine, it's quite remarkable. And we've measured that, and it's all in the four-year data that we've provided, as I said.

Samanth Kulkarni, Analyst — CounterContinuity

So clearly Zerimnarsin has components of its efficacy profile that are super important, if not, you know, way more important than reduction in seizure frequency, but some on the investing side still ask us the question, what would be a meaningful reduction in seizure frequency to be considered a success when you report Emperor Phase 3 data, knowing that this is going to be over on top of the standard of Yeah, I mean, Jason's Chief Patient Officer, I'll just help you understand, because I'll have Jason comment on a couple of things.

Speaker 3

I'll comment first, but Jason's Chief Patient Officer, what that means is that Jason's our Chief Commercial Officer. He's also Head of Medical Affairs and Manufacturing. And Jason can comment in terms of what we're hearing from both prescribers, physicians, and caregivers, and that broader community. But I would start with, first of all, the powering of our study takes into account of what is meaningful. And so we have powered the study for something that's of 40, 45% or so delta in terms of treatment. And what we saw in our phase one, twos, and what we've continued to see over a four-year period in our OLEs is we've seen 70% to 80% reduction in seizures. These patients are already on standard of care anti-seizure medicines. And the way that they're recruited to the trial is there is an eight-week screen period, so we can get confidence that they're on a stable background of anti-seizure medicines. And these children are on three to five anti-seizure medicines already and a stable background, polypharmacy. And then we dose our medicine on top, and we're still seeing a 70% to 80% reduction in seizures in the higher dose group that we're studying in the phase three. And so I start there. But the study itself is powered to something like 40%, 45% treatment benefit. But overall, the study is actually powered off the secondary endpoints, which gives even more power to the primary endpoint. But in terms of what's meaningful, I think, you know, I would say, you know, even if it's 45, it's on top of standard of care medicines. Jason can comment on what we still hear from families in terms of the seizures and the impact on their life and the children, and also the link to SUDEP, which is sudden death because of a seizure.

Speaker 2

Yeah, it's interesting. I think it's a really pertinent question because when you ask either caregivers or epileptologists, pediatric neurologists that are caring for these patients what the primary unmet need in Dravet syndrome is today, almost exclusively, we hear persistent seizure burden. The fact that so few patients ever achieve seizure freedom. And, you know, not far after that, you hear either quality of life or the neurocognitive impacts that, you know, we're seeing impact from addressing the underlying genetic cause of the disease. So I completely agree with Ian, right? We need, you know, the seizure piece is both critically important to caregivers and doctors, but it's also one of the primary value drivers for payers. So I think if we hit, to Ian's point, that threshold of how we powered the study, I think we're going to be in really good shape from a seizure reduction perspective.

Samanth Kulkarni, Analyst — CounterContinuity

So that was reduction in seizure frequency. Now on your secondary endpoints, you mentioned the studies powered based off of those, and those could have really important implications for what this product could mean in the real world. How are you thinking either qualitatively or quantitatively on what you need to hit on the Vineland scales Yeah, it's a good question, Saman.

Speaker 3

The study is powered off the secondary endpoints to show those behavioral and cognition gains. It's actually, to be kind of, let's say, precise about how the study was powered, it's off the receptive communication secondary endpoint. And what we did there is we wanted to understand what is clinically meaningful. And clinically meaningful is a two to a three-point score. As I mentioned, if you ask a question and they do it often, then that's a two-point score. And so it's powered off that receptive communication to at least achieve a two- to three-point treatment benefit. And just to help you understand, the natural history is that they don't gain function. And so natural history is close to a zero. But we did do a natural history study, and we took the data from that natural history study, added on two to three points, and then calculated the pairing of the study based on how many patients we needed to recruit, which was 150, but we also assumed a discontinuation of 15%. So it was based off 125 to 130 valuable patients. Where we currently stand is we recruited 162. At this point in time, we have zero dropouts. So obviously, that benefits the powering. I can't give you the precise numbers of back calculating, but the study is well-powered to hit those secondary endpoints. And then the other secondary endpoints follow after the receptive communication endpoint.

Samanth Kulkarni, Analyst — CounterContinuity

So with a product like this and the goals that you have in terms of syndrome versus symptoms, you have the luxury of having really long periods where you can follow patients over time. So in that context, how do you expect the phase one slash two five-year data to impact your label and what that might mean from a real world or even commercial perspective?

Speaker 3

It's such a great question, Sumat. And I want to first of all kind of really try and help understand the uniqueness of this position. Dravet is a disease where a child will live you know potentially you know 30 40 50 years old one out of five of them do actually pass away before the age of 18 usually linked to seizures but I'm still trying to figure out is there another disease where you have that longevity of life, potentially, yet you have seizures, these dramatic seizures, and you stop developing cognitive-wise and behavioral-wise at the age of two. Yet we've now got a medicine that can add function, reduce seizures, and add function for each year that you're on the medicine. So you start to acquire skills and cognitive skills and behaviors that you would never get as a Dravet child if you stay on the medicine. That's what the four-year data or the five-year data says. It's not just one year and it's a one-time benefit, it's actually you get a benefit in the second year and you get a benefit in third year and a benefit in the fourth year. And that's what the data shows, that there's a compounding effect. And so it's unique in that it's a genetic disease and when you treat genetic diseases, typically you stabilize the disease or you slow the decline of the disease. Yet what we're doing is is we're suppressing seizures, but we're also giving back function to these children that do actually live, you know, a longer life. And so, you know, that's what we see in the data. And that's the OLE data, which we believe is so important when you understand that this is a chronic disease in children that stays with them for the rest of their life. And so that chronic data in terms of chronic dosing is fundamental to understanding what benefits of the medicine, not just a one-year study. And usually, if you don't mind, we get asked a lot, as in, what are you going to do with the FDA with the OLE data? And each time we've got year two, we've filed for breakthrough designation for syndrome. Year three, we spoke to the FDA last year to potentially even file an NDA on the basis of the phase one, two, and the OLE data. And then later this year, it's part of our pre-NDA meeting that we have with the FDA, because again, we're going to go to the FDA and show them the benefits of this medicine when it's dosed chronically, because the FDA guidance is they want to put all your clinical study and the totality of that data within the label to educate what your medicine may do for a patient.

Samanth Kulkarni, Analyst — CounterContinuity

It's in their guidance and so that's why we're doing it as part of the pre-NDA and that's I mean it's for the benefit of the patient this medicine is is unique when it's dosed you know chronically in a disease that plateaus at 24 years of 24 months of age so yeah understood so that means you know you have your data coming in 3q27 but you expect to start a rolling drug new drug application or NDA in 1q27 I guess the gating factors then remain like what data you can generate on the open-label side in terms of time, which you can augment that initial part of the package Is that the way to think about it?

Speaker 3

The way to think about it, so first of all, Smead, you are correct, as you usually are. And Q1 is when we anticipate initiating our rolling submission. We have to validate that with the FDA in this upcoming pre-NDA meeting that we have. But we anticipate starting the rolling submission in Q1 and completing the rolling submission in Q3. And the sequence of submission would be CMC first, which it usually is. And Jason's responsible for that. And he can tell you that we're in very good shape there. And then we follow with preclinical module and then the clinical data in Q3 after we complete the study. And so that's the plan in terms of the rolling submission. And then hopefully complete the submission, obviously in the second half of the year I just point out the reason we want to do a rolling submission is if you look at breakthrough medicines that have rolling submission you tend not have to wait the full PDUFA period most of the breakthrough medicines it's it's within six months of of your last filing or your submission and summers you know can be as short as two months like Spinraza for example I think was precisely 59 days after they completed their submission and we think our medicine is that important so I'm actually a chemical engineer by training and you said CMC so that might lead me down a different rabbit hole but I'm not going to go there for a product

Samanth Kulkarni, Analyst — CounterContinuity

like this it's it's really important in the larger scheme of things in Dravet syndrome given all the things you've mentioned all the things you're doing as part of the emperor trial to tease out you know all the stuff that this product brings to the table how do you think about the value proposition in terms of pricing given we have financial types we have to ask those kinds of questions.

Speaker 3

Yeah, well, I'll fill in while you're, did the microphone go off? Oh, mine's still on, sorry. As we think, so Jason's our chief commercial officer. I'll ask him to comment because he's been doing a lot of work with the payers. I'll start with, you know, the more and more data we get in terms of longitudinally what this medicine may be doing, the durability of the seizure reduction on top of standard of care, plus this gain of cognition and behaviors consistently, what we've seen now, year one, year two, year three, year four in the OLE. I'm not sure how you value a child that may not be able to listen to their patient, parent, communicate with their parent, and year two, three years later, maybe having a conversation. I don't know how you value that. Other than I know that it's high value. And so, you know, it'll be based on the totality of the data when we come to, you know, pricing the medicine. And because we need to look at what it's doing for the patient and as well as just the seizure reductions. And so Jason has been doing a lot of work with the payers to educate them with all the data that we have. And so, Jason, maybe you could give some feedback on all the work we've been doing.

Speaker 2

Yeah, absolutely. I got so excited about that question, I threw the microphone. No, I think it's a good question, Simone. I think, you know, we've been doing a lot of work over the last couple of years to help educate payers around the unmet need and Dravet syndrome, the totality of the syndrome itself, knowing that to date the only thing payers have had at their disposal, to your point, are symptomatic treatments. And the proposition of what Zareva Nursin brings is different. I think, first and foremost, addressing the underlying genetic cause of the disease, unlike any other treatment that's on the market today. And the impact that that's apparently having across multiple manifestations of the syndrome is, by definition, a greater value proposition than what is had today. And in our opinion, is reflective of, you know, other genetically targeted disease-modifying treatments that are in the market today. treatments like Spinraza, for example, from Biogen, the Exxon Skippers from Sarepta, even Debut from Acadia could potentially be good pricing analogs. We've done extensive market research with payers that, you know, most recently earlier this year, we asked specifically what, from their perspective, would be the most compelling piece of evidence we would have at the time of a potential approval. And we walked through different potential label scenarios of what could be in the label, what we could see in terms of a result from phase three. And the answer we heard was that payers will view the long-term data as the most compelling piece of evidence they could have. And, you know, that's consistent with what we hear from doctors as well. Naturally, if you have a patient sitting in front of you and a chronic, lifelong treatment, you want to understand the long-term safety and efficacy profile of the treatment. And so, you know, consistent with, you know, what we've said previously, doctors and payers are looking at the totality of the evidence and the long-term OLE data are probably going to be the biggest driver of both prescribing and medical policies reflective of a disease-modifying treatment.

Samanth Kulkarni, Analyst — CounterContinuity

Thanks for that. All well-made points. I was going to say moderated hundreds of these things, but first time I had a company do a mic drop on me.

Speaker 2

First time's for everything, Sumon.

Samanth Kulkarni, Analyst — CounterContinuity

We have a couple of minutes left, so I do want to go into You're not just the Reveners and Entraway Syndrome, you have other programs as well. So could you talk about the Osprey data, what do you expect in an autosomal dominant optic atrophy or ADOA?

Speaker 3

So we're also following on with a second disease area, it's ADOA, which is a genetic progressive loss of eyesight. We're in a phase 1, 2 study, single dose escalating study. We're through its four cohorts of dose escalation. We're through our first cohort of dosing and into our second cohort. It targets OPA1 gene. It upregulates that, which increases mitochondrial function within the eye. And we're targeting to see improved vision. This is a disease where you lose vision, but we're hopeful that because we upregulate the OPA1 gene that we actually improve vision. And so we'll be measuring the patient's potential improved vision, low contrast visual acuity, as well as measuring through fluorescent FPF, it's a fluorescent protein, measuring the activity. And if that activity correlates to improved vision as measured by improved numbers of letters in a disease where you lose letters in terms of vision, we'll anticipate moving to a multi-dose registrational type study. And with ADOA, we would be down with the FDA very quickly to talk about how that registrational study may look like. So we hopeful would be able to use real-world evidence, a natural history study, be able to use biomarkers that we're testing in the Phase I-II study. But yes, more data on that. Just to give you kind of a visual of when the data may be coming, but cohort three and four is when we would anticipate potential efficacy readout, which would be in the first half of 2027.

Samanth Kulkarni, Analyst — CounterContinuity

We actually do have some time here because the next company doesn't have a presentation here. So we cross the bridge, we get to your partner on the North American side of things, that's Biogen. How collaborative is the relationship with Biogen and what do they bring to the table given they already have a couple of anti-sensory or the nucleotides on the market?

Speaker 3

Yeah, first of all, I'll go all the way back before we had the collaboration with Biogen. I sat on the board of Stoke at the time. I was also an advisor to the company, and I helped lead the process with the collaboration with Biogen. We made a decision as a company that we needed added capability beyond the borders of North America to get the drug to the patient faster. and Biogen was our chosen partner but you know we ran a competitive process and Biogen won that process for many different reasons but you know a lot to do with financials but also capabilities and as you point out Samantha they have a number of ASOs they have manufacturing they've got a big footprint around the other other countries outside North America so they're the ideal partner um for us um and and then since then we've been in that partnership now for 18 months roughly um and uh the partnership is a wonderful partnership with biogen dawn calmar who's sitting in the front row is actually the chairperson of the steering committee and uh speaks with biogen team on a uh daily if not daily definitely a weekly basis and um and that it works we've got the normal governance um functions set up with a steering committee a development committee commercial committee with jason and manufacturing and it's been a wonderful relationship with us and i think biogen when they're on their own calls and talking about their pipeline i i think you you find very very positive commentary around stoke but also zareeva nursin and the opportunity that Zareeva Nursen has outside North America. Thanks, I think we're out of time. So thank you to the company for being here and everyone attending as well.

Samanth Kulkarni, Analyst — CounterContinuity

Thanks for tuning in. Okay, thank you.