I think we'll get started on the next fireside chat. My name's Charles Duncan. I'm a senior analyst with the firm, and I'm really looking forward to introducing Stoke Therapeutics to the investors in the crowd. Not that the investors haven't heard of Stoke. Stoke's had a really interesting last couple of years, and they are taking an entirely different approach to treating genetic diseases, including central nervous system diseases, which I find intriguing. Their lead candidate is a drug in development to treat the underlying cause of Dravet syndrome. Had pretty interesting data, especially when you compare against other seizure medicines in the last year.
So we're gonna hear a little bit about that, and we're gonna hear about their next steps, which hopefully will include a pivotal program to operationalize here in the near term. So with me today is Dr. Barry Ticho, the company's Chief Medical Officer, and Tommy Leggett.
Leggett. Mm-hmm
Leggett, the company's Chief Medical Officer or Chief Financial Officer, and he actually recently joined the firm, so that's why I didn't know his name well. But maybe we'll start with you, Tommy, a softball.
Mm-hmm.
Why'd you join Stoke Therapeutics this last twelve months?
Yeah. Thank you, Charles, and thanks again for hosting us, and this is a great conference, so we really appreciate you guys in the back behind us. Look, I mean, I joined in May of this year. For me, Stoke was honestly almost a no-brainer for me, no pun intended, where you know, we have the ability to truly impact the lives of these Dravet patients. And that, to me, when I saw the data in March, but even knowing the story behind the company and the smart science, got me very, very excited to join Barry and the team, where they've got a lot of experience getting drugs like this approved. So, you know, when I think about that-- And I would say the last thing is we have a really exciting platform.
You know, with clinical validation for upregulating proteins the way we can, is quite exciting. So as you mentioned, we're starting off in CNS, but we can move into other areas as well. So for me, as a CFO, I think of that as a lot of different opportunities beyond even Dravet.
So it's a broad platform that can be hopefully applied very broadly. But you have had some really interesting validating data in this last year. So Barry, why don't you tell us a little bit about yourself and why you decided to become involved with Stoke?
Oh, well, thanks. I myself am a clinician. I'm a pediatrician and have been treating patients with genetic diseases. I have over 25 years of industry experience now. Most recently, I was at Moderna, before I joined, so I'm definitely an RNA medicines person, and that's definitely why I joined Stoke, because we had this opportunity here. What's unique about Stoke is we're using oligonucleotides, so short pieces of RNA, to increase protein levels inside the cell.
Yeah.
That's different from what is typically used for an antisense to knock down.
Mm-hmm.
We can do this in a very cell-specific way, and we can modulate how much upregulation there is. This is, this is a combination of a very unique ability to treat especially genetic diseases, and we're focused now on diseases of haploinsufficiency.
Mm-hmm.
So that means that there's a wild type or a normal copy of a gene and a mutated copy.
Mm-hmm.
That mutation typically will cause a loss of function, so that protein coming from that mutation no longer has any effect in the cell.
Yeah.
And there's then effectively only half the normal amount of protein in that cell, and it causes a range of diseases, over three thousand diseases.
Mm
-that are autosomal dominant-type diseases.
Okay.
We know very well what the genetic cause is in these diseases.
Mm-hmm.
But in order to actually correct it, there has to be a doubling of the protein back up to normal.
Mm-hmm.
Many of these proteins, if there's too much, there can be a problem as well. To be able to titrate just to the correct amount is a unique ability that we have with our technology.
Really a novel platform and, you know, excited to hear more about where you plan to deploy it. We have one on offer now, Dravet, and a second one, soon to come into actual clinical testing, autosomal dominant optic atrophy, right?
Mm.
So, why, why'd you start with Dravet? I mean, there are seizure drugs, so why, you know, why would you start with Dravet? That seems like a tough putt.
The advantages that we saw in treating Dravet is that although the seizure part of it is somewhat controlled, 90% of patients still continue to have seizures.
Yes
-despite all these anti-seizure medications,
Yeah
.- over 20 that are available.
Yeah.
Patients, more than 90% continue to have seizures. So even the seizure part of this disease is not taken care of.
Sure.
But, besides the seizure, there's a whole range of other manifestations of the disease that in some ways are actually worse than the seizure part. These patients with Dravet syndrome, they will develop to be about two years of age in terms of their functioning.
Ah.
And then, they continue the rest of their lives functioning at a two-year-old level.
Mm-hmm.
We've shown now in a natural history study, where we studied patients and followed them for two years over a wide age range, and we show that these patients, when we looked at their scores on cognition and behavior measures, they will reach a certain point by two years of age, and then their scores do not change. Whereas neurotypical would increase every year, their score stays the same the entire way. As you can imagine, these are families now who have, in some cases, twenty-year-olds, thirty-year-olds, who are functioning at a two-year-old level. They can't talk to them.
Mm-hmm.
They develop a difficulty walking, so they all end up in wheelchairs.
Mm-hmm.
One out of five then die from SUDEP before they even reach their teenage years. A horrible disease, and no treatments available for that. But yet we know very well what is the genetic cause of this disease.
Mm-hmm.
One of the best predictors of success of a medicine to get approved and used is that it's addressing the actual genetic cause of a disease.
Yeah.
So when we can predict that and know it, and here we know the biology, we know exactly what we need to do in terms of the protein levels and where we need to do it, we can give the medicine locally, just in the brain. Another key aspect that helps for success in a medicine is target one that is limited in terms of its scope in the body.
Mm-hmm.
And we know that the Nav1.1 is limited almost exclusively to the brain. So we're targeting a medicine that with this medicine a target that only is gonna be effective in the brain, and we can deliver it there directly. So there are good animal models for this disease.
Yeah.
We've shown with a mouse model that we can reduce the number of seizures, reduce the sudden death that haven't happened in these animals. For all these reasons, this was a perfect opportunity.
A great, great place to start from the standpoint. So sodium channel 1.1 , deficient in these patients, unfortunately at least about half the amount that you'd expect.
Mm-hmm.
And it does seem like seizure reduction is something that could be measured. But how do you know from the animal models that you might be able to improve cognition or behavior?
Yeah, so that is a challenge in mice.
Yeah.
For the mouse model, what we did was we implanted electrodes into the brains of these mice, and we recorded how many seizures they had.
Mm-hmm.
We showed that with the treatment, there was an 80%-90% reduction in the number of seizure events that the mice had. That we could have, but the behavior part is, it was more difficult. Luckily, there are good clinical measures that we can use, and that's what we've done in our phase I and II study-
Yeah
-- to actually look at-
Yeah
-cognitive behavior in patients.
Now, we conducted a KOL call and have done a lot of diligence in this area, and it turns out that we discovered and heard, and maybe that's not such a discovery, but patient or caregivers of Dravet patients are less concerned about seizure reduction than they are about improving the quality of life for the patient and for the family-
Mm-hmm
-through improving cognition or stabilizing cognition, improving sleep, behavioral challenges, et cetera. Yet, they still want to know that seizure reduction is happening. So why don't we talk a little bit about the study that you conducted and the types of patients that you enrolled that gives you confidence in seizure reduction, and then we'll talk about some of these other syndromic effects as well.
Yeah. And so seizure reduction, it has been now established as an endpoint.
Yeah
-over decades of measurement of other medicines for epilepsy.
Yeah.
This is done typically by a daily record that the family or the patient keeps, where they record-
Mm-hmm
--how many seizures they have, and this has been established by regulators all over the world as an accepted measure. So in our first, to start out with, in our natural history study, we followed patients over two years with these seizure measurements as well. And what we showed is that even though they are on multiple different medications, half of them are on four or more medications, and half of them were on fenfluramine, which is thought to be one of the-
Yeah
-more effective forms-
Yeah
-treatments for Dravet syndrome, the patients continue to have high levels of seizures.
Mm-hmm.
So they're having seizures, almost one major seizure, the whole body shaking, every other day.
Mm-hmm.
Over two years, that didn't change at all. They continued to have-- Despite being on medicines, that level of seizure continued. In our phase 1/2 study, we treated patients up to 70 milligrams with intrathecal zorevunersen.
Mm-hmm.
And we gave them up to 70 milligrams for up to three doses, and then tracked the seizure record every day in those patients. And what we showed is that over the course of treatment, we could have an 80% reduction in the number of seizures that the patients were having in the highest dose treatment group. And so this, again, is on top of or in addition to the standard medications they're receiving. This is further reduction in the seizures, and again, in a very well-accepted form of measurement.
Now, the timelines for activity are a little bit different than an oral anti-seizure medicine.
Mm-hmm.
Did that surprise you, or did that fit with the biology? And do you think that that'll prove to be acceptable, should you achieve effect sizes that are notable in the commercial setting?
Yeah, it was very much what we expected because we have animal data now where we've looked in non-human primates, as well as other animals, and shown that it takes somewhere between four to eight weeks for the Nav1.1, the sodium channel that's deficient, to reach-- to be doubled in the brain-
Yeah
-in the animal. So we knew it was gonna take some time. The other reason it takes time is that whereas a symptomatic anti-seizure medication just blocks a channel-
Yeah
-- and has a very rapid onset of effect.
Yeah.
What we're doing is rewiring the brain.
Yeah.
Because these patients now, without having normal sodium channel interaction, the communication there, there's a whole new network, an abnormal network that gets set up in the brain-
Yeah
to compensate. In order to fully treat this disease, we have to reverse that, and
Yeah
-- establish and get the new or the normal network established in that brain. That takes some time.
Yeah.
It may take months, perhaps even years, in some of these patients who have had decades of disease.
Mm-hmm.
We did show that within three months after the last dose of treatment, that's where we were seeing the maximum in terms of seizure reduction.
Mm-hmm.
We showed also in the phase 1/2 study, that when we followed the patients either three months or even six months after their last dose, that they were having improvements in cognition behavior-
Mm-hmm
-- especially in areas of communication, in areas of interpersonal relationships, as well as, gross motor skills. And these, these are the things that, as you were talking about, these are the things we've actually gone out and talked to families, and there was a formal meeting with the FDA, a patient-focused drug development meeting, where they asked the families: "What are the most important things that you would wanna see change in this disease?
Mm-hmm.
Communication. They wanna be able to talk to their child. Can you imagine that they have these children now who can't communicate? They really-- Some of them are talking in grunts-
Yeah
--saying very few words, so communicating, just being able to know when my child wants something, that they can say that they want that, or if I say to them something, they can respond in a way. That's what these families want. They want to be able to have a child who has their behavior somewhat under control-
Mm-hmm
-- because some of these, especially older adolescent boys, can become quite violent. They also have autism spectrum disorder.
Sure.
It's very difficult to manage these children every day. Just improving their behaviors is another thing, and having them be able to walk or not be confined to a wheelchair, be able to go to school and play. Those are all important things, and these are all things that we measured in what's called the Vineland Measure of-
Mm-hmm
-- Adaptive Behavior.
Mm-hmm.
And showed improvements over and above what was seen in the natural history study. As I said, there were no changes there. So we're seeing now improvements in this, both in the phase 1/2 study, where we followed them for up to nine months, and in the open-label extension study, where we followed them with treatment every four months.
So total remodeling, if you will, of the brain in these patients. It would seem to take some time. Makes sense that it takes time to create sodium channels and then rewire the brain and reconnect it, and then turn that into improved behavior that you can see. So what is it that you want to study, or evaluate, primary endpoint-wise, in a pivotal study that you think is gonna be really clinically, value-creating for these patients? What will the FDA want? Will it be seizure reduction, and then you'll have to show something else, or will it only be seizure reduction, or will it have to be a longer study than usual?
We're fortunate that we have a very nice database of eighty-one patients who've been treated.
Mm-hmm.
And we have data on patients who got two or three doses of 70 milligrams, which is a loading type of phenomenon that we expect to use in the phase III. So we have a wealth of data that we can bring to the regulators. We have ongoing discussions right now on our phase III design with FDA, with the European Medicines Agency, with the Japanese PMDA.
Mm-hmm.
So this is all part of what we anticipate will come into an agreed-upon phase III study, which we hope to be able to talk about later this year publicly. But the primary endpoint likely is to be seizures-
Okay
-- because that is, has been the regulatory precedent.
Yeah.
And we do have very nice data, as we just talked about, showing that we can reduce seizure frequency in these patients.
Yeah
-- with the type of dosing regimen that we're proposing.
Oh, pretty profoundly, 50%, and on top of current optimized standard of care.
Exactly.
Now, your sample sizes are not huge, right? You did mention, call it 80 total patients exposed. But do you have confidence in being able to replicate that kind of seizure reduction, or is that not necessarily needed, especially if you can create, you know, longer term benefit for these patients?
The seizure reduction will be part of the package, because-
Yeah
-- since we're treating the base cause of the disease, if we improve the seizures, then we're also likely to improve the cognition and behavior and these other measures. So it all is gonna come together. The seizures, as you said, is something that's relatively straightforward to measure and has been the established path. So we anticipate being able to show that, and we will power the study in order to show that in a statistically significant-
Okay
-- way.
Okay.
But the other endpoints, the secondary endpoints, will also be part of the phase III, and we anticipate powering those in order to show benefit in some of these cognition behavior effects as well.
Yeah. So primary endpoint will be driven by seizure reduction, and that makes sense. It's quantitative. We like that. It's hard to fake a seizure or fake not having a seizure, so that's good. But the question is, from a regulatory strategy, and maybe we're a little bit ahead of you know, cart ahead of the horse or something, but do you think that you'll be able to file on a seizure reduction endpoint?
-- Well, this is all part of ongoing discussions with the regulatory agencies.
Okay.
But certainly, the precedent has been that showing a statistically significant reduction in seizures is sufficient to get-
Yeah
-- an approval.
Yeah.
What is the twist here is that we have what we think is going to be the first disease-modifying therapy-
Right
-- for an epilepsy.
Right.
That requires showing effects in multiple different aspects of the disease.
Yeah.
So seizure modification would be one of them, but the other non-seizure effects will be important as well. And so that would be an important part of showing statistical significance in the study as well.
Also clinically meaningfulness. I mean, that creates value for patients and, you know, families and hopefully reimbursement authorities. But you wanna, you know, be compensated. I mean, you want, if you create clinical value, you want that to be recognized in the marketplace. So you probably need that kind of data to really be able to appropriately price and enhance access to the drug, correct?
Correct. Yeah. The having evidence of this disease-modifying effect will be important in our discussions with payers as well.
Mm-hmm.
And it would also be a motivator to try, because this is an intrathecal medication.
Yeah.
So it isn't taking just a pill.
Yeah.
And so we do have to have an extra motivator for families and clinicians to want to take this medicine.
Yeah. Yeah, for sure, but it is on top of current standard of care, and there's pretty profound data, so I'm looking forward to that data.
Yeah.
Or looking forward to that phase III protocol, hopefully by the end of this year.
Right.
Would you anticipate it to be large and long or right-sized and not all that long? I mean, given seizure reduction could happen over three to six months for a primary endpoint.
Again, this is all part of our discussions with regulators, so.
I'm trying.
Nothing, nothing's finalized.
I'm trying, Barry.
But the study itself will include the secondary endpoints that measure cognition and behavior.
Okay.
Those we know from our phase 1/2 study. We've been able to show that effect within nine months of starting therapy. We also have data from open-label extension studies showing that within a twelve-month period, we can have clinically meaningful improvements that were in addition to what was seen in the phase 1/2. Those are approximate time ranges of how long a study might run.
Okay. So zorevunersen. Zorevunersen?
Zorevunersen.
Zorevunersen.
Yeah.
Was that Tommy or was that Ed who named that?
We chose a name-
Tommy, is that your fault?
-- that we would be difficult to say, so people would remember it.
That's right.
It works. Yeah. I've been practicing for the last couple of days. Zorevunersen. Love it. So, data may be 2026 or so, you think? At least enrollment data before then.
Once we have the full phase III study-
Okay
-- lined out, we'll be able to give better ideas about study start as well as potential when we might have data.
Okay, very exciting. So second candidate for-- Well, you have a deal with Acadia, which is interesting. No one talks about that, at least those people that cover Acadia. Do you have a good collaboration with Acadia?
We've had a very good collaboration with them. Yes, they-
Yeah
-- We have three programs that are in development with them.
Yeah.
One is on Rett syndrome, which is obviously something they have a great deal of expertise on, and-
Yeah
-- that's part of what caused it to set up the collaboration.
Mm-hmm.
The other is with a disease called SYNGAP1-
Yeah
-- which in many ways is similar to Dravet syndrome, in terms of it being, having both a seizure component and a developmental component. And then, the other, the third one that we haven't disclosed yet, but that has been proceeding, and we're quite satisfied with our partnership there.
For Rett, MECP is underexpressed or a similar biological concept?
It's similar, yeah. In for MECP2, it's expressed only at half the normal level. And the challenge there is that too much MECP2 causes another type of syndrome. So one has to be very careful about how much-
Yeah
-- MECP2 gets expressed, and that's why our approach is well suited for this disease.
You really need to titrate, and again, you have seizures in Rett, but you also have a lot of neurodevelopmental deficit.
Exactly.
Right.
Exactly.
Yeah. Interesting.
And then, the other program we were talking about was the autosomal dominant optic atrophy.
You brought it up.
Exactly.
Yeah. Yeah.
And so that's a fascinating disease. Again, we know the biology very well there. It's caused by a haploinsufficiency of a protein called OPA1.
Mm-hmm
-- which is a mitochondrially functional protein. It's nuclear encoded, but it functions in the mitochondria, is necessary for mitochondrial structure and function. And in these patients who have half the normal amount of OPA1, they have a progressive form of blindness, which-
Yeah
-- starts in the first decade of life. The retinal ganglion cells are probably the highest energy-requiring cell in the body.
Mm-hmm.
And if you can just imagine, you know how much energy your computer takes to show a video image. You can feel how hot it gets-
Yeah
-- and how much energy it takes. Similar in the eye, the eye cells, especially these ganglion cells, require a tremendous amount of energy. So by having only half the normal amount of OPA1 protein there, the mitochondria are not able to keep up with the energy demand of those cells. So those cells eventually actually start to die because they just can't function normally--. So in this disease, we can administer the antisense oligo to increase the OPA1 protein, and we have data now from animals, from injections into rabbits and into non-human primates, where we can show that the oligo gets into the retina and can double, or nearly double, the amount of the OPA1 protein in the retinal ganglion cells. And so we're intending to do the same in patients.
We hope to dose the first patient before the end of this year.
In that case, you're now talking about an intrathecal injection.
It's an intravitreal injection-
Yeah
-- which is tolerated. There are hundreds of thousands of these injections now because-
Yeah
This is the anti-VEGF treatments that are well used, so it's a very straightforward and relatively uncomplicated procedure.
And when would you evaluate clinical activity for that program? What kind of timeframes are we talking about? Getting back to, call it, you know, the Dravet syndrome, taking a little bit more time than, say, investors had anticipated, but it's 'cause it's new.
Mm-hmm.
How about for this? When would you best like to see activity?
First of all, there are no treatments available for this medicine, so this is an area that has
Yeah
-- a great need. We have an ongoing natural history study, where we're looking at over a dozen different assessments of the retinal ganglion cell function, in terms of vision, in terms of thickness of that layer of the retina, and we even have a measure that can actually look, in a non-invasive way, at mitochondrial function itself. We have data from patients' cells who have ADOA, that have half the normal amount of OPA1 and abnormal mitochondrial function. We've given the oligo to those cells. The OPA1 levels increase, the mitochondrial function improves and returns close to normal. So the expectation would be, in the patients, that we can actually improve mitochondrial function and potentially improve vision.
Yeah.
And so we'll use these natural history data, where we follow the patients now for two years, and so far we've been seeing that they, again, in these measures, do not have any improvement. There's no spontaneous improvement in this disease. And so if we were to able to show improvement, that would be a substantial benefit to the patients, and also could be done in a reasonable period of time.
Yeah, yeah. Let's talk about reasonable improvement in sight. Is this three months, six months, one month kind of timeframe? Are there biomarkers you could evaluate over a short time?
Again, the timing will have to wait till we do the trial.
Okay.
Um, really-
Okay
-- to get that. But, there are markers. As I said, we have this non-invasive measure of mitochondrial function-
Okay
-- and we have multiple other measures of vision that we can use, and we'll be following those patients after a single dose. Another unique part of this treatment regimen is that we think that this may be a once a year injection.
Okay.
The oligonucleotides get taken up, and they last for nearly a year or even longer in the retina.
Interesting
-- this could be a relatively infrequent treatment, but a single dose can also treat patients for a whole year, and we'll be following them over that time.
Much less frequent than, say, in the Dravet situation.
Yeah, which-
So you're really not gonna help me out with clinical data milestones, are you? So I'm gonna ask you a question, a last question. Unfortunately, we're almost out of time. If anyone from the audience has something, just yell. But the question that I wanted to ask you is, what do you think-- It's a softball, absolute softball.
Okay.
So what do you think is least well understood by investors about Stoke and your prospects? Not so soft.
Maybe I'll start, and Barry, feel free to jump in.
Yeah, sure.
Look, I think any time you've got a novel approach to a disease, even though biologically it really does make a lot of sense, you know, you're gonna face some pushback. I also think, the results that we saw in our data in March were startling in a very positive way. But I will tell you this, having joined the company only a few months ago, having spent time with some families, gotten to understand what the caregivers have to go through, these secondary endpoints truly are meaningful. You need to improve this quality of life. These patients, yes, they may have seen some seizure reduction in the current standard of care, but they're looking for something new because, as we've talked about, this is like a life sentence for, not only the individual, but the caregivers and the family.
And so when you see a caregiver, a mother or father, who sleeps next to their child every night, out of fear that they're gonna die in their sleep, and you realize if we can improve that, not only from a seizure perspective, but so they can actually communicate with their parents, that, to me, is game changing. And I just think when you see this kind of profound data, it makes sense to be met with skepticism, but we'll just keep showing it in more, more patients.
So far it's been pretty interesting. It's gonna be a great year for you in terms of that protocol and then operationalizing it. Unfortunately, we're pretty much out of time, so I appreciate you spending time with us. I appreciate the audience's interest in Stoke, and let's look forward to the next year. Thank you. Thanks.
Thanks, Charlie.
Great to be here.