Hey, everyone. Thanks for joining us for the last session of the first day of our conference. I'm Andrea Tan, analyst at Goldman Sachs, and I'm pleased to be joined by the Stoke management team, Ed Kaye, CEO, and Barry Ticho, CMO. To start, Ed, maybe if you'd like to walk us through the progress that you've had here in the recent data disclosures.
Yeah. So, just briefly, Stoke Therapeutics is a RNA company that's focused on upregulating protein production. And we had recently announced our end-of-phase II data in the end of March, which showed improvements, dramatic improvements of 70%, 80% in patients who were already pretreated with maximum therapy and reduction in seizures, but more importantly, improvements in cognition and behavior. So let me walk people through this. So, as I said, my name is Edward Kaye, and I am the Chief Executive Officer. And I will be making some forward-looking statements, so please look at our SEC documents for full disclosure. The disease that we're focused on now, primarily in the clinic, is Dravet syndrome, and it is a genetic epilepsy that affects one in 16,000 babies.
It affects every ethnic predilection, it is a spontaneous mutation, and it's seen throughout the world. We've estimated that there are about 35,000 patients with Dravet syndrome in the U.S. and Canada, Japan, and in the big three in Europe, in the EU, and also in the U.K. One of the important things about this disease is it's despite the fact that many anti-seizure medications are used, seizures are not adequately controlled in about 90% of the patients. And what we can see also, that it has one of the highest rates of sudden unexpected death in epilepsy, and about 20%, 16%-20% of patients will die by the time they reach adolescence and before adulthood.
The other aspect of the disease, that isn't always appreciated, it has significant challenges in cognition and behavior. So it is a disorder that's much more than epilepsy. And what we see are very significant intellectual deficits and delays, problems with movement and balance, gait, sleep abnormalities, mood disturbances, and problems with growth. And one of the challenges, of course, is that treating the seizures will not affect these other abnormalities that are related to the underlying deficiency of an NaV1.1 protein. And this is what we're attempting to do at Stoke. We're attempting, really, to be the first company that addresses the underlying genetic cause of a genetic epilepsy.
Treating seizures is fine and has been done for the last 150 years, but it doesn't address the primary genetic cause. What we've seen is that majority of the patients, the disease is caused by a haploinsufficiency of the SCN1A gene, and that results in a 50% decrease in the NaV1.1 protein. It's a sodium channel protein that's very important in development, and that 50% deficiency causes Dravet syndrome. What we're trying to do with our product, zorevunersen, it's an antisense oligonucleotide. Our founder, Isabel Aznarez, several years ago discovered that there were elements that were retained on the pre-messenger RNA, and they interfered with the full-length message.
But if you spliced out that, sometimes we refer to as a poison exon, it's an NMD exon that causes a breakdown. If you splice it out, you can actually increase the amount of full-length message and increase the full amount of protein. And what we showed here is that without the zorevunersen, what we see is that a certain percentage of the transcripts are non-productive. So you don't have any protein made. But if we add zorevunersen, what it does is it enhances the excision of the splicing out of that poison exon, and it actually increases the amount of full-length message. So what you get is a completely normal message that's only expressed in those cells that normally express the transcript.
And I think one of the focuses for us is we're trying to really be the first treatment to treat the underlying cause of Dravet and not just a symptomatic treatment of seizures. And if we look at seizure management, despite all of these therapies that have been used and continue to be used, including some of the newer therapies that have been developed, 90% of the patients still have seizures that are incompletely controlled. And with zorevunersen, what we're hoping to be, again, is the first potential disease-modifying treatment to address Dravet syndrome. One of the things we did early in the course of this study is to actually do a natural history study. And we knew that some of the natural history was identified pretty well, but what happens with seizures over time?
There was a misconception that as these patients age, the seizures just simply go away and they get better. But what we saw when we followed patients of a variety of ages over a 2-year study, the seizures did not improve. They stayed the same, and it continues to be a problem through adulthood with these patients. So the natural history is that the seizures do not get better over time; they continue to be refractory. The other thing that we had looked at is we looked at something that was never done before: what happens to the development in these children?
Well, what we saw, if we look at cognition using the Vineland-3 Adaptive Behavior Scale, we saw that there were significant declines in receptive and expressive communication and problems with fine motor. So there either a decline or a lack of improvement, which developmentally at this age should be getting, continues to improve or get better. So these were these patients were in essence stagnant or worsening over time. And I think what we showed at our recent data release is that when patients received the drug and they had a loading dose of 70 milligrams, so 2 or 3 doses, and what we saw is at 3 months, we had an 85% reduction in seizures, and at 6 months, a 74% reduction in seizures.
And then when we followed these patients over time, receiving in an open-label extension study, receiving a maintenance dose of 30 or 45, we saw clinically meaningful reductions, not only in seizures, but improvements in multiple measures of cognition and behavior, and that was over a 12-month period. And overall, the drug was generally well-tolerated, and patients continued to take the drug. And this is really some of the data, and I'll focus you on that green line. And this was using 70 milligrams of zorevunersen, that's either 2 or 3 doses. And what we saw is that we saw, again, this dramatic reduction that continued following the third dose.
I'll remind you that these patients, then after the 2 or 3 doses, received no further medication throughout this time, and we're seeing a very long-term effect on these patients in regards to the reduction in seizures. This is, this has been a consistent finding. If we look then at, again, at 1, 2, or 3 doses of zorevunersen, what we see that even with a single dose, at 3 months after the first dose or 6 months, we're seeing again, very dramatic reductions in seizures of 43% and 57%. And as I said before, using 2 or 3 doses, we're seeing, again, these dramatic reductions in seizures of 85% and 74%.
And if we look basically at how many of these patients received at least a 50% responder rate, what we can see is that we saw 80% of the patients who received two or three doses of the loading doses of zorevunersen had a basically 50% or greater improvement in seizures. So again, and this was at a variety of ages that we're seeing, and both really with two or three doses. We didn't see a marked difference between whether they received two doses or three doses.
and again, when we followed these patients, and that green line is patients who had received 70 milligram and had received at least one dose of 45 milligram as a maintenance in the open label extension, we continued to see this persistent reduction in seizures, following in the open label extension. And when we followed patients who had either received much lower doses, that's at 30 or 45 milligrams, we also saw continued reductions in seizures over time in the open label extension. And probably the most important part of this data release, however, was the improvements that we saw in cognition and behavior over time, and this was over a 12-month period.
And I think what was important is that the receptive and expressive communication, which was considered one of the most essential areas, for both the families, the caregivers, and the physicians, we saw, again, very significant improvements. And then we saw improvements in personal skills, interpersonal relationships, and fine motor. So again, this was really unexpected because I think overall there are no spontaneous improvements in some of this cognition and behavior. And typically, when the patients reach about a two-year developmental stage, they stay at that stage despite their chronological age. So again, this was by increasing the NaV1.1, these are the improvements that we saw in cognition and behavior. And again, this was the overall clinical, global, global impression of change, both for the caregivers and for the clinicians.
What we saw was a persistent improvement over time, and in this case, a downward score is improved. So we saw both at 4, 8, and 12 months, continued improvements compared to the natural history. And these are, again, patients who had received either 30 or 45 milligrams of a maintenance dose. And just to summarize the data, what we saw with patients who received the 70 milligram, we saw really significant reductions of seizures that was persistent and continued in the open label extension, and also improvements in cognition and behavior that we saw. And we saw these improvements in the initial part of the study, when they received the 3 doses, 2 or 3 doses, and continued improvements in the open label extension.
Our other disorder that we're going after and very close to being in the clinic is a disorder called autosomal dominant optic atrophy. And it's a severe genetic cause of progressive optic disorder. For the most part, it is a defect in the OPA1 gene, and it results similar to Dravet in a haploinsufficiency, 50% of the OPA1 protein. It's a disorder that is found in typically in 1 in 30,000 births, and has a much higher incidence in Denmark and Northern Scandinavia, about 1 in 10,000. There are over 400 different mutations that have been described so far, and we know that about half of the patients end up legally blind, and 80% of the patients become symptomatic by the end of the first decade.
The estimate is that the U.S., Canada, Japan, Germany, France, and the U.K. have about 18,000 patients who have been identified. It's a disorder that not a lot is known, and there are no therapies for it. But what happens in the simulation is the patients begin to have an enlargement of the blind spot. Now, everyone has a blind spot where the optic nerve goes into the retina. These patients, it continues to get bigger because there is a slow decline in the optic nerve. So imagine looking at a computer screen, and what you can't see is the center of the computer screen. It is a disabling defect, so they have to rely on their peripheral vision. It's typically diagnosed when children are in school.
They have a visual defect and a problem with acuity, but it can't be corrected by glasses. And when they get sent to an ophthalmologist, what they see, you see a normal optic disc on the left, and a patient with ADOA has a very pale optic disc, and that's because some of the optic nerve is degenerating, and it causes the pallor. But unfortunately, nothing to date has been able to improve any of the vision in these patients, and it continues throughout life, and it does not improve. So what we are expecting to start this later this year in 2024. What we've been able to show is that we've been able to increase OPA1 protein and also ATP-linked respiration.
So it actually improving mitochondrial activity in patients' fibroblasts, who have ADOA. We've also shown dose-dependent increases in the OPA1 protein, both expressed in the rabbit retina and in the non-human primate, directly in the retinal ganglion cells, which is this target cell that we're looking at. We've identified a non-human primate model of the ADOA that has the same, basically, physical and structural and electrophysiological, features as in the human. And we've shown that it's well tolerated for up to 29 days after an intravitreal injection in the rabbit. And we've shown that single and multiple doses were well tolerated in non-human primates. So this is our pipeline, Dravet. We are expecting to go into a phase III study.
We're having discussions with regulatory authorities in the FDA, the EMA, and in Japan, and we'll report the results of those meetings later this year. We also have programs with our partner, Acadia, in SYNGAP1 and Rett syndrome. That continues. Those are preclinical programs but are progressing quite well. And as I just mentioned, we have our ophthalmologic indication for OPA1; we plan to start a phase 1/2 this year. So overall, our priorities for this year is really to advance zorevunersen for Dravet syndrome as a registrational study. We already had the Q1 data, the end-of-phase II data readout. We'll be meeting with regulatory agencies in the second half of this year, and we'll be able to announce what that phase III study looks like.
We'll be starting our phase II STK-002 study for ADOA and continue to expand and develop our pipeline. We ended at the end of March, we had $300 million in cash and cash equivalents. And so financially, we're in a solid position at this point. So I will end this here and happy to have questions. Thank you.
Any questions from the audience? Please.
So, with the first drug you were talking about, is there any evidence to suggest that over time you could reduce the dosing and the cognitive behavior continues to improve and as less seizures occur over time?
Well, one of the things I think that's been a misconception and that our natural history study was able to show is that for a long time, I think clinicians thought that the cognitive and behavioral declines were directly related to the seizure. I think what we've heard from clinicians, but even from our own natural history study, is those really the underlying cognitive deficits are caused by that NaV1.1 protein deficiency. So it's a much more severe disease than you'd expect simply from the seizures. And what we're seeing, I think, which was interesting-...
We're seeing improvements in cognition and behavior, that's not related to age. So even the older patients, we studied patients from 2 to 18 years of age. So even older adolescents are still seeing the same magnitude, improvements in seizure reduction and also in cognition and behavior. So it does suggest that there is the capability to really have some repair within a brain, because we know that Dravet is really a disorder of synaptic connections. And we know that there's a lot of changes that occur in other ion channels, other sodium channels, and it probably takes a while for that, remodeling of the brain to occur over time. And what we're seeing is that the longer patients are on it, the better the response we see.
This is atypical for, I think, a lot of medications for seizures, where typically you become refractory. If you're on it for a while, then... That's the problem with Dravet. They cycle through drugs over and over and over again. What we're seeing so far in our open-label extension, these patients continue, and we've seen patients now a couple of years out, continue to show an improvement. They're not becoming refractory. I think because we're not just simply treating the seizures, we're addressing the underlying genetic cause.
Recognizing that you're going to engage with the regulatory agencies, to think about the forward path, but maybe you could provide some early thoughts on what a phase III trial might look like, what would be endpoints that would be, you know, that you would consider exploring here, and particularly to be able to capture the benefit both on seizure reduction as well as the cognition, and behavior that you've seen in the prior study?
Barry, you want to answer that?
Yeah, thanks for the question. Well, in terms of the study design, again, this is all still to be agreed upon with regulatory agencies, but we would likely have a primary endpoint of seizure frequency. This has been what's used, what's been used for other treatments for seizure reduction in Dravet syndrome. And that would be, again, looking at comparison from the baseline number of seizures to number of seizures after. The secondary endpoints would be also quite important there because those would be measures of cognition and behavior, and that is what would set this treatment approach different apart from the other treatments that are available for patients with Dravet syndrome, as well as actually be groundbreaking in terms of a new treatment for epilepsy in general, which would be a disease-modifying therapy.
This is disease-modifying potentially because it's treating the actual cause of the disease, as Ed mentioned, and it's also treating multiple aspects of the disease. So not just treating seizures, but the other aspects, such as cognition and behavior. So those would be important endpoints for us to measure, and we'll be looking at those, especially, as Ed mentioned, likely something like the Vineland measure, which has been well-established and is used to track the effects of, on developmentally delayed children in general. So those would be the main effects that we would look for in a phase III.
What would the length of duration of this trial be? Like, what would be... Would six months be enough? Would one year of a treatment be enough to really elucidate those benefits that you're looking to show here?
Again, we will have to wait till we conclude our discussions with regulatory agencies to have a final determination of the length of the trial. But we do have data that Ed showed as well, that within 9 months of treatment, patients are certainly having substantial reductions in seizures, but also having improvements in cognition and behavior, especially at that 70 milligram dose level. And we also have data from our open-label extension study that patients, even on the 30 or 45 milligram level dosage, are having improvements in cognition and behavior, and that can be measured within a year's time as well. So that gives a rough timeframe as to what we might have as a trial duration going forward.
Can you remind us what you saw in terms of the AE profile here?
Yeah, overall, the medicine was quite well tolerated. This is given intrathecally, so into the spinal fluid, and as a result of that procedure, patients do have what's called an LP syndrome, lumbar puncture syndrome, where they develop a headache and nausea, and that was commonly reported. That was one of the most commonly reported adverse events. The other commonly reported event was an increase in the protein levels inside the spinal fluid itself. And this is something that has been reported with other intrathecal oligonucleotides, but those were laboratory findings only. There were no clinical effects noted with that. But those are the things that we noted in the trial. But otherwise, overall, it is a relatively favorable safety profile.
As you think about the utilization of this longer term, is the idea for this to be kind of an add-on therapy to other anti-seizure medications, or would it stand alone? Would it have the capacity to be a monotherapy?
The way we've studied in the clinical trials right now is as an add-on on top of therapy. These are quite severely ill children. You know, they're having on average a full convulsive, full-body seizure every other day when they entered in this trial. These were patients who were already on; half of them were on 4 or more medications at the time they enrolled in the trial. Half of them were on fenfluramine, which is thought to be one of the more effective medicines for lowering seizures in these patients. Despite that, they were having this high level of seizures. So when given on top of that, the dramatic reductions that we were seeing, 85% reduction in seizures, is quite notable considering how refractory these patients were.
That's how we will likely study it in phase III as well as an add-on on top of other therapies. We know from clinicians who we've spoken to, that they would like to be able to use this earlier on in treatment. First line maybe, or near first line, would be likely a way that they would start trying to use the medicine.
I guess maybe based on the mechanism, that Ed showed us here, is there any reason to believe that monotherapy would be insufficient?
Well, this is treating the actual cause of the disease. It would likely be a lifetime of therapy, but in theory, if we could correct the sodium channel levels back up to close to normal in the brain and have the network in the brain functioning normally, then there should be no need really for any other anti-seizure medication. That's a tall order in these patients, especially some of whom who've had years or decades of this disease. To expect to be able to restore everything back to normal in those patients is a high expectation, but in theory, it could be used as a monotherapy.
One of your earlier slides touched on the addressable population, but maybe put a finer point on that. What is the specific patient population that you'll be targeting here with?
Yeah. So, we will doing— In the phase III study, we'll be doing patients, we'll be studying patients from 2 to 18 years of age, which is what we've done before. We do have another study planned for younger patients. It'll be a different endpoint because it's a slightly different disease years, and we'll be looking at more in development, and that'll be for patients for 6 to 23 months of age. I think, you know, based on my experience with a lot of other products that have been approved in rare diseases, I would expect to, you know, we would have a broad label that would say for the treatment of Dravet syndrome. But, you know, I think what we need to do is to look at the various different ages and see what the effect is.
I think so far, what we've seen in the 2- to 18-year-olds, we're not seeing any difference based on age or breakdown, and patients seem to be responding despite some of the patients have had the disease for a couple of decades, and they still seem to be responding. So, obviously, we don't know in adults greater than 18; we haven't really studied that. But I think the expectation is that, you know, we're not seeing this definitive line that at some point or some stage of development, they're not responding. So far, all the patients do seem to respond.
Was that finding surprising to you, that there was no difference based off of age or disease severity?
Well, well, well, both Barry and I are pediatricians just to begin with, so I think our natural inclination is to try to treat as early as possible. But I think, you know, the honest answer is we didn't know. We didn't know if there would be a difference between the early patients and the older patients, and I think it does suggest, from what we did know, is that it's not a classic neurodegenerative disease. In other words, the neurons aren't dropping out. They're more dysfunctional neurons, and it's more of a disorder of synaptic connections. And so I think, by restoring those connections, I think our hope was that it would work in a lot of different ages. And I think it, what we're seeing so far, that seems to be playing out.
Maybe with your second program here, just maybe walk us through the mechanistic rationale for STK-002 here, for this indication.
Well, the retinal ganglion cells are the origin of the optic nerve, so they're a specialized neuron. And, that's where the optic nerve starts, and it ends up in the occiput of the brain. It's also the most metabolically active cell in the body. And what's interesting in these patients is they're missing the OPA1 protein in all the cells, in all the ganglion cells appear to be affected. And the reason for that is that they're so active, smaller reduction in energy, metabolism is enough to cause a problem. I think for us, though, there are literally thousands of mitochondria in these cells... themselves die quickly. We think that by restoring that OPA1 protein and restoring mitochondrial structure and function, we have the capacity to actually improve vision.
And so this is very different from a lot of the, you know, disorders of congenital blindness, the, you know, the retinal pigmentary causes of blindness. That this really is a different disease, and it has the potential more for restoration of, let's say, other genetic-
Think about the capacity here to improve mitochondrial function. What does that open up in terms of other potential avenues, other indications where this may have relevance?
Yeah, that's a... That's something we've given a lot of consideration to. And one of the things that we know that there are other that have downregulation of the OPA1 protein. This is in glaucoma, geographic atrophy, and it's been noted in other diseases, and also mitochondrial diseases of certainly of the central nervous system have a basically decreased ATP synthesis. So what we've shown in actually normal cells, we can take just normal cells, upregulate the protein, and increase ATP synthesis... So there is the potential to use this drug for other indications outside of just a deficiency of OPA1. We think it could be used for other diseases, to basically stimulating ATP synthesis.
Interesting. And maybe I can ask you one on your partnered program with Acadia in Rett syndrome. Obviously, they have a drug DAYBUE now that's approved there. How do you think about maybe the overlap usage of DAYBUE with the asset that you're developing? Or would they be independent of one another?
Well, they certainly could be used together. Again, DAYBUE is a drug that has been shown to work and improve symptoms in patients, but it is symptomatic treatment. So the approach that we're taking is actually, again, aimed at the cause of the disease. So the MECP2 protein itself is deficient in patients with Rett syndrome. We are looking to, again, increase levels of that protein in the brain cells to try to lower the effect. This would be something that could be used complementary. If we were able to restore full function, or close to full function in the MECP2 protein, then that would allow for potential improvement in the outcomes of these patients. And again, this is a disease-modifying therapy.
Maybe in the last couple minutes here, where should investors be focused on in the next 12 to 18?
Well, I think, you know, the really, the thing that we're focused on is, Barry's working very hard on having the regulatory meetings. And what is to have sign-off both with the FDA, EMA, and the PMDA in Japan, that what is that, that phase III study gonna look like? How long is it? How many patients? And we can give guidance on how that protocol is gonna look and how long it's gonna take before we have a readout. So I think people are looking for that to just to know that we have regulatory clearance to do that study. I would say that's really the most pivotal. And then I think they're looking for us is, you know, what is our next program?
And I, you know, I'm pleased that we have another program ready to go in the clinic, and that we can really continue to validate the platform. And obviously, you know, we're very pleased with the work with Acadia for some of the other programs, for SYNGAP1, and those continue. But we have a lot of other programs that we have the potential to develop. As you can imagine, with a small company, we can't do everything, and we have to be focused on what our main priorities are. And the main priorities is clearly Dravet, get that across the finish line, but then hopefully closely followed by our ADOA program.
You had on your slide there, your ending cash balance, your cash runway. And to your point that you do have a portfolio here, how do you think about resource allocation beyond that initial program in Dravet?
Well, I think, you know, we're looking at a number of potential avenues to fund the programs. With our data release, we've had a lot of interest from potential partners for other geographic regions. And I think our overall philosophy for partnering is, if we can have a partner that can do it faster and better than we can, then we'd consider having that discussion. And as our focus is, how do we get the drug to patients who need it as quickly as possible? And as you know, in certain geographies, it's harder than others. We are focused, however, on making sure that we maintain the U.S. We can certainly do that. We just hired a new Chief Commercial Officer, who has a lot of experience in doing that.
So, but I think, you know, we'll use that. We'll look, you know, obviously at equity financing. But, you know, we're looking at a lot of things, and obviously, we have an ATM that will be opening. So a lot of ways, I think, of financing the company to be able to really maximize the platform.
Perfect. Well, with that, thank you both for joining us. Thanks, everyone.
Thank you. Thanks.