It's my pleasure to now introduce Edward Kaye from Stoke Therapeutics, the CEO. Just a reminder that this will be a 20-minute presentation with a five-minute Q and A.
Right. Well, good morning, everyone. As you heard, my name is Edward M. Kaye, CEO of Stoke Therapeutics. And as I will be making some forward-looking statements, we ask you to refer to our SEC documents for full disclosure. Simply put, Stoke is a company that really is an RNA medicines company that is focused on protein upregulation. And we do this by splicing and by increasing the amount of pre-messenger RNA full-length message to increase protein. We are focused. Our product that's in the clinic right now and ready for a Phase 3 is zorevunersen, which is for Dravet syndrome. But we have other programs. We have a program that's ready to go in the clinic for autosomal dominant optic atrophy. And we have a relationship with Acadia for SYNGAP1 and for Rett syndrome.
We have identified an additional 6,500 genes that have what we refer to as a TANGO signature. One of the challenges with Dravet syndrome is that it is a developmental epileptic encephalopathy, but it's much more than seizures. We know that it is a disorder that begins typically in the first year of life, and it affects about one in 16,000 infants that are born. It does not have any predilection or geographic concentrations. We know that approximately 35,000 people in the U.S., Canada, and the Big Five in the E.U. haven't been identified. One of the challenges of Dravet syndrome is that it has intractable epilepsy. Then we know that about 90% of the patients continue to have seizures despite multiple therapies. The other severe abnormality is about 20% of the patients will die typically from a sudden unexpected death in epilepsy.
Again, they do this before they reach adulthood. The other thing that's really important about Dravet is not simply seizures. There's been, I think, a misconception that somehow all of the disabilities are related to seizures. But what we know is that the underlying genetic defect is responsible for cognition and behavioral disorders and movement problems. It's a very significant disease that encompasses a lot more than simply seizures. One of the challenges, of course, is that multiple drugs are used to treat Dravet syndrome, but unfortunately very ineffectively. If we look at the number of drugs that are used, certainly for Dravet syndrome, the consistent aspect of this is they're all anti-seizure medications. If we look back, we haven't changed the management of seizures for the last probably 170 years.
If you go back in history and even a mile away from here at Queen Square, sodium bromide was used to treat epilepsy. And sodium bromide just suppressed electrical activity in the brain. And all of the current therapies for seizure management are really trying to control the seizures by suppressing electrical activity. But they have a lot of side effects. And unfortunately, this approach does not address the rest of the syndrome for Dravet syndrome. And it really is, how do we manage the rest of the symptoms? And I think what we're trying to do is to be the first company that develops a disease-modifying treatment and treats the underlying genetic cause. And one of the challenges, I think, that we've learned, and Dravet was described back in 1980, but the gene wasn't identified until 2000.
I think 25 years ago, before the human genome was cloned, we thought that 50% of epilepsy was idiopathic. And the way I remember idiopathic is the doctor is an idiot and the patient has a pathology. It means we didn't understand what was going on with the disease. We now know that that 50% of idiopathic epilepsy is genetic in cause. And so the focus, I think, of the next generation of epileptic therapy is to treat the genetic underlying cause and hopefully have a much better outcome. So this is how we're upregulating protein. And I think one of the, and this is called the TANGO approach, targeted augmentation of nuclear gene output. And what we're doing, and one of the things that is important is that most of the patients with Dravet syndrome have an identified mutation in the SCN1A gene.
This results in a haploinsufficiency of the Nav1.1 protein, an important subunit of the sodium channel protein. What we're doing is not addressing the mutated copy of the gene. We're actually focusing on the normal copy of the gene to compensate for that missing 50% protein, so what was discovered a number of years ago by our co-founder, Isabel Aznarez , that is heading our research now at Stoke, is that there were retained elements on the pre-messenger RNA that interfered with the development of a full-length protein. These were NMD exons, or sometimes they're referred to as poison exons, that if you splice them out, you actually can increase the full-length message and the amount of protein, so what you can see on the left, normally present, there is only a small amount of this NMD is spliced out by the cell itself.
What we're doing is, in fact, enhancing splicing with using an antisense oligonucleotide. So on the right, what you can see is that we use the ASO to enhance splicing. And what we're able to do in a dose-dependent manner, increase the amount of protein back up to that 100% level or as close to as possible. So one of the things that we looked at before we started this study is we did look at a two-year natural history study. And what we determined is that despite maximal treatment with a number of drugs, and that we knew that almost half of the patients were on the most effective treatment, which was fenfluramine, that there was no change in the convulsive seizure frequency despite maximal therapy. These patients continued to have seizures despite multiple therapies.
More importantly, what we found is that, and it was not related to the number of seizures, but that these patients had significant disabilities in their cognition and behavior. This is using the Vineland Adaptive Behavior Scale. And what we saw is that over, again, this is looking at 12 months, most of the patients declined or had minimal improvements or flatline in their skills, suggesting that, again, this is a disease that doesn't get better spontaneously, even with improvement in seizure control. And what we showed, and we will be showing more data next month at the American Epilepsy Society, but despite being on multiple seizure medications, we saw an 85% reduction at three months in seizure frequency. And that was maintained at six months at 74%. I think more importantly, though, is we saw reductions not only in seizures, but improvements in cognition and behavior.
This was in the open label extension study that we followed patients for 12 months. This was at lower doses at 30 and 45 milligrams. We showed a significant safety profile at even up to 70 milligrams single and multiple doses. They were generally well tolerated. What we learned from this study is that a loading dose of 70 milligrams was really critical. It wasn't a dose-dependent matter. We saw that even a single dose at three months and at six months showed a dramatic reduction in seizures of 43% and 57%. We used a loading dose of two or three doses at 70 milligrams. What we saw was, again, at three months, we saw an 85% reduction. At six months, it was maintained and had a 74% reduction. Again, this is on top of maximal treatment.
Most of these patients were on at least three medications and most on more than three medications. This is what we looked at from a 50% responder rate. We saw that 80% of the patients had a 50% or more reduction in seizures. Again, a very consistent response. This was independent of the age of the patient. We saw it respond at many different ages. But more importantly, I think what we saw was that when we looked at the patients who were treated with the 70 milligram multiple doses, and these were three dose 70 milligram patients who had received at least one dose of 45 milligrams, what we saw is that we saw this dramatic reduction that was maintained.
And then on the orange line, what we saw is these were patients who were on a much lower dose at 30 or 45 milligrams, but they also had maintained a reduction in seizures. And again, looking at what we saw at 12 months with the improvements in cognition and behavior, what we were able to show is that when we look at our ADMIRAL study, which is basically looking at 36 weeks, again, we saw really significant improvements in the Vineland in multiple measures. And then when those patients continued over in the open label extension, they continued to improve. So they had an initial improvement in cognition and behavior, and that continued and continued to increase when we looked at one year following. And again, this would be on patients who were at 30 or 45 milligrams.
One of the aspects that we looked at is what was basically over 12 months, what was the improvement between the Clinical Global Impression of Change or the caregiver. It was a very consistent response. We were able to match patients to our natural history study. What we saw was, again, the natural history study did not show any of the improvements. The lower score is a better score, so it was a flatline for the natural history over following a year. When we compared this to our treated group, we saw that both for the clinicians and for the caregivers, there was a significant improvement in the impression of overall improvement and change.
So just to summarize, I think the priorities for us, the focus for the remainder of this year is to really advance our phase three program, a registrational study. We will have discussions, and we're continuing with discussions with the FDA and our global regulatory agencies. We expect to have an update on the status of the Phase 3 protocol by the end of this year. And we also will be having further data looking at open label extension data at the American Epilepsy Society. And we'll be doing that in a couple of weeks. So I will end here and open it up for question and answer. And with me today is Tommy Leggett, our CFO, and Barry Ticho, Chief Medical Officer. Yes.
Yes. Thank you for the presentation. In one of the last slides, you showed the improvement in clinician and caregiver scores, I think, right?
Yes.
There was a, you know, I'm not an expert in this disease or anything, but there was a difference in the clinical assessment was more positive than the caregiver assessment. In light of the fact that you don't have, you cannot have a real placebo group here, can you elaborate a little bit how that difference? You know, it's not diametric, but there's a difference. How did that come about?
Hi, this is Barry Ticho. So I'll address that. Actually, when one looks at many other clinical trials, actually the caregivers or the patients tend to have a more favorable view of the response than the clinicians because their clinicians tend to be a little bit more objective and scrutinizing. Here, we were actually quite surprised that, as you said, the clinicians actually had a more favorable impression of how the patients were doing than even the caregivers.
This is based partially on the fact that the seizure reductions were occurring in these patients, but also, more importantly, that they were showing improvements in their communication, in their motor skills, in their skills of daily living, and that we captured that in the Vineland score. But this is also what was being noticed by the clinicians when they saw the patients at the study visits.
Thank you again. Quick question. It sounds like Dravet is more than just about seizures. It's a syndrome. You know, a lot of your data talk about reduction of the seizure frequency. But is that the most relevant endpoint in this population? And wondering in terms of approvability, would that be the most relevant endpoint, or could you or would you design a study to look at some of the other aspects of Dravet?
Thank you. So the answer is yes. For a primary endpoint, we would still look at seizure frequency. That's what's been the precedent for other treatments that have been approved for Dravet syndrome. But in this case, as opposed to other treatments where they did not look at some of these other seizure and cognition behaviors as part of the Phase 3, we will be capturing those as key secondary endpoints. So especially focused on something like the Vineland, which Ed just showed you, we showed substantial improvements in the patient's scores on that Vineland. That would be included as a key secondary endpoint. To the point that what we're developing here is a disease modifying therapy based on the fact that our medicine is treating the actual cause of the disease, and it is showing benefit to multiple different aspects of the disease. So not just the seizure control, but the non-seizure aspects as well. So we would include all of that as part of the clinical trial.
Any other questions? Okay. No other.