Good day, and thank you for standing by. Welcome to Understanding Dravet Syndrome: The Unmet Need and Potential for Disease Modification Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentations, there will be a question-and-answer session. To ask a question during the session, you will need to press Star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press Star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, to Edward Kaye, CEO of Stoke Therapeutics. Please go ahead. This is Edward Kaye, CEO of Stoke Therapeutics. Welcome, everyone, and thank you for joining us for today's educational webcast. Before we get started, I'd like to remind everyone that this webcast may include forward-looking statements, which are based on our current expectations and beliefs. They are subject to risks and uncertainties, and actual results may differ materially. Please refer to the risk factors discussed in our SEC filings. I'm grateful to be joined today by several of the world's leading experts on Dravet Syndrome. They are here to review our current understanding of this disease, including the impacts on seizures, behavior, and cognition, and what those mean for patients and their caregivers. They will take you through the latest findings from our studies on zorevunersen. Through data and anecdotes, today's presentations are intended to enhance the appreciation for the potential real-world impacts of disease and modification on patients and their families. Since the discovery of the SCN1A gene in 2000, we have learned a lot about Dravet Syndrome, what causes it, and its impacts. It has become clear to all of us that many people still do not understand the full impact of Dravet Syndrome. While seizures are becoming more well understood and anti-seizure medicines have improved, there is a lack of awareness and understanding of the substantial effects on behavior and cognition for this disease. This lack of understanding makes it hard to envision how different and life-changing potential disease-modifying new medicines could be for patients and their caregivers. For the past decade, Stoke has been working to develop potential first-in-class medicines for diseases that are caused by insufficient protein expression. We are doing this by upregulating protein expression with RNA-based medicines. Rather than address genetic diseases by replacing, repairing, or editing faulty genes, we aim to increase, or stoke, protein output from healthy genes to increase full-length, fully functional protein expression from a variety of healthy genes. This is an entirely unique approach to treating diseases. As we work together to move toward a new era in the treatment of Dravet Syndrome, with the development of potential new medicines like zorevunersen, it is critical that we establish a greater appreciation for this disease as a syndrome and thus the need for medicines that go beyond seizure management. On behalf of Stoke, I want to thank all of today's presenters for their tireless efforts to help people living with Dravet Syndrome and their families, and to work with us to do something that has never been done before: develop what could be the world's first disease-modifying medicine for Dravet Syndrome. And with that, I'd like to turn over the presentation to Dr. Joseph Sullivan. Hello, everyone. My name is Dr. Joseph Sullivan, and I'm a professor of neurology and pediatrics at the University of California, San Francisco, and in these next few minutes, I am going to review the natural history of seizures as well as the developmental deficits that are observed in patients with Dravet Syndrome. We now know a lot about Dravet Syndrome, and it really is the prototypical genetic developmental and epileptic encephalopathy. It is now very well accepted that over 85% of patients with Dravet Syndrome do have a pathogenic variant in the SCN1A gene that leads to haploinsufficiency, resulting in an overall 50% reduction in the expression of the NaV1.1 protein. It's actually also much more common than we initially thought. Estimates are now that it affects about one in 16,000 live births. And unfortunately, even with current treatments, up to 20% of these patients will die before adulthood, largely due to SUDEP or seizure-related accidents and infections. And even despite having many new therapies, upwards of 90% of patients with Dravet Syndrome do not have adequate seizure control. If we first look at the overall frequency of seizures over time, the Butterfly Natural History Study followed patients in an observational manner where principal investigators were allowed to make changes to their background medications as clinically indicated. In this figure, we can see a model of disease progression illustrated over that 24-month period of time, starting at month zero and going out for two full years. Each of these little circles here is meant to represent an individual patient over that period of time. As we can see the summary of this disease model as shown by this line, there really is no meaningful improvement in the overwhelming majority of patients with Dravet Syndrome. That is despite us being able to, investigators, as I mentioned, able to make changes as we saw fit. The most commonly used medications in these patients are shown in the table over to the right. They really are the most commonly used medications that we have come to see as being the most effective. I'll highlight here that two-thirds of the patients were on clobazam, and almost half of the patients were actually also on fenfluramine. Looking at this in a different natural history study, this was the Envision Natural History Study that also looked at the different types of seizures by their age of onset and how they emerged and evolved over time. As we have long known, generalized tonic-clonic or focal motor seizures peak in that first year of life. But then, as the patients get older, other seizure types emerge. And for those of us who care for patients with Dravet Syndrome, it's very important for us to understand when these different seizure types can occur because we can counsel families as to when to report them to us so that we can then make some treatment changes as we also see clinically indicated. In this study also, the average number of medications that these patients were on were three anti-seizure medications, further highlighting the fact that these seizure types continue to evolve and emerge despite best current standards of care. So I know we spend a lot of time focusing on seizures, but there's a reason why Dravet Syndrome is called a syndrome. Dravet syndrome is much more than just seizures. This figure is really meant to highlight all of the different domains that impact central nervous function, with a specific focus on the cognitive and behavioral impairments in each of those subdomains. I think we could all agree that speech and communication, learning, sleep, behavior, and motor function are very important elements to normal day-to-day functioning. All of these are negatively impacted to some extent in the overwhelming majority of patients living with Dravet Syndrome. That was highlighted very nicely in a long-term natural history study conducted by Dr. Andreas Brunklaus and his group, where patients were followed over a 10-year period of time with a series of developmental questionnaires and assessments that were done by the caring provider. What this figure is meant to show is individual patients. And we can see to the left in between the zero and five years of age that some of these patients do actually start out in the normal or average range, but many of them already do have mild to severe impairment. Then, if you extrapolate out over 10 years and follow those individual patients, we can see this unfortunate sharp decline in their overall standard score and developmental quotients. Now, this is not meant to mean that these patients actually worsen or regress over time, although that sometimes can be seen during episodes of seizure exacerbation or status epilepticus, but rather is meant to highlight that over a 10-year period of time, when compared to their age-matched peers, they continue to fall farther and farther behind so that by the age of around 15 years, the majority of Dravet Syndrome patients are in the severe to profound level of cognitive impairment. There's a lot of different ways that we in child neurology and epilepsy can evaluate behavior and cognition over time. The Vineland-3 is one that actually has been very commonly used both in clinical practice as well as in many clinical research studies. This is a tool that is a structured interview by a skilled interviewer that has training in the Vineland. The caregiver will respond to each of these questions on a scale of zero, one, or two, meaning never, sometimes, or usually. I won't go through every single aspect, but there are four main domains with 11 subdomains that are looked at so that we can tease out if there are different salient aspects in individual patients that represent relative strengths or weaknesses. One common question that we actually get asked is, how meaningful is a two-point change on the Vineland? Someone that goes from never doing that skill to usually doing that skill. We just kind of put out a couple of specific questions that are on the Vineland. This first one here in expressive communication would be using three basic gestures. So for example, a head nod for yes, a head shake for no, reaching or pointing towards something, waving and clapping. So someone may never do that, but then over a period of time, say over one year, if they usually do that, that would actually represent that two-point change. And then these questions are asked in a developmental manner, right? If you can do one thing usually, then you go on to the next question and so on. And as you get further on down into the developmental trajectory, we can see that development progresses. So in expressive language, patients will say at least 50 words. And when we asked our caregivers what would that mean for a patient with Dravet Syndrome living with Dravet Syndrome to sometimes or usually have 50 words, that would actually be described as life-changing. You can see the other sort of examples here for gross motor and fine motor that are called out as some questions on the Vineland. So this was actually looked at in the Butterfly Natural History study. In many ways, you could actually say that this is a mirror image of the prior figure that I showed from Dr. Brunklaus's group, showing this overall downward slope of the adaptive behavior composite score over time. Again, not representing regression, but we can see what the slope should be at the top. In someone who's neurotypical, they remain at the sort of level of 100, but over time, as these patients get older, they fall farther and farther behind their neurotypical peers. Since we illustrated all of those different subdomains, here are two figures showing two of those subdomains and how those patients actually performed with this same disease model over a 24-month period of time. So bear with me here. This is a model that really accounts for multiple mixed effects of repeated measures over time. Again, it is a model of disease progression for the actual cohort. We can see here the estimated mean age equivalent at entry into this study was 22 months for expressive communication and 23 months for gross motor skills. When we do this disease model over time, we can see that line remains relatively flat, right? This means that these patients are really making some small gains, but really they are not statistically significant over a two-year period of time. And then when you compare that to what we would expect their neurotypical peers to do over this same period of time, we can again see illustrated here that widening gap in that function over time. And so this is just looking at with a little bit more granularity in each of these two domains. We did look at many other domains as well. But for the purpose of efficiency here and not showing too many figures of all of those different subdomains, please take my word for it that there were also no improvements in those areas either. Going back to that same Envision Natural History study where I highlighted the earlier occurrence of seizures, that study also looked at the Vineland subdomains. This study was a little bit different than the Butterfly study in that they really tried to identify and enroll younger patients under the age of five years of age, and that's why we actually have on the x-axis here their chronological age going all the way down to about six months. What I would like to highlight here are the two separate black lines each in the receptive communication figures, with there being an inflection point in the receptive communication at around two years of age and a little bit later in expressive communication, showing that in those first two years of life, more significant improvements and gains are made in each of these domains, but then there's this inflection point and relative plateau that occurs. And you can almost imagine this continuing on with the other figures in older patients, again, showing that flatness of the overall line. So how do we put all of this together? Hopefully, I've shown you in these few minutes that patients with Dravet Syndrome, as a syndrome, experience a wide range of symptoms that go well beyond seizures that include a lot of the important determinants in overall quality of life because of the underlying impairments in learning, behavior, and speech and communication. These non-seizure symptoms do start early. So I think we have an opportunity here to try and intervene and prevent this widening gap over time. And as Ed mentioned, these non-seizure symptoms really do highlight the need for a disease-modifying therapy that goes well beyond just getting us improvements in seizures. I will now turn it over to Veronica Hood and Mary Anne Meskis from the Dravet Syndrome Foundation. Hello. My name is Veronica Hood. I'm the scientific director at the Dravet Syndrome Foundation. And today, I'll be presenting with Mary Anne Meskis, the executive director at the Dravet Syndrome Foundation, on clinically meaningful improvements in symptoms of Dravet Syndrome from the community perspective. The patient family community has indicated the strong desire for treatments that address symptoms beyond seizures. In 2022, the Dravet Syndrome Foundation held an externally led patient-focused drug development meeting where caregivers were asked in two different contexts, one pre-meeting survey related to disease-modifying therapies and one during a live meeting poll about prioritization of symptom burden and/or symptoms that have the highest therapeutic need. While seizure control certainly still remains a top unmet need for the patient community, you can see from this ranking in the graph here that other symptom domains like cognition, behavior, speech, movement, and sleep were also commonly reported as a high priority by caregivers for which treatments are desperately needed. All of these symptoms greatly impact patient independence and quality of life, not only for the patient, but for the entire family. However, establishing the treatment benefit for non-seizure outcomes in Dravet Syndrome is challenging due to a lack of validated assessments. While relying on statistics to indicate significant changes in endpoint data is critical to an unbiased and dependable result, understanding the real-world perspectives of patients and their families on what level of change is meaningful in their daily quality of life should be used to guide endpoint development and assessment. This is a view outlined by the FDA in their patient-focused drug development guidance series. As already noted by Dr. Sullivan, the Vineland-3 assessment is commonly used to assess behavioral outcomes in Dravet Syndrome, but thresholds of what meaningful change is to patients and families has not previously been established. When caregivers were asked to rank the subdomains in order of importance for improvement, the results are somewhat similar to the rankings that we observed in the previous community surveys that I just presented on the previous slide that were associated with the externally led PFDD meeting. In particular, in this assessment with the subdomain specific to the Vineland-3, we saw that after seizures, expressive and receptive communication subdomains were ranked as the most important to change with treatment. Furthermore, as Dr. Sullivan has already alluded to, caregivers provided insights into what meaningful change would look like for them and for their loved one living with Dravet Syndrome within each of these subdomains. Generally, changes of two to three points in gross scale values were considered as meaningful to at least half of caregivers. The individual impacts of Dravet Syndrome are incredibly unique, and meaningful change may look somewhat different from patient to patient and family to family. But these ranges provide at least a common baseline to understand broadly what meaningful improvements look like to an average family navigating the symptoms of Dravet Syndrome. And hopefully, these insights will provide additional color to the results from the current study of zorevunersen, as many of the subdomains in the Vineland-3 assessment show changes that would fall within or beyond this range for meaningful change as defined by caregivers. Again, statistical confidence is incredibly important, but we must take into account the real-world lived experiences of patients when we are interpreting data around outcomes, particularly in rare life-altering diseases like Dravet Syndrome. And to that end, I'd like to now hand it over to Mary Anne Meskis, who's a founding member and executive director of the Dravet Syndrome Foundation, and importantly, who is also a caregiver to a son living with Dravet Syndrome. And she can speak a bit more to the lived experience and reflect on what some of these changes that we're describing in the Vineland scale might really mean to patients and families who are living day-to-day with Dravet Syndrome. Hello. My name is Mary Anne Meskis. I'm the executive director of the Dravet Syndrome Foundation and the caregiver to an adult son with Dravet Syndrome. From the patient and caregiver perspective, the option of a treatment such as zorevunersen that could not only potentially reduce or eliminate seizures as well as offer some level of disease reversal would represent a profound breakthrough for individuals living with Dravet Syndrome. It could change Dravet Syndrome from a profoundly life-altering and debilitating condition into a more manageable challenge, providing the opportunity for patients to live a more fulfilling and independent life. After watching the videos that Dr. Brunklaus will be showing shortly, I can't help but reflect on what these types of changes could mean for my son. It can be hard to fully grasp the profound impact that even small changes might have on a patient, but try to imagine needing help with everything all day, every day, and what it would mean to suddenly gain some independence and autonomy. At almost 25 years of age, my son, Elliott, requires help with every aspect of his daily life. Each morning, my husband and I assist him with bathing, brushing his teeth, and getting dressed. We prepare all of his meals, cutting everything into small bite-sized pieces. He needs support navigating stairs and walking short distances. We provide constant supervision not only to ensure his safety in case of a seizure, but also to prevent accidents or him wandering off into potentially dangerous situations. His disruptive behavior prevents him from currently participating in the day program, and even at night, one of us is there co-sleeping with him. Treatments that could provide what might be seen as minor measurable improvements in daily living skills would have a profound and meaningful impact for the patients in our community. It would also ease some of the significant caregiving responsibilities that my husband and I shoulder. For Elliott, gaining more independence in any of these areas would be life-changing for him and for us. And with that, I'd like to turn it over to Dr. Brunklaus. My name is Dr. Andreas Brunklaus. I'm a child neurologist and professor at the University of Glasgow. And following these previous presentations, I will now focus on the potential for disease modification in Dravet Syndrome. And what we have seen previously on data on ASM that do support improvement in non-seizure outcomes, but what we notice is that the neurodevelopmental gap observed in the natural history studies remains. And this is illustrated from this study looking at treatment with fenfluramine showing improvements in everyday executive functioning in children with Dravet Syndrome, as illustrated here in the graph versus placebo. But what we notice is that despite these treatments and the natural history study data that Dr. Sullivan showed earlier, this neurodevelopmental gap that we observe still remains despite these conventional anti-seizure medications. And so far, in terms of the treatment landscape for Dravet Syndrome, we really are moving beyond seizure management to address this unmet need of, in particular, these comorbidities. We have so far many anti-seizure medications that have been identified, in particular, for seizure management. However, to address the syndrome, there really is an existing treatment gap. Recently, we've had the development of two potential disease-modifying therapies that are currently in clinical development for the treatment of Dravet Syndrome. On the left, you can see ETX101, and this is an AAV9 vector-delivered gene regulation therapy. The purpose of this therapy is to increase the SCN1A expression through the delivery of an engineered transcription factor that regulates the SCN1A production. The phase one, two studies are ongoing for this new disease-modifying therapy. On the right, you can see zorevunersen. This is an antisense oligonucleotide ASO therapy. The aim of this therapy is to upregulate voltage-gated sodium channel NaV1.1 by leveraging the wild-type copy of SCN1A to restore NaV1.1 to physiological levels. The phase one and two A studies have been completed, and the open-label extension is ongoing. Currently, the phase three of this product is being planned. Now, focusing on the safety and efficacy of zorevunersen, which were evaluated in the phase one, two, and open-label extension studies. These were the Monarch study in the U.S. and the Admiral study performed in the U.K. The Monarch study had the single ascending dose up to 70 milligrams per dose and multiple ascending dose up to 45 milligrams per dose. In the U.K., it was multiple ascending dose up to 70 milligrams per dose. There were 62 patients dosed in the U.S. in the Monarch study and 19 in the U.K. in the Admiral study. Overall, the endpoint was that of safety and tolerability of single ascending and multiple ascending doses, as well as human PK and CSF drug exposure. The secondary endpoints were the change in convulsive seizure frequency and overall clinical status, as well as quality of life, which is really important. In the open-label extension studies, this has been Swallowtail in the U.S. and Longwing in the U.K. In both of those, we have ongoing doses of 45 milligrams per dose every four months. 81 patients in total have been treated. Just to give an overview of the population description, these were patients at a median age of 10 years. What is really important to highlight is that all these patients have been on a number of concomitant anti-seizure medications, often more than three or four anti-seizure medications. Up to 50% of these patients have been on concomitant fenfluramine. So they have been receiving the optimal standard of care for Dravet Syndrome in terms of conventional anti-seizure medications. The baseline convulsive seizure frequency per 28 days was a median of 17 seizures per 28 days. Now, in the initial doses of up to 70 milligrams zorevunersen, followed by long-term maintenance doses, these were generally well tolerated. What we can say for the phase 1/2 studies, where we had 81 patients, is that 30% of patients experienced study-related TAE. Most common was CSF protein elevations in 13.6% of patients, as well as procedural vomiting. However, there was no clinical implications of these protein elevations. 22% of patients experienced TAE, and all were unrelated to the study drug, except there was one patient with a SUSAR. In the open-label extension studies, we had 74 patients, and 79% of patients had CSF protein elevations. However, there was no clinical manifestation that was observed in these patients with elevated CSF protein. One patient discontinued treatment due to elevated CSF protein. However, this patient did not have any clinical signs associated with this. Looking at the patients treated with 70 milligrams zorevunersen in the phase one, two studies, which experienced a substantial and sustained reduction in convulsive seizure frequency, which is illustrated here. Here, you can see the median% change in convulsive seizure frequency from baseline in the phase 1/2 studies. You can see on the y-axis the median change from baseline. On the x-axis, you can see the periods over time. Here, with those patients, those with 70 milligrams one dose or 70 milligrams two doses or 70 milligrams three doses, this sustained reduction in convulsive seizure frequency down to 80% in some cases. Looking at the open-label extension studies, these are patients treated with 70 milligrams zorevunersen experienced a durable reduction in convulsive seizure frequency of over 50% through to month eight in the open-label extension studies. Here, you can see the results from the Swallowtail and Longwing open-label extension with a median% change in convulsive seizure frequency from baseline. What is obvious here is that in those with 70 milligrams, one dose, 70 milligrams, two doses, and 70 milligrams, three doses, over the course of the open-label extension, that there's durable reduction in convulsive seizure frequency. Now, looking at the convulsive seizure frequency from the phase one, two baseline, which were then observed with continued treatment with zorevunersen. Here, illustrating the reductions in convulsive seizure frequency that were sustained through month 24 of the open-label extension. Here, particularly in orange, the enrolled patients at each time point. And in green, particularly the 70 milligrams, one, two, or three doses of the phase one, two, and over 30 milligrams in the open-label extension, clearly showing this sustained reduction in convulsive seizure frequency. However, what was earlier illustrated by Dr. Sullivan and also by Veronica Hood and Mary Anne Meskis, the comorbidities are really, really important in Dravet Syndrome. Here, what we can report is the improvements in cognition and behavior that were observed within the first year of treatment in the Admiral Study and continued with ongoing treatment in the open-label extension. See, on the left-hand side, you can see the graph illustrating the Vineland changes in the Admiral Study at nine months. What we can clearly see here is an improvement in the Vineland subdomains, such as receptive communication, expressive communication, and gross motor skills. This is clearly different to what we would expect in the natural history studies, therefore showing an improvement following treatment in the Admiral Study. On the right-hand side, you can see the Swallowtail and Longwing open-label up to 24 months, again illustrating the Vineland subdomains and improvements in receptive communication, expressive communication, play and leisure, as well as gross motor skills. This is really in contrast to the data from the previous natural history studies that showed that these expected improvements are not expected in patients with Dravet Syndrome. What we see here in the Swallowtail, Longwing open-label that we have a clear improvement in these Vineland subscores. So clearly, we can show evidence to support the potential for zorevunersen to be the first medicine to treat the underlying cause of Dravet Syndrome beyond seizure reduction, also improving comorbidities and cognitive aspects. I can summarize that the development of patients with Dravet Syndrome lags behind in their neurotypical peers, and the gap widens over time despite the use of best available anti-seizure medications. Small impacts on non-seizure symptoms have incredibly large impacts on the day-to-day life of patients and their caregivers. Patients treated with zorevunersen experienced really substantial and durable reductions in convulsive seizure frequency that were observed through month 24 in patients already receiving the best background anti-seizure medications, with the largest reduction in patients who received larger dose of 70 milligrams loading doses in phase one, two, and 30 or 45 milligrams doses in the open-label extensions. Patients treated with zorevunersen experienced durable improvements in multiple measures of cognition, behavior, and overall clinical status. These are really important comorbidities, which continue to improve through 24 months of the open-label extension with ongoing maintenance dosing, which is different to natural history data that we've previously seen. And this multiple maintenance doses of zorevunersen up to 45 milligrams were generally well tolerated. And finally, I would like to give you an example of what disease modification might represent for patients. And this is the example of a 12-year-old child of mine with Dravet Syndrome. She presents with a typical history of the first seizure occurring at four months of age with a generalized tonic-clonic seizure from sleep. She then had subsequently generalized tonic-clonic and hemiclonic seizures triggered by fever and often prolonged with episodes of status epilepticus seizures that last over half an hour. She had a de novo pathogenic SCN1A missense variant identified, and her development was assumed normal prior to the seizure onset. However, cognitive difficulties were noticed around two to three years of age. She currently has a baseline intellectual disability with an IQ of 55. Her baseline anti-seizure medications at study entry were Sodium valproate, clobazam, stiripentol, cannabidiol. Despite these conventional standard treatments, she still is having four to five seizures per month at baseline. She was then enrolled in the Admiral Study at the age of 11 years. These videos of her were captured at baseline and then subsequently eight and 12 months after start of zorevunersen dosing. As a reminder, this is a single patient experience, and this is the only patient I treated in the Admiral Study. Each patient is unique, and this may not be representative of patient population as a whole, nor is it intended to depict what an individual patient may experience. And what you will see in the videos is, first of all, her buttoning a shirt at baseline, and then at follow-up, then she will perform a finger-nose testing, illustrating her dexterity, but also her understanding of the test, then a counting task, and finally, her kicking a ball at baseline, and then after eight months of treatment. And finally, we will show her handwriting skills prior to treatment and then after eight months of treatment. Right. Touch my finger. Yeah. Touch my finger and touch your nose. And then touch your nose. Oh, no. With the same finger. That's okay. Good. With that finger, touch my finger. Yeah. Touch my finger and touch your nose. Touch your nose. I can't move then. That's right. So what you do, look, look, look, look, look what you do. Like that. Look, like that. Yeah, you do that. Exactly. Like this. Touch my finger and touch your nose. Touch my finger, touch your nose. Touch my finger, touch your nose. Touch my finger, touch your nose. Oh, if you do that. Really good. Finger, touch your nose. Great. Touch my finger, touch your nose. Touch my finger, touch your nose. Touch my finger, touch your nose. Touch my finger, touch your nose. Touch my finger, touch your nose. That's really good. How well can you count? Can you count from one? I don't know. I was just keeping counting. Can you count from one to ten? One, two, and then three, three, four, five. Well done. Can you count from one to ten? One. Two, three, four, five, six, seven, eight, nine, ten. Fantastic. Well done. Which school do you go to? Oh, you're a teacher. Ms. O'Neill. And what's your favorite topic? What do you like best at school? Handwriting. Handwriting. You've got a neat handwriting, have you? Mm-hmm. That's fantastic. [Foreign language]. [Foreign language]. [Foreign language]. One more time, one more time. [Foreign language]. [Foreign language]. [Foreign language]. [Foreign language]. [Foreign language]. [Foreign language]. Okay. So on this slide, you can see the improved handwriting. She's, this is more accurate. She's got more uniform letters and has consistent spacing. And in the previous videos, you could see her improved gross motor skills when she's kicking a ball, her better posture and coordination, her improved fine motor skills when she was buttoning her shirt. In the finger nose testing task, this illustrates better understanding and coordination. And in the counting task, she had better eye contact, less, she was less gaze avoidance. There were less autistic features, and she was just engaging better with me during the task. And generally, from a cognitive perspective, this was a child that previously had no concept of the days of the week. She was just living day by day. And now, suddenly, she's telling her parents, for example, that next Monday she's not going to school because it's St. Patrick's Day. She never participated in any dinner conversations. And now she's very eager to interact with her family. The family go to church. She's now suddenly asking, "Why is the priest wearing a different color gown on different days of the week?" And she's been telling her teacher that she's had too many thoughts in her head. At the age of 12 years, these are significant changes that we would not expect as part of the natural history of Dravet Syndrome. So finally, I would like to thank all the families to take part in the study. And I would like to thank the Stoke team for developing this life-changing treatment for our patients. Operator, we'll now move it to a Q&A, please. Thank you, sir. As a reminder, to ask a question, you will need to press star 11 on your telephone. To withdraw your question, please press star 11 again. We ask that you please keep your questions to no more than two, but please feel free to go back into the queue. And if time permits, we'll be more than happy to take your follow-up questions at that time. Please stand by while we compile the Q&A roster. Our first question comes from the line of Laura Chico from Wedbush. Please go ahead. Good morning. Thank you very much for taking the question. I have one for—I think I'll direct this to Dr. Sullivan, but if Dr. Brunklaus has additional commentary. And then I have a follow-up for Stoke. Given your patient load and experience in treating Dravet patients, I'm wondering, can you speak to how the experience shown in the video might contrast with other study participants you've treated or perhaps even seen in other Dravet studies that you've participated in? Sure, absolutely. I mean, maybe I'll just start out with other studies that I've participated in. I certainly have not seen, like Andrea said, this degree of change that we can attribute to, say, just improved seizure control. Certainly, when we get improved seizure control, we see kids brighten up a little bit and need less rescue medicines and things. But all of these different developmental domains that were highlighted in the videos really do, in my opinion, go far beyond what we would expect from just reducing seizures and really does suggest that disease modification. After Andreas showed me these videos a few months ago, I certainly have patients in the Stoke trials who have had this really dramatic benefit. It actually made me feel like I should have done some videos. So I actually reached out to a few of those families and really just unsolicited, just said, "Would you mind just sharing with me your experience so that I can maybe share that with others?" And if you actually don't mind, I'd like to just read the email response that she actually gave to me. So this is an eight-year-old who was actually in the 45 milligram multiple ascending dose. And actually, it was one of the patients back a year ago when there was the partial clinical hold. Actually had to go down to 30 milligrams and then is now back up at 45 milligrams. And I'll just say, so his balance and gross motor skills have improved. He used to need a large harness on his service dog to help him walk without tripping and falling. We've removed that harness, and he is now holding the leash to actually walk his service dog. He's also learned how to ride on cars. Before, he was not able to grasp the concept of doing two things at once, such as steering and using the foot pedals. He's also learned how to ride a bike without training wheels, which is something I never imagined. He's finally able to pump his legs and swing on his own at the playground. His overall balance and coordination are much better. He plays on three special needs sports teams: basketball, baseball, and flag football. In the past two years, he has made improvements with actually learning to throw, catch, hit a ball thrown to him, not from a tee, and has also joined his school's cross-country team and was able to run a half mile without walking. One other thing about this child is he had a lot of photosensitivity, which we commonly see in Dravet Syndrome. He was not even able to go outside. The family comments that everything that triggered seizures (light, sunlight patterns, illness, temperature) do not seem to affect him anymore. He's a different kid, and we are living a different life now. Our quality of life has made an improvement I never thought possible. We are able to travel, enjoy amusement parks, movie theaters, festivals, etc., all things he was never able to partake in. I think this is a narrative that really is very much in line with the videos that you saw with Andreas. I do have a few other patients that maybe not to this extent, but you're getting the sort of theme here that those things are improving more than we would have anticipated. Just a quick follow-up for Stoke. I know we'll be getting a more fulsome update on the phase 3 plan in the coming weeks here, but how are you thinking about the loading regimen now? Should that be two or three doses? Because it's a little tricky to see a differentiation in the responses here, but thank you very much. Yes. Hello, Laura. This is Barry. Thanks for the question. As we've shown, the two and three 70-milligram dose regimen in terms of seizure reduction are quite similar. That's both in the phase 1 and 2 study as well as in the open-label extension study out to those eight months. So that gives us a lot of confidence, even though it's small numbers, in the magnitude and the duration of the effect and tells us that a loading dose is the proper regimen that we should propose for phase three as well as a 45-milligram maintenance dose. And so we are in active discussions right now with the regulators to determine whether those two or three doses will be used for loading. Thanks very much. Thank you. And I show our next question comes from the line of Tom Schrader from BTIG. Please go ahead. Good morning. Congratulations. Boy, that's quite a movie, really, I have to say. I'm a little. If you can give us a sense of what you think is happening with seizures, are the seizure types changing as if the children are backing up and they're getting more seizures that are characteristic of early Dravet? And I can't really figure it out from your data. Do you have children that have become truly seizure-free? Thank you. So, clearly what we see in our patients is a reduction of overall seizure counts. The patients still experience their typical seizure types, but at much less frequency. You could see in the 70-milligram dosing cohort, this reducing down to 75%. There are some children who've become seizure-free as part of the trial. So to answer your question, we see a significant reduction in seizure types, but they appear to be the typical seizure types. Yeah, I guess the only thing I'll add, seizure freedom, at least how we measured in these studies, right, it's hard with anything in this disorder to have persistent seizure freedom. Once you have one seizure, you therefore can never be seizure-free again. So I have at least three or four patients who are having these three- to four-month periods of seizure freedom. Then they may have a single seizure, whether that be during an illness or something. And that compares to the baseline, as we know, for many of these patients who went into it having the requirement was four or more seizures per month, but many of these patients were having 10 to 15 seizures a month. So three- to four-month periods of seizure freedom has been quite remarkable. Great. Thanks for the detail. Thank you. And now our next question comes from the line of Yaron Werber from TD Cowen. Please go ahead. Right. Thanks for doing this event and really showing the natural history. It's really useful in the videos. Maybe I have a couple of questions maybe for the company and obviously for the KOLs as well. When you're thinking about the secondary endpoints, we've seen a lot of data now based on the Vineland-3 and looking at receptive and expressive communication, different elements of behavior, and interpersonal skills, and then something to do with coping skills, anxiety, and obviously gross and fine motor. Which ones do you think are, as you think about secondary endpoints for the phase 3, are sort of most clinically meaningful but also most sensitive based on the Vineland-3 to really detecting a benefit? And then secondly, as you think about phase 3, do you think there's going to be a sham or a placebo in that study? Yeah. Hi, this is Barry. I'll take that question. So the Vineland-3, as you mentioned, has multiple different subdomains. We actually have done a study where we looked externally, talking to both caregivers as well as clinicians to ask them that exact question, which are the most important subdomains that they would want to see changed in their child with the treatment. The response was quite uniform, actually, that expressive communication, receptive communication, the interpersonal skills, the personal skills, care for themselves, those were ranked among the highest. Those happened to be the same changes that we're seeing improve with zorevunersen in the open label extension study as well as even in the first nine months after treatment in the phase one and two study. Yeah. I mean, I would agree. I mean, I think what the videos highlight, right, is a significant, arguably somewhat life-changing change. But even benefits at a smaller scale that I think are easily measurable over a relatively, I won't say short, but medium period of time, we can see just going from understanding gestures to be able to speak a few words. If you imagine how that translates into the day-to-day sort of activities and how to parent and raise these children, I think it is going to be measurable and something that we can anticipate to see in the phase 3 trial. In regards to the status with the regulators right now, we're in active discussions. We're having very positive relationship discussions with them. As far as the secondary endpoints, the regulators around the world are quite familiar with the Vineland, as we've talked about. And so that's likely to be something that we would include as a secondary endpoint. Oh. As far as the sham goes, the control arm will be an important part of the phase 3 study. We know that these are patients who have good responses to what we've seen in our phase 1 and 2 studies, but those were open label studies. So having a control arm will be important. Whether it will be sham or what constitutes that control arm is something that's still under discussion with the regulators. Barry, is the age group maybe final follow-up? They're going to be the same as the phase 1/2? As you think about other age groups, is there going to be kind of a supplementary study in the future? Thank you. Yeah, that's still under discussion with the regulators, but we have shown the data for the 2 to 18-year-olds previously. That would be the basis for our proposals for the phase 3 study. In terms of other age groups, we are interested in studying patients under two years of age in terms of how they respond. We know that likely earlier treatment is important, but adult treatment is also equally important. We hear from many of our caregivers and the patient advocates that they want to make sure that this potential treatment is available for the older patients because they want to see a response. We do have data now in older patients, 18 patients who are 18 or even 19 who are continuing in our open-label extension study showing that they do have a response in terms of both seizure reduction and improvements in cognition and behavior. That certainly is an age group that we would be interested in studying as well. Thank you. Our next question comes from the line of Jessica Fye from J.P. Morgan. Please go ahead. Hey, guys. Good morning. Thanks for taking my question. Question for Dr. Sullivan and Brunklaus. What do you think the placebo response on these various Vineland domains would be with an intrathecal placebo or sham procedure? So I think this is really reflected by the natural history data that we have. So we've collected Butterfly Natural History Study data over a period of two years where you can see what the natural history is. In terms of the Vineland data, you can really see that amongst many studies, we studied this across really many patients, and myself also, we did 10-year follow-up studies where we can actually see that over that period of time, the gap between the patients and their peers becomes ever greater. Yeah? So we can see that what we would expect is that these children actually plateau and compared to their peers, they're actually falling behind. And this is something that we've now seen and what I've shown you really diverges significantly from what we would expect from the natural history. And in the sham arm, what we would expect the control arm, that we would see those natural history data being reflected. Thank you. Thank you. And our next question comes from the line of Sumant Kulkarni from Canaccord Genuity. Please go ahead. Good morning. Thanks for hosting this informative event, and thanks for taking our questions. I have two. For Dr. Sullivan and Brunklaus, do you foresee any logistical challenges in the ability to carry out the relevant measurements needed to ascertain the potential cognitive and behavioral benefits of zorevunersen in a registrational phase three setting? So let me make sure I understand the question. So practical challenges with measuring the assessments or the metrics? Yes. Measuring that in a consistent and, I guess, reliable way in a phase three setting. Yeah. No, I mean, I don't see there's any challenges. I mean, I think we learned a lot, as Andreas said, from the natural history study. And those natural history studies were very involved with a lot of assessments. The phase three is likely not going to include as many assessments because we now have the luxury of knowing which ones correlate well and which ones are most efficient and reproducible to assess that change over time. And this is part of what we're actually doing in clinical care, right? When we're seeing these patients for clinical visits, yes, we talk about seizures. But most of the time, we really try to get into the details of what are they seeing developmentally. So I think the Vineland and these other assessments are well positioned to sort of tease out that change over the time period and duration of the study. Just to say, the Vineland questionnaire is a parental interview, which is very easy to perform. Yeah? So this is something that doesn't cause any logistical or practical issues. It's a really standardized, easy-to-perform task. And I wouldn't foresee any difficulties with performing this going forward. Thanks. For the company, does the recent grant of breakthrough therapy designation by the FDA afford the potential to shorten the timeline for the actual conduct of a phase three trial to bring this important product to patients? Well, I think we're very pleased with the breakthrough therapy. I think what the real significance of this is it allows us much greater access to the FDA, especially to senior management at the FDA. So I think it'll help expedite our discussions. And we look forward to continuing those discussions with very senior people at the FDA. So it's a very helpful tool for us as we go through the phase three study and discussion. Thank you. Thank you. And our next question comes from the line of Joseph Stringer from Needham & Company. Please go ahead. Mr. Stringer, your line is open. If you have your phone muted, please unmute your line. Hello, Mr. Stringer. Can you hear us? Okay. Moving on to the next question. And I see our next question comes from the line of Marc Goodman from Leerink Partners. Please go ahead. Yes. For the physicians, I guess the question is, are you comfortable treating all ages? I mean, are there any types of Dravet patients that you're not comfortable treating? And then I was curious, and this could be for the company or for the physicians, but are there any synergies that we're seeing with particular ASMs? Have we seen anything where one particular drug that they're on might be a good con med for them? And I guess also just for the KOLs, how do you think about this protein elevation? There may be no symptoms, but how do you think about this as far as a safety issue? Thanks. I can address the question about the ages. So clearly, the age range here was from two to 18. So it's a broad age range, particularly. We would also be interested clinically to treat younger patients, which would be relevant. And in terms of the results, we've seen good results across the age range, which is important. And it's very encouraging. For example, the patient that I showed you is 12 years old. So seeing such encouraging results, even in older patients, is really very encouraging. And I wouldn't foresee clinically any limitations with regard to ages in terms of treatment. Yeah. And I can maybe take the one on the ASMs and synergy and the protein. We only have so many ASMs that we commonly use in these patients. In my experience, there has not been a sort of combination or cocktail, so to speak, that works better or worse with zorevunersen. I think the important thing is that we keep medications stable for a period of time, and then when we have the stability, some patients are actually, we're starting to engage in the discussion of whether or not we'll come off medicine. So I think that's something very exciting that we'll actually hopefully have more data in the coming year. In terms of the CSF protein, we've looked into this a lot early on in the study. We didn't really know what direction things were going to go and how common it was. We can now, I think, say that it's not dose-related. It seems to be related more to duration in the study, and they all have different trajectories. However, none of them go up dramatically within the four-month period where it's necessarily a surprise or a safety concern. And in all of my patients, they've all plateaued. And then even though we haven't changed the dose or interval of the dosing, we are starting to sort of trickle down. So individual patients, I think, have their own sort of trajectories. But so far, there hasn't been anyone that has continued to rise. And most importantly, no one has had any clinical symptoms of increased intracranial pressure or any other symptoms that could be referable to an elevated CSF protein. So something that's still ongoing. But as a clinician investigator, nothing that I have huge concerns about. And there's no specific type of Dravet patient that you would feel uncomfortable treating? I mean, you talked about age, but any specific type, or they're all eligible? No, I think they're all eligible. I mean, I think based on the inclusion criteria, we're already self-selecting, arguably, those that are more treatment-resistant. In a perfect world, I wish we could actually enroll kids that are maybe only having two seizures a month because then maybe the disease-modifying potential could be even greater in those patients. But as far as the study, I think, yeah, the only patients that maybe I could think of as someone who's having frequent episodes of status epilepticus, if there is going to be a placebo sham arm, we want these patients to be as stable as they possibly can be to enter the study. But in the same breath, that might be the exact patient that could really benefit from this. So I really don't think there's any patient subtype or phenotype that I would have concerns about enrolling. Yeah. I think what's really important to highlight is that, of course, Dravet syndrome, it's a loss of function SCN1A-related disease. So we know about gain of function SCN1A disease, which is completely different. So it's a different phenotype. So Dravet syndrome is a loss of function and disease. So for all those patients, this will be appropriate. Thanks. Thank you. Due to the constraints of time, we ask that you please limit your questions to one at this time. Thank you. And our next question comes from the line of Joseph Stringer from Needham & Company. Please go ahead. Hi. Thanks for fitting me back in, and thanks for taking my question. I had a follow-up question, maybe the previous one, just for the KOLs, Dr. Sullivan and Brunklaus. Based on the zorevunersen data to date, can you just comment on where you see the drug being potentially used in the current treatment paradigm? I know you touched on it in the previous question, but would you anticipate that it could be widely used as a first-line treatment, or do you feel that it would be more reserved for refractory patients, i.e., those that don't currently have adequate seizure control with their standard of care? Yeah. That's a great question. I mean, I really think that this would be a first-line therapy. Of course, we're going to be somewhat limited, I guess, by the initial labeling if it does end up at being two years and greater. And thankfully, we are making the diagnosis of Dravet syndrome earlier and earlier. So you can imagine that patient, six-month-old, who has a confirmed diagnosis of Dravet syndrome. We use a standard Dravet ASM to try and manage that patient and get them to whatever point we can actually prescribe the medication. So I think this phase 3 of 2 to 18 and then maybe a subsequent study looking at the younger age group. I would be starting this medication as soon as I possibly could with that confirmed clinical diagnosis. Of course, in the presence of a pathogenic SCN1A variant, I would be starting it as soon as I could. Yeah. I would absolutely share that view. I think what you could see from the disease-modifying aspect, not just on seizures, but all the different comorbidities in terms of fine motor and gross motor cognition. That's really, really important. That's currently not addressed by any of the anti-seizure medications that are on the market, not addressed in sufficient detail. So I think this is really a great opportunity to modify the disease, and we should do that as soon as we possibly can. Thank you. And now our last question in the queue comes from the line of Charles Duncan from Cantor Fitzgerald. Please go ahead. Hey. Good morning. Hopefully, you can hear me. Dr. Sullivan, Brunklaus, as well as members of advocacy, this has been very helpful. Thank you for sharing your views. I had a question regarding the minimum time of improvement for, let's say, a pivotal study. Would you think that nine months is optimal, or would you prefer maybe a greater signal-to-noise out of 12 months, or could you see even a six-month period being sufficient to detect a signal that is predictive of improvement? And then just going on to slide 29, I guess it is, in the Admiral Study, curiously, play and leisure went backwards. And I'm just kind of wondering what you think about that, especially since it improved significantly in the open-label extension. Can you help us reconcile those two observations? Hi, Charles. I'll start. This is Barry. Thanks for the question. The data that we showed show that in the phase 1/2 study, the multiple 70-milligram dose group did have improvements even within nine months of starting treatment. And then those effects were also demonstrated in the open-label extension study in patients who had even had lower loading doses within 12 months. So certainly, in that nine to 12-month range is where we're seeing the benefits in terms of seizure reduction as well as the improvements in cognition and behavior. So that would be a guideline approximately for what we would expect to see for a phase three study. Helpful. Yeah. And any thoughts on? Yeah. The play and leisure, it's a good question. This is Dr. Sullivan. The two figures that we showed on the slide do have very different N's, right? The Admiral Study, around 20 patients, whereas the open-label extension includes all patients. And we can see that there is, and we also have a longer period of time in the open-label extension to give that an opportunity to change. So I don't have a great explanation other than to say it's a small n and maybe just some noise in the data for the Admiral. But overall, I wouldn't expect any treatment to really sub-select out a worsening in play and leisure because you can imagine all of the other skills that we're seeing improvement in. One would think that that would contribute positively to the play and leisure activities as well. But I don't have a great explanation for the small sort of relative, I guess, worsening in the play and leisure in the smaller study. So just to add to that, and Dr. Brunklaus here, really from a statistical point of view, the play and leisure in the open-label follow-up study up to 20 months is actually one of the greatest improvements we see. And it's much more powered in that combined cohort. So, I think the result from the Admiral is based on, because there's a small patient number, the error bar actually crosses zero, so it's not significant. And what we see actually with 12 and 24 months, really strong signal that that's one of the areas that actually improved over time significantly. Yeah. So, I'd like to close this and thank everyone for participating. I think what this exemplifies this call is it really does take a village to get a new therapy to patients. What we've seen is we have the patients, the families, the advocacy groups, our investigators who have really all helped us and the Stoke team getting this together to try to develop a new therapy. It is not easy, but I think we're all really trying to make sure that we get the best therapy to patients as quickly as we can. So I want to thank everyone for all their help with this. Thank you. That concludes today's conference call. Thank you all for attending. You may all disconnect.