Good day. Thank you for standing by. Welcome to Stoke Therapeutics Analysis of STK-001 for the treatment of Dravet syndrome conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Eric Rojas, Head of Investor Relations. Please go ahead. Thank you, and good morning. This is Eric Rojas, Head of Investor Relations at Stoke Therapeutics. On today's call, we will discuss new safety and efficacy data from patients treated with STK-001 in the ongoing Phase I/IIa clinical studies, MONARCH and ADMIRAL, and the SWALLOWTAIL open-label extension study in patients with Dravet syndrome. Our speakers today are Dr. Edward Kaye, Stoke's CEO, Dr. Barry Ticho, Chief Medical Officer, and Dr. Kimberly Parkerson, Head of Neurology Clinical Development. We are also joined today by Shamim Ruff, Chief Regulatory Officer. As you listen to this call, we recommend that you access the webcast live in the investor section on our website. This call is being recorded, and a replay will also be available on the Stoke website later today. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation, those regarding Stoke's Dravet syndrome program, are based on management's current intentions, beliefs, and assumptions. Actual outcomes and events could differ materially. Except as required by law, we assume no obligation to update any such forward-looking statements after the date of this presentation or to conform these forward-looking statements to actual results. I will now turn the call over to Dr. Kaye. Thanks, Eric. Good morning, everyone. I'll start my comments on slide 5. Today, we are pleased to share with you new data from our ongoing Phase I/IIa clinical studies of STK-001, the first potential medicine to treat the underlying cause of Dravet syndrome. These data are significant because they provide the clearest evidence to date that by addressing the root genetic cause of the disease, STK-001 may be able to change the way Dravet syndrome is treated. We are now seeing increasing evidence that STK-001 may be able to reduce seizure frequency and produce improvements in behavior and cognition. Stated simply, STK-001 has the potential to be the first disease-modifying medicine for Dravet syndrome. Despite progress, the fact remains that there is no medicine to treat the challenges these patients face in their activities of daily living, such as talking, walking, and following instructions. The totality of these data underscore the potential for STK-001 to treat many aspects of Dravet syndrome. There are three takeaways from this new dataset that support our confidence in the potential and the promise for STK-001. The first is the pattern of response observed among the cohort of patients treated with an initial two or three doses of 70 milligrams. These patients experienced median reductions in convulsive seizure frequency of 80% at three months after the last dose, and 89% at six months after the last dose. While we need to collect the remaining data from the rest of the 70 mg cohort, the pattern of response is very highly differentiated from what we have seen with earlier single and multiple lower dose groups. Importantly, these improvements are being observed on top of the best available anti-seizure medicines, including fenfluramine. Second, data from our Swallowtail open-label extension study, where over many months of continued treatment and follow-up, we are seeing sustained reductions in seizure frequency and improvements across multiple measures of cognition and behavior. This is a first in the field of Dravet syndrome. Third, we are also very encouraged by the safety findings in the 74 patients included in today's analysis. These data are reassuring as we continue to advance STK-001. In short, our goal is to fundamentally change the way Dravet syndrome is treated. By addressing the root cause of the disease, we aim to treat both the seizures and other aspects of the syndrome. With these new data, it's becoming increasingly clear that STK-001 is different from anything in the field, that the field has seen to date. We are also learning that it takes time for STK-001 to circulate in the brain and rewire the neuronal connections before it can produce a clinical effect. We are on track to complete the Phase I/IIa studies by year-end and anticipate presenting those data, along with additional data from our two open-label extension studies, in the Q1 of next year. We plan to use these data to initiate discussions related to our Phase III design with the FDA and other regulatory agencies. We anticipate sharing an update on our plans in Phase III study design in the H1 of 2024. Before Barry and Kim walk you through the data, I'd like to share a bit of background on the disease and patient population, starting on slide six. The vast majority of cases of Dravet syndrome are caused by a haploinsufficiency of the SCN1A gene, which results in insufficient NAV1.1 protein expression. Although Dravet syndrome is considered a rare disease, it occurs in about one in 16,000 births. The different types of seizures change with time, and consequences present a persistent threat, impair development, and interfere with activities of daily living. These effects impact patients and their families. Despite dozens of available antiseizure medications, seizures are not adequately controlled in 90% of patients with Dravet syndrome. One of the most serious and tragic consequences of this syndrome is SUDEP, or sudden unexpected death in epilepsy, which takes the lives of approximately 20% of these children before the age of 10. Children with Dravet syndrome appear healthy at birth. They typically achieve their early developmental milestones by the age of 2. They reach a plateau and then fail to develop further. They may stop talking, develop issues with movement and balance, and are unable to care for themselves. Children frequently sleep with their parents, who fear that their child may not wake up in the morning. By the time they reach adolescence, most of these children require a wheelchair. Patients with Dravet syndrome, as you see on slide 7, require polytherapy of 3, 4, and sometimes more medications to treat their seizures. Families often agonize over treatment decisions as they consider the trade-off of a potential benefit with the known side effects of these medicines. The need for a new way to treat this disease is clear and urgent. STK-001 remains the only potential disease-modifying therapy currently in the clinic and is our number one priority here at Stoke. The scientific illustration on slide eight depicts how targeted augmentation of nuclear gene output, or TANGO technology, aims to boost protein production by leveraging the wild type copy of the gene to increase productive mRNA. The initial indications for TANGO are diseases such as Dravet syndrome, caused by a haploinsufficiency, whereby a mutation in one copy of the gene results in half of the normal protein production. For Dravet syndrome, the underlying cause is insufficient NAV1.1 protein levels that result from the SCN1A mutation. STK-001 is designed to boost NAV1.1 protein levels. As I turn the call over to Barry, I'd like to take a moment on behalf of the team here at Stoke to thank all of the patients, families, caregivers, clinicians, and advocates who have put their trust in us. Together, we are charting the course for a new disease-modifying treatment that may change the way this disease is treated. Now I'll hand the call over to Barry. Thank you, Ed. Good morning, everyone. I'm pleased to review the results of an analysis of the data from the MONARCH and ADMIRAL studies. Slide 10 reviews the design of our two Phase I/IIa studies, MONARCH and ADMIRAL. These are open-label studies of children and adolescents, 2 to 18 years of age, who have an established diagnosis of Dravet syndrome and have evidence of a mutation in the SCN1A gene. The primary goal of these studies is to determine if STK-001 is safe. A key secondary objective was to assess the impact of STK-001 on convulsive seizure frequency when added on top of a patient's current antiseizure regimen. In the U.S., patients in MONARCH are treated with either a single dose up to 70 milligrams or 3 doses of up to 45 milligrams. In the U.K., patients in ADMIRAL receive up to 3 doses of up to 70 milligrams. As noted on the slide, the ADMIRAL study protocol was amended to provide the option to administer 2 or 3 doses of 70 milligrams. All patients are followed for 6 months after the last dose before they are eligible to enroll in one of the open-label extension studies, SWALLOWTAIL or LONGWING. Today, we are sharing data from the patients treated with up to 3 doses of STK-001, ranging from 30 milligrams to 70 milligrams in MONARCH and ADMIRAL. Slide 11 provides demographics on the 74 patients who were enrolled in MONARCH and ADMIRAL. These patients received at least 1 dose of the study drug, up to 70 milligrams. Patients were evenly distributed by age, race, and sex across all dose cohorts. Patients enrolled in these studies had severe disease. More than 80% of them were taking 3 or more anti-seizure medications, and 50% were taking 4 or more. Approximately half of the patients in these studies were treated with concomitant phenobarbital. Mean convulsive seizure frequency at baseline was 17.5 per 28 days. I will now share the results of our efficacy analyses, starting on slide 12. This first series of slides present the time course of patient response for the 45 clinically valuable patients in the 30, 45, and 70 milligram dose cohorts of MONARCH and ADMIRAL, broken down into different time intervals. These studies are ongoing, so there are fewer patients who have reached the 6-month time point, as shown in the legend. The x-axis shows the study period broken into 4-week intervals, and the y-axis shows median% change from baseline in convulsive seizure frequency for those intervals. Here you see the green line, which shows a clear distinction in the pattern of response for the 70-milligram cohort. Reductions in convulsive seizure frequency are more substantial and sustained in the 70-milligram group and are more evident with time for the three patients continuing out to six months after the last dose. With more data and a better understanding of how STK-001 works, we are beginning to see that the desired clinical response to treatment is unlike existing anti-seizure medications.... that have a more rapid onset of effect. I want to now show you individual patient data for the 30, 45, or 70-milligram dose cohorts. These graphs are on slide 13 and provide a compelling view of the effect of STK-001 on convulsive seizure frequency. As you can see, there are patients who respond at each dose level, but the 70 milligram cohort demonstrated a more consistent and durable response. This effect is differentiated from every other dose group to date. Slide 14 shows all 11 patients treated with 70 milligrams. Dark-colored lines are the patients who have been treated with three doses. The yellow-colored lines are the patients who have been treated with two doses of STK-001. Five of the six patients who reached three months after their last dose received three doses of 70 milligrams. As you can see, the three patients who reached six months after the last dose were treated with three doses of 70 milligrams. We need to continue to follow all of the patients to the end of the study, but we are very encouraged by what we are seeing here. End of study data are anticipated in the 1st quarter of 2024, when we will have data from all 11 patients at 6 months after the last dose. Remaining patient data from ADMIRAL will consist primarily of patients treated with two doses of 70 milligrams. Moving to slide 15. As we did in the past, we measured the median% change from baseline in convulsive seizure frequency, using an analysis that captured data from day 29 through three months after the last dose. This average was then compared to baseline. The 70 milligram cohort showed a 42% reduction in convulsive seizure frequency. A median reduction of 18% was observed among patients treated in the 45 milligram multiple dose cohort, and 28% among the patients in the 30 milligram multiple dose cohort. A thorough analysis has been used for the evaluation of existing antiseizure medications, which typically have a very early onset of action. Our preclinical data suggested that a robust clinical effect would be observed starting at day 29. You saw in the previous few slides, the full effect of STK-001 on seizures appears to take longer, so measuring the effects from day 29 does not adequately characterize what we are seeing. With more clinical data and more experience with STK-001, we believe that measuring the effects at specific time points later in the time course of treatment is more appropriate. The bar charts on slide 16 show results for patients treated with 30, 45, and 70 milligrams. Median reductions in convulsive seizure frequency observed among the patients in the 70 milligram cohort were both substantial and sustained. At three months, an 80% median reduction was observed compared to baseline. At six months, an 89% median reduction was observed compared to baseline. Turning now to individual patient responses on slide 17. You can see that all patients treated with three doses of 70 milligrams experienced median reductions in convulsive seizure frequency of greater than 50%, as shown on the left at three months and on the right at six months. One of these patients was seizure-free at three months and six months. Patient treated with two initial doses experienced a reduction of 26%. The clear takeaway is that the impact on convulsive seizure frequency is differentiated and profound in this group. Moving forward, we plan to use this type of analysis at specific time points to evaluate the effect of STK-001 on seizures. I'd now like to introduce you to Dr. Kimberly Parkerson. She is a board-certified neurologist who specializes in epilepsy and has been here with us at Stoke since 2020. Dr. Parkerson leads the clinical development of STK-001. I'll now hand the call over to Kim. Thank you, Barry. We'll now review findings from SWALLOWTAIL, the open-label extension study for patients who completed treatment in MONARCH. Patients in the SWALLOWTAIL study received treatment with STK-001 every 4 months while continuing treatment with their background regimen of anti-seizure medicines. In addition to sustained reductions in convulsive seizure frequency, new data from assessments of daily living, including cognition and behavior, support the disease-modifying potential of STK-001. The analyses I'll review with you over the next few minutes were conducted on a subset of patients who entered SWALLOWTAIL following treatment in MONARCH. To be included, patients had to complete treatment in MONARCH and receive only doses of 30 milligrams or 45 milligrams in SWALLOWTAIL. 26 patients met these criteria when they began treatment in SWALLOWTAIL. On slide 20, durable reductions in seizure frequency are evident throughout the course of treatment, including among the 8 patients who reached 1 year in SWALLOWTAIL at the time of the analysis. We will continue to follow these patients and look forward to sharing more data from this study in Q1 2024. Now we will review the results of the additional effects observed among patients in SWALLOWTAIL. As we have discussed, Dravet syndrome is more than just seizures. Patients suffer from other severe comorbidities. Multiple aspects of daily living are affected, some of which are shown on this slide. In SWALLOWTAIL, we are measuring the effects of STK-001 on several of these comorbidities, including cognition and behavior, using well-established assessments. Findings from our BUTTERFLY natural history study support the use of these assessments in studies of Dravet syndrome. What you will see here is early evidence of meaningful improvements demonstrated across multiple of these assessments, which support the potential for disease modification with STK-001. On slide 22, we describe the Vineland-3, which is a standardized measure of how a person performs in daily situations. The Vineland measures certain adaptive behaviors, such as an individual's ability to perform daily living skills, communicate, move, and socialize. For the analysis of these data, we have selected Growth Scale Values as a way to measure changes in the scores from the Vineland. Growth Scale Values, or GSVs, are designed to measure results linearly, regardless of where the patient starts on the scale, and are an indicator of absolute rather than relative changes. We selected GSVs because these can more accurately capture change across the range of this heterogeneous population. The results of our analyses begin on slide 23. In the following slides, I will be sharing data from a series of assessments based on data collected at 4, 8, and 12 months in the SWALLOWTAIL data, in SWALLOWTAIL and compared to baseline. These data were analyzed using mixed model repeated measures, incorporating all available SWALLOWTAIL data to assess changes from baseline. In addition, in order to compare these results to what may occur during natural progression of the syndrome, we also incorporated observed data from our BUTTERFLY natural history study into a mixed model, in which baseline characteristics were matched to those of patients in SWALLOWTAIL to reduce potential bias in the comparison. On this slide, the graph shows changes in GSVs over time, as measured by the Vineland in two modes of communication: receptive and expressive. Receptive communication measures the ability to understand and comprehend. Expressive communication measures the ability to convey meaning to others, such as wants and desires. The analysis indicated substantial improvements among the group treated with STK-001, including a trend toward continued improvement over time, as shown in the red bars. These improvements observed in the treated group are in contrast to data from our natural history study that showed little or no improvement. Moving to slide 24, delayed motor movement is observed in the majority of children with Dravet syndrome. Examples include things like stability, core strength, walking, and running. Typically, these issues begin around 2 years of age. The graph shows improvements in gross motor skills as measured by the Vineland, using the mixed model analysis among the group treated with STK-001, shown in the red bars. In contrast to those in our natural history study, shown in the gray bars, who remain below baseline over time. In the group treated with STK-001, we can also see a trend toward improvement over time. On slide 25, you see the results from our mixed model, incorporating data from the BRIEF-P, a tool used to measure executive function in children, such as the ability to organize thoughts and have working memory. For this assessment, negative scores indicate improvements in executive function. The red bars show notable improvements compared to what we saw in our natural history study and are another sign of potential clinical effect of addressing the underlying cause of Dravet syndrome. Lastly, on slide 26, you see the results of the Global Impression of Change assessments completed by clinicians and caregivers. The assessments use a seven-point scale to rate changes in a patient's overall condition from the start of the study. A score of four equates to no change in status, and less than four indicates improvement. Substantial improvements in overall condition were noted by both caregivers and clinicians, shown in red, with a trend toward more improvement over time. In contrast, natural history data suggests little to no change in status over time, as shown in gray. Overall, the consistency of these findings across multiple assessments is encouraging and support the potential for STK-001 to go beyond seizure management. I'll now hand the call back to Barry. Thank you, Kim. Turning to the safety findings from the studies. On slide 27, you see that single and multiple doses of STK-001, up to 70 milligrams, were generally well-tolerated among the 74 patients treated in MONARCH and ADMIRAL. There were no discontinuations due to study drug. Overall, 32% of patients experienced a treatment-emergent adverse event that was classified as related to the study drug. The most common related treatment-emergent adverse events were CSF protein elevations, vomiting, and irritability. 20% of patients had a treatment-emergent serious adverse event. One patient, who was treated with 3 doses in the 70-milligram cohort, experienced SUSARs that were attributed by the investigator to STK-001. That patient completed the study. Subsequently, an amendment was made to the ADMIRAL study that allowed investigators to decide whether to administer 2 or 3 doses of 70 milligrams before patients would be eligible to enroll in the LONGWING open-label extension study. The amendment helped ensure eligibility for more patients to continue treatment in LONGWING, where we will be able to assess the effects of ongoing dosing with 45 milligrams. Safety findings from patients who continued in the SWALLOWTAIL open-label extension were consistent with the findings from MONARCH and ADMIRAL, with the exception that 64% of patients had at least one CSF protein value greater than 50 milligrams per deciliter. No clinical manifestations have been observed in these patients, although one patient discontinued treatment in SWALLOWTAIL due to elevated CSF protein. I'll close my comments on slide 28 by summarizing the data we provided today. We now see clinical benefits, including reductions in seizures and improvements in cognition and behavior, in patients with Dravet syndrome treated with STK-001. The benefits were observed on top of a background of standard anti-seizure medications. In the initial treatment phase, II or III doses of 70 milligrams resulted in substantial and sustained reductions in convulsive seizure frequency, and a differentiated response compared to all lower dose groups. Median reductions of 80% at 3 months and 89% at 6 months after the last dose are especially meaningful, as patients in these studies have severe and intractable disease. Data from SWALLOWTAIL provide evidence of the potential for disease modification with ongoing treatment of STK-001. Durable reductions in convulsive seizure frequency were observed throughout the course of treatment, as well as substantial improvements from baseline in multiple assessments of daily living, including cognition and behavior. STK-001 has been generally well tolerated in patients treated with single and multiple doses, from 10 milligrams up to 70 milligrams. The totality of these data support our goal of addressing the syndrome, not just the seizures associated with Dravet syndrome. We look forward to sharing these data with the scientific and medical community in September at the International Epilepsy Congress annual meeting in Dublin, and also in December at the American Epilepsy Society meeting in Orlando. I'll now hand the call back to Ed. Thank you, Barry. As you've heard today, we have made significant progress in developing STK-001 as the first potential disease-modifying medicine for Dravet syndrome. These data have continued to de-risk the program. We are confident that the remaining data anticipated in Q1 of next year will enable us to choose a dose and dosing regimen for a phase III study to discuss with the regulatory agencies. We plan to provide an update on the plans for our pivotal trial of STK-001 in the H1 of 2024. This is an exciting time for us here at Stoke, and for me personally. I came to Stoke in 2017 because I believed in the science, and I saw the potential to transform the treatment of Dravet syndrome. At the time, it was a hope. Today, we are seeing clear evidence that STK-001 could be a significant advancement in the treatment of this disease. Knowing this means feeling the pressure to move quickly but carefully. The Stoke team will remain focused on achieving our goal of bringing STK-001 to patients as quickly and effectively as possible. Operator, will you please open up the line for questions? Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Laura Chico from Wedbush. Hey, good morning, guys. Thank you very much for taking the question. I've got two here. You know, if I, if I step back, you're seeing a stronger signal in the 70 mg cohort, some more muted effects at 45, but longer term, you're seeing changes in the Vineland-3 as we look at SWALLOWTAIL. First question, if you could just expand further on what gives you confidence the 70 mg data would remain at this level going forward with more patients added in there. Second, is this a SPINRAZA type of situation where you need a loading dose and then maintenance? I guess, you know, if that's the plan as you advance, how should we be thinking about the dosing regimen? Thank you. Thanks, Laura. You know, I think maybe just to, and I'll have Barry Ticho comment on this. I think one of the things that have been really challenging for people to understand is we are treating Dravet syndrome in a completely different way. Everything you learned before, you have to forget. We're going where no one's gone before... I think that means that we have to really think about this disease in a different way. One of the things I think, you know, we've learned is it takes time for this drug to work. I'll give you the analogy. You know, if you have arthritis in the knee, you can take a shot of cortisone, and in a day or two, you're gonna feel a lot better. If you really want to have long-term benefit, you got to replace the knee. You don't care what happens in the first few weeks of life. You know, after the surgery, you're gonna have pain, swelling, it's gonna be miserable. What you're gonna care about, what are you doing in 3 months? Can you walk up and down the stairs without pain? Can you get in and out of your car? What happens in 6 months? Are you back on your bike? Are you playing tennis again? That's what we're trying to do with Dravet syndrome. We're trying to change the disease. It does not happen immediately. I think what we're learning is we gotta give high doses, we have to give a loading dose, we gotta give a maintenance dose, and we just gotta give it some time for that, you know, the brain has to acclimate to our treatment. I think, you know, it's a lot of tough data, but I think it's really important for people to figure out is, this is a really different way of treating epilepsy and Dravet syndrome. Barry Ticho, maybe you can comment on this? Yeah, thanks for the question, Laura. We have a great deal of confidence in the 70 milligram group, mostly because, as we showed in the data, the response at that 70 milligram dose is differentiated from what we saw before. There were patients at 30 milligrams and even 45 milligrams who were having some response, but it was more variable. With 70 milligrams, we're seeing a sustained and consistent response. That tells us that when we get to the right dose level, which we think we have, we have now, we will get a response among all patients that's going to be notable. The question about the loading dose is something we're still working out, but it does certainly appear from all the data we have and from the results of our studies, that a phenomenon where we start with 70 milligrams and then potentially go to a lower dose, and we've seen now with the lower doses at 30 and at 45, that with longer-term treatment, we are seeing sustained reductions in seizures with those lower dose levels, and we are seeing improvements in cognition and behavior. That tells us that those lower doses, when given over a longer period of time, can have a highly beneficial effect for the patients. Thank you very much. If I could just sneak one last one in. I believe you have a partial clinical hold in the U.S. on the 70 mg dose, so I'm just trying to think through. What is the cadence of events that needs to occur on the regulatory front here over the next 6-12 months if you had to switch to a 70 mg load? Thanks very much. Thank you for the question, Laura. Shamim Ruff here. Great question. Certainly we're on partial clinical hold, that is really related to the current studies. As you know, in the U.S., we're allowed to dose up to 1 dose of 70 milligrams. If we move forward with multiple doses of 70 milligrams, say 2 or 3 doses of 70 milligrams, we are going to have to go and speak to FDA. We're going to have to have their permission to move forward. Certainly, we have a whole body of data now. By the end of the year, we will have safety and efficacy findings from 74 patients. We'll have data from all 11 patients on the multiple doses, 70 milligrams, as well as the data from our single dose of 70 milligrams, plus all the other data from the other doses. We'll certainly provide and present these data to the FDA, before we move forward in order to agree our phase III design. As you're aware, we've gone back to FDA multiple provided clinical data and have been allowed to move to a higher dose. Thanks very much. Thank you. One moment for our next question. Our next question comes in the line of Joseph Stringer from Needham & Company. Hi, good morning. Thanks for taking our question. My question was on the 70 mg data in terms of the seizure reduction. Just wondering if you could comment. Looks like you're seeing a better signal across all age groups, at least from the data you're presented. That's a little bit in contrast to some of the 30 mg and 45 mg data, where it seemed to work better in general, in the younger cohort. Just wondering if you could comment on the 70 mg data, and if you see that, an explanation for that, if you think that trend would continue as you get more 70 mg data. Thanks. Thanks, Joey. This is Barry. Yeah, we are encouraged by the fact that at that 70 milligram dose level, we are seeing that the majority of patients are responding regardless of age. This, to us, is an indication that when we get to this higher dose level, we get the appropriate amount of STK-001 into the brain and have a long enough period of time for this medicine to act and for the clinical effects to be seen, that appears right now not to be a differentiation based on age. We know that the size of the brain and the spinal fluid levels in people are, for the most part, the same, starting already at young ages of 3 or 4 or so. We would expect. between the ages of 2 and 18, which we were studying, there should be equivalent levels in the brain of the medicine. That's why we could anticipate that we would be seeing similar effects once we get to a high enough dose level, as we have, we think, with the 70-milligram group, that should allow for the effect of the medicine, regardless of the size or the age of the patient. Great. Thank you for taking our question. Thank you. One moment for our next question. Our next question comes from the line of Tom Shrader from BTIG. Good morning. Thank you for taking the question, and congratulations on all the data. Can you give us some more detail on the one patient? Specifically, what I'm interested in is this a relatively common genetic mutation? I think we've talked in the past about the potential danger for some of the rare mutations, but was this a normal Dravet mutation, and what else can you tell us about this patient? I have a follow-up. Tom, sorry, this is Barry. Can you just clarify which one patient are you referring to? The patient that had the serious adverse event. Okay. Yes, I can tell you a little bit more about that patient. That patient was in the 70-milligram dose group and received 3 doses of 70 milligrams. The patient had an SCN1A mutation. We're not aware that there was anything unique about that mutation that predisposed the patient to any adverse effects. At this point, we're continuing to evaluate that patient, and we are working with the investigator to understand further. The patient did have some neurologic and behavioral and ophthalmologic changes. We have not seen those changes reported for any of the other 73 patients who have received STK-001. As we are continuing to evaluate this, we have our safety monitoring committee, which is part of the studies, reviewing the case. They did not indicate any changes to the protocol or dosing based on the results of the investigation to date. Of course, we kept regulatory agencies apprised of these events as well. Okay, for background, at the lower doses, you almost get a bifurcated response. It looks like a some subset of patients get a beautiful, smooth curve, and a lot of them get what looks like noise. You have as much natural history data as anyone. How often do you see fluctuations of reductions in seizure frequency of 50% or things like that in your natural history trial? Yes, thanks, Tom. This is Barry again. There is certainly variability in the seizure frequency in patients with Dravet syndrome. It can vary very much based on the weather or infections or a variety of other triggers that can cause the patients to have changes in their frequency. What we do not see in the natural history study is that patients have sustained reductions of seizures the way we were seeing now with the 70-milligram dosing group. Yes, we are, we are thinking about the 45-milligram group, and we did see that variability, but there were response, patients who did respond, as you say. As we got to higher dose levels, we were able to see that effect was consistent now more among all patients. Great. Okay. Thanks for the detail. I'll add that, you know, when we look at the totality of the data, where we're looking at the effects on cognition and behavior, in addition, that is where we're seeing that even at the 45 milligram dosing group, we're seeing a difference in response in these patients to what's been available to them for treatment before. This is now a new approach where we can treat the syndrome and not just have a symptomatic reduction in the seizures, and that's what is very heartening to us. Got it. Thank you. One moment for our next question. Our next question comes from the line of Charles Duncan from Cantor Fitzgerald. Yeah. Hey, good morning, Ed and Barry. Congratulations on being able to conduct this very difficult study, especially in these very heavily otherwise treated patients. I'm really intrigued with the seizure effects, given the background therapy, but I also really am quite interested in the behavioral improvements because our diligence suggests that that just does not occur. My question is related to SWALLOWTAIL mostly and the non-seizure effects. I guess I'm wondering how do you interpret those changes being that it was a, you know, it's obviously a non-blinded study? Do you think that those changes could be the result of, you know, call it caregiver hope? in these patients, or are they changes that you wouldn't expect to see, you know, just by being involved in a clinical trial? Sure. Thanks very much for the question. I'll say a few things about that. One is, I think the multiple assessments across which we're seeing changes, speaks to the fact that this likely is not just, you know, wishful or hopeful thinking by others making a change. I think when you see things in communication, motor movement, executive function, and then both the clinicians and caregivers, rating these patients as having improvements, I think it's much less likely that this is just a, you know, hopeful effect. Hopefully through that, we're really seeing something, you know, that's really a change in these patients. I think on top of that, you know, we have looked at this, as you can see in the graphs in our natural history. These patients really over time, don't make, you know, changes. Really, there's little to no improvement, you know, in these using the same measures, there. Yeah. Charles, I think the other important thing is there's been a lot of studies in Dravet syndrome with a lot of different antiepileptics. Nobody's ever seen this before. Yeah. I think that's what we were really hoping for, that we could actually treat the underlying cause and not just treat one symptom, which were seizures. Yeah, that makes sense to me. I know it's a little bit early to be able to speak about this, but I guess I'm wondering about, say, a registrational trial. I guess I'm wondering if you could imagine, say, a 6-month trial for accelerated approval based on seizures, and that perhaps a 12-month trial to really discern differences in behavioral change, and if you could imagine. That could drive more of a full approval. I guess, you know, I know it's difficult. You haven't talked to the agency, you haven't finished this work, but what can you imagine to be the registrational paradigm? Thank you for the question, Shamim Ruff here. I think it's an excellent question, and obviously, we're thinking about all of these various options. Your suggestion of having some form of interim analysis with seizure as the endpoint and then continuing and gathering all the other endpoints, 'cause I think it's been clear, you know, based on our data, that it takes time to see the behavioral, cognitive, and other improvements. I think that's an excellent comment, and these are the kind of things we're discussing and talking through. Certainly, when we see our data at the end of the year, we'll look at all these data in totality, and then we do plan to go and talk to the agency early next year. Okay. Last question, just one for Barry. It's kind of a housekeeping question, and that is relative to the patients who had 70 milligram dosing. Can we assume that they were similar? I think you alluded to this in the baseline characteristics, but relative to, you know, the patients in 30 and 45 milligrams, did they have, call it, the same dose density and experience and age, et cetera? There are nothing about them phenotypically that could have driven, you know, the very profound reduction in seizure frequency despite being on the background therapy. Yes. Thanks, Charles, for that insight. We have looked at the patients who have, in the 70 milligram dose cohort, had these substantial changes, as you mentioned. We are not seeing anything in terms of the characteristics that would highlight that there is a group of patients who are responding better than others. At this point, although we've looked at the type of mutation they have, their age, as you mentioned, and other characteristics, it seems that there is the open potential for most patients to be able to potentially benefit from our medicine, and there is not apparently a subgroup that we will limit the treatment for. We are seeing again, that at the 70 milligram dose group, the effect is quite consistent in these patients, and that means to us that there is a large group of patients who may potentially benefit from the medicine. Okay, very good. Thanks for taking our questions. Interested to see more data later on this year. Thanks, Charles. Thank you. One moment for our next question. Our next question comes from the line of Yaron Werber from TD Cowen. Hi, guys. This is Brendan on for Yaron. Thanks for taking the questions. Can I first just say, sorry if I missed it. Can you just confirm exactly what the seizure actually was, maybe beyond just neurologic issues? Can you also confirm at which time point the patient developed symptoms? Was it actually after the third dose, or maybe kind of how long after they finished dosing? I have a follow-up. Thanks. Yeah. Thanks, Brendan. This is Barry. It is a complicated case, and we are still continuing the investigation. I can tell you that the patient did receive 3 doses of 70 milligrams. Approximately 2 months after that third dose is when this constellation of effects of the neurologic and behavioral and ophthalmologic changes occurred. Those again, are unique to this patient. We have not seen them reported in any of the other patients to date. The effects also in this patient were noted in the seizure response. Like the other patients who received 3 doses of 70 milligrams, this patient did have reduction in seizures, but I can tell you that in those 70 milligram patients, otherwise, there were no substantial safety issues related to study drug that were reported. Okay, got it. Just for the CSF protein elevation, can you confirm maybe to what extent you actually saw, like maybe the range of actual elevation that you saw? Did you actually measure NfL specifically, the neurofilament light chain, and if you saw any specific changes there? Thanks. Yes, this is Barry again. Thanks for noting that. On the CSF protein elevations, first I'll reiterate that we are not seeing any clinical manifestations from those elevations. These are standard laboratory follow-up that we're doing for all patients when they get their dosing and follow-up, and we test the CSF protein level as a routine. We are highlighting here that there's a percentage of patients who get a level that's noted that is greater than 50 milligrams per deciliter, and that is a cutoff that's roughly assumed to be the normal cutoff at most laboratories. There's variability, and it changes by lab and by age, but 50 is what we use. What we're reporting are the percentage of patients who had levels above that. Again, this is something that we're continuing to monitor on a routine basis but have not seen any other clinical manifestations. I will note as well that the elevations in CSF protein are something that are commonly seen in other intracerebrally administered antisense oligonucleotides. In fact, in the two approved oligonucleotides that are approved for other indications, SMA, for instance, and ALS, they're reporting similar levels of increases of CSF protein. This appears to be something that may be related to the intrathecal administration, but we don't have any evidence that it's related to the actual mechanism of our medicine. As far as the neurofilament light goes, that is an experimental and investigative protein right now. There is evidence that in patients who have seizure disorders, they do have elevations in NfL as part of having seizures. We are not using that as a direct measure for any biomarker of efficacy at this time. All right, great. Thanks very much. Appreciate it. Thank you. One moment for our next question. Our next question comes in the line of Kyle Mikson from Canaccord Genuity. Hello, this is Kyle speaking for Sumant Kulkarni. Maybe a few questions for us. At what time point do you expect the drug to fully work, given the 2, 3-month and 6-month efficacy differentials seen across the cohort? Well, we are seeing that already at that 3-month time point. At the 6-month time point, we are seeing those substantial reductions. That's telling us that it takes a while for the medicine, when we get to the correct level, for it to have its full effect. That effect is sustained. In fact, we're seeing it continuing in the open-label extension, when we continue to give the patients doses even below 70 milligrams for every 4 months. I can't tell you that we've seen a maximum effect yet. We continue to see improvement, and as Dr. Parkerson was showing you in the slides for the behavior and cognition, we are seeing that over time there appears to be continued improvement. We certainly expect that by 3 or months or certain time points after the end of dosing in that loading period, we are seeing a substantial effect, but that effect may continue and improve over time. Okay. I know it's a bit early, but can you disclose, or can you give your thoughts, regarding what the target dose for phase III could be, and also, what could be the powering for the seizure reduction? Any call, that would be great. This is Barry Ticho. We're continuing to learn quite a bit about STK-001 as well as Dravet syndrome from our studies right now. It does appear that a loading type of approach seems to be one that gets us very meaningful reductions and sustained effects and consistent effects in patients. We would likely have some sort of a loading phenomena. We're continuing to gather the data, as we mentioned, that we will have data in Q1 of next year based on the longer-term follow-up of the patients who've gotten either 1 dose of 70 milligrams, 2 doses of 70 milligrams, or 3 doses of 70 milligrams. That's gonna be a very useful package of data for us to make our final determinations. We have not made any determination yet about what the phase III study design ultimately will be, and that will be something that we will talk about more the H1 of next year. Okay, thank you. Thank you. One moment for our next question. Our next question comes from the line of Greg Harrison from Bank of America. Hey, good morning. Thanks for taking the question. With respect to the through versus at analysis, is that potentially an approvable endpoint when you get to pivotal stage? How typical is that analysis in epilepsy? How would you expect the trend to be as far as the through versus at maybe converging as you follow these patients for a longer time period? Thank you for the question. I'll take the first part of your question regarding approvability of the endpoint. As you're aware, convulsive seizure frequency reduction is an accepted endpoint and has been for multiple drugs already. We're talking about potentially a different time point, but the endpoint stays the same in terms of, you know, measuring convulsive seizure frequency reduction. This is something, again, as part of our Phase III discussions with FDA and other regulators, we will be discussing all these different aspects. I think we're pretty confident that convulsive seizure frequency reduction, whether we measure it 3 months or 6 months, is an acceptable approval endpoint. I'm now gonna hand over to Barry for the second part of your question. Yeah. As we continue to learn about the medicine, we are learning that we may have to make some adjustments. This is something that's quite common among other medicine programs, that the endpoint may need to be adjusted based on the mechanism of the medicine. That's what we're learning here, is that with the effect having to take a little bit longer and go to higher doses, we're realizing that averaging the effect over time is not the most appropriate way to assess the impact of STK-001. As far as whether the through analysis will eventually combine with the at what we're seeing right now is that by looking at later time points, and we haven't finalized exactly which time points those are, but by looking at later time points, we know that that is a better way to assess the impact of this medicine. I would not anticipate that we would use an average over time because we're seeing these effects, most notably at certain time points later on after dosing. Just to add to, Barry's comment, there is precedence for this. Kalydeco was a great example of going from a through analysis to an at analysis, so there's certainly precedence for this. Hello, operator. We'll take one more question, please. Thank you. One moment for our next question. Our next question goes to the line of Rudy Li from Leerink Partners. Hi, thanks for taking my question. I have a question regarding the dose response. When you look at the CSF data for the 3 doses, do you see a clear separation between 30, 45 or 70 mg? A quick follow-up, like, what additional data should we expect in the next coming readout in the Q1 of 2024? Thanks. Hi, Rudy. Thanks. This is Barry. The question about the PK is a good one. We have 2 ways of looking at the drug levels. We look in the plasma to see, that's a relatively rapid transfer of the medicine from the CSF to the blood. What we're seeing when we go from 30 to 45 to 70 is a very consistent and predictable increase from that up to that 70 milligram dose level. That appears to be something that is not, is consistent with the dose level and is dose relative. The CSF levels, we're still looking at, so we don't have data right now fully on the CSF levels at the 70 milligram dosing group to talk about. That gets to your second question in terms of what data we'll have in Q1 of next year. We will have the CSF protein drug levels for all the patients who have received 70 milligrams. We're going to have, again, 11 patients who have received multiple doses of 70 milligrams in our ADMIRAL study. We also will have patients who have gotten single doses in the MONARCH study. Then we'll also have data from the, what we call our LONGWING study, which is the open-label extension study in the U.K., where patients are receiving 45 milligrams every 4 months as well. That is going to be quite a very sizable database for us to be able to use to make decisions about the design and the dosing regimen and interval for Phase III. That, that's what we will have those data to release in Q1, and then further data about the phase III design and our plans there in the H1 of next year. Got it. Very helpful. Thank you. At this time, I would now like to turn the conference back over to Eric Rojas for closing remarks. Thanks, everyone, for joining today. The investor relations team is available today to answer any follow-up questions you may have. Operator, you can now end the call. This concludes today's conference call. Thank you for participating. You may now...