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spk01: Good morning. My name is Audra and I will be your conference operator today. At this time, I would like to welcome everyone to the Stoke Therapeutics interim analysis of STK001 for the treatment of Dravet syndrome. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press the star key followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. At this time, I'd like to turn the conference over to Eric Rojas, Head of Investor Relations. Please go ahead.
spk08: Thanks, Audra, and good morning. This is Eric Rojas, Head of Investor Relations at Stokes Therapeutics. On today's call, we will discuss results from the interim analysis of the Phase 1-2A clinical studies of our investigational medicine STK001 for the treatment of Gervais syndrome. Our speakers today are Dr. Edward Kay, Stokes CEO, and Dr. Barry Tico, Stokes Chief Medical Officer. As you listen to this call, we recommend that you access the webcast slides in the Investors 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 SEC. These statements, including without limitation those regarding Stoke's Dervet Syndrome Program, are based on management's current intentions beliefs, and assumptions. Actual outcomes and events can 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. Thank you, Eric, and good morning, everyone.
spk11: We're pleased to share with you today the positive interim results from our ongoing phase 1 to 8 clinical studies of STK001. And to frequent and prolonged seizures, patients experience significant non-seizure comorbidities. What you will see today is new evidence that STK001 continues to be well-tolerated and is reducing seizures in children and adolescents with Dravet syndrome. Importantly, these improvements are on top of the best available anti-seizure medicines with more than half of the patients taking fenfluramines. Today, we are also sharing very preliminary evidence of the drug's effect on non-seizure comorbidities. Together, these results give us confidence that we are honing in on an effective dose level and dose frequency. We look forward to sharing additional data in 2023 that will inform our plans for pivotal studies. Before Barry walks you through the specifics of the data, I'd like to share a bit of background on the disease and patient populations. Privé syndrome is a severe and progressive genetic epilepsy. It's caused by a haploid insufficiency, which results in half of the normal NAV1.1 protein expression. One out of 16,000 babies around the world are born with this devastating disease, and it is not concentrated on any particular geographic area. There is a real and urgent need for better medicines that treat seizures and the myriad of non-seizure comorbidities. The non-seizure aspects of this disease, some of which are listed on slide six, significantly impact the quality of life for patients and their caregivers. The combination of anti-seizure medicines that make up the current standard of care are burdensome, do not control seizures for the vast majority, and come with a host of side effects. With our butterfly observational study, we are learning more about the natural progression of Dravet syndrome and the clinical assessments that we can use to measure changes in neurodevelopment. Born without symptoms, these children develop fairly normally, but begin to regress with age as the disease advances. The goal of treatment today is seizure management, but what these patients need is syndrome management. Our number one priority at Stoke is to advance STK001 as potentially the first disease-modifying approach for the treatment of Dravet syndrome. one that will control seizures and address the non-seizure comorbidities. From the start, we have set a high bar for success. The majority of patients enrolled in our studies are taking at least three and often four anti-seizure medicines. Despite this, they continue to experience seizures and many of the debilitating effects that characterize this disease. Based on what we are seeing in the clinic, we believe that producing a consistent and durable clinical effect for patients will require reaching a steady state of drug levels in the brain to boost and sustain normal protein levels. Three factors play a role in this process, dose level, dose frequency, and time on drug. We expect that additional data in 2023 will answer our remaining questions and unlock the path to pivotal studies. I'll now hand over the call to Barry.
spk06: Thank you, Ed, and good morning. Before I get into the clinical data, I'd like to quickly remind you of the science behind STK001, an antisense oligonucleotide. The cartoon on slide 10 shows how our targeted augmentation of nuclear gene output, or TANGO technology, aims to boost protein production by leveraging the wild-type copy of a gene to increase productive mRNA levels. The initial indications for TANGO are diseases caused by haploinsufficiency whereby a mutation in one copy of a gene results in half the normal protein production. Dravet syndrome is typically caused by a hapoinsufficiency of the SCN1A gene, which results in insufficiency of NAV1.1 protein expression. SDK001 is designed to address the root cause of Dravet syndrome by restoring NAV1.1 levels. Turning to slide 11. You see schematics of our two Phase I two-way 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 a Dravet syndrome and have evidence of a mutation in the SCN1A gene. The goal of these initial studies is to determine if STK001 is safe and to identify the best dose, one that maximizes efficacy and minimizes treatment frequency. to advance to pivotal studies. In the US, patients in Monarch are treated with either a single or multi three-dose regimen up to 45 milligrams. In the UK, patients in Admiral receive multiple doses up to 70 milligrams. The multi-dose regimens consist of three doses as shown here. All patients are followed for six months after their last dose before they are eligible to enroll in one of the open label extension studies, Swallowtail or Longwing. Most of the data you will see today comes from a combined analysis of patients treated with multiple doses in Monarch and Admiral. In addition, I will share some very early data from the Swallowtail open label extension study. On slide 12, you see a summary of patient demographics. Our safety analysis is based on 55 patients who were enrolled in Monarch and Admiral and received at least one dose of the drugs up to 45 milligrams. Patients were evenly distributed by age, race, and sex across all dose cohorts. Patients enrolled in the study had severe disease. More than 75% of the patients enrolled in the study were taking three or more anti-seizure medications as maintenance therapy, and more than half of the patients were taking four or more anti-seizure medications. More than half of the patients were treated with concomitant fenfluramine. The observed median baseline convulsive seizure rate ranged from 8 to 64 by cohort over a 28-day period. The most common convulsive seizure type was generalized tonic-clonic. Looking at the safety profile on slide 13, single and multiple doses of STK001 up to 45 milligrams were well-tolerated. All adverse events related to the study drug were mild to moderate in severity. Twenty-seven percent of patients experienced a treatment emergent adverse event that was classified as related to the study drug. Twenty-two percent of patients had a treatment emergent serious adverse event. None of these SAEs were related to STK001. The most common treatment emergent adverse events were vomiting, headache, and seizure, and none led to study drug withdrawal. Thirty-three percent of patients experienced CSF protein elevation after dosing. To date, no associated clinical manifestations of this protein increase have been reported. Overall, these safety results are very encouraging and support further clinical development of STK001. Turning to PK on slide 14, A dose-dependent increase in study drug exposure was observed in plasma. The 45 milligram levels are clearly separated from 30 milligram, although 20 and 30 milligram levels appear less differentiated. On slide 15, CSF exposure was measurable up to six months following single and multiple doses of STK001, indicating sustained exposure of STK001 in the brain. These data continue to support a potential four- to six-month dosing schedule. Turning to our modeling results on slide 16, based on the preclinical modeling, we anticipate that the majority of patients would achieve pharmacologically active levels of drug in the brain following three doses of 30 milligrams. These drug levels were conservatively defined as ones that could result in a two-fold increase in NAV1.1 protein in the brain. Clinical data indicate that the majority of patients treated with three doses of 20 or 30 milligrams have achieved these pharmacologically active levels at some point during dosing. Most importantly, based on the effect that we are seeing in the 45 milligram dose groups, we now believe we are entering a therapeutic range that is leading to a clinical effect. These findings are consistent with our understanding of the biology of the disease and the mechanism of STK001. To have a clinical effect, we need to reorganize the electrical circuitry in the brain, which requires both getting STK001 into the brain and time to produce a clinical effect. We'll now review findings from a preliminary interim analysis of seizure frequency on slide 17. A secondary objective of the Monarch and Admiral studies is to assess clinical effect as an adjunctive anti-seizure medication. These data were captured by caregivers who keep a daily diary of countable seizures. Based on data available from 27 patients who were treated with three doses of STK001 at 20, 30, or 45 milligrams and followed for at least three months after the last visit, 20 out of 27 patients, or 74%, demonstrated a reduction from baseline in convulsive seizure frequency as measured from day 29 after their first dose to three months after in groups in both studies. This is why the seizure reduction was assessed after day 29. Median reductions from baseline in convulsive seizure frequency were observed across the multiple dose cohorts. The 45-milligram cohort produced the most robust response, demonstrating a 55% reduction in convulsive seizure frequency. We observed a median reduction of 20% among the patients treated in the 30-milligram group and a median reduction of 41% among those in the 20-milligram cohort. These benefits were observed on top of various anti-seizure medications. At least half of the patients were on fenforamines. No clear dose response was observed between the 20 and 30 milligram multiple dose cohorts. To understand why, we looked at the underlying drug exposure levels. As you saw in the previous slides, there was no meaningful difference between the 20 and 30 milligram cohorts, which we believe may account for the lack of dose response and seizure reductions observed in these cohorts. However, we see a separation in plasma PK and CSF exposure in the 45 milligram group which corresponds to a greater reduction in seizure frequency. As you can see on slide 18, the reduction in convulsive seizure frequency was also observed across age groups. The green lines here show that the effects were more evident at the highest dose and in younger patients, including the two patients who experienced median reductions of up to 74% in the 45-milligram treatment group. We believe the older patients who have been living longer with this disease may benefit from longer durations of treatment at the higher dose levels. Turning to slide 19, we're pleased with these interim data and believe we have entered a therapeutic range. With Monarch and Admiral ongoing, we are gathering important information about the initial dosing regimen of STK001 up to 70 milligrams. Once through their initial treatment, patients are eligible to enroll in one of the two open-label extension studies, Swallowtail in the US or Longwing in the UK. Following recent interactions with regulatory agencies, we agreed to limit chronic dosing in the extension study. Dosing is now ongoing in Swallowtail at 30 milligrams and in Longwing at 45 milligrams. This decision was based on a review of interim chronic toxicology data from a study in non-human primates. In this study, the total drug administered to NHPs was higher than we would anticipate giving to patients. Because of this, we do not know whether there is any clinical relevance to these findings. We believe the effects seen in NHPs may be the result of an accumulation of drug in the brain due to a long-than-expected half-life of STK001. We plan to conduct a new chronic toxicology study in NHPs that will better reflect our clinical dosing plans. Turning to slide 20, as Ed mentioned earlier, today we are pleased to be able to share very early findings from a small number of patients who have continued dosing with STK001 in our Swallowtail open label extension study. Overall, the safety profile for patients in Swallowtail was similar to Monarch. Reductions from baseline and convulsive seizure frequency were maintained with multiple doses. Preliminary results from a small cohort of patients who received 30 milligrams during the study showed improvements in executive function as measured by the brief P, a standardized rating scale designed to measure the range of behavioral manifestations of executive function in children, such as the ability to organize thoughts and have working memory. As shown on the right side, the lower data points at week 16 and 32 demonstrate improvements in executive function compared to baseline. I want to reiterate that these results are early and based on a small number of patients. Seeing changes in non-seizure aspects of the disease at this stage was somewhat unexpected. Longer follow-up in more patients is needed to validate these findings. but we see these data as another indication of potential clinical effect of addressing the underlying cause of Dravet syndrome. Before I hand the call back to Ed, I'll summarize the key takeaways and next steps for the program on slide 21. Multiple doses of STK001 up to 45 milligrams were well tolerated. The majority of patients treated with multiple doses experienced a reduction in seizures which was more evident at the highest dose and in younger patients. These benefits were observed on top of a background of standard anti-seizure medications. The very early non-seizure data indicate our confidence that we are addressing the root cause of this disease. The studies remain ongoing. We are treating patients in an expanded 45 milligram multi-dosing arm of Monarch. We are also working to expand 70-milligram multi-dose arm of Admiral pending a safety review. We look forward to sharing these data with the scientific and medical community at the American Epilepsy Society annual meeting in December and to reporting additional data in 2023. I'll now hand the call back to Ed.
spk11: Thanks, Barry. In short, what we see today furthers our confidence that we're going to be able to address the underlying cause of Dravet syndrome to change the course of this disease for patients and their families. In addition to the effects we are seeing on seizures, the early non-seizure data support the idea that we are on our way to developing a drug that will address the syndrome in addition to the seizures. We have a lot of work to do, but we're well on our way. Our job here at Stoke is to continue to push forward into the clinic so that we can get additional data that we need to be able to take STK001 into Pivotal Studies. This is not something we do alone. I'd like to thank all of the families who have trusted us and made significant sacrifices to participate in these studies. I would also like to thank the teams of people at the clinical sites who are at the front lines of patient care, including the investigators, study coordinators, and support staff. Finally, I'd like to thank the entire team here at Stoke who continue to work tirelessly to progress our clinical studies and generate data that will continue to advance STK-001 as potentially the first new medicine to treat the underlying cause of this devastating disease. As someone who has spent his entire career understanding genetics and applying insights to the development of treatments for rare diseases, I understand the urgent need to move quickly to advance potential new medicines like STK-001 to patients. Operator, will you please open the lines for questions, please?
spk01: Thank you. At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. We'll take our first question from Joseph Stringer at Needham & Company.
spk12: Hi, good morning. Thanks for taking our question. Just curious if you could provide some more detail on why you think you're seeing greater seizure reduction in the younger patients. You've kind of seen this of data releases here. You know, is it more just the advanced nature of the disease in the older patients, or is there some element of different mRNA levels in those various age groups? And then the second question is, I'm just curious if you can comment on the treatment emergent adverse events Any dose relationship there? Were they higher in the 45 mg cohort? Thanks.
spk06: Hi, Joey. This is Barry. Thanks for the questions. So the first one, we are very pleased to see that in that your younger dose cohort treated with 45 mg, we're seeing 74% reduction in seizure frequency, which is a tremendous response. you know we're using other compensatory mechanisms. So that has to be reversed, and that takes time. That rewiring back to normal after we restore the sodium channels back up to normal takes a while. So that's why we think in our advisors earlier and potentially the older patients will take a little bit more time to be on drug and perhaps at higher doses as well. As far as the adverse events go, We have not been seeing any dose relationship with the adverse events. So as we go to higher doses and to a longer treatment, we have not seen an increase in the treatment emergent adverse events. And again, we have not seen any, in this current data set, we have not seen any of the series adverse events related to study drug.
spk12: Great. Thanks for taking our questions.
spk01: We'll move next to Laura Tico at Wedbush Securities.
spk04: Hey, good morning, guys. Thanks very much for taking the question. I have one on efficacy and one on safety. And Barry, your comments were helpful in the opening remarks here, but either for Barry or Ed, realizing there's no control group in either monarch or admiral, but help us understand contextually the expected placebo response after, you know, 120, 140 days period. What would have been the type of reduction expected in a placebo cohort for this type of population? And essentially, what gives you confidence that you're seeing a true signal at the 45 mg cohort? And then I have one follow up.
spk06: Yeah, Laura, thanks for the question. This is Barry again. So yeah, we were very pleased with the 55% reduction that we were seeing in that 45 mg cohort. And to give you a sense of the, the relative levels that have been seen in other placebo-controlled trials, we have some data in the literature that show a variety of responses. Other placebo-controlled, 10% increase in the seizure rate to somewhere around 20% or so reduction in the seizure rate. So that gives you a sense. Also, that the The fact that it takes several weeks to see the onset of effect, which we're seeing consistently across all those cohorts, and they were seeing a difference between the younger patients and the older patients, and they were seeing a dose response, all would indicate that this is based on the mechanism of action of the drug and not just a placebo response.
spk04: Thanks, very helpful. Maybe the safety question then that I wanted to ask was just with respect to the CSF protein elevations, could you comment on that a little bit further? And wondering if you could talk about it in the context of the dosing interval. So I think you've mentioned you're exploring potentially expanding the dosing interval. Is this something that is linked to the frequency? And just how are you thinking about that going forward? Thanks.
spk06: Thanks, Laura, for the question. I didn't quite hear the whole question, but I think in terms of the dosing frequency, the results that we're seeing right now in the patient.
spk04: Sorry, this is Laura Chico. If I might try to re-ask the question, apologies. So, Barry, you had CSF protein elevations in about a third of patients. Just wondering if that's corresponding or related to the dosing frequency in the study. If you're extending that dosing interval going forward, How would you think about that in terms of the potential impacts on that adverse event? Thanks.
spk06: Yeah, this is Barry again. So the CSF protein levels that we saw above normal were not associated with any clinical manifestation. And we did see them in about a third of the patients. This is something that's a known phenomenon for patients with epilepsy. And so some reports have shown that up to half of patients with epilepsy have CSF protein levels above normal. And in fact, we were seeing almost 10% of the patients at baseline before dosing had elevations in CSF protein. It's also a known phenomenon for patients, for people who have been getting intrathecal antisense oligonucleotides. And even in the Spinraza case, as well as other reported cases, there have been 30 to even 50% of the patients who have had elevated So this is something that we're monitoring as part of the routine monitoring that we do in the study. It's not clear exactly what the etiology is. It may be related to the frequent number of lumbar punctures that get done. And so we're expecting perhaps that as the number of LPs gets spread out in our patients because right now we're doing them, as you know, every month in the initial studies and then we're spacing it out to every four months in the open-label extension studies. So we'll be monitoring on the open-label extension studies what the rate of this is. But at this point, again, it's not causing any clinical consequence, and we're continuing to see a very favorable safety profile overall. So it's just something that we're keeping an eye on.
spk04: Thanks, guys.
spk01: We'll move next to Jessica Faya at J.P. Morgan.
spk00: Good morning, everyone. Thank you for taking our question. In your prepared remarks, you noted the older patients might benefit from longer treatment. Can you elaborate on that comment and what it means for development plans as you think about the age groups to include in future trials? And I have a follow-up.
spk06: Yeah, thanks. So we know that based on the mechanism of action, and we're seeing it now, that as we get to higher dose levels, we're expecting to see more of a response, especially in terms of seizure reduction. And of course, we are seeing in terms of some of the non-seizure effects now with longer dosing. So we do think that having sufficient dose levels as well as time on drug at the proper dose frequency is going to be what's needed to show the full effect of this medicine. In terms of the older patients, we are continuing to enroll those patients in our trials and following them in the open-label extension study. So we've had a very high rate of rollover into our open-label extension study. 96% of the patients from the Monarch study rolled over. So those will include the older patients as well as the younger patients. And so we'll be able to continue to monitor them and see whether they're, as we theorize, that the patients will benefit from longer time on drugs.
spk11: Yeah, and Daniel, this is Ed. I think, you know, again, it's really important to remember that our approach is completely different from every other anticonvulsant therapy that's been tried. We're trying to, again, kind of reorganize the brain. And as what we've seen, the older patients have been, you know, basically had the disease for a longer period of time. There's a lot of compensatory mechanisms that occur, and it takes time for that to re-equilibrate. I think the really important thing, though, is that the older patients have a very severe need for new therapies. And so we want to make sure that we're not only addressing the younger patients, but also making sure we're addressing the needs of the older patients.
spk00: Got it. And one question on the CSF elevation. As you have mentioned in the prior question to Laura, and also what we have observed in the literature showing as much as 60% of elevation in epileptic patients, Maybe can you compare that to the amount you saw at baseline and at different time points in the study?
spk06: Well, yes. So at baseline prior to dosing, almost 10% of the patients that we evaluated had CSF protein levels above normal. And then as we mentioned, that percentage did increase to 33% of the patients. at some point during the dosing period. That includes the open label extension study. So it's something that we continue to monitor. We have not seen any clinical effects of that at this point. And we are not sure exactly of the etiology, but again, as we think we may space out the number of procedures of lumbar punctures the patients have, that may be able to address some of the increases.
spk00: Got it. Thank you very much. Congrats on the progress. Thanks, Diane.
spk01: We'll go next to Yaron Werber at Cowan.
spk09: Great. Thanks for taking my question. I got a couple. Maybe just the first one. It sounds like you said that between 20 and 30, in terms of exposure in the brain, there was a slight increase, and that's in your slides. But in your slides, you don't mention between 30 and 45. I think you spoke to that and you said you saw... more or you didn't see a difference between 30 and 45 exposures? If you could just elaborate on that. And then secondly, what did you see in the non-human primates with respect to tox that is now capping the chronic dosing at 30 and 45? And at this point, are you saying you're not going to go and do chronic dosing at 70 mg from that point onwards until you have more data? No.
spk06: Yaron, thanks for the questions. This is Barry. So the first issue was with the exposure levels. So what we showed on the slides were the plasma levels in blood in the first 24 hours, which are indicative of the levels that are achieved in CSF and the brain. Those were not substantially differentiated between the 20 and 30 milligram dosing group, but at the 45 level, we're seeing a big step up there. And in the CSF levels, we were seeing the 20 and 30, again, which do reflect the brain levels, that 20 and 30 milligrams were not substantially different from each other. There was a slight increase in the 30. But the data, we didn't show the data, but we have data that the 45 milligram dose CSF levels are substantially higher. So there is a big step up, which could potentially explain the difference and the 55% reduction that we're seeing at that 45 milligram level in those patients.
spk09: And just curious, why didn't you include that in the slides? And is that going to be at AES?
spk06: Those data will be at AES. Yeah, that will be in the presentation at AES. So as far as the non-human primate data, so again, that study, the chronic toxicology study that we did in the non-human primates was a dose regimen in terms of level and frequency that is not reflective of what we're doing currently right now. So the results that we saw in those monkeys were not reflective and we don't think are relevant to the current dosing paradigm. And again, otherwise, the safety profile that we've had so far in the clinic has been very favorable, and we're not seeing any effect there. So we did have discussions and determined that we would limit the dosing in the U.S. to 30 milligrams and in the U.K. at 45 milligrams for the open-label extension studies. The Admiral study continues in the U.K. at 70 milligrams, so we'll be able to We will continue to get data at 70 milligrams in that study. And we anticipate that we will move forward with the open label extension studies to collect additional data that we will use to determine the dose level for phase three. As far as what dose level we ultimately will have in the open label extension studies, that's going to be a matter of negotiation in the future with FDA and, again, with other regulatory agencies. We are running a second study in the NHPs that is more reflective of what the current dosing regimen is, and those data will be very informative for us in terms of going forward. So, yeah, you're on.
spk11: I think one of the things, of course, that we saw is that the half-life was, as we find out more about the drug, the half-life is longer. So, 30 and 45 milligrams, I think, is going to give us some really important information because we're going to want to know what what the dose level for the maintenance therapy is going to be. Obviously, we have the potential if we need to go to higher levels based on the human safety data. But I think we're in a range where, you know, we're ranging, you know, chronically from 30 to 45, and then we're going up to 70 milligrams per We're going to have a lot of information that will tell us what the dose is that we're going to need to go to in the phase three. So I think these are going to be very informative studies. Okay.
spk09: Great. If you don't mind, just a quick follow-up. So why not dose then 70 chronically in the UK in long tail? Why cap it at 45 if everything is safe and 70, you're thinking 70 is okay, and you've only seen that issue with much higher doses. Thank you.
spk06: Yeah, Yaron, we're just collecting now the data at 70 milligrams in the Admiral study. So we have to complete that. In fact, right now, we've enrolled the initial four patients. We are intending to enroll up to an additional 10 patients in that 70 milligram dosing group after a safety review. So we'll be collecting those data, and then at this point, those patients are not even eligible to roll over into the open-label extension study. So once we get to that point, we'll see what the outcome is. But right now, we're still collecting just the data on the three doses in the admiral study.
spk09: Okay. Very useful. Thank you.
spk01: We'll take our next question from Tom Schrader at PTIG.
spk10: Good morning. Congratulations. I apologize if I missed some stuff. The line's going silent for me a lot. But the big reduction in the 45-mig group, can you tell us, is that being driven by a handful of patients or is it across the board? I think you said your highest reduction was 70% and your average was 55%. Is that correct?
spk06: Hi, Tom. This is Barry. Thanks for calling in. So what we did see was that at the 45 milligram group as a cohort, there was a 55% reduction in median seizure frequency. In the younger patients, and it was just two patients at the younger group, but they did show a 74% reduction. So that to us was quite meaningful. The reductions were quite broad across the entire population. So we are seeing 74% of patients overall were having reductions. And even in that 45 milligram dosing group, we saw that again, that of the patients there, they were fitting that same pattern where at least three quarters of the patients were having reductions. These meaningful results are not based on just one or two patients driving these. This is a phenomenon that's occurring across the board generally in the patients. And again, these are still patients who are on top of fenforamine and other anti-seizure medications.
spk10: And maybe a little clarity on your PK comment. So you're saying you're measuring oligo in the plasma. why do you not assume that you're saturating your target at something like 30 and then stuff is starting to build up in plasma is not that not the way to think about it does it leak before it sees the target well so that the goal for us is to get the oligo to as many parts of the brain as possible at high level as well as to have a sustained effect over time and we know that
spk06: it requires time on drug in order to really see these benefits, and that's what we're seeing in that oval-label extension study with the non-seizure assessment. So what we think is that the CSF, when we inject in the CSF, the oligos do go to the blood relatively quickly, and that's what we're seeing in the first 24 hours is when we see the peak of oligo in the blood. That's not... really a receptor or a substrate-related phenomenon. That's just based on CSF flow. So the oligo gets into the blood, but it also gets into the brain readily. And so what we're seeing is in the CSF as well, which is a better reflection of brain levels, that we are seeing a dose-dependent now increase from the 30 milligram up to the 45 milligram And that's what we think is explaining some of the big bump in effect that we saw in terms of seizure reduction. Yes.
spk11: So, Tom, what I think is helpful to look at this, you know, we saw that mark reduction in seizures at 45. And that really corresponds very nicely with the increase in the plasma and, more importantly, in the CSF. So it looks like we're at 45. We're getting into that therapeutic range where you're seeing clinical efficacy. And so I think it does seem... The story seems to make sense to us now. Got it. Thank you.
spk01: We'll go next to Charles Duncan at Cantor Fitzgerald.
spk02: Hi, it's Oliver. I'm Novick online for Charles. Thank you for taking our questions. I have one on the brief P findings. I was wondering if you saw if there was any correlation between response in brief P as well as reduction in seizure, and if the younger patients performed better on brief P as well, just as they appear to do so in seizure frequency. Thanks.
spk06: Yeah, thanks for the question. So on the brief P, again, The natural history study, the butterfly, we saw over that one year no reductions, and that was a consistent phenomenon across age groups as well. And then in the open-label extension, these are small numbers of patients. So we had eight patients at the four-month time point and five patients at the eight-month time point, where we continue to see a consistent response there in terms of an improvement in the overall score. But those numbers are relatively small, and so breaking it down by age or by seizure response really makes it more difficult to interpret. So we're looking forward to having additional patients as we go forward where we'll be able to follow them over time. And at that point, we'll have a better sense in terms of breaking down and looking at the subgroups.
spk02: Okay, that's helpful. Thank you. And then I guess one quick follow-up is with respect to the seizure frequency, the reduction seizure frequency at three months. Could you, I guess, broadly talk about how to compare to what you saw at months one and two and, you know, just generally what are you seeing with respect to reduction seizure frequency over the course of time? Thanks.
spk06: Yeah, so what we do see consistently is that in the first month after dosing, there is relatively little effect. The seizure levels stay pretty much at baseline. And then after that, we start to see reductions that lead to that peak three months after the last dose where we saw that 55% reduction in the 45 milligram dosing group. And that's about the consistent phenomena that we're seeing across the dosing groups and across patients. So it does indicate to us that this is mechanism of action based because we know that it takes, from the monkey studies, several weeks, if not up to four weeks, to see the increases in the NAV1.1 levels in the brain and the restoration of normal levels we expect in the patients. And so this is a phenomenon that we're expecting to see. And as I said, is consistent with the mechanism of action and consistent with what we've been seeing across all the dosing groups now. In terms of going forward, we did see in the swallowtail study that the reductions that were seen in the monarch study were maintained in the swallowtail study. So it appears that that every four-month dosing regimen may be sufficient to provide adequate seizure control and seizure management. And then, of course, We're also very eager to see the additional data where we're looking at syndrome management, where we're going to be able to assess whether over time the other non-seizure parts of this disease, which are quite devastating for these patients, can be addressed as we've already started to see with the brief P measurement.
spk02: Okay, wonderful. Thank you for taking our questions and congratulations on the progress. Thank you.
spk01: We'll go next to Greg Harrison at Bank of America.
spk03: Hey, good morning. Thanks for taking the question. I know it's a little early, but curious what characteristics you would target for a pivotal study, things like number of patients, you know, placebo control, or would it be sufficient to have a comparison to baseline on seizure frequency?
spk06: Hi, Greg. This is Barry. Thanks for the question. Good to hear it from you. So in terms of phase three, the first thing is that we need to identify the dose level and the dose frequency that we would bring into phase three. And we think we're very well on our way towards that right now. The data that we revealed today indicate that we are now reaching the therapeutic range for our drug dosing. and it's going to give us a good idea of what the potential for the correct dose level and dosing interval will be. Once we get there, then we do have the precedent of other medications that have been approved for Dravet syndrome, which used a placebo-controlled trial with a primary endpoint of seizure frequency at a three- or four-month time point. So that certainly will be the guide for us and likely would be the path that we follow, but we still have to have discussions with our clinical advisors, with regulatory agencies before we can finalize those plans. But we have, as I said, a trodden path already that we can follow. The part that's also not as well worked out, of course, are these non-seizure effects because The currently available therapies are symptomatic treatments that are used for seizure management. But since we're bringing a completely different paradigm with a new approach for treating Dravet syndrome and the only approach that's going to be addressing the root cause of the disease, this management of the syndrome in general and the non-seizure assessments is something that we're going to also talk to the regulators about. and how we assess those in our pivotal studies. But again, the likely primary endpoint would still be a seizure endpoint.
spk11: Yeah, and Greg, I think one of the things that helps us a lot is, you know, we've learned a lot from the butterfly study on what are the appropriate, you know, tests that we can be used in this various age group. So, it's very likely we'll use a lot of the tests that we learned about in butterfly. And again, as Barry said, we're really going to be emphasizing, which is different from most anti-seizure medications, is really trying to focus on what's the quality of life, but some of the non-seizure comorbidities. And so that will be an important part of some of the discussions we have with regulatory authorities.
spk03: Great. Thanks. That's helpful. And then just one quick follow-up on that. Do you have a time point in mind when you would expect to see significant non-seizure benefits that, you know, could be measurable or stat-figged? And how would you expect that to vary according to patient age? You know, some of the KOLs we've talked to have suggested, you know, if you treat patients beyond, you know, or if you don't start until they're a certain age, maybe there's, you know, permanent damage that's been done that's not fixable.
spk06: Yeah. So, Greg, it's difficult. question that we're trying to answer with our clinical trial, so it's difficult to give an answer right now. We know that these are patients who are highly refractory to treatment. They're on three, four medications. Some of them are up to seven medications and are still not having adequate seizure control. Even on fenforamide, they continue to have seizures. And so in this case, as our clinical advisors have told us, in these patients, where they have no treatment options to offer to these children and their families, any reduction in seizure is going to have a benefit from a clinical perspective in these patients. And that holds for the older patients as well as the younger patients. So we think that, as we are seeing, the older patients are having a response. They are having consistent and dose-dependent reductions in seizure frequency. We saw that, again, with the 45 milligram, we're seeing more of a response And we are seeing substantial reductions in even the older patients. So at this point, we think that older patients could benefit from our medicine. We don't see a reason to exclude them from treatment. And so as we move forward, we will continue to enroll both older and younger patients in our studies.
spk03: Got it. Yeah, I mean, I guess that question was more towards the non-seizure benefits. I don't think there's any question that everyone could benefit on seizure frequency, but more of the cognitive sort of aspects.
spk06: Yeah, that's an even more uncertain question. We're doing something for the first time here for all of seizure management. This is something new for the epilepsy field where we are bringing a medicine that's actually addressing the root cause of the disease. Here we're going to restore sodium channels back up to normal in these patients. That's never been done before, so it's not clear exactly what to expect, but certainly our hypothesis is that if we see benefits on the seizure front, which means that the nerve cells are now functioning normally and are reducing the number of seizures, that that in this disease should go along with the change in the non-seizure effects as well. So we would expect that as patients are on the medicine for a long enough period of time and the restoration of normal connections in the brain happens, that the non-seizure effects should also improve. But that's something that we obviously have to see over time.
spk11: Yeah. And Greg, one thing to the differentiation between DREV-A and and some of the neurodegenerative diseases, you think of Parkinson's or Alzheimer's disease, where you're losing nerve cells all the time. Privé syndrome is really a disorder of connectivity of the axons and synapse and dendrites. And I think what we're hoping is that we can have an effect in these children because the neurons are still there, and the hope is that we can make those connections and get some of those children, especially some of the older children, to have some improvements.
spk03: Great. That's really helpful. Thanks for taking the question.
spk08: Hi, Audrey. We'll take two more callers.
spk01: Thank you. And the next one will come from Judah Frommer at Credit Suisse.
spk07: Yeah. Hi. Thanks for taking the questions and congrats on the data. Just a question kind of on background for the patients. You know, do you have a sense for where the patients were and kind of seizure reduction achieved by the background meds before they got into the study? effectively seizure reduction versus when they initially presented at clinic before you guys got a hold of them?
spk06: Thanks for the question. So these patients have been treated with pretty much the standard course of their medicines. And this fact that half the patients were on three or four or more medications when they enrolled in the trial is not unusual for Dravet syndrome. We know that there's a high, essentially, failure rate of the anti-seizure medications as symptomatic treatment, and that patients continue to have seizures despite escalations and additions of new therapies. And the standard way that Dravet is treated is that a medicine is tried, that the patients continue to have seizures, then another medicine is added on, and it continues to add on in this way. And that's why we're seeing patients who have up to seven treatments that they're getting. We know from even the trials that were done with pentforamine that there is a very low rate of complete seizure freedom in these patients. So seizures continue to happen despite some relatively effective medicines. And that's basically what we were seeing in this trial. We know that the rate of seizures that we're seeing that enrolled in the Monarch and Admiral trials was similar to what was seen in the other Phase III trials. So these are patients who, in terms of severity, are equally if not more severe than were enrolled in other Phase III trials, and yet we're still continuing to see seizure reductions on top of all of that. So that, for us, was a very encouraging sign.
spk07: Okay, that's helpful. And then just if you could kind of further connect the dots on, you know, the 20 and 30 MIG-CSF exposures, versus seizure reduction. You know, the seizure reduction in the 20 mg, you know, looks compelling. Obviously, it's a small number of patients. Is your contention that that 20 mg line on slide 17 might move toward the 30 mg line if more patients were dosed?
spk06: Yeah. So, Judah, the data that we have right now, did show both in the plasma and the CSF that the 20 and 30 milligram levels were not substantially different. Our expectation would be that if we had more patients in the 20 milligram group, more than those four patients, that we would probably continue to see that the levels were slightly below the 30 milligram, but not substantially differentiated. So that's why we were very encouraged to see with the 45 milligram group that as we were seeing in the seizure reduction, that we think that we're now getting into a therapeutic range with the medicine and with the levels that we're achieving in the brain to have a substantial clinical effect.
spk05: Okay. Thank you.
spk01: We'll take our final question from Rudy Lee at SVB Securities.
spk05: Thanks so much for taking my question. Congrats on the data. It seems like we have seven patients who did not respond, that they did not have seizure reduction versus baseline. How many of patients from each cohort are they including the median seizure reduction data? Any additional color here would be helpful.
spk06: Sure, Rudy. So, what we did see was that three-quarters of the patients were having seizure reductions, and that was pretty consistent across all the different cohorts. Again, this is not something that's being driven by one or two patients. It's relatively consistent that we're seeing in all the dose cohorts some degree of reduction. It's just that at that 45 milligram dose group, we were seeing even more reductions than we were seeing at 20 or 30, and that's how we got to that 55% reduction. And again, even within the younger patients, we are also seeing that there is a consistent response in the younger patient groups. And in fact, that amount of 74% reduction was seen at the level in the patients at that very younger group.
spk05: Got it. Just a quick follow-up. So what data should we expect at upcoming AES conference?
spk06: Yeah, we're very excited to be able to present data next month in Nashville. What we will be presenting, we have multiple presentations there. We will be presenting some additional data on the combination from the Admiral and Monarch studies in terms of the seizure reduction. It won't be more patients, so we aren't going to be adding additional patient data in terms of total number, but we'll be adding additional data, especially in terms of the safety and PK data. And we will have a separate presentation on PK that will show, again, more data that we showed from the plasma and the CSF levels. We'll have data from the monarch, sorry, from the butterfly study, our natural history study, where we now have data out to one year. And then the exciting part are the swallowtail data, where we're starting to see some of these non-seizure comorbidities affected. And so we'll have data on that brief P. Again, not... an increased number of patients, but we'll be able to show those data for the brief P again. Got it. That's very helpful. Thanks. The other thing that we will be showing are some EEG data. So we do follow EEG in these patients, and we have some data that will be worth looking at for EEG changes that we see in these patients.
spk08: Okay, thanks everyone for joining today. The IR team is available for any follow-up questions the rest of the day.
spk01: And this concludes today's conference call. Thank you for your participation. You may now disconnect.
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