Hello. Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Stoke Therapeutics, a company I cover. I'm pleased to introduce Ian F. Smith, CEO, and Jason Hoitt, the Chief Patient Officer. With that, start off with a brief intro of yourselves, snapshot of the company, the pipeline, and key milestones that will shape the company over the next 12- 18 months. Thanks, Pete. You can breathe now. Pete just arriving. Thank you for the introduction. Happy that you took time out of your day to listen to the Stoke story and go through the Q&A with Pete. Today, Stoke is a company that has a phase III medicine to treat Dravet syndrome. We've fully recruited that phase III study. Anticipated readout should be the middle of next year, probably within the next 12 months. I'm happy to answer all questions regarding the opportunity of that phase III readout and how we think about it, how the trial is going, and also how post-data and also approval, how we think about the market. That includes patients and what this medicine may be doing for those patients, as well as the value of that medicine, not just to the patients, but also to Stoke as a company, given that this medicine was created by Stoke from the bench- All the way through, hopefully, to the patients. We've advanced as a company significantly over the last couple of years, rapidly and growing. We also have a growing pipeline. We have another medicine focused on ADOA, which is a genetic form of loss of eyesight, loss of vision. That study is progressing nicely in a dose escalation phase I/II study. We're into our second cohort of patients and expect to be soon into our third cohort of patients and talk about that. Financially, the company is in a very strong position. The balance sheet data that we provided to the investment community as of June 30, we had over $400 million of pro forma cash that took us through to early 2028. We're well capitalized and in a good position to continue to develop our medicines through to launch. All right. Just a high overview. There is a lot going on at Stoke. You mentioned phase III, phase I ADOA trial. If you're sitting here a year from now, and I ask you in the last 12 months, what have been the key value-creating accomplishments for Stoke, what would you like to say? Obviously, the data readout from our phase III, that's within the 12 months, if we transport ourselves forward in that time machine. Looking back the 12 months, yes, clearly the readout from the phase III is a very important value-creating event. It'll establish the medicine. It'll establish the profile of the medicine. The design of the study goes beyond treating seizures for Dravet syndrome, but it goes to maybe a disease-modifying medicine to treat both the seizures and also cognition and behavioral morbidities within this disease. That would be the one big achievement, looking back. I think also, throughout the next 12 months, if I now transport myself back to today, looking into the future, I think as the trial progresses and continuous updates on the trial and how the patients continue to move through the trial and potentially into a second treatment period in open label study post the 52-week trial, I think those are important metrics of how the study progresses. On the ADOA side, I do feel as though with cohort 3 and 4 in a four cohort for phase I, phase II, we start with cohort 3 and 4 getting into what we think is a therapeutic level of dosing. And we have potential to show that impacting OPA1, which is the genetic target, but impacting OPA1 does upregulate mitochondrial function and therefore enhances vision, as in improves vision. Doesn't just stabilize vision, but improves vision. That's also within the next 12 months, and I think would be a defining event for the company as well because it'll be also emerging pipeline. All right. Moving into some of the clinical data that you generated with zorevunersen. In the phase I/II, there were initial loading doses where substantial seizure reductions were observed, remained durable in the OLE. Just contextualize the magnitude of reduction in seizures in these patients, especially in the backdrop of the anti-seizure med that they were on, including any data that you may have presented this weekend in Athens, Greece. Yeah. To be honest, it's a long answer because when I think about the medicine itself, zorevunersen, just to give you a brief understanding of its mechanism of action, its target, this is a genetic therapy targeting the SCN1A depletion. What that means is that when you have a mutant gene, you're not producing enough protein, NaV1.1, which is the root cause of Dravet syndrome. Going from the bench targeting SCN1A to upregulate the protein NaV1.1 has always been the principle of this medicine because it addresses the root cause of the disease. Our studies preclinically have shown that we can get to potentially wild-type levels of NaV1.1 in our animal models. Translating that through to the dose that we're using in the clinic and ultimately through to the Phase III, because you're addressing the root cause of the disease, our anticipation is that you would significantly reduce seizures, which we do see. To one of your questions, Pete. Also, we're seeing these patients that plateau at the age of 18 months- 24 months. We're starting to see them gain function when they go onto medicine. What I mean by gain function is like gaining tasks and ability to do certain tasks, the ability to communicate, ability to receive communication. We've seen all of that. What is really interesting today, and to your point, Pete, is the data that we have in our open label study. Once these patients were through the phase I, II study of this medicine, they had the opportunity to go to an OLE study, and certain patients have been in that OLE study now for four years. This is a chronic disease, and we dose the medicine chronically. As we dose the medicine chronically over a longer period of time, the seizure reduction has been sustained at levels of 75% ±. Also, we see this continuous gain of function and task as measured through a questionnaire called Vineland-3. You do see improved communication. You do see improved motor skills. That's what's been really fascinating about the longevity and the durability of the OLE data to support a chronic disease, but you're giving back function the longer they're on medicine, as well as sustaining those reductions in seizures. Now, we have to now proceed and run a phase III trial that has seizure reductions as a primary endpoint and cognition and behavior as the key secondaries. We are well into that, and the trial is progressing very nicely. We did host a really great call with the Dravet Syndrome Foundation over the summertime. I think it is underappreciated. There were a couple of points that came out. One of them is the residual seizure burden these patients have, even though they are on, quote-unquote, "optimized" ASMs. They went through in detail their seizure plans, including rescue medication, how often these patients have to go to the ER, how they spend a day, two days, three days, disrupts the family's schedule, and especially when you have other kids. It turns things into a little bit of a mess, and it has a high impact on quality of life. These facts, I think, point to the residual seizure burden and whatsoever zorevunersen has brought to these patients. We did actually ask them, since they are close to individuals who are in the OLE, how is it viewed? They said that there has been profound, across-the-board reduction in seizures, and really promising, and feels something very different than from what has been shown by other anti-seizure meds, especially on the durability front, where it is not a honeymoon phase. Pete, I do not mean to introduce it. It is actually more that I want to add to what I said before relating to seizures, which is that our patients or the patients that are on our medicine are actually screened before they come into the phase I/II, and obviously then into the OLE. That screening process is very similar to the patients we are recruiting, or we recruited into the phase III. But these patients, notably, are already on standard of care anti-seizure medicines. They still have significant seizures. The actual seizure itself, the tonic-clonic seizures, which are very dangerous and often related to SUDEP. SUDEP is sudden death, unfortunately, from these seizures. There was a number of presentations this weekend at EEC that showed that. Not only are we reducing the severity of the seizure, but we are reducing the severe seizures. And that's on top of standard of care medicines that these patients are already taking. In the OLE data that you referred to, and I spoke about before, these patients are on anywhere between three and five anti-seizure medicines already, yet we're still reducing those seizures. The reason why we're reducing the seizures to the extent of 75% is because of that root cause of how we address this disease by upregulating NaV1.1. So it, in a way, in layman's speak, it goes around the mechanisms of the anti-seizure medicines and goes to the root cause of the disease in the brain. Fortunately, we are reducing these seizures even further with this 75% reduction. It is one of the most acute events of this disease that the parents and families suffer from while their child is suffering from. It's probably the scariest, and as I said, is linked to SUDEP. Anything you want to point out from your presentations this weekend before we move on to the phase III? Overall, we've got a large presence at epilepsy conferences these days. We'll probably have a large presence in the American Epilepsy Society Annual Meeting, which is in early December this year. We had a large presence this weekend over in Athens. We're well supported by the physicians, and they're utilizing the data that we've been able to take from our phase I/II, and four years worth of OLE data now, and look at it in all different ways. And whether it's a focus on seizures, seizure reduction, severity of seizures, looking at different dose levels to see a dose response in terms of seizure reduction, then also looking at cognition and behavior, and looking at the cognition and behavior responses in the different domains and comparing them to how they would be to a patient out of natural history, and showing that these patients are gaining function based on this data. We've got a big presence. It's a first-in-class disease-modifying medicine to treat Dravet syndrome. Very excited where we are with the phase III, which gives you the nice introduction to the phase III. Yes. But I will say, yes, I was at AES last year, and definite excitement. Yeah. Saw them around your posters and had a number of discussions with neurologists there. Overall, the impression that I get is that they're excited about this coming forward. Yeah. To the phase III, EMPEROR study. Recent update is that the trial has completed enrollment ahead of schedule, and top-line data is locked in for 3Q of 2027. Just walk us through the study design and the key endpoints. Yeah. The study design was initially designed for 150 patients, to be treated with four doses, two loading doses of 70 mg on day one and then week eight, and then two doses of 45 mg at week 24 and week 40. Key secondary endpoints, I am going to take a moment on this as well, Pete, because we have had a number of questions from investors, just frankly in the last week, about the key secondary endpoint, so I do want to make sure there is clarity on that. Sorry, the key primary endpoint or the primary endpoint. First of all, the primary endpoint is seizure reductions as measured at week 28, and I am going to come back to that in a moment. The key secondary endpoints that measure Vineland-3 domains in a hierarchical manner at this point in time. We do have a meeting with the FDA to discuss a number of topics, including a statistical analysis plan. I will talk about that in a moment. Coming back, that is the design of the study, a 52-week study, 150 patients, and it is a lumbar puncture sham-controlled study, which is very important to keep the blind, and so we can truly measure the treatment effect against the sham control. The key secondary endpoint, which I wanted to clarify, we have had a number of questions of how do you measure it? I want to be very clear on how we are measuring that. Sorry, the key primary endpoint. How we are measuring that primary endpoint. It is the four weeks leading into week 28. That means week 25, 26, 27, 28. We measure the seizures in that period and then compare that to baseline, and then compare that to the sham. We have had a number of questions asking, do you measure the seizures from basically day one? Therefore, are you taking a risk of the separation from the mechanism of action of the drug and the onset of action of the drug? The answer is no. We are not taking any risk regarding that at all. To see the seizures reduce compared to baseline, it typically is around month three to month four to see that 70 +% separation from baseline. Yet, we are measuring the seizures at month seven, the four weeks leading into month seven. So we are well beyond the onset of action of the medicine to see the seizure reduction. That is the primary endpoint of the study. The secondary endpoint as of now- Just- Sorry, yep. The dose, the second dose is given when, relative to the seventh month? Well, actually, there is three doses before month seven. Day one is 70 mg, week eight is 70 mg, and week 24 is 45 mg. So you are getting three doses. But even when you look at the onset of action of the loading dose, you are starting to see 70% reduction in seizures at about month three to month four. So three to fur months ahead of measuring the primary endpoint. You started with the secondaries. Secondaries right now is designed and agreed with the FDA in 2024. That was when the company had discussions with the FDA about the design of the phase III. The key secondary endpoints were designed to be measuring individual Vineland domains in a hierarchical measure. What that means is you measure one domain, you test the p- value. If you hit a p- value, then measure the second domain, and so on. There was five that were there, and ordered in a way that we thought was important for a patient to understand that this is modifying the disease. But also important in terms of what the caregiving community wants to see from a disease-modifying drug, which is mainly focused around communication, receiving communication and giving communication. So that is the secondary endpoints. We are going to the FDA to discuss three topics. One of them, though, is actually the SAP and specifically the secondary endpoint. We want to move away from the hierarchical assessment towards a composite measure, and I'll just spend a moment to why. The progress from late 2024 to current date, so a two-year period nearly, with the education of the FDA about what Dravet syndrome is, and also what our medicine may do for a patient in terms of how it may benefit a patient. We've been able to take this body of data and evidence from our OLE and help the FDA understand not just seizure reduction, but also the comorbidities in this disease. Once there is a greater understanding with the FDA, and we also have a greater understanding of how our medicine is impacting these patients, we actually look at this and say, "We want to measure the comorbidities." Because what we know about this disease is these comorbidities, whether they're receptive communication, expressive communication, motor skills, interpersonal skills, social skills, they all develop at a different rate in different patients. To try and pick a hierarchical methodology to say, "We want to hit all those in this order," it's a little, I would say, academic in terms of trying to pick one, two, three, four, five. It's better measured, I would say simplistically, by taking four or five or six endpoints that you know you benefit in, but at different rates, combining them to show that you have a statistically significant treatment benefit. What I mean by that is a composite score is you measure the five individually, you then add them together, but frankly, you just then divide by five, and you get effectively an average composite Vineland score. We've powered the study to get a treatment effect of two to three Vineland points because that's defined as clinically significant. We want this to be measured as a composite as opposed to an individual domain. We'll probably provide the individual domains, whichever way we go with our secondary endpoint, to the FDA part of our NDA submission anyway. Would the individual parts of the composite, would they be weighted differently or equally? No, the plan and the discussion with the FDA is that it really is. I am trying to simplify this as saying, let us say you score a total of, I am going to say 3 on 5 domains. That means for 5 domains, you have scored 15. But you then take that 15 and divide by 5, and it gives you a composite average of 3, and that would be clinically significant. It is straightforward as that. There is no weighting. Okay. You will have the five-year data by the time you start a rolling submission in the first half of 2027 for the phase I in OLE. What strategies can you pursue to have these sort of data reflected in the label? The reason I ask is if you do miss that sig on Vineland in EMPEROR, is there a way to reflect the disease-modifying activity in the label? Yeah, it is a good question. First of all, I want to clarify the question in that we are very confident in hitting our secondary endpoints. When I say we are confident of hitting our secondary endpoints, the study has been designed and powered in a way that gives us that confidence. So I just want to spend a moment on the powering of the study before we go to the OLE, if that is okay. We have actually powered the study off the secondary endpoints, which gives you a lot of powering for the seizure reduction. The way that we have powered those secondary endpoints is we have powered it that told us that we need 128 evaluable patients. We have powered it off data that we have received, obviously, from natural history and also the phase I/II and the OLE data. But the powering told us we need 128 evaluable patients to reach a statistical p- value of anywhere between 0.01 or 0.05 to get a treatment effect of 3 Vineland points with a 90% confidence level. So that is how the study has been powered. Interestingly, as of beginning of August, when we updated you on the key metrics of the study, I cannot do it today because of just Regulation FD. But we had 162 patients recruited and 162 patients still in the study. At that point, we already had, I think it was 60- 80 patients that were through three doses and moving into the primary endpoint. So if we have less dropouts, and frankly, we recruited 162 patients, there is going to be incremental powering that also comes from the retention within the study and the recruitment of 162 patients. But the study was initially powered to detect a treatment difference of 2- 3 Vineland points on an individual domain basis. If we end up in a composite, we do benefit on a powering a little more. What was the dropout assumption? Dropout assumption was 15% because we powered the study to recruit 150, 15% dropout or non-evaluable patients, which got me to the 128 evaluable patients, just for clarity. I do want to emphasize, we are confident in achieving the secondary endpoints on the basis of data we've collected on the dosing levels that are similar to the phase III and the well-designed phase III study and the powering based off the secondary endpoints, which gives you a lot of power for the primary. To your point of if we miss the secondaries and how would you approach the FDA in terms of label, we look at the regulations from the FDA that state that you must include clinical studies that provide information and evidence of how your medicine benefits a patient within your submission for the label. The OLE, this is a chronic disease where the patient unfortunately doesn't develop beyond the two years of age, yet our medicine is dosed for their life. So we look at the four-year, which will be five-year data next year, and say, "This is the potential result." It's certainly informative evidence of what the medicine can do over a chronic period of dosing with a Dravet syndrome patient, both from a safety perspective, but also as a clinical benefit. Because that data has shown seizure reductions that have been durable and stayed around that 75% level of that from the higher dose level patients. And what it's also shown from Vineland is there is a continuous gain. The gain of function as measured from baseline to all the way out to year four now is greater than when it was, let's say, one year. we believe that that's important for a physician to understand and why it will be part of our NDA submission. So All right. Even though you feel confident, I'm just going to ask it anyways. How important is it actually to hit on the phase III of Vineland sub-domains, either composite or- Yeah individual to support premium pricing? I actually appreciate you asking the question, Pete, because I want to decouple the two. It does feel as though there is a heavy indexing to investors' thoughts about pricing and the secondary endpoints. And yet we'll take a moment here because Jason is our Chief Patient Officer, but that also means he's our Chief Commercial Officer, and we've done a lot of work with payers. A lot of work, and Jason's about to tell you all about that. The importance of hitting the secondaries is because when you get a p- value and you hit a secondary endpoint, it goes on the label. The importance of the label is promoting the drug. We would be able to promote the drug in a way that is, I'm going to say, better for the patient to understand what the medicine would do for it. That's the promotion of the drug. Hitting a p- value on the secondary will definitely help us with reaching the patient, as in prescribers, because we'll be able to promote to prescribers, so they'll be able to explain the medicine because of the label. There is less attachment to the pricing, because the pricing is more about the totality of data that you have that you share with a payer, and so the payer understands the pharmacoeconomic benefit of the medicine. I'm going to turn to Jason to talk about the work that we've done with the payers, and the total body of evidence that we have. Yeah. We went out-- We're consistently engaging with payers. But earlier this year, we went out and specifically asked payers and epileptologists, neurologists the question around different potential label scenarios and different data scenarios at the time of potential approval and wanted to understand, from a payer perspective, what will be the most compelling pieces of evidence for them as they're thinking about writing a medical policy for coverage of zorevunersen. From a clinician perspective, which pieces of data are going to most influence their decision of whether or not to prescribe zorevunersen for the patient that's sitting in front of them. The answer that we got from both audiences was consistent, though, that at the time of a potential approval, the most compelling piece of evidence that they'll have at their disposal is the long-term open label extension data. Because naturally, if you're a clinician or if you're a medical director of an insurance company and you're writing a medical policy for a chronic lifelong treatment, you want to understand what that treatment's going to be doing over the long term. To Ian's point, it's more important to have those OLE data in the label from a promotional perspective, because from a payer standpoint, they told us the label doesn't matter as much. We're going to look at the totality of the evidence. We're going to look at all the publications. We're going to look at everything that's been presented in a peer-reviewed scientific meeting context, and that will all inform our decision around coverage. To answer your direct question, Pete, it's probably less important than people are indexing to have it in the label or to hit statistical significance on the Vineland. I think if we're directionally moving in the right way, I think we'll be fine from a pricing perspective. But to Ian's point, we also have full conviction based on the way we designed the study that we're going to hit on the secondaries. All right. We're pretty much out of time, but I'm going to ask this quick question. If you do secure a disease modifying label or there's activity seen in the phase III, so what's a commercial analog for uptake and launch trajectory, but also pricing? Yeah, it's a good question. I think from a commercialization ramp perspective, I think looking at other disease modifying genetically targeted treatments that were a paradigm shift are good analogs. I think drugs like Vyondys 53 and Amondys 45 from Sarepta or CASGEVY from Vertex are pretty good analogs to look at. Okay. Anything to add, Ian, or No. Thank you for your time. Yeah, thank you very much for joining us at the Cantor Global Healthcare Conference, and looking forward to updates from phase III and then your rolling submission. Thank you. Thanks, Pete.