Okay, well, good morning, everybody, and thank you so much for joining us for the 2024 Genetics and RNA Summit. I'm Yaron Werber from the TD Cowen Biotech team, and it's a great pleasure to moderate the first session of this two-day summit with Stoke Therapeutics. Both Ed and Barry need really no introduction. Ed Kaye is the CEO, and Barry Ticho is the Chief Medical Officer of Stoke. Gentlemen, thanks so much for joining us. We appreciate it. Thank you, Yaron, and good morning. Thanks, Yaron. It's a pleasure. So for the audience, if you have any questions at any point, either email them directly to me at yaron.werber@tdsecurities.com. Notice we have a new email address, or for those of you who are logged in through the Wall Street Webcasting website, you can actually put questions on there. I can see them, and I can take them anonymously on your behalf. So lots to discuss, we have a half hour, and lots to discuss, both on 001 for Dravet, and I definitely wanna leave a lot of time for 002 for ADOA. So let's start with the Dravet update that you gave about three months ago, three or four months ago. You run two separate phase I/II studies in Dravet, the MONARCH in the U.S. and SWALLOWTAIL OLE, and ADMIRAL in the U.K. with LONGWING is the OLE, open-label extension. You showed up to an 85% reduction in convulsive seizures at the higher dose. This was the latest cut from the phase I/II data. What are your main conclusions from this data? And based on that, how are you thinking about designing the phase III? Yeah. Thank you, Yaron. You know, I think obviously we were very excited about the data, and I think the reason is this really is a completely different approach to treating Dravet syndrome or any genetic epilepsy. And what I mean by that is we're trying to correct the underlying genetic defect, and what we're doing is we're upregulating the NaV1.1 protein to get it back up to that 100% level, from a 50% level to a 100%. So there was two things we were really hoping to see out of these studies, and one of which was, and which we I think we learned, is we learned that we really do need a loading dose to see the maximum effect. What we saw when we treated patients with two or three doses of 70 mg and followed by a 45 mg, we were seeing up to an 85% reduction in seizures. I think the more important aspect of this study, however, was that not only were we treating seizures, we were actually addressing the behavior and the cognition. So we were treating two different aspects of the disease, and this really hasn't been done before. I think the genetic approach suggests that this is the way we need to treat genetic epilepsy because you're actually addressing all of the symptoms of the disease and not just one symptom, and by addressing the underlying cause. So I think what we learned from this is, I guess, first of all, we need a loading dose of that 70 mg. And then I think the second thing is that we do need some time to be able to show the improvement in cognition. We saw it in our basically 70-mg study, that it, we saw improvements by nine months, and then in the open-label extension, we saw improvements in cognition and behavior by around a year. So, somewhere between nine months to a year is the time that it takes to see those changes in cognition and behavior. So I think that was the take-home message that we learned from these studies. Okay, great. As you're thinking about designing the phase III, so I think you've talked about two or three loading doses of 70 mg. Have you decided which one it would be? Would it be two or three? And then did you, at this point, decide to go with the 45 mg as a maintenance dose? Yeah, Barry, I'll let you answer that. Yeah, well, the data that we have right now show that the either two or three doses of 70 mg as a loading dose have substantial effects in terms of seizure reduction. Also we've shown now that within the 9 months that the patients get started on that 70-mg dose, there also are improvements in... that are noticed, as well as improvements in their overall clinical status, as judged both by the caregivers as well as the clinicians. In terms of the two or three doses, that's still being determined, and it's gonna be something that we will have as part of our discussions with regulatory agencies as we plan and finalize the phase III study design. In terms of the 45 mg maintenance, again, we have data now showing that patients who received three doses of 70 mg as a load, and then received a 45 mg dose in the open- label extension study, those patients, when we followed them for four months, continued to have substantial reductions in their seizure levels. So that would indicate to us that that 45 mg dose is sufficient as a maintenance dose. As a reminder, the data we have right now from our open- label extension study, where we followed many patients who were getting either 30 mg, for the most part, or some of them getting 45 mg every four months, those data show that those patients continued to have meaningful reductions in seizure levels, as well as improvements in their cognition and behavior. I'll just take you back to our natural history data, where we follow these patients, similar patients over two years, and show that those patients did not have any reductions in seizure levels over the time, despite the fact that they were receiving maximum anti-seizure medication treatment. That those patients had no changes in their behavior or cognition scores on multiple different assessments. The fact that we're showing now with treatment every four months, that they're having sustained reductions in seizures and improvements in cognition behavior, this is in stark contrast to what the usual course would be for these patients. This all harkens back to the fact that, as I mentioned, we are addressing the actual genetic cause of the disease. We're using RNA as a medicine here, in this case, to increase protein levels inside the cell. That, that's not an easy thing to do. We have the biology to say that these patients with Dravet syndrome, they have reductions in a key sodium channel that's necessary for normal brain function. When we use our antisense oligonucleotides, which are an RNA medicine, to increase the sodium channel levels in the brain to a degree that is needed in order to compensate for the lack that these patients have, we're seeing that now is being translated into a beneficial clinical effect. Just remind us, in that study, after the first loading doses, there was a four-month lag right before you started the maintenance doses. Would that be the same in the phase III, or would you shrink that to maybe start that sort of 3 months, and then I believe you're gonna treat monthly thereafter? Or would you treat every 3 months thereafter maintenance? Yeah, just a minor clarification. So those patients were actually followed for 6 months before they started in the open-label extension study. And so what we would plan, and again, this is still up for discussion, would be that the patients would start 4 months after their 70 mg loading dose to get that 45 mg maintenance. So it would be... Yes, it would be a shorter time than what we have tested now from the phase I/II to the open-label extension study. But it is in keeping with what we know from both the level of response that we've seen with every 4-month dosing in the open-label extension study, as well as the data that we have showing that the half-life of the medicine in the brain is about 4 months, so that would fit with every 4-month dosing regimen. Even the maintenance doses will be Q4 months? Correct. That's the current proposal, right? Again, this all has to be finalized, but that would be the plan. Yep. Okay. As you're thinking about the phase III, is the primary endpoint of seizure reduction on an annual basis, the percent ARR reduction, would you look at that primary endpoint at 12 months? And, you know, sort of how would that work? They'll get a monthly dosing for 3 months, then Q4, right? So 0, 4, 8, and then every 16 weeks, so it'll be 24 weeks, and then the next dose at is gonna be 40 weeks. So would you try to sort of synchronize when you're doing the primary analysis to coincide with the last dose, or how would that work? Yeah, this all has to be discussed with the regulators. So, in terms of the phase III design, we can't really talk much about that until we have final agreement. But what you're thinking is along the lines of what would be a potential study design, exactly, that the patients would get their loading dose. The first two doses would be two months apart, eight weeks apart, and then a third dose, if we did it, would be a month after that. And then they would start every four-month dosing, and then we would time the study. You know, we want to be able to show the effects on cognition and behavior. This is what truly differentiates this approach as a disease-modifying therapy and makes it different from an anti-seizure medication, which is not based on trying to treat the cause of the disease. And so in order to make sure that we can show those changes in cognition and behavior, we'll want to follow the patients for a sufficient period of time to be able to show a statistically significant difference in the treated group from the control group. So we certainly will intend to design the study in order to show that, as well as the reductions in seizures. Yeah. And obviously, Yaron, you brought up a good point about what's the optimal time to really see a reduction in seizures. And I think certainly what we saw in our previous studies, we saw at 3 and 6 months, we saw a very nice reduction. One of the things is that, which is quite different from other anti-seizure medications, since this is a genetic approach, is that it takes time. So we actually see better reduction in seizures over time, and what we think is happening is once you get the NaV1.1 levels up, there really is a rewiring, a re-equilibration of the brain, where some of those synapses are again reforming. So it takes a longer period of time. If you look at most studies using anti-seizure medications, it's typically, you know, basically, you know, 12-16 weeks. Ours very likely, you know, we see a much better effect at 6 months, and then we're continuing to see a sustained effect. It doesn't, it doesn't remit at all. And so we'll have that discussion with regulatory authorities, but certainly something, you know, like at 6 months or a year, may be a possibility for what that endpoint would be. As you're thinking about the cognitive endpoints, I, if I remember correctly, you're looking at the CGIC, the CaGIC, and the Vineland you're looking at as secondaries. Can you go over maybe some of those, and which one would you potentially carry forward on the cognitive side for the phase III? Yeah, again, all of this still has to be finalized with regulatory agencies, but the Vineland, we have found, is a very appropriate measure for measuring cognition behavior in patients with Dravet syndrome. The Vineland, for people who are not familiar, is one of the most commonly used assessments for tracking a developmental delay in neurotypical as well as affected children. So this has been tested in thousands and thousands of children, and we have found that the age range for the Vineland, which is very, very broad, is appropriate for the children with Dravet syndrome, as well as potentially for adults with Dravet syndrome. The measure itself is a measure that can recall over time, so it's not as dependent on a one-time assessment that can be done with these children. This is something that looks at over a period of time, so it's not as variable depending on how examination. What we did show was that in multiple different domains of the Vineland, we showed an improvement in the scores of the children with treatment. The changes that we saw were especially evident in expressive and receptive communication. We've also gone and done with an independent assessment and a review of what are the important changes in the Vineland scores that both clinicians as well as caregivers think are the most relevant for their child. What we found is that most commonly parents and caregivers of children, as well as clinicians, want to see changes in communication as one of the improvements of a medication. And they also gave us an idea of what the score range would be on that Vineland. And what we showed was that the improvements that we're seeing with STK-001, or what we're now calling zorevunersen, is in the range after treatment that the families and the clinicians are saying is important. So we're seeing a clinically meaningful effect on those scores in those communication scores that do reflect a meaningful change that the families want to see. Okay, now a question from the audience: What is the next update that we should be expecting? I think you've noted you're gonna have data at a medical meeting or in the second half. And would we be able to further quantify the activity at the 45 mg Q4 months maintenance dose at that point? Well, we're certainly continuing to collect that. The data that we released earlier was on the first three patients, who, at the time of the data cut, had rolled over and gotten 45 mg dose. We are now continuing to follow additional patients who have rolled over. We're very happy with the rollover rate. We have more than 90% of the patients in our phase I/II study that rolled over into the open-label extension study. So it's giving us a wealth of data in order to follow patients long- term. We are right now really focused on our upcoming discussions with regulatory agencies, so we haven't gone back and timed out yet exactly when we'll do our next data cut. But we are going to continue to follow those patients. We are going to have those additional data that we can release, and that we will guide to at a later date. And so, as of now, the data in the second half of the year, is it a chance that it's gonna be at the European meeting, sort of late August, early September, if I remember correctly, or is it much more likely to have that data at AES in December? Well, what we're guiding to right now really is more an update on the regulatory discussions and the Phase III study design. So that we're guiding in the second half of this year, that we'll come back once we've had a more full agreement with regulatory agencies and a better idea of what the Phase III study will look like. We'll be able to guide to the exact study design, as well as when we expect to start enrolling patients into that study. We haven't guided yet in terms of when we'll have additional data. You are correct that there are some medical meetings coming up, and again, the American Epilepsy Society meeting in December is one that we certainly plan to attend and present at. But whether how much data we'll have at that point, we're not guiding to yet. And then, Barry, do you need to do another data cut before you officially go to FDA? I mean, wouldn't they want to see at the very least, the latest safety, and maybe, obviously, the latest efficacy as well? 'Cause the last data you have was, you know, was data cuts that will continue to obviously be analyzed, but dating back to November and December of last year. Yeah, again, as you mentioned, a large safety database. We have 81 patients in our phase I/II study database. That's a large number for a phase I/II set of studies, and we are very quite pleased with the safety profile that we've seen to date. So in terms of safety data, we'll have, we think, ample data to be able to support the plans for phase III, which is really what we're going to talk to the agencies about. In terms of what exactly will constitute that database, we are planning that right now, and we'll come back to you later. Once we've had those discussions, we can tell you exactly what we discussed with the agencies. It sounds like you've said that the enrollment in the phase III is gonna be, you know, fairly similar. Does that mean patients have to have sort of three prior anti-seizure meds? And as you then think about what the label could be, which is this is a unique drug, as you said, 'cause it's really a genetic therapy, which is for Dravet syndrome. So you're not just looking at reduction in ARR, you're looking at neurodevelopmental endpoints as well, but you are starting inevitably at the relapsed refractory setting. So would the label require patients to be sort of experienced, or even with this study, assuming you're enrolling patients with three or more baseline meds, you can still potentially get a broad label because of the secondary endpoints? Yeah. So I can comment on that, Yaron. I think one of the thing, almost by definition, Yaron, the Dravet syndrome patients almost any time are a refractory group of patients. And I think what we're seeing is that, you know, 90% of the patients are still continue to have seizures despite the best medications. And I'll remind you that these patients were on maximum treatment. Half of them were on fenfluramine. And so really the standard of care for, you know, the vast majority of the patients, they're all on multiple drugs, and they've all been on previous drugs. And typically, you cycle over and over again with different anticonvulsants. So, you know, I don't think we're too concerned that we would have a narrow label. I think it would... Yeah, my expectation, and again, we haven't had discussions with the regulatory authorities, is it would really be for the treatment of Dravet syndrome with an SCN1A mutation. And again, it is treating the entire syndrome, not just the seizures. And that's what we're gonna focus on in our discussions with regulatory authorities. Yeah, and in terms of the phase we study, again, we feel we're in an advantageous position that although it hasn't been finalized again, the patient population that we're intending to study in phase III are very similar to what we've studied already in phase I/II. The dose levels that we're planning to study in phase III are very similar, identical to what we've tested in the phase I/II studies and open-label extension studies. The endpoint that we're using for phase III, that we're proposing, the seizure frequency, we've already shown an effect on that in phase I/II. So in many ways, we already have quite de-risked the phase III program by the data that we were generated in phase I/II, and that's a unique position to be in, as far as a company moving into phase III. Yeah, so just, again, 'cause these are the questions we get a lot. So for the audience, note, if you look at the Epidiolex label, it's a broad label for the treatment of Dravet. There is no quantification for how many prior therapies they must have failed, despite having that criteria for enrollment. So as you know, Ed and Barry said, this would qualify for a broad label. Okay, that, that's very useful. As you're thinking about enrollment, and I know we're kind of, again, jumping the gun a bit, but how fast do you think you can enroll phase III? And maybe just remind us, how many sites did you have in the phase I/II? In phase I/II, we had sites in the U.K. and in the U.S. We had a total of more than approximately 24 sites there. The phase III study, we're intending to be a global study, so that will be in multiple countries, including U.S., Europe, U.K., Japan. We're proposing a single trial right now, and that right now, we, we have, as I said, a good idea of what the study design will be. We have had quite a bit of interest in the phase III trial based on the data that we have generated in phase I/II. And so that's been encouraging to us that as we move forward, there is a high level of interest from clinicians as well as families in gaining a potential access to this medicine. Would you- is the, the enrollment, age-wise, would it be sort of pediatric and adolescent, or would you include adults? Now, again, this still has to be finalized. Our current plan would be to enroll similar patient populations, so that would be patients 2- 18 years of age in the phase III trial. But we will generate data in other age groups as well. So we are planning to do a separate study in patients from 6 months - 23 months of age. And we are already generating data on adult patients because there are patients who are being followed in our open-label extension study, who are 18 years and older. So those are already data that we're collecting on adult patients, and we'll continue to follow those patients. Now, we have patients who've been treated for 3 years in our open-label extension study, and we'll continue to collect those data.... That will be data that we will have on adult patients as well. Yeah, and so Yaron, we're having discussions with payers and with experts in the area, and having discussions about, you know, what would an adult study look like? We certainly wouldn't do it as part of this phase III, but we are looking at how could we supplement and a lot of it, of course, would be to help us with reimbursement and what could add more value to older patients. So that's under intense discussions right now. Is this study, are you planning on speaking with FDA, and then EMA, and the MHRA, and the PMDA, all sort of in sequence to get them on board with the study design? Or do you first start with FDA and just sort of assume, and then engage with EMA and PMDA sort of later after you start the study? Well, we will be talking with multiple regulatory agencies. You know, the timing is really more based on their schedules than ours at this point. We have prepared packages for discussions. We have quite a solid database, we think, to be the basis for those discussions on phase III, and in terms of the timing, that really we're not discussing right now. Yeah, but our plan is that we would have a single phase III in multiple geographies that would be approved by multiple regulatory authorities, and that's our base case. Okay, let's talk about STK-002, which, if I recall correctly, is planning on commencing the phase I in the second half of the year. Just give us maybe a little bit of a status update. What's the rate-limiting step to starting that study? Well, it's, we're very, we're nearing starting on that. We've got approval for CTA in the U.K., and the study will also be done in the EU. So, that's actually moving forward. We don't anticipate any hurdles. It's just site initiation and getting the sites up and running and enrolling. You know, this is a, this is an interesting program for us. It's very similar from a genetic standpoint in what we were doing for Duchenne syndrome, and in other words, we're skipping out a poison exon, an NMD exon, that interferes with production of full-length protein. So we've been able to demonstrate in rabbit and non-human primate, that we can get our ASO into these retinal ganglion cells, and more importantly, we can show upregulation of the OPA1 protein, which is a primary defect. Even, you know, more data that we have, we've demonstrated that in patients with who have ADOA, we can increase the ATP synthesis in oxidative phosphorylation that occurs in mitochondria and improve the structure of mitochondria. So not only can we increase the protein, but we can demonstrate that we can actually improve the defect that's caused by the protein deficiency. So it's an exciting program, and I and, you know, I think we're looking that this could have a significant effect on patients with ADOA. Currently, there is absolutely nothing that can be done, and I think the one differentiating point is, you know, there are thousands of mitochondria in the retinal ganglion cells, and obviously, they're not functioning at a normal rate, but it takes a long time for the retinal ganglion cells to die. And I think our hypothesis is that if we can improve mitochondrial function, that we can actually improve the health and the function of the retinal ganglion cell. And actually, our expectation is to demonstrate improvement in vision, once we correct the underlying genetic defect. This is an intravitreal injection, right? How, how often would you need to inject? That's correct. It's, it's directly going to the cells that are affected by the disease, so it'll be intravitreal. We, we haven't finalized the dosing right now, but the data indicate that this could be potentially a once-per-year injection. The, the oligos persist in the eye and continue to function for a long period of time, so it could be a quite infrequent intravitreal injection. Intravitreal injection is being done in millions of patients right now for anti-VEGF treatment, so this is a relatively standard procedure and has relatively low risk. And Barry, I imagine that, you know, sort of an annual injection scheme would happen after some kind of a loading experience, right? And then- That's still to be determined. We're gonna be testing that right now in patients as we start the study. But it could be that it's one standard dose just given on a very infrequent basis. Okay, so how... Maybe a last question, 'cause I know we're on the half hour now. How would you do that in phase I? You would have a obviously single dose initially. You'll start probably somewhat lower and maybe kind of dose escalate up, and then just follow patients for vision? 'Cause I imagine you probably don't wanna be stuck in you know, a year or a year and a half into a follow-up when you realize, hey, maybe we wanna give a second shot sort of six months into it. Yeah, again, the dosing needs to be worked out. We do have a natural history study where we are following patients for two years. This is going to be the longest prospective study that's been done on these patients. We have over a dozen different assessments that we're including in that study, many of which we would, we will include in the phase I study. So we'll have multiple ways of tracking the effect of the treatment in these patients. It's not all strictly just visual acuity. There are - we can measure the field defects, we can do electroretinography, we even have a way of directly, non-invasively measuring mitochondrial function in the retina. So all of these can be utilized in order to show potential progress in these patients, and improvement. Okay, well, Ed and Barry, thank you so much for joining us. Good to see you. Likewise. Thank you, Yaron. Thanks, Yaron. Have a great conference. We will follow closely. Ed, congrats, and to me as well, and whoever else, on the Celtics win. Thank you very much. Good to see you. Thanks, everybody. Thanks. Bye now. Cheers. Bye-bye.