Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Stoke Therapeutics, a company we cover. I'm pleased to introduce Ian Smith, Interim Chief Executive Officer and Director of Stoke Therapeutics. Welcome, Ian. Let's start off with an introduction of yourself, a brief description of the company for those not familiar. You recently took the role of an Interim CEO. What drove that decision?
A few questions there, Pete. First of all, thank you for joining us today, and those that are listening online as well. I have to tell you, there is a safe harbor statement for all comments I make. You can check our SEC filings for that safe harbor statement. Let me think of your first question, Pete, which is an introduction to myself. I've been with Stoke for nearly two, two and a half years now. I'm a board member of Stoke, and I was an advisor to the company for two years, beyond just regular board work. I recently took the Interim CEO job in the transition of leadership.
I was asked to do it because of my familiarity and how close I've been with the company for the last couple of years, but also my former life or career, most of my professional career in biotech was with Vertex Pharmaceuticals . I saw the progression of hepatitis C medicines from bench to patient. Most importantly for Stoke, I saw the progression of cystic fibrosis medicines all the way from bench all the way to patient and saw those medicines change the lives of young children and also change the families that surrounded those children. There is a similarity and a familiarity that I have with Stoke, not just because I was working closely with them, but also a genetic medicine that should be dosed in these children as early as possible to potentially change their lives.
It goes to the root cause of the disease in terms of the disease being haploinsufficient to the SCN1A gene, which upregulates protein expression of NaV1.1. Similar to CF, the pathophysiology of the disease is well known in Dravet syndrome, just as it was in CF. We go to the root cause of that disease. The progression and the data that the company has had over the last couple of years has shown that this company not only treats seizures, but goes far beyond that. It treats the whole syndrome, which means that it's helping these kids potentially neurotypically develop or more neurotypically develop compared to a normal Dravet syndrome progression of a child. That was really exciting to me. The familiarity is what drove my decision.
That's also a discussion of a description of the company and what has been going on, which to me, that was the matching of me coming in and saying, yes, I'm happy to help the company and I thoroughly enjoyed it and look forward to doing more with the company as we progress.
Thank you for that. You mentioned that you are, the company is focused on Dravet right now. Can you just give us an overall, you know, your perspective on the incidence and prevalence of Dravet?
Yeah, so Dravet is a, it's a highly prevalent disease, yet it's a mainly unknown disease, I would say. It affects close to 40,000 people in the main geographies of the world. That's just seven geographies of the world. It's much larger because if you went to China and Australia and other countries, it's way beyond 40,000. 40,000 in the U.S., U.K., Japan, and Europe. Its incidence is about one in 15,000, 16,000 births. That translates to 40,000 patients. In the U.S. alone, it's probably 15,000 - 20,000. It's a large patient population that has no treatments other than for its seizures right now. The disease itself, just to help you understand kind of a journey of a Dravet child, they will be born, unlike CF, where every childbirth is, every born child is screened for CF at birth. That doesn't occur with Dravet.
They're born, they start to have seizures six months, one year old. They go to the pediatrician and they will be given anti-seizure medicines. Those anti-seizure medicines may calm the seizures down, but they'll continue to have seizures. The child will go back to the physician and ultimately the physician will order a screening. That screen will show a depletion of a functional SCN1A gene. That's when, unfortunately, the child generally finds out around two, three years old that they have Dravet syndrome. Dravet syndrome then progresses in terms of significant rates of seizures continued. Even when you're on anti-seizure medicines, they may be calmed down a little bit, but there's still significant seizures. Unfortunately, the neurodevelopment of a Dravet child is that they don't go beyond a two-year-old for the rest of their lives.
If you ever meet somebody with Dravet, recently I spent time with a 16-year-old, the family of a 16-year-old as well. That child's in a wheelchair. Unfortunately, they're not receptive of any communication from their parents. They don't know what the room is around them. They've got a cuddly toy in their hands. It's really sad. They really are in a state that they've not developed beyond a two-year-old. What our drug, you know, hopefully what our drug does is it gives them more development, more neurodevelopment back. It's a very important medicine. Yes, it reduces seizures, but it has the potential to put them on a better path for neurodevelopment.
Okay, you know, I guess you sort of mentioned it, you know, the competitive landscape. Your drug, zorevunersen, it sort of stands out as a potential disease-modifying technology. You know, and you're going to be able to likely impact the broader disease. You know, and right now when you are on those anti-seizure medications, is there any impact at all on neurodevelopmental? Or are they just paused?
No, there's no medicine that treats the neurodevelopment of a Dravet child. It's not available. The labels and the studies that have been run for these anti-seizure medications, and they're good. They're very important to these children. The best standard of care medicines reduce seizures, maybe 50%, maybe a little more sometimes. They don't have any impact on neurodevelopment. The reason is that these anti-seizure medications focus on calming down the brain, the neurons in the brain. What we do is we put functional protein back into the brain and we upregulate NaV1.1, which is the source of the pathophysiology of the disease. We would expect in reducing seizures on top of standard of care medicines, because we've got a different pathway.
Which we'll get to in a minute.
Yeah, because of the reduction in seizures and the pathway, we would expect to see behavioral and cognition benefits. That's what we've seen. As you know, we now have data that we call three-year data, but it's actually four-year data because they were nine months in a phase I-II study. They rolled over into an open-label extension study and we've followed them for three more years. We've seen this continued improvement in terms of their neurodevelopment, as well as the durability of the reduced seizures. The data is quite spectacular.
All right, you were sort of talking about the phase I-II study, the MONARCH in the U.S. and ADMIRAL in the U.K. Focusing on the subjects that received multiple doses, what were the key efficacy outcomes regarding zorevunersen's anti-seizure activity that you want to highlight?
The anti-seizure activity, first of all, I'd start with our patients that have come into all our studies are on standard of care medicines, actually three to four standard of care medicines. We then dose on top of that, and with our high-dose group, which is the dose that we've taken into phase III, is a 70 mg initial dose. With those doses, we reduce seizures to a median of 85%, again on top of standard of care medicines, which is dramatic. Just this weekend, we released more data in terms of seizure-free days, which is, you know, we're providing these patients and families, you know, more seizure-free days than even though they're still on anti-seizure medicines.
The durability is, it's underappreciated, I think, in terms of what that means in that sometimes there is a cycling of anti-seizure medicines, whether it's resistance, breakthrough, you know, they're not always consistent and durable. We've now followed these patients over effectively a four-year period, even at low doses, and these seizure reductions have stayed down. That durability, based on the chronic dosing as well, is really important in terms of managing the seizures. One of the things I, you know, unfortunately, didn't mention earlier, it's really sad, but the mortality rate is 20% of these children actually die before they're 18 years old.
Yes.
Sometimes that is, it's neuro-related, but it's also these seizures. This seizure reduction and this durability of seizure reduction is really important. I don't want to diminish the already very good anti-seizure medications, but we do more on top of that, and that's really important.
What has been some of the feedback that you've had in KOLs in terms of the anti-seizure reduction? The KOLs that I've spoken to, they're actually impressed. You know, like you mentioned, they're actually on multiple anti-seizure medications, you know, and then to actually further reduce it, you know, 70%-80%. They say it's profound, but your perspective?
I don't need to add anything more to that. It is profound, the fact that it's on top of standard of care medicines. Maybe another word I'd add is it's important as well.
Yeah. I guess last month you did provide an update on the OLE, but walk us through that data, including patients that were on less than 70 mg in the initial studies in the phase I-II studies and those that would actually receive 70 mg doses.
Could I just clarify the question, Pete? Are you asking me both on seizures?
No, just seizures right now.
Just seizures still. Okay, yeah. There was a differentiation between the seizure reductions on the lower doses versus the higher doses. That is why we ran the phase I-II studies. It was a dose escalating study, started as low as 30 mg, went to 45 mg, then went up to 70 mg. We saw a big difference between the lower doses and ultimately the 70 mg dose that we were taking into phase III. The low dose groups, maybe there was a median around 60%, again, still on top of the standard of care.
Yeah, yeah.
It is very, very important. We saw 85% reduction of seizures when dosing at 70 mg. However, the one consistency between the lower dose and the higher dose is the durability of response when you go out for three and four years. They continued at that level that they'd had their seizures reduced to. An interesting point in the data is for those patients that started on a lower dose, when in the open-label extension at a consistent dosing of 45 mg, started to get closer to the higher dose reduction, which was, and it's all in the data that we provided over the last month or so and at the medical conference last weekend.
That line of the lower dose patients, when you take it out to three years, you can see it continued to decline in terms of the reduction in seizures, which is really important and good for the patients.
Definitely a deepening in response.
Yeah.
The KOLs we've spoken to say that that's important. One question that I throw out to them is, you know, how can you see this sort of, can you see patients coming off of their anti-seizure medications and just one or two of them and reduce exposure? I'm sure there will also be benefit there.
Yeah, it's a good question. At some point we should study that. Part of the challenge of the current anti-seizure medications is they, I think the nicest way I'd describe it is they put the patient into a sleepy, docile state, which is then calming the patient down. Sometimes that can be a challenge for families. If we still have the ability to manage the seizures without the standard of care medicines, because of going to the root cause of the disease with the protein, we will study that at some point. Right now we're focused on being a disease-modifying therapy, running a phase III on top of standard of care medicines and being able to treat the whole syndrome.
Okay. You did mention you did see effects on cognition and behavior. Can you just sort of describe the scale that's used? I think some investors may be a little bit not familiar with the Vineland-3. What exactly is that and what outcomes did you measure with that?
Yeah, so we're measuring cognition and behavior with a study or a scale called Vineland-3. What that is, it has multiple domains that relate to how we live our daily lives. There's a domain for communication, there's a domain for motor skills, there's a domain for societal interactions during the day. Each of those domains has multiple questions, five-10 questions. A simple question is when I go, "Hey Pete, you just looked at me," is a question in receptive communication. You get a score for that. When I said, "Hey Pete, you looked at me," looked at me again, what that means is you will score a two. The maximum score is a two because every time I ask you this question, you respond to it, you score a two. If you did it one out of two or infrequently, you'd score a one.
I'm sorry to say, but Dravet kids don't recognize their name. They don't recognize their parent talking to them. It's very sad, but they would score a zero. We've run a natural history study. We ran a natural history study in these Dravet patients that were on standard of care medicines. We measured Vineland-3 in these key domains, five key domains that we're using in phase III. You basically see zeros, ± one, ±two score over a 24-month period. When you look at data that we provided externally about a month ago, we provided at a medical conference called EPNS at the beginning of August. We showed data on patients that were dosed at a similar level to the one we're using in phase III. We measured Vineland-3 with those patients. The result was they were scoring eight, nine, 10, 11 in these domains.
To understand the magnitude of an eight, nine, 10, 11 a physician and neurologist will tell you that a Vineland-3 score of a one or a two is clinically meaningful. We'd scored eight, nines, and 10s. That data's out there. The comments from the physicians of what's clinically meaningful is also consistent to natural history. That's Vineland. We're measuring the five key domains in our phase III clinical study. There are a number of, these are real stories. They've been presented at medical conferences. One December 2024, (AES), a physician provided videos. Our investor relations group is happy to provide them to people. Physicians have presented stories of these patients on our drug. We have seen non-ambulatory patients become ambulatory. We have seen a young lady who can't do the buttons on her blouse being able to do the buttons on her blouse.
A patient couldn't write; now they're writing lists in nice, neat order. These are motor skills. There is a video of a patient where before they're on drug, they're talking to the doctor, and the doctor's asking their name, asking them to kind of touch their fingers and have an interaction, and there's no interaction. Move a year on, same doctor, same child that's been on drug is kind of touching fingers and waving and recognizing a name and giggling. It was presented at (AES) in December last year. That is practically helping you understand what a high Vineland-3 score is. That is what happens, because those are the questions, kind of the receptive communications, motor skills, things like that.
You have the original phase I-II data, then you have 12-month data, then you have 24-month data, and then you have 36-month data. Do you hit a plateau or are you consistently growing in terms of these scores?
To be seen. I mean, when you look at the three-year data, which is, I continue to say, is effectively four-year data, in multiple domains, there is this continuous growth. Just this last weekend, we also put out data on quality of life measure. What you see in year one, there's improvement in quality of life. Year two, it's even higher, measured on a scale again. Year three, it's even higher. We put that data out this weekend at a medical conference. We put a press release out as a company, I think, on Tuesday this week. You can see that as well as quality of life measure. We see this kind of improvement, continuous improvement. The question really for us is, what is the rate of improvement when you dose a child that might be two years old?
The patients that we've been dosing in our clinical studies are aged between two and 18 years old. We're seeing these benefits that I'm talking about with seizures and cognition and behavior in a broad range of age patients. What happens when you dose it, you get an early diagnosis based on screening and you dose a two-year-old and you've got the continuous dosing? What kind of rate of development neurotypical, do you put them close to a neurotypical development? We don't have that data as yet. The mechanism of action, putting protein back into the brain and upregulating, it's to be seen how much benefit we're providing these kids if you dose early.
My assumption is the earlier you go and the more connections that you allow to be on a normal, you know, functioning neurotypical child, bringing closer to there, my assumption is you're going to have greater gain. I think that's the overall thought in neurodevelopmental disorders, whether Hunter syndrome or whether, you know, any other disorder. The earlier you go and you sort of, you know, stop the underlying, you know, pathobiology and driver of disease, the more improvement.
I agree. It was also true in cystic fibrosis, which, you know, the airways remained open earlier on. If you could treat early, you could have bigger benefit and you could put them on a normal progression. I think the neuroplasticity of the brain does reside or remain for a long period of time. I'd still like to be able to early screen these patients, identify the disease and treat as early as possible and give these kids a chance and their families.
Yes, yeah. I guess you just initiated the AMBER study. It's the phase III. Can you just give us the study design overall, and what are the powering assumptions for both the primary and the key secondaries?
Yeah, the study is a 52-week study, has an eight-week lead-in. That eight-week lead-in is obviously to screen the patients to make sure they're appropriate and they're consistent with the patients that we've had in the phase I-II studies in the open-label extension. It's also to ensure that they're on a stable background of medicines. We don't want people switching medicines while they're in the trial. It's a 52-week period. We measure the primary endpoint at week 28 and that's seizure reductions. The secondary endpoint in terms of a hierarchy starts with continued reduction in seizures or durable reduction in seizures. Other key secondary endpoints are the Vineland-3 and there's five key subdomains that we're measuring. It's 170 patients. It's being run in the U.S., U.K., Japan, and Europe. We're underway, we're dosing and we're opening trial sites rapidly.
We anticipate that we should be fully enrolled come the second half of next year. Recently, we've helped people understand the rate that we're going at. We already have over 150 patients in pre-screening for this 170-patient study. It is going very well. If you go to a medical conference where we're presenting and our physicians are, you'll see that the awareness of the medicine, the trial, is very high. There is a great demand to get into the studies. People travel cross-country, people travel from countries to countries. They want to be in the trial. It started off very well.
You said that the AMBER study is designed to closely replicate your successful phase I-II. Are there any elements that are, what elements are identical and what have you refined to increase the probability of success?
The main change from the phase I-II is that this is a, the phase I-II was two or three or one dose of a certain, you know, either 45 mg, 70 mg, and then they rolled over to an open-label extension. What we've done with the phase III design is we've actually merged the two studies of the loading dose and the open-label extension. That's really the only design change. The patients that are coming into the study are the exact same, ages two through 18, the exact same, a certain number of seizures need to have occurred during a certain period of time. That's all the same. The only real change is that it's two loading doses and then dosing of 45 mg every four months. It's the same.
Okay. I guess one key question on investors' minds, and I'm sure you've probably heard it multiple times today, is the possibility of a faster path to market. You have 36-month OLE data in hand. You also have the BUTTERFLY study, natural history study, with the FDA guidance for accelerated approval for serious conditions in mind, which according to the documents is a disease or condition associated with morbidity that has substantial impact on day-to-day function and is irreversible or persistent. For a drug that provides meaningful advantage over the available therapies, which it seems your drug may, what are the odds of actually going to the FDA and them agreeing on an accelerated approval based on the phase I-II OLE data?
There was a lot in that question, Pete. Maybe just to help understand the background of this, which is that we got given breakthrough therapy designation late 2024, actually at the same time that we aligned on the phase III design with the FDA. When you get breakthrough therapy designation, there is a requirement from the FDA for you to go down and do what's called a multidisciplinary meeting. For that meeting, you prepare a briefing book. What you do in that briefing book is you talk about the pathobiology of the disease, you talk about your mechanism of action of the drug, you talk about your safety and efficacy data, and you have a discussion also about the development and regulatory pathways. We have not had that meeting. We are going to have that meeting.
What is different than normal though is that we have four-year data of safety and efficacy. I say safety and efficacy because sometimes it's overlooked that we have four-year safety data that is a well-tolerated drug. We will create that briefing book. Within that briefing book, there will be questions about expedited filings and pathways, and it'll be an interesting discussion with the FDA. Overall, because of the breakthrough therapy designation and what we're seeing in this data, we have a responsibility to see how fast we can move this drug to the patient. That is the process that's ongoing. We anticipate meeting with the FDA before the end of this year and look forward to that meeting and the outcomes to it.
You've already started the briefing book for how you sent it?
We're having a meeting in the second half of this year. I don't want to put a pin on the map in terms of date.
All right. Thinking about if you were able to actually move the Vineland-3 subdomains as you did in the phase II or phase I-II in the phase III, how does that translate into the label and payer value?
I'll take it in reverse if you don't mind, but the payer value is going to be in the medicine's value to the patient and their families. To be first dose, being a medicine that reduces seizures on top of standard of care medicines, to the extent that we do, already defines a medicine that is high value. Beyond what value there is with the current standard of care, because we're adding benefit on top of standard of care. The true value is in the neurocognition and behavior measures. If those are on the label based on being successful in the phase III, that value is enormous to the patient and the families and to managing the whole syndrome. Therefore you will be, you know, appropriately valuing the medicine with payers with all that data.
It starts to become a medicine that is more like, I keep referring to it because of my familiarity, but it becomes more like a CF-type medicine or even a Spinraza-type medicine. Spinraza is an amazing medicine for SMA that Biogen has. It's an amazing medicine and it's life-changing for those young babies and their families. That's the kind of value you're providing to the patient and that should be recognized in the value of the drug.
You ultimately could command, you know, sort of high pricing, you know, ASO drug-like pricing rather than a high-priced ASM like (Ventapa).
It's a good question.
All right. I think we're out of time, but if we're sitting here a year from now, what would you like to say Stoke has accomplished to create value?
To bring the patient closer, to bring the medicine closer to the patient. I think that would be thrilling. I referred to my time at Vertex. There is nothing better than actually building a company because it creates a medicine that can change these kids' lives and the families that support them. I hope that we're closer to doing that, whether we've done that. I have no idea at this point in time, but I hope we're closer to doing that. That could be measured as a fully enrolled phase III. It could be we're on the way to filing. There are so many other things, but right now for Stoke, it's about Dravet, even though we have other programs in the pipeline now based off our platform of haploinsufficient diseases. That's where our priority is right now.
Thank you very much for attending the Cantor Healthcare Conference and look forward to all the progress this year.
Thank you, Pete.
Thank you.