I mean, it truly does differentiate your medicine.
Right. Are you ready?
Yep.
Okay, we're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for joining me today. It's my pleasure to have Stoke's Interim CEO, Ian Smith, by my side today. Welcome, Ian.
Thank you, Andrew. Thank you.
Yep. Maybe spend the next couple of minutes discussing Stoke, what milestones we can expect over the next 12 months- 24 months. You're the Interim CEO. I would also be curious to learn what made you want to join Stoke for the time being.
Oh, thank you for the question, Andrew. Thank you for everybody joining us today, those here in person and those that are online. I've been working with Stoke now for about two years. I first got involved with the company, fortunately, when we unveiled the first 70 mg data from the phase I/II study. I've worked with the company beyond being a board member, also as an advisor to them. Therefore, I've been very close to the company with some of the achievements they've had in the last two years, notably progressing into the phase III, a very important strategic alliance with Biogen, and actually also strengthening their balance sheet over that period of time. I knew the company well as a board member as well.
Working with Ed Kaye, who was the original CEO of the company, we talked about a transition. That transition came at the time between closing of the Biogen deal, but before the beginning of our phase III trial. Why did we choose at that point? Why did we talk with Ed about it being at that point? It is because it would have been disruptive during the phase III trial, and it would have been disruptive while we were in negotiations with Biogen, frankly. That calm period provided us the opportunity to place the interim on my title. When we do find the permanent CEO, we will be able to announce that, and there will not be speculation of disruption or intrigue, let's say. The company is progressing. We are advancing the company into the phase III, as you know.
You probably saw that this morning we announced that we've actually initiated the phase III trial in the U.S. as of last week. We are moving along swiftly.
Fantastic. Congratulations on the execution. The whole process makes sense, too. At a high level, then, maybe talk about the differentiation of zorevunersen. What do other drugs in Dravet not have that you have to offer, ultimately?
Yeah, thanks for the question, because if I think about Stoke Therapeutics and think about where I feel as though it's underappreciated, one, Stoke Therapeutics is creating a genetic medicine, disease-modifying medicine for Dravet syndrome. One, I don't believe that people truly understand the devastation of Dravet syndrome, nor the prevalence of Dravet syndrome. We should talk a little bit about that today. Going along with that, I also think there is an underappreciation of what Stoke's medicines, or even zorevunersen, does for these Dravet children, and how it is differentiated from other medicines. Obviously, we'll talk about, I'm sure, today, about the trial we've designed to show how our medicine is effective in changing the course of these kids' lives. To that point, Andrew, regarding zorevunersen, it differentiates itself from other medicines by it is more than a seizure-reduction medicine.
The other medicines that you're referring to focused on reducing seizures in patients. We do that, but we do something that's much more than that. The medicine is designed to go at the root cause or the pathology of the disease. It puts functional protein back into the organ of the brain. That functional protein upregulates NaV1.1, which is the underlying cause of Dravet syndrome. If you can upregulate 1.1, you address the pathology of the disease. What that is causing us to see, based on following our longitudinal data, is that we actually cause cognition and behavioral benefits. We've continued to measure those.
In the second half of this year, we'll be disclosing at some point the three-year open-label study data, which we hope will continue to show this continuous improvement, something that's a more neurotypical behavioral pattern in these patients because they've been on our drug for the last three years. We should talk about that as well. That's the true differentiation. There's not another medicine at our stage of development that may be offered to these children that may just change the course of their lives, especially if you treat them as young as possible.
Right. Should this ultimately have disease-modifying potential, specifically on cognition behavior, what kind of price point do you think you could command, ultimately?
It's a little early for me to give you a price. However, I'm happy to talk about value. The disease-modifying benefits, particularly measured by cognition and behavior, allow you to understand the value to the patient and to change the course of the children's lives. Think about other medicines that are disease-modifying therapies. I worked at Vertex Pharmaceuticals for a couple of decades, and I had the opportunity to see how CF medicines changed the course of children's lives when they were dosed as early as two-year-olds. We corrected a mutation on a protein back then. Doing that effectively really drove value for those kids' lives. That's how we think at Stoke about our medicine. If we can drive that kind of value in changing the course of a child's life, that is a high-value medicine. There have been medicines that are similar to ours.
Ours is an ASO medicine. Spinraza is another, I think, incredible medicine in the last decade that was created and gave life and behavior to little babies, frankly. That is a very valuable medicine. This is a high-value medicine because of what it does in these children and changes their lives.
Right. So the point is, my takeaway is several hundred thousand dollars, ultimately. You do not have to confirm or anything. As we think about peak sales potential, remind us the prevalence and incidence pool. Ultimately, is this drug, you think, going to capture more the incidence market or prevalent market or both?
Both. The reason I say both is because as you create disease-modifying therapies in this rare disease space, what you find is there's more patients available, and people go and get screened when they potentially do have Dravet syndrome. There's more awareness of the disease. It is a capture of incidence, and it is a capture of prevalence. To give you a few numbers, I do think it's one of the areas that is misunderstood in terms of the prevalence of the disease. In the seven major countries in the world, there's 35,000-40,000 patients that suffer from Dravet syndrome. In the U.S., it's probably around 15,000-20,000. That does divide up between the children, as in younger than 18 and older than 18. It starts at roughly 6,000 children younger than 18 that have Dravet syndrome, and then 18 and older.
There's about another 9,000 that have Dravet syndrome. It is a highly prevalent disease and therefore a significant market opportunity. Something I often quote is that the prevalence of the disease might be more than half of cystic fibrosis kind of prevalence. I've only quoted the seven geographies in the world, the major ones. Start to think about places like China and other places. There is a large market opportunity. Frankly, ironically, this morning, after, I don't know, five investor meetings, two, maybe three of them referred to somebody they know with Dravet syndrome and was asking how they could direct them to a site that was initiated. One of those people was from China and asking if they could go over to our study in Japan.
What we're finding is as people become more aware of the medicine, more aware of the disease, people are more aware of the medicine, sorry, once they become aware of the disease, and the momentum is building.
Right. Okay, that's a nice anecdote. You did receive a breakthrough designation for this compound. What is the precise language of this breakthrough? I thought it was somewhat unique. Should your phase III study succeed, ultimately, what would the front-page label claim say?
We did receive breakthrough designation. We received breakthrough designation last year. Obviously, breakthrough designation affords us a better discussion with the FDA. We probably should talk about that as well, in that what we're seeing with our discussions with the FDA is an open dialogue. We're seeing the same people that we saw last year, which is a good thing.
Good to hear.
There is an understanding of our medicine and what it can do for these children. In terms of rolling forward a success in the phase III trial, because of the breakthrough designation and the trial design, we would anticipate a label that would be to treat children two years and older. It would show the reductions in seizures because that is the primary endpoint. Frankly, it would talk about Vineland scores, which would allow us to talk about the kind of a more neurotypical development of these children and translating what is kind of a technical analysis of behavior and cognition, but translating that into plain English to help people understand how it affects their child's growth.
Great. Congratulations on starting the phase III trial today, EMPEROR trial. Remind us what the latest guidance is on the data.
Yeah, the trial is, first of all, just broadly describe the trial, then it'll understand the timeline for data. The trial is a 52-week trial that just initiated. It will recruit approximately 150 patients, maybe a few more, depending on how enrollment goes. It will be run in the U.S., U.K., Japan, and a few countries in Europe. The primary endpoint is seizures at week 28, and the secondary endpoint is the Vineland scores at week 52. The timeline for data readout would be the second half of 2027. Obviously, how we're going to work against those timelines, I'm happy to tell you that we did initiate last week. In the U.S., where we'd anticipate recruiting 100 or so patients, we already have over 100 patients pre-screening while we only initiated last week.
It is just another measure of how quickly this is going once there is this greater awareness. The company has done a wonderful job at medical conferences with the data it has had to increase the awareness of the disease and also what the medicine can do for these children.
Okay. And so the top line release, are you planning to wait for the 52-week Vineland scores to play out, or do you press release once you've hit the week 28 endpoint?
Yeah, it's a good question, Andrew. I mean, I'd step back and say I would like us to get this medicine to the children as soon as possible. Again, very much like cystic fibrosis, treat the child as young as possible and try and create something that's more neurotypical development as well as preventing the seizures. I want to convey there is an urgency to get the data, one, to the investor, but to get the data so we can file the drug for approval and get it to the patients. We will not cut the data at week 28 and break the blind of a study where there is a secondary endpoint that shows neurotypical behaviors.
However, a separate topic, and this is not me changing any kind of guidance, but we should have an urgency and an understanding of what this medicine can do for the kids. One of the aspects of the development of zorevunersen is that after these children went through a phase I/II study, they rolled over into an OLE study. 90% of the patients that were studied in the phase I/II study rolled over into the OLE. We're actually coming up on the third year of that OLE study. We continue to measure seizure reductions, and we continue to measure the cognition and behavior aspects of the disease. What we've seen so far, because we have disclosed the 24-week data from the OLE study, what we show is this continuous reduction, or let's say stabilization of the reduction, which is good, of the seizures.
When they go down, they stay down. Also, what we're seeing is this continued progression of cognition and behavior in a positive way. Therefore, the longer you're on the drug, you continue to actually develop more neurotypically in terms of cognition and behavior. We will gather the 36-month data from that study shortly. We should look at that data to understand the magnitude of benefit of how these children now that may have started the study as a five-year-old but may now be a nine-year-old and to see how they measure. Seizure reduction, we anticipate, will still be there. How much have they actually improved their cognition and behavior? Pending all that data, given that we have breakthrough designation, we should anticipate having a discussion with the FDA, not changing the timelines for when data will be available.
It should be a prerogative of ours as a company, given that this is a pediatric disease, which is truly very, very harsh.
Right. That's interesting. Three-year data, second half 2025. Will you be able to prepare the street by providing some natural history data just to show if left untreated, what would these patients do on cognitive and behavior, ultimately?
We have already run a natural history study. We've published on it. I think, again, it should be an important initiative for the company to remind and publish again that study. It is anticipated to be published for 24 months. We've got 24-month data, and that should be published shortly. We're trying to find a publication and publish it through a well-known publication. What you will see in that data, because we have disclosed it already, what you will see in that data is that, unfortunately, these children, as they get to roughly a two-year age, they then stabilize in terms of their growth and development through the rest of their lives. As a 20-year-old, you're still a two-year-old, unfortunately.
That is what the natural history over a 24-month period when measuring Vineland and also seizures and the effects on seizures on the Vineland scores or the behavior and cognition scores. If we show that there is an upward curve, I'm hoping that curve is as steep as possible because it means that you're affecting the children in a positive way, the maximum amount possible. If that line continues to separate after 36 months, as it has done already after 24 months, I think that is the data we should be really leading with. There will be challenges in it. I want people to understand. The FDA will be asking about how we ran the natural history study. They will also ask about an open label study. It's not a well-controlled trial. It was not designed to be a labeling study.
It was provided to give the patients the option to roll over after they've been in our phase I/II study. We'll see. It'll all depend on the data.
Right. Maybe backtrack to the phase III. Ultimately, we still want to succeed on the primary endpoint of seizure reduction. How did you power this study to show on placebo-adjusted change in seizure reduction?
It's powered to a 0.01 on basically the Vineland score and high significance on seizures. Seizures are a dramatic reduction from placebo or baseline, even on top of current available medicines. I want to be clear about this. Again, it's an aspect that may not be clearly understood. The children that have been coming into our phase I/II study and will be the same nature of children that come into our phase III study are on a stable background of the standard of care medicines, generally three to four medicines already. We dose on top of that. We still have an effect. We have an effect because we go to the root cause of the disease by upregulating NaV1.1. Those patients will come into the trial as a similar nature that they were in phase I/II.
The seizure reductions we're seeing in those patients with our medicines are above 80% reduction in seizures. Powering is very strong for seizures. We've powered the study for the Vineland secondary endpoint to a 0.01. That's because we're running around 150 patients, or maybe a few more, depending how enrollment goes. It's a well-powered study.
Okay. That's very good. Going to the Vineland and digging in further a little bit, for it to be included in the label, do you need to show stat sig, or can you show trends on Vineland?
We would want to show statistical significance. That is how the study has been designed and powered. I think it will be an important aspect to our labeling. This is why we are powering the study the way we are, because we want to show this cognition and behavioral benefits that we are providing these children. The data from our OLE study has measured these children, and we see continuous improvement. There is an upward slope from lower left to upper right. We want to show that and put that on our label.
Makes sense.
Makes it a valuable medicine.
Right. When I think about Vineland, there are a whole bunch of individual components like communication, personal skills, relationships, play and leisure, and so forth. What does it take actually for Vineland to be stat sig? Do each of these individual components need to be stat sig? How does this work? Do you know by chance?
Yeah. It's a great question. Again, this is an area where it is our responsibility to help people understand and play in English. If I was to look at you and say, "Hey, Andrew." Yep, you just nodded and looked at me. For those that are online, Andrew just turned his head and looked at me and nodded. Somebody with Dravet syndrome doesn't acknowledge their name, doesn't look at their parent, and doesn't have those receptive communication skills. To help you understand how Vineland is then administered, if a child does that to their parent and they do it frequently or always, they get assigned a score of two. If they do it occasionally, they'll get assigned a score of one. If they do it never, which is baseline, they get a score of zero. That's how Vineland is administered. There's a number of domains.
With each of those domains, whether it's receptive communication, expressive communication, motor skills, those are all the domains that are done through a questionnaire. The questionnaire is done by a neuropsych doctor. We're using four of them that will look at all patients in the U.S. and then similarly in other countries. That's how Vineland is administered. Hopefully, it'll give you an idea of the devastation of this disease in that these children do not receive communication from their parents. Just to kind of bring it more into an understandable world, some of the results that we've seen in our studies to date, and these have been published at medical conferences. They are not anecdotal. These have been published by doctors. They've been showing videos. That is part, actually, of our study. They showed videos.
We have children that, frankly, are non-ambulatory in a wheelchair. After a couple of years of being on the medicine, they're actually ambulatory. I want to be very clear on that. Motor skills is one of the domains. We have a young lady in the trial that can't do the buttons on her blouse. Being on the medicine, she can do the buttons on her blouse. She can't write a list of words before the trial. She's in the trial for a year or so, and she can write a perfectly 1 through 10 nice list. We have somebody who struggles to walk who is now kicking a soccer ball. They're not anecdotal. These have been published at AES in December last year. I'm trying to give you an idea of the impact of this medicine on these children.
Ultimately, when you topline the data, is it safe to assume the placebo-arm Vineland score will remain at zero at baseline?
Yes.
You're that confident, essentially?
Yes. I mean, the way that we've powered the study is that we took our phase II results. We did take a conservative view in terms of numerical sense. If something is a 10, maybe we assumed it was an 8. Same with a placebo. If it was a 0, we assumed there might be a 2 or a 5 or a 10. We have powered the study in an appropriately conservative manner. I don't want to answer it by saying it's a 0 in placebo. It's actually the way we powered the study is we did conservatively apply expectations from our phase I/II data.
Understood. Maybe just to give us a little bit more context on Vineland, what kind of score change, total score change did you see on Vineland overall? What is a clinically meaningful score change, ultimately?
I think the best data I could give you that is somewhat comparative is the OLE data, because that data was after a 12-month dosing of the drug. We also did it over a 24-month. The study is a 52-week study. The best comparative data, and you shouldn't really compare trials, to be honest. If you're asking for a comparison, the 12-month data from the OLE study saw scores in the various domains of anywhere between 3 and 7 and 8. A statistical significant response over a 12-month period would probably be about a 2.
Understood.
To help you understand. Yeah.
Are you able to rank order your level of confidence within these individual components, which are more likely to succeed than not? Which one do you feel the best about?
Ironically, or maybe it's fate, but the one that really does show up strongly is receptive communication. The reason I say ironically, receptive communication is the number one need in these families that have Dravet children, unfortunately. There is a hierarchy. Most of them respond. The one that sometimes is a little lower is gross motor skills. There may be a rationale for that, as in these kids are coming out of recovery, as in they've been in the house. They do not go outside. They are scared of the light. They have got to come out of that period kind of even mentally to have the confidence to start assuming a normal life. We see a positive response in all the domains. We should expect that, given how this drug acts on the disease.
Understood. We've been talking about efficacy and shifting gears to safety. I totally understand. If you do show something meaningful on Vineland, the benefit-risk profile of this drug is humongous. Now, on the safety side, remind us what you've seen. Were there any SAEs in phase I/II or anything that concerns you?
There's nothing that concerns me on the safety side. I don't want to sound overly confident. Dravet is the lead drug for the company. It's a very valuable medicine. We need to run the phase III to prove it out. We haven't seen anything meaningful on the safety side that should give us concern. However, we need to run the phase III study and collect the results. Anything that was reported in the prior studies was not related to drug, as the doctors checked the boxes. The other thing from a safety side, understand that of the approximately, I believe, 80 patients, 90% of them rolled over into the OLE study and have now been on drug for close to three years, maybe beyond three years. We've administered over 800 doses over this three or four-year period.
We go into the phase III trial with a high level of confidence. We do need to run the trial.
Understood. Remind us your latest cash balance. Do you have enough cash to see this through? I understand. I mean, there's an option to talk to the FDA possibly later this year to be a little bit more aggressive. Just base case, if the data is second half 2027, do you have enough cash?
Yes, is the simple answer. Let me walk you through the summation of the cash. We had close to $250 million-$300 million of cash when we closed on the Biogen deal that provided us with $165 million upfront. At that time point, we had over $400 million of cash on our balance sheet. Plus, we have Biogen funding 30% of the costs of the R&D regarding this product. When you measure that all the way forward through to data readouts, the data readout is anticipated in the second half of 2027. Yet our cash is funded through to mid-2028. Yes, we're well capitalized. We're focused on the execution of the phase III trial and, frankly, communicating our story for the benefits of what this medicine does for these Dravet children.
Last 30 seconds. If you are quite confident about the cognitive behavioral side, why not be a little bit more aggressive about this compound and go after other indication areas?
I would say that we are very confident of our approach at Stoke with haploinsufficient disease areas and with our ASO approach. We are already in another disease area. It's called ADOA. We're still working through preclinical efficacy and safety models. With slow progressing diseases, you want to go into the clinic understanding you can develop the medicine without having to run a very long-duration trial. The way to shorten a trial is that you put functional protein that actually improves. It doesn't slow the progression of a disease, but it actually improves the efficacy, upward efficacy for the disease. We are waiting on our preclinical models on the efficacy side for ADOA, which is a slowly progressing loss of eyesight, genetic disease.
Further back in our pipeline, we are working on other haploinsufficient diseases, which we hope later this year we will start talking to you all about. We also have a partnership with Acadia, where we are focused on a haploinsufficient disease area called SYNGAP1, which is epilepsy as well.
Okay. I think that's all the time we have with Ian. Thank you for this nice conversation and great data points shared today. Thanks, everyone.