Good morning, everyone. I'm Sumant Kulkarni, a Senior Biotechnology Analyst of Canaccord Genuity. I'd like to welcome you to our Stoke Therapeutics presentation here today. It's actually not a presentation, it's an interactive Q&A. Please feel free to raise your hands in case you have any questions. You had some really interesting data last night. We'll go into that. Before that, thanks for making it here. We have Ian Smith, the CEO, and Jason Hoitt as the Chief Patient Officer. Out there in the audience, we have Doug Snow, who knows everything about the company as well. With that, I'll turn it over to you guys to make a brief intro, and then we'll go into Q&A.
Yes, thank you for joining us today. I'm Ian Smith.
am the Interim Chief Executive Officer of Stoke Therapeutics. I look forward to the next 24 minutes as it ticks down and answering your questions. With me, I've got Jason, who can introduce himself as well.
Yeah, I'm Jason Hoitt. I'm the Chief Patient Officer at Stoke Therapeutics, responsible for commercial, medical affairs, and manufacturing.
Please refer to our SEC filings for safe harbor statements. Just a quick update. We did have a quarterly conference call yesterday evening where we had the opportunity to update investors and the analyst community of the progress the company has been making with its lead program in Dravet syndrome. We believe it's a disease-modifying medicine, and we were able to show last night for the first time data from patients that have now been on drugs between three and four years. What that data showed last night was significant reductions in seizures in these patients that were durable and maintained out through a longer term. We also see cognition and behavioral benefits over a longer term as well.
Going to the profile of the medicine to treat Dravet, for those of you that are not familiar with Dravet syndrome itself, it's a genetic disease where, unfortunately, children develop through two years old, but then they pretty much exist in a vegetative state from two years onwards. They suffer from severe seizures and neurocognitively do not develop. They can be 20 years old, having severe seizures, and still be like a two-year-old. What our medicine is doing in the studies that we've seen so far is it is significantly reducing these seizures. That seizure reduction is on top of current standard-of-care anti-seizure medications. The medicine is also causing a more neurotypical development of these children as they stay on the medicine. The medicine works by upregulating NaV 1.1 in the brain, which is the root cause of Dravet syndrome. We are very happy with the results to date.
This week, we also announced that we have commenced our phase III program, and I'm sure we'll talk about that today. We are well on our way. The pipeline is also expanding. We announced going into another clinical program last night to ADOA, which is optic atrophy, and it's a progressive loss of eyesight. Treating it in a very similar way to Dravet syndrome where we're upregulating OPA1 and increasing mitochondrial function to help with vision. That study is starting in the second half of this year. The company's financial position is strong. We ended the quarter with $355 million of capital, and we continue to receive funding from Biogen. They have a partnership, an ex-U.S. collaboration, ex-North American collaboration, where they also fund 30% of Dravet development. The company is fully capitalized, fully funded through to mid-2028, which is beyond when the phase III should read out.
Happy to take questions and look forward to this.
Thank you, Ian, for that really nice summary. You placed the unmet need in Dravet syndrome. Given that you have between three to four years data now and given the unmet need, what's the best thing you can do to get this product much faster in the hands of patients?
Appreciate that being the first question. Just to talk about the data and the medicine itself, first of all, Dravet is a horrific disease. I mentioned it briefly that these children are born with it, and by the time they're one or two years old, they're suffering from seizures. They then start to plateau in terms of their neurodevelopment. If you've ever met a Dravet syndrome patient, it's effectively maybe a teenager or a 20-year-old, and they're effectively a two-year-old. They're still suffering from seizures. Our medicine in earlier trials has shown that we reduce these seizures, but also show that we improve cognition and benefit. We took that data to the FDA in 2024, and we were ascribed breakthrough therapy designation. I say that importantly because the FDA gave us breakthrough therapy designation for Dravet syndrome, not for treating seizures.
It was for the syndrome itself, which therefore the FDA acknowledged safety and efficacy data that does actually treat both the seizures and the cognition and behavioral challenges that these children go through. Given the status of the drug and the data that we've had and the data we showed last night, we're going to take all that data under breakthrough therapy designation and talk to the FDA in the second half of this year. I will point out that that is a perfunctory process of breakthrough therapy designation where following gathering the designated class of breakthrough, you've got a responsibility to go to the FDA, explain the magnitude of the disease, explain the data of the medicine, and how that may address the disease. We plan on doing that in the second half of the year.
To your question specifically, we're going to have a discussion about how we can get this medicine to the patients as fast as we possibly can. That could be in a number of different ways. That's the discussion that will ensue with the FDA with all this data in hand in the second half of this year. I'll just close by saying we're also happy that we have a phase III study that has commenced. First dose was just recently. We have, it's a 150-patient study, and we already have 150 patients in pre-screening. That will be part of the discussion with the FDA because as of now, we're planning to run a phase III program.
You've said FDA a number of times. We've seen the FDA in the news a number of times over the last few weeks, if not months, on all the changes that agency seems to be undergoing. Given that, has the composition of the team that you've been speaking with remained largely the same? How have the interactions evolved over time? Has the agency expressed any kind of view or desire to be regulatory flexible in this context?
I'd start more on the macro, which is, yes, there's been a lot of changes down at the FDA. For us personally, given the medicine that we have, given the disease area that we're working in, it is a genetic pediatric disease. We're not seeing any changes. When we, for the people that we work with at the FDA, I would say that when we look from the outside in and look to see what's shuffling around at the FDA, we don't actually see impact in rare pediatric diseases, especially ones that have this massive, significant unmet need. It's part of the reason why we're actually looking forward to going to the FDA to discuss all this data. We're actually seeing the FDA leaning more forward to these kinds of medicines in these kinds of disease areas for kids.
Knowing that you have these quite striking 36-month data in hand, what would be a specific mode of approval or the pathway that you could potentially use to get a faster approval? I'm not using the word accelerated specifically, but.
Yeah, I mean, we'll have to see. It's difficult to name pathways because I believe it's an iterative process. At this point in time, we're sharing the data. We're helping them understand the magnitude and the horrific nature of this disease. That's a broad discussion. For me to sit here today to say this is the pathway, I'm not in a position to do that. It will be an iterative process. The overriding goal is how can we get this medicine to patients as soon as possible. I will also note that part of the three-year data, despite showing the durability of seizure reductions and the extension of cognition and behavioral benefits, there is also now three to four years' worth of safety data. We've dosed, you know, there's probably more than 800 doses of this drug.
We've been dosing over a period of up to four, maybe longer than four years as well. That will be a very important aspect of this discussion with the FDA.
You have reduction in seizure frequency on top of standard-of-care. You have Vineland-3 scores. You have a bunch of things that you've collected data-wise. Is there anything in that that can be used as a biomarker for the basis of an accelerated approval?
When you refer to accelerated approval in that way, Sumant, that's capital A, capital A, as in you go to the FDA, you've got a correlated biomarker that correlates to clinical benefit, and you get approval based on the biomarker and run a confirmatory phase III. I want to be clear. That's not the route that we're going down. If we had a biomarker in this disease, it would be able to measure NaV 1.1. We're unable to measure NaV 1.1 unless we were to do brain biopsies, and we're not about to do brain biopsies. It's a broader discussion in terms of all the clinical data, in terms of do you believe the benefit we're providing? Do you believe the safety profile would support the drug going to the patient earlier? That's why it's a discussion and a collection of all this data.
Right. I guess in terms of milestones that we can expect from now through the end of the year or maybe a little into the next year, the key one is going to be your meeting with the FDA and the outcome of that meeting. Is that right?
I don't look at that meeting as a single milestone and a yes/no, just to be clear. I look at it, the regulatory interactions are an ongoing process, sharing data and having discussion, asking questions, getting responses, coming back and answering their questions, frankly. I don't look at it as a binary yes/no. I look at it as more of an iterative, longer-term process. If anything was to change from our current guidelines in terms of running a phase III program, which we anticipate we'll fully recruit in the second half of next year, and therefore data in the second half of 2027, we'll update immediately. At this point in time, understand the FDA and regulatory interactions are a discussion, iterative process, and we're focused on executing on our phase III program.
Right. We've focused mostly on the U.S. so far, but you do have a partnership with Biogen. First, could you just go a little bit more into how all that came about? Second, are there any geographies outside the U.S. where you can get this product out to patients faster given the data that you've generated?
Yeah, so Jason on my right-hand side here is our Chief Patient Officer. What that means is he's responsible for commercial, medical affairs, and also manufacturing. I'll ask him to talk about the markets outside the U.S. In terms of the Biogen process, I was working with the company through that process, and it was the usual decision by the company, which is you only do a collaboration if it enhances the company's capabilities to deliver a medicine to patients faster. Most people look at it, a lot of people look at collaborations as being a way to finance the company. That was not the primary purpose of doing a collaboration. The primary purpose of doing a collaboration was to add the capability to the company that we didn't otherwise have.
That was to get the drug to patients outside of North American markets as fast as possible in these single-payer markets, which are a challenge. We ran a competitive process, as you always do. We always were leaning into Biogen. The reason we leaned into Biogen was because they have Spinraza, and they've been shown to be excellent with their expansive capabilities outside of the U.S. We hope for Biogen, and they were there as a kind of a lead candidate to do the collaboration. Because it was competitive, we were able to manage the economics that were secondary but important that actually enhanced the company's balance sheet, partially funded the phase III trial. From a financial position, it's put the company in a position where we don't need to raise capital. We can run our phase III program, gather the data, and get into launch readiness.
We're very happy it's Biogen. The partnership's been in place now for about six months. It's been excellent, excellent collaboration. The teams are working very well together. We go backwards and forwards across the Atlantic, frankly, in medical conferences recently. We're about to go to one at Labor Day. With that, I'll turn that to Jason.
I think, from a partnership perspective, one of the things that really appealed to us with Biogen is the fact that, as Ian mentioned, with Spinraza being available in more than 70 markets around the world, they have that in-market infrastructure that would take us years to build. We felt an obligation to make sure that we were able to get this important medicine to patients as fast as possible upon a potential approval, right? With Biogen having that infrastructure already in place, it's just a seamless process for them to be able to get to revenue into patients far faster than we could have done ourselves. We're really excited about the way the partnership has started and the way that we're engaging with their teams throughout the world. Frankly, there's a really high level of executive engagement in the partnership, which is great to see.
Maybe touch on some of the markets outside North America and beyond, let's say, the key geographies.
In terms of
what other countries could we go to other than U.K., Japan, Europe?
They're in more than 70 markets across the entirety of Europe, into Asia, into markets in Latin America, Australia, other markets that frankly wouldn't have been the first tier for us to build in-market infrastructure. We would have been prioritizing the seven core markets, which would be the E.U., U.S., and Japan. Through the Biogen partnership, we are now able to get this into all of the countries in Europe and beyond, essentially right after an approval, which is really exciting for patients and families.
It's a global disease, right? It is. Any specific regions within those that are amenable to a faster pathway towards getting the product to patients?
Europe specifically, and Europe and U.K., you know, one could cast an umbrella over Europe and U.K. Certainly, they have regulatory processes that you can appeal to, I would say, based on data. That would be a primary one. We'll see how it progresses. We'll have to work with Biogen. That's their territory commercially. We'll work with Biogen to discuss that.
Last one on the Biogen collaboration. How do you discuss going about eventual pricing, commercialization activities, and all that with the partner?
Yeah, we're in active conversations with Biogen. I think we have a strong desire to have one global brand with global brand elements that are consistent around the world. Obviously, from a pricing perspective, we control North America and they control everything outside of North America. We won't have any input on their pricing strategy and they won't on ours. Across elements of branding and messaging and ultimately patient access, we're actively working together and learning, frankly, from some of the experiences they had in launching Spinraza in many of the markets around the world.
I want to move to the phase III. You've just started a trial for zorevunersen in Dravet syndrome. Could you give us some context around how enrollment is progressing, pre-screening, all of that, and how that might help you pull off this trial in a really successful way?
Yeah, so thanks, Sumant. I'll first of all start by describing the phase III trial. It's 170 patients. It's being run in the U.S., U.K., Japan, and Europe. Its primary endpoint is at week 28, which is a measure of seizure reductions against sham control. Week 52 is the secondary endpoint, which is durability of seizure reductions, but then also cognition and behavioral benefits as measured by Vineland-3. That's the design of the study. It is dosing of two 70 mg doses of the drug and two doses of 45 mg throughout that 52-week period. The study is up and running. We've dosed the first patient. We announced that earlier this week. I mentioned it's a 170-patient study. As of last night on our earnings call, we did also announce that we've got 150 patients in pre-screening.
Obviously, the challenge is not just bringing those 150 patients into the study all at once. We'd love to do that. The rate-limiting feature here is opening up all the treating centers or the clinical trial sites. We're working through that process. We've made great progress. We anticipate fully recruiting the trial into the second half of next year because it's a 52-week trial delivering data from the phase III trial in the second half of 2027.
Given this is a disease that can be tracked over time once people are on the product, is there a potential for an interim readout in your phase III that could be before your primary endpoint?
Yeah, I would say that possibly there is potential for that. I think that would all be under that discussion we had earlier, Sumant, which when we talked about the discussion under breakthrough therapy designation, I think that's one thing that we could have a discussion with the FDA about. You have to be careful with breaking the blind at week 28 because of the hit on the alpha and the powering of the study. I would put that under the headline of discussing under breakthrough therapy designation with the FDA pathways to the patient faster. If anything changes on our timeline, whether it's recruitment or filing, obviously we'll update investors immediately.
Right. We haven't really seen any approaches like this where you're trying to manage the whole syndrome for Dravet before. You're in a phase III now. How confident are you that your phase III trial includes a long enough timeframe to get a symptom management claim on an eventual label on approval?
Yeah, it's a good question and one that's often asked by investors. Maybe in terms of the mechanism of action and the onset of the benefits, seizure reductions happen pretty quickly early on in that 52-week period, and very comfortable with that. That's been shown in our phase II studies. What we've also shown in our phase I-II studies is actually the onset and the benefit of cognition and behavioral benefits, which also occurs after nine months. More recently, just a couple of weeks ago, I think it was two or three weeks ago, we showed data at a medical conference where we showed a dosing level that's similar and consistent to our phase III and what the cognition and behavioral benefits were of that. We showed these dramatic improvements in cognition and behavior from that dosing level that was similar and consistent to the phase III.
The study is well-powered in terms of the 52-week period and the number of patients that are coming into the study. I'll give credit to the team back at Stoke because the way they designed this study was actually for basically a p-value of 0.01 and a 90% confidence level. That's what you should do with these medicines. You don't want to cut corners. Running a 100 or 120 patient study for timeline is just short-term thinking. We've powered the study adequately based on the phase II data that we have, and I would say somewhat conservatively. We did decide to run a 52-week study so we could see that full benefit from dosing of the medicine.
Going to the syndrome management aspect, you have the Vineland-3 scale. What aspects of that scale are most relevant? What sort of, could you reiterate what sort of point changes are clinically relevant on that? Because that, I think, is a key point.
Yeah, another great question because Vineland is not known by many people. Vineland is a score that is done by neuropsychologists. For the phase III, we basically have central readers of this. They meet with the patients at baseline, and then they score them at different points towards the end of the trial. Vineland has multiple domains that range from expressive receptive communication, motor skills, fine motor skills, and leading to quality of life measures. What we're told by physicians, family members, caregivers, is that, frankly, the two most important measures are expressive and receptive communication. What that means is if I was to turn to you and say, "Hey, Sumant," and you looked at me as you are doing, that's really important to parents. That will get a score. If you do actually look at me, you get a score.
I have to understand that these kids do not recognize their parents. They do not look up. They do not recognize their name. What we've seen is that our medicine does actually give back that ability over a period of time. We're told from the neuropsychs and the understanding of Vineland that a clinical score or a Vineland score of two to three points is clinically meaningful. If you look at the EPNS data from the conference I spoke about just now, if you look to see what kind of measures we're getting in from that dosing level that's similar to the phase III, you're seeing scores of eight and nine. I would also add, fortunately, the scores are higher in the expressive and the receptive communication domains.
I would also add that in AES, another medical conference, December 2024, physicians presented data in terms of the practicality by showing videos of these patients that have been on our drug. We're thrilled that the physician did this. We have patients that, frankly, can't do buttons on their blouse. They go on our medicine. They can do buttons on their blouse. They can't write notes, so they can suddenly write nice clear lists of one through 10. We have a physician telling us that there's somebody that was in a wheelchair and now is no longer in a wheelchair. These aren't anecdotal. They've been presented by physicians at medical conferences. There are actually videos of them if you want to see them from AES, December 2024.
Those are the key domains of what we're trying to measure and trying to help you understand the practicality of real life of what a Vineland score means. It is two to three points. In that EPNS data, you see that we're getting effectively eight, nine, and 10 points of Vineland.
Got it. We have a few seconds, so I'll just squeeze in two questions. One, with a disease state like this and with a potential therapeutic approach like this, it's about risk-benefit. You've seen some cerebrospinal fluid level elevations. What does that truly mean if it means anything at all? I do want to touch upon your ADOA or autosomal dominant optic atrophy program. What made you decide to start that now?
Yeah, so on elevated CSF protein, it is generally a function of an intrathecal lumbar puncture, which is how we administer our drug. It's been seen with many drugs that are a lumbar puncture. We have seen elevated CSF. However, we've seen no clinical manifestation of it. The drug is well tolerated. As I mentioned earlier, we've now administered over 800 doses, and we've been administering this drug now over a four-year, maybe longer than a four-year period. It's well tolerated. As far as ADOA is concerned, that's autosomal dominant optic atrophy. It's another genetic disease. It causes a progressive loss of eyesight. As of last night, we announced that we're going into the clinic with an approach that's very similar to Dravet in that we're delivering a deficient protein to the eye. That protein or gene is OPA1.
We express OPA1 into the eye, which increases mitochondrial function and energy, which is what the eye needs. Unfortunately, that is what the eye is losing in an ADOA patient. The key data that we had actually was a non-human primate study where, believe it or not, there are non-human primates that have ADOA. This is not a model, like a xenograft model in oncology. This is actually a non-human primate that has ADOA. We were able to inject that monkey, the non-human primates, multiple models on multiple non-human primates. That data actually showed, based on a fluorescent protein marker, that we upregulated and we improved vision. Not stabilized, we actually improved vision.
That was the kind of the aha moment preclinically, as well as safety and Jason's work in identifying the patient population and our CMO's work, Barry Ticho, his work to say how would we do development of the drug. That was the day that said we have a development pathway. If you can potentially improve vision in these slowly progressing loss of vision patients, then you have a development pathway. That was what caused us to move into the clinic and be excited to run the phase study.
Thanks a lot for that. Thank you everyone for coming and for tuning into the webcast.
Thank you. Thank you for joining us today.