All right. Good morning, everyone. Welcome to Guggenheim Healthcare Innovation Conference. My name is Yathin Suneja, one of the Biotech Analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, Stoke Therapeutics. From the company, we have the Chief Executive Officer, Ian Smith, who recently became full-time CEO from an interim CEO. Thank you, Ian, for joining us. Why don't you make some opening comments? You have been associated with the Stoke story for a long time, but you just became sort of a CEO. What led? How did that happen? And what are some of the milestones that we should be focusing on? Then I'll go into some of the Q&A.
Sure. Welcome to Stoke Therapeutics this morning. I'm happy to be here, and happy for those that have joined us online as well. I've worked with Stoke now for nearly three years. I was a board member. I was also an advisor with the company. Ironically, when they received their first phase I/II data in their high-dose group, where they showed a demonstrable reduction in seizures at that time in Dravet syndrome. From that point onwards, I worked with Ed Kay, the former CEO, and the board, and advised them with items such as planning for a phase III, a collaboration with Biogen, which has been highly productive over the last year since inception with Biogen. Also financing and just organizational build. Earlier this year, I was given the opportunity to transition with Ed Kay, the former CEO, into the CEO position.
At the time, I felt as though it was an interim position. As months went on, and up to recently, I was then given the opportunity to move forward more permanently in the seat. Why did I do that? Firstly, there's a lot of familiarity for me with Dravet syndrome, a haploinsufficient genetic disease. I was a long time with Vertex Pharmaceuticals, and they focused on cystic fibrosis. There's a lot of familiarity with a pediatric disease of this nature, a genetic disease, correcting a protein deficiency or a mutation to upregulate protein to actually cause the organ to function properly. That's what I saw at Vertex for many years. I saw that here at Stoke Therapeutics. The data suggests that we're really having a big impact on these patients, these children that, unfortunately, with Dravet, you start to have seizures.
You do not have neurotypical behaviors from 18 months to 24 years old, and you plateau for the rest of your life. Yet we are having the opportunity to put protein back into the brain and cause these children to reduce their seizures significantly. We will talk about the data, Yathin, and then potentially improve the rate of neurodevelopment of these children. We have data that suggests we are. We are in phase III with the medicine. We have a pipeline that goes all the way back to other diseases that are in phase I or preclinical, but all haploinsufficient diseases where we are looking to upregulate protein.
Got it. Could you remind our audience, what is the medicine all about? I think you just touched on some of the data. If you can put those data in context to the standard of care, whether it's the durability or the magnitude of effect.
Yes. I'll start with really our platform approach, which is ASOs, upregulate protein. Dravet syndrome ultimately is a lack of NaV1.1 in the brain. That is a result of a mutated SCN1A gene. We actually upregulate that gene to produce NaV1.1, and therefore less deficiency, maybe no deficiency, but less deficiency in NaV1.1, which corrects the function. It goes to the root cause of the disease. If you can go to the root cause of the disease, there is the potential that the organ operates more normally. Therefore, you do not have these seizures, or you have less seizures, plus you have the opportunity to develop more neurotypically. That is how our medicine works, given that it goes to the root cause of the disease.
The results in the studies at this point have suggested that we are delivering significant NaV1.1 protein because of the magnitude of the reductions in seizures on top of standard of care, which you mentioned, Yathin. I want to talk more about that. We are also, for the first time, a medicine that shows that these children are actually showing neurotypical development, maybe not completely neurotypical, but certainly beyond their Dravet peers. I am looking forward to talking about that data with you today.
Yeah. So I think, yeah, I just want to double-click on this. I think not only you have shown some very remarkable reduction in seizure frequency, but if we see the benefit that you're providing on cognition and behavior, that also, in my view, I think it's pretty remarkable. Just put that in context. How meaningful these results are?
Yeah. So it's important to understand what Dravet is, first of all. The journey of a Dravet child starts around one year old or 18 months old, where they will start to have significant seizures. They will go to the pediatrician, neurologist, and they'll usually be put on anti-seizure medicines. There's not necessarily a diagnosis of Dravet at that time. Unfortunately, the anti-seizure medicines, although good, don't take away the seizures. The statistic or the medical statistic is still 50% of patients that are on these anti-seizure medicines, whether it's two, three, four, and five anti-seizure medicines, are still having a significant rate of seizures. That continues. When the child gets to maybe 18 months, two years old, unfortunately, they stay there in terms of their neurodevelopment. What that means is, as an 18-year-old, unfortunately, you're still really a two-year-old. Many can't walk. They don't have the motor skills.
They don't express themselves. They can't talk. They can't receive communication. They effectively have plateaued from 18 months to two years old, even though they still may grow as an adult. What our medicine does is actually reduces seizures. The data shows that we reduce seizures in these patients that are on these anti-seizure medicines by up to 80%- 85% median reduction in seizures, despite whether they're on anti-seizure medicines or not. That reduction in seizures now we've tracked for nearly four years. We've shown that the reduction in seizures is sustained and durable out through four years, which is unique. Anti-seizure medicines, you can cycle through them, and the seizures come back. I think because of our addressing the root cause of this disease, we're showing these sustainable reductions in seizures.
From a cognition and behavioral benefit, we've tracked these children now for three and four years. It is really thrilling to see that these kids, as measured by a score called Vineland- 3, and I'll talk a little bit more about that, but it has multiple domains where you test the expressive communication, the receptive communication, their motor skills, and the fine motor skills. It is a questionnaire, and you can measure these children. Just to give you an example of baseline, if somebody was to ask a child, use their name to the child, ask them to touch a finger or touch their nose, unfortunately, these children are not even aware of the question. They are just unreceptive to that communication, and they do not communicate back. What we've seen when these children, these patients, unfortunately, have been on our medicine, we're seeing them respond.
That is measured by the Vineland score. We have even presented videos at medical conferences, not us, but the treating physicians have presented videos at medical conferences of the astounding results that we are seeing while these children are on the medicine for three and four years, where we are seeing children being able to actually at baseline being unexpressive, where they are on, they are laughing, they are talking, they are playing games, pointing fingers on noses. We have had other people that, unfortunately, are getting out of wheelchairs that were once in a wheelchair. This has been presented at medical conferences. It is not anecdotal. We are having a remarkable benefit from cognition and behavior skills of these children.
Got it. Thank you for putting this in context. Remarkable results on the efficacy side. Could you then put safety in context as well? What do you see, how favorable it is? Any particular thing of concern there?
Yeah. So again, we studied the patients in a phase I/II study, and they rolled over into a phase III study. An important marker is 90% of the patients that were in our phase I/II study rolled over into an OLE study. In that OLE study, they've now been tracked up to three years and beyond three years. Some are obviously still earlier in that study. The safety profile is generally well tolerated. We've dosed children now, as I said, over a period of nearly four years and over 800 doses. This is dosed every four months in the OLE study. It is over 800 doses in these patients.
I believe 90% or 80%-90% of the 90% that rolled over are still in the OLE study, which, again, is a really wonderful statistic to show you of the safety profile, as well as the meaningful impact that the drug is having on these children.
Got it. I think you do see some increases in CSF protein. What is the mechanistic understanding and any relevance of that?
The mode of administration of zorevunersen is actually a lumbar puncture. Very typical with lumbar puncture, you see elevations of CSF protein. We are seeing that in patients. What I would say is there is no particular pattern. It does not persist. In a certain patient you may see it. It does not particularly appear at a common period of time. It is more random. We are seeing CSF protein elevation, but no clinical manifestations over a period of up to four years now.
Got it. Can you talk a little bit about the dosing? How did you adopt the regimen that you're using right now, which is 70 milligram, two doses, and followed by 45 milligram?
Yeah. I affectionately use the phrase internally of patchwork quilt. That's not to undermine the phase III design. What that actually means is we took a really nice patch, which was the phase I/II dosing of two doses of 70 milligrams. It then rolled over into an OLE study where they receive 45 milligrams every four months in the OLE study. Going into the phase III, we effectively put those two patches together. You have a dosing of two 70 milligrams and then 45 milligrams dosed every four months over a period of 52 weeks in the phase III. It's actually an enhanced regimen versus what these children have been on before. Because going from the phase I/II and into the OLE, there is the six to seven-month gap where they don't receive a dose.
Our drug does not have the PKPD profile to reside in the brain to that length of time. They then go into the OLE where they effectively have to kind of restart in a way dosing. In the phase III, we do not have that gap. It is two doses of 70 milligrams as loading dose. Then three, four months later is a dosing, a maintenance dose of 45. Ironically, very typical for ASOs, probably familiar with Biogen and Spinraza, which is an ASO which has two loading doses and then a maintenance dose as well. Very similar to ourselves.
Got it. Very good. That was a great review of the phase II or phase I/II data and the safety. How is the phase III set up? What are the key differences? Where are you on the enrollment front? If you can walk us through.
Yeah. I always like to start with saying the patients that are going into our phase III are exactly the same patients we've studied in, well, not the same patient, but the exactly same criteria of patient that went into the phase I/II, and then into the OLE, which is really important. Phase III setup is there is a screening period, a six-week screening period. If they meet the criteria, as in numbers of seizures, SCN1A depletion, then they can move into the study and get randomized into dosing. The primary endpoint is at week 28, which is a reduction in seizures. Secondary endpoints are at week 52, where there is a durability of seizure measures, but then also the Vineland score, which is what I was just discussing, which measures the five key domains in terms of cognition and behavior.
Study is powered to a 90% confidence level for a 0.01 result. It is a well-powered study. We took the phase I/II data and the OLE data. We did look at that data conservatively to ensure that we're powered adequately. We're well on the way in the study. We've dosed over 20 patients so far, randomized and dosed over 20 patients. The study started in August of this year. Dosing started in August of this year. There is another 30-40 patients that are in that pre-screen period that if they pass the screening, they will enter the study.
Any particular expectations you have set for the primary endpoint?
No. I mean, in terms of expectations, we've looked at the primary endpoint in terms of the phase I/II data and then the durability of result. One of the key criteria of patients entering the study is that they maintain a stable background of medicines. These patients in the phase I/II study were on three, four, and five anti-seizure medicines. We want them to be on a stable background. We've used that data to predict the powering and the outcome of the phase III.
Yeah. So given the numbers of patients, 20 already dosed and 30-40 in the screening right now, seems like a little bit ahead on the enrollment front. What is the guidance by when you can achieve full enrollment, and when should we expect the data?
The study is 170 patients. The guidance we've provided is to fully recruit the study by the second half of 2026, which would mean a data readout in the second half of 2027. When we look at the patients that are in the pre-screen period and then the screening to go into dosing period, as I said, we've dosed over 25 patients. I think the number, to be more precise, is 25- 26 patients at this point in time. There are 30-40 patients that are in that six to eight-week screen period to potentially roll into randomization for the study. The study is going very well. A lot of it has been education around the disease through advocacy community and also congresses with the KOLs. The demand from the families to come into the study has been significant.
That's what's helping the study move so well.
Very good. You do have a breakthrough therapy designation meeting scheduled with the FDA, right, coming up. I think it's next month. Could you maybe talk about, are there opportunities to expedite the approval pathway?
Yeah. Just to give background, first, I mentioned earlier in my comments here that there's a familiarity of being at Stoke after being at Vertex, but used to dealing with breakthrough designated medicines. Stoke got breakthrough designation in December 2024. I want to be clear that it got breakthrough designation for the treatment of Dravet syndrome. That's really important to understand because what that means is the FDA acknowledged that there was a safety and efficacy profile to treat the disease, which means that reduction in seizures as well as neurocognition. Cognition and behavioral benefits were observed by the FDA when granting us the breakthrough designation to treat Dravet syndrome. One of the required steps within breakthrough designation class and how you work with the FDA is you're required to go down to the FDA and have what's called a multidisciplinary meeting.
That gives you the opportunity to talk about the pathophysiology of the disease. It helps the FDA understand the mechanism of action of your drug. You can share safety and efficacy data. That is the meeting that we have in December. One of the unique things about where we are in the development of this drug is, one, we have an ongoing phase III that is going very well. Two, the data we have is three and four-year data of safety and efficacy. Normally, when you go to the FDA, you have much earlier safety efficacy data. You have a much lower number of patients. We have a large number of patients, three to four-year data of safety and efficacy. We filled a briefing book with questions and all the safety and efficacy data.
Frankly, we're going to work with the FDA and ask the FDA about whether they would support an NDA filing given this phase I/II data and the OLE data. We'll have a good discussion around it.
Most likely will be on phase I/II . Are there potential to maybe do some sort of an interim readout for this phase III study or maybe seek an early approval based on the primary endpoint of seizure reduction?
I would put it in terms of priority in terms of working with the FDA. First of all, the data set that we have now of the phase I/II , and the OLE data, plus a natural history study, and providing that data to the FDA and asking about whether we can file, whether they would support filing of an NDA, that'll be the first priority. Second priority in terms of looking at interim results of the phase III, I would say they're much lower down. We believe our medicine is something that is treating the whole syndrome, seizures, cognition, and behavior. That is the label that we think we want for these patients so they understand the medicine and what it can do for them.
Because we have an ongoing phase III that is recruiting very well, I would say that's the second priority, just to focus on execution of that phase III while seeing if we can move more quickly right now with the FDA.
Got it. How quickly or how early you will be able to provide an update to the street after this December meeting? Do you have to wait for the minutes or just how are you thinking?
Yeah, definitely wait for the minutes. My experience has been that you can have what you think is a very good meeting, or you can have what you think is a very bad meeting, and you get the minutes back, and they're not necessarily reflective of what you heard or thought. We will definitely wait for the minutes. The meeting is in December. In terms of disclosure and outcome from that meeting, I think about it as in how does it affect timeline? Right now, base timeline is running the phase III. I've provided guidance on that timeline this morning. If we move from that timeline or we anticipate that we're moving from that timeline, that would be the disclosure that we would provide and the rationale behind it.
Got it. Very good. Very helpful. I want to spend some time on ADOA, but could you put in perspective the commercial opportunity in Dravet? What is Biogen doing here? What rights do they have? How is the OUS piece?
Yeah. The opportunity, commercial opportunity, is significant. Dravet syndrome patients diagnosed prevalence is probably between 15,000 and 20,000 in the U.S. alone and probably a similar number, if not more, when you go outside the U.S., which is the outside North America, which is the Biogen territory. Maybe 35,000-40,000 patients globally. What I would say is that when you have a medicine that's treating a rare disease, a genetic rare disease, and the medicine works, you always identify more patients than you think is out there. That has been the history of rare diseases. Significant patient population. There are subsets within that patient population, such as pediatrics and adults. There will be different times to get to those patients and address those patients.
I would start with saying that in the U.S., where obviously we at Stoke are focused at this point in time, there are probably about 6,000 patients that are immediately addressable that we can track in terms of they have Dravet syndrome. They are on medicine. We can target those upon approval, potential approval, and treat those patients. The patients that go from the 6,000 up to maybe 15,000-20,000, we'll have to diagnose some of those, which we can do. We are working on that right now in terms of our go-to-market model and also identify the adult patient population where we'll probably run another study at a later point in time.
Got it. Very good. Thank you for that. Maybe moving on to ADOA, Autosomal Dominant Optic Atrophy. What is that program? Where are you? What are some of the key milestones there in that program?
Yeah. First of all, ADOA. I'm glad you pronounced it all out. I'll just call it ADOA. It is a genetic disease again, and it's a slow progressive loss of eyesight, unfortunately. We are in phase I. The target is OPA1, again, haploinsufficient disease where we upregulate OPA1. Upregulating OPA1 actually increases mitochondrial function. Probably many of you know that the highest working cell in your body is actually in your eye. Increasing the energy into the cell with improving mitochondrial function actually has shown to us in non-human primate models that we can actually improve vision, not stabilize vision, but improve vision. We're running a phase I/II dose-escalating study in ADOA. We do not anticipate hitting the efficacious ranges of dosing probably until late 2026.
There is data out there that suggests that OPA1 is a validated target in helping with vision improvement for ADOA.
Got it. So the study that you're running, we basically have to wait until the second half of this year to get more meaningful view. How big is the study? What type of patient and where is it being conducted?
It's initially being conducted in the U.K. and Europe. There's approximately four doses. It could be extended, but it's a dose-escalating study of three to six patients. You move through the first three, then go to patient four, five, six. In parallel, you then go to the next level of dose. It's a standard dose-escalation study.
Got it. Very good. You also have a preclinical program. Where is that in development?
That preclinical program is SYNGAP1. SYNGAP1 is actually very similar to Dravet syndrome, seizures, and neurodevelopment issues. That is in preclinical development. We anticipate having a development candidate in early 2026 and would follow a very similar pathway, we believe, as to Dravet syndrome. It is a haploinsufficient disease where we upregulate the protein.
All right. Final question. How is the financial health of the company? How's the balance sheet?
It's very strong. We finished Q3, just announced last week, of capital, including we did raise a little bit of capital through an ATM block sale. We're closer to $400 million of cash on a pro forma basis. That will carry us all the way through to mid-2028. When you compare mid-2028 cash runway to running our phase III study and investing in these other programs, the results read out in, even if we go the full duration of the phase III, the results read out in the second half of 2027. Very well capitalized.
Very good. Ian, thank you so much. That was great.
Thank you, Yathin.
Thank you.