Good day, everyone. Thank you for joining the 23rd annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Stoke Therapeutics. Joining us today from Stoke is CEO Ed Kaye and CMO Barry Ticho. For those of you joining on the webcast, if you want to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. So with that, we'll get started. Ed and Barry, thank you so much for joining us today.
Thank you, Joey, and we appreciate the invitation.
Thank you, Joe.
First of all, congrats on the recent data. Very impressive. Can you just briefly summarize these data for your lead program at Dravet syndrome? What has investors excited as well as the patient community?
Yeah, Joey, I think what's gotten people really excited is that this is really the first time in a clinical trial that you can see 70%-80% reduction in seizures on top of maximally treated patients on a number of previous medications. But I think what's gotten people very excited is that we're now showing in a clinical study improvements in cognition and behavior. And I think that is really what has gotten people very, very, very excited. And if I think back at when we actually first came to the company, we had really hoped that we could address some of the autosomal dominant genetic diseases where you're missing 50% of the protein. Because everybody's been focused on recessive diseases.
The idea that we can upregulate very exactly the missing protein and the genetic epilepsy and show the kind of results in showing results in cognition improvements, I mean, frankly, it was better than I had expected. We thought that by addressing the underlying genetic cause, that we would see improvements. I think we've been surprised that even as early as nine months, we're starting to see improvements in cognition and behavior. That's what's, I think, gotten everybody excited, that this is really a disease-modifying therapy. I think it's gotten a lot of people excited.
Great. And digging into the dataset a little bit more, what we thought was really impressive, you had two patients who had a complete response in seizure reduction, both at the three- and six-month time point. I think one new patient in the latest dataset. What can you tell us about those two patients and maybe why they had such a great response?
Well, you're definitely reading the data correctly there. There were two patients there who were seizure-free. That's the 100% response rate there. In fact, the principal investigator who took care of one of those patients was so excited to tell us about the fact that since the time that patient was diagnosed, that patient had never been seizure-free and had been sustained seven months seizure-free after starting the STK-001 treatment. So quite a dramatic result. And it points to the potency, especially of that 70 milligram dose. It shows the profound levels of reduction that we're seeing consistently now among the patients getting those two or three doses of 70 milligram.
Yeah. And Joey, I think even more exciting, though, is, Barry said, the consistency of response. So what we had is 80% of the patients had a 50% or better improvement. That to me is it's not just you have a couple of outliers that had a great response. And that's always wonderful. But the fact that everybody had a response and most of them had a very significant response suggests that, okay, we now have the right dose. And that's what I think it took us a while to really understand how to use this drug. But we now know that a loading dose is really important and that 70 milligram is well differentiated from all the other lower doses.
Another interesting kind of sticking on those two patients who had that complete response. I know in a controlled clinical setting, relatively stable background anti-seizure drugs, of which these patients are on several, and they have significant side effects. But just curious if it raises the possibility that some patients would consider, say, in the real world, coming off these background anti-epileptic drugs if the side effects are bad, maybe not all of them at once. But is that something anecdotally that you're hearing or it could be a possibility, say, in a real-world setting?
It certainly could be a possibility in a real-world setting. As you mentioned, the anti-seizure medications have substantial side effects. They cause sleepiness. This is something that we hear quite a bit from the families who tell us that, unfortunately, in order to prevent their children from having seizures, they basically have to make them almost sleep all day long. So that is a side effect that is well known among these anti-seizure medications. They're also difficult to work with because they have interactions with other drugs. So there is definitely going to be an impetus to try to remove some of those medications. On the other hand, these are very sick patients and have been very difficult to manage in general. So I think the clinicians and their families are likely to be somewhat reluctant to quickly change their treatment regimen.
This is the standard way that in the past, the norm is to add medicines on top of each other and keep adding and adding. But we certainly anticipate that as the efficacy of STK-001, the benefits are seen, that there'll be more comfort in starting to remove some of these other more toxic medications.
Yeah. And Joey, I mean, actually, in clinical practice, that's what I used to do. Many times in patients with pediatric patients with epilepsy, you start one drug and then you add another. And then what you realize is that that first drug, maybe it's not working, but you're a little hesitant to take it off. So typically, once you get somebody well controlled, then there's a process of slowly trying to wean off. I think the big advantage that we have is that unlike other anti-seizure medicines, we're not seeing that sedation. Again, because it's a targeted genetic approach and you're not suppressing brain activity. We're just replacing that protein. So that's a huge advantage that I think people appreciate, that you're having seizure control, but you're not falling asleep because of it.
Yeah. No, that's a great point. And I just want to confirm something on the seizure reduction endpoint itself. You are reporting seizure reduction at time point X, whereas if you look at approved drugs for Dravet syndrome, like Fintepla, those are approved based on a reduction of seizures through a treatment period. So can you talk about the differences here? And what gives you confidence that FDA will be on board with the at-time point interval for a pivotal trial?
Yeah. I think, Joey, that the main difference is that up to now, we've been talking about anti-seizure medications that work other than for the actual cause of disease. Here, we're now talking about a disease-modifying approach. This is going to take a different way of thinking about the clinical trials and assessing the impact of the medicines on the patients. And so we know that STK-001 takes a little bit longer to work than an anti-seizure medication. That's because it's actually addressing the cause of disease. It takes time for the sodium channels to reach the full level back to close to normal in the brain and have the impact. And again, these patients have had substantial rewiring of the brain because of their disease. So now we're having to undo all that abnormal wiring and set up the normal network.
So it takes some time for this medicine to work. But so that's why we look at three months and six months after the last dose. But that also points to the durability of the effect, that this is now six months after their last dose of drug. They haven't gotten any STK-001 in that meantime. And the drug is continuing to have a sustained effect. So that's something that's quite different from what we see with the anti-seizure medication. And then we also need to look at these cognitive and behavioral endpoints. So that's going to also we know we've seen that within nine months or so. But we're going to also need to have a period of time to observe those full effects.
Yeah. Joey, just to get back to your point, there certainly is a precedent for using the at-time period. It's been used by the FDA for other indications. I think for us, based on the mechanism of action, this is the most appropriate way to assess how our drug is working. Because like Barry said, if you look in the first few days after you give the therapy, well, it's not going to work. It takes at least a month before we start to get the protein. I think what's different is typically over time, the anti-seizure medicines in Dravet start to wane, and they're no longer effective. Ours is just the opposite. Over time, it gets better. So it makes a lot of sense. I think we can certainly have that discussion with the FDA.
We feel pretty comfortable that this is the most appropriate statistical analysis.
Got it. That makes sense. You both mentioned the improvements in the cognition and behavior. We won't have time to get through everything, all of the recent data on this call. But I wanted to ask specifically on the Vineland-3. Is that something that is appropriate for all age groups? And are there any restrictions or limitations here for using that in a potential pivotal trial?
So the age range for the Vineland is actually from birth all the way through over 90 years of age. So certainly, the age range that it's designed for covers the patients that we're looking at. The other important thing is that when we surveyed clinicians and caregivers, and we've done this now in a formal study, the things that they say they want to see improved in the patients and those children are things such as cognition, sorry, such as communication and socialization. And these are the things that are assessed best in terms of using the Vineland. So we think that the Vineland is appropriate for measuring those skills that are important to show a difference in. And we've shown that now with the open-label extension study, especially, and even in the phase I/II study, the improvements in cognition and behavior with the Vineland.
The Vineland-3 is one of the most commonly used assessments to track and diagnose neurodevelopmental diseases. This certainly is an appropriate one. The agencies are quite familiar with it. The Vineland-3 has been used commonly. Approved drugs in secondary endpoints. This is likely to be something that we will use in phase III. It seems to be quite appropriate from our perspective for measuring the effects in these patients.
Yeah. And Joey, one of the things that we really like about the Vineland is that there's a number of tests where the patient comes in on the day of their clinic visit, and they have to be tested. And remember, these are children who have a number of neurological disabilities. They may have had a seizure. They have to travel. They're tired. So the Vineland allows us to capture how these patients are improving over time, not on a single day. Because the child could be in a really bad mood, and we've seen that in our own children. You can't get them to cooperate in a test if they don't feel like they're doing it. So this way, it's a little bit more of a uniform assessment of how the patients are doing long term.
I think we feel pretty comfortable that this is a pretty reasonable test that'll give us an accurate picture of how these children are doing, not just on one day, but on the last month or the last two months.
Got it. For the OLE data that you presented in March, I just wanted to clarify why only 48 patients in the Open Label Extension seizure analysis, and what patients from the total of 81 were not included in this?
Those 48 include patients who got 30 or 45 milligrams every four months in the open-label extension studies. That was what we think is the appropriate dosing level. So we were just trying to collect the data in the patients who got adequate dosing. That's the patient population where we've shown that they had sustained reductions in seizures over time and the improvements in cognition and behavior. As a reminder, those patients were still on their standard anti-seizure medications. These effects are still happening on top of the standard of care that they were receiving.
Yeah. It's important that also 90% of the patients had rolled over into the Open-Label Extension. We didn't exclude patients, but you had to have a minimum amount of drug before you got followed in the seizure control. Some of the patients had very low doses, 10 and 20 milligrams of a loading dose. You had to have at least 30 milligrams to begin with. Then we followed them at 30 and 45.
I see. Got it. You had once every four-month dosing in the OLE. Any chance you could or would consider stretching this to twice a year, so every six months based on your modeling? And how much of a difference would that make, Q4 months versus twice a year, in terms of adoption, potential adoption?
Yeah. So in the Open Label Extension study, as you mentioned, we were treating the patients every four months. And that's where we saw these very impressive results. So at this point, we're planning to continue with that dosing regimen. Why not for success, basically? At this point, the every four-month dosing regimen is the one that we would propose for phase III.
Yeah. That fits with what we believe is the half-life of the drug. Every four months used to fit very nicely with the half-life and what we're seeing for efficacy.
Great. So post-phase II data, you have a rich dataset here. What are the next steps with FDA? And when do you plan to update the Street on a pivotal trial design?
So we are working feverishly right now to get briefing documents together. And our plan is that we're going to have discussions with the FDA, the EMA, and PMDA in Japan. And we'll have a single global well-controlled study internationally. And that is our plan. So what we have to do is talk with all of the agencies, get an agreement on the phase III design. And we expect that in the second half of the year, we'll be able to get back to you and let you know what that design looks like. And then we can really have a much better estimate as when the studies start would be, what the duration is going to be, and what we think the enrollment time, etc. So we should have a pretty good idea in the second half of the year with estimates.
Yeah. Maybe a best-case scenario, is it possible you could start a phase III by the end of this year?
Although we would love to do it, I think practically, I think by the time we hear back from regulatory authorities from all three, I think it's unlikely.
Okay. Fair enough. And just given that, in general, you've seen better efficacy in younger patients, what's the risk of having an all-comers trial, inclusion of older patients in the phase III? What's the risk there of hitting on a primary endpoint?
Well, Joey, I'll just correct that a little bit because we're really seeing efficacy across the age groups right now. In that 70 milligram dosing group, we are seeing the older-age patients responding as well as younger-age patients. So we're really not seeing any differential in terms of age right now. And we know that the older-age patients, there's still a tremendous need for better therapies for that age population. We hear from the families frequently saying, "Please make sure that your medicine is available to our older child, even adults." So we, at this point, have no intention of limiting to anything but what we saw already from the age groups for the phase I/II study. We will stratify to make sure that there's an equal distribution among the ages between the control group and the treated group.
Other than that, we don't see any need to limit the age enrollment for the study.
A common investor question we get is on the cognition and behavior. You've presented data through 12 months, the improvements you're seeing in Vineland and Global Impression of Change. But is 12 months sufficient in a placebo-controlled trial to see those improvements?
Well, we're very pleased with the results that we're seeing at 12 months. In fact, even in the phase I/II study, we were seeing results at nine months in terms of improvements in cognition and behavior. So to us, it's very, very encouraging. Right now, we're going to be trying to put together the best study that we can in terms of being able to assess the full effect of the medicine. As we talked about before, we want to capture and demonstrate the effect on those cognition and behavior endpoints. So we're in the process right now of designing the best study. We're going to propose that to the regulators. Then after we've heard back from that, then we'll be able to give you a better idea of what the length of the study will be. But at this point, it's pretty much it.
Where do you stand on long-term safety exposure requirements for STK-001? Do you need to do any additional work to satisfy the requirements? Would you have to do this in parallel to phase 3?
Well, right now, we have 81 patients who received the medicine. Overall, the safety profile shows that the drug is quite well tolerated. We have patients, as I mentioned before, who have had three years of treatment. Some patients have gotten up to 10 doses of the medicine already. So that's a substantial safety database already to be going into discussions with the regulators about phase 3. We think that that will be sufficient to allow for a good discussion about the phase 3 study design. We're not anticipating there's going to have to be any special changes right now in terms of the safety database.
Yeah. Joey, I will say, having been team lead for a number of approved rare disease products, this is the largest phase II I've ever conducted. So I have more safety data now than many of the products that we had at the end of phase III and are approved. So I think we're pretty confident that we really have a lot of patients and long-term exposure. So I think we have a pretty full database from a safety perspective.
Now that you have that full, complete phase II dataset, what's your current view on the addressable patients for STK-001? Any more insight on which patients you think would be early adopters and maybe which ones could still be a little bit hesitant to use the drug?
I can tell you that based on the response that we've had to date, both even when we were running the phase I/II studies and now that we've announced the data, we are getting a tremendous amount of interest from clinicians, but also from families. We interact quite a bit with the patient advocacy groups. We just recently had a large call with many of them. They are continuing to be very supportive and helpful for us. We think that this is going to be well adopted across the range, even across the world. We get requests. I'm getting almost daily emails from people, families around the world requesting to know how to get access into the phase 3 trial at this point. We expect there to be a very brisk interest and uptake by both clinicians and families.
Great. Fantastic. Well, that was Dravet Syndrome. Great progress there. I want to ask a couple of questions on your other program, the ADOA. First, can you give us a high-level overview of what ADOA is, the unmet need, and the potential market opportunity here?
Yeah. Happy to talk about this one. We've become really very interested in this program. I think ADOA is a similar mechanism of action of how we upregulate the gene. It's the OPA1 gene and the OPA1 protein. So this is really the most common genetic form of optic atrophy. Unfortunately, there are no current therapies for this disease. So you have children who have normal vision at birth, and then by the end of the first decade, they start to have visual loss. And it's very disabling. It's a loss of central vision. So they have problems reading. And half of the patients go on and are legally blind. So there's a lot of excitement that we think we might be able to have a significant effect on this disease. And the reason is the retinal ganglion cells, it takes some time for them to really die.
They're obviously specialized neurons. This is a disease of the mitochondria. It's a mitochondrial protein. And we know that there are thousands of mitochondria in the retinal ganglion cell. It's the most metabolically active cell in the body. So what we're hoping is that by replacing that protein and we've shown in patient cells that we can actually improve the structure and the function of and increase oxidative phosphorylation in these cells. So I think the chance that we can actually restore some vision and show some improvements in addition to slowing down the loss of vision, I think, is high. So that's why people, I think, are getting very excited about this. And I used to run a mitochondrial lab. And one of the things that we had always hoped for is, is there a way to increase efficiency of mitochondria?
This is the first time that I've ever seen actually a drug increase the efficiency of oxidative phosphorylation. So it opens up a lot of potential. We're looking at even broader indications in ophthalmology such as glaucoma and dry AMD because we know that those diseases have problems in mitochondrial metabolism. So it opens up the potential for a lot of different exploration. The other, we're also very interested in our programs that we're working with Acadia on. That's our Rett and SYNGAP1. And we have another program. They're in the preclinical stages, but also very similar to what we're trying to do for Dravet. And we continue to make good progress on that. And we have other early-stage programs in kidney and heart that we're looking at also. So a lot of opportunities using this TANGO mechanism to upregulate protein.
Yeah. I want to go back to ADOA. Just one or two more questions on that. How predictive are the preclinical animal models for ADOA? I guess what gives you confidence that the preclinical data that you've seen will translate into humans?
Yeah. Yeah. I'm happy to answer that. First, going back to the unmet need there, this is still a relatively underdiagnosed disease. That's partially because there isn't a treatment, as I mentioned. It really requires attention from clinicians to diagnose this disease and to be able to do the genetic test and to follow these patients. That typically will not happen until there is a treatment available. My brother is a pediatric ophthalmologist. Ever since I told him we're working on ADOA, he started paying more attention. Every once in a while, I'll get a thing from him. He'll say, "Oh, I saw another ADOA family. I can't believe I keep seeing more." Once the attention is there, people start to realize it about the disease.
Another aspect of this disease, though, is that many of these retinopathies that happen very early in life cause what's called a cortical blindness, which means that the brain needs to be getting signals from the eyes in order to develop the vision centers in the brain. When children who tragically go blind very, very young in life, they lose those signals. Then the brain centers either never form or they disappear. This is different from the autosomal dominant optic atrophy, which, as I mentioned, they have relatively normal vision early in life. Those vision centers in the brain are established. So all it takes is continuing to have those signals or even boosting the signals coming from the eye to improve vision.
What we have seen right now is that we have taken cells from patients, actual tissue cells from patients, and looked at the mitochondrial function in those cells. We show that the OPA1 levels in the cells from patients are lower, half normal, which is what is to be expected. Mitochondrial structure and function is abnormal. When we've applied STK-002 to those cells, we see that the mitochondrial function, mitochondrial structure improved. This is something quite unique because it's very difficult. It's quite rare to actually have any sort of treatment that can improve mitochondrial function. But that's what gives us the most confidence that as we move forward, we're going to be able to potentially even improve vision in patients.
Yeah. And you mentioned about the animal models. Unfortunately, there are some murine models, but the TANGO signature is only seen in higher primates. So it's not in rodents. So we can't, unfortunately, use those models. But what we've done is used human cells to really demonstrate. And we've been able to show in non-human primates and in rabbits that we can actually upregulate the protein in the cell that we want to. So I think that gives us some confidence that the ASO gets to where we need. It increases the protein. And we've shown in a couple of species. And then, as Barry said, in human cells, we showed that it actually works. So I think we're pretty confident that this is going to work. And so the next test is to see what happens in humans.
Yeah. No, very, very exciting application. Can you run through the details of the STK-002 OSPREY trial? What are the specific metrics that you're going to be looking at, visual function, etc.? And when can we see data from that trial?
So much of the design of that trial was based on a natural history study that's going on right now that we enrolled 48 patients across a broad age range from 6 all the way up to 60 years of age. And those patients are now going to be followed for two years. We have over a dozen different assessments of visual function and eye structure in that study. That's been very informative to us in terms of what are the best assessments potentially used in an interventional trial. One of the more exciting ones is a way to actually directly measure visual—I'm sorry—mitochondrial function through a visual assessment.
So this is a non-interventional test where we can, using a color that's emitted from the mitochondria, show that there are areas in patients with ADOA that have worse mitochondrial function or more, I should say, more mitochondrial dysfunction than in healthy people. So that is a way that we can potentially track this intervention over time directly in the retina itself. So the OSPREY study is designed to incorporate some of these measures. We also can look at visual fields. So, as we mentioned, the visual fields of these patients are quite contracted. So we can look at whether this treatment that starts to expand back towards a normal range. Again, we can look at how patients can look at letters and identify letters under very different types of contrast.
We've also shown in our natural history study that that's a very sensitive way to pick up minor differences in vision in these patients. So we have a good set of tests right now that we are quite confident are going to be able to detect changes in these patients. And so the OSPREY study, which we're intending to start this year, will use those assessments to track the patients after just a single dose of the medicine.
Last question from us, Ed and Barry. What's your current cash position and cash runway expectations?
Yeah. So, as we announced in our 10-K, we ended the year with $201 million. And as you know, we had a very successful financing of $125 million recently. What we're looking at is, what is the expense for our phase III trial going to be? So we're waiting on what is the duration of the trial going to be based on our discussions, the number of patients, the endpoints that we're going to be using in the trial. And once we have all that data, I think we'll be able to give a pretty good estimate of what the cost will be and what our run rate will be. And we'll get back to you in the second half of the year with a little better guidance.
That's great. Well, thank you, Ed and Barry, for participating. And it was a very helpful discussion.
Thank you, Joey. Always a pleasure to see you.
Thanks for your time, Joey. Appreciate it.
Thanks, everyone, for joining us on the webcast. Everyone, have a good day and a good rest of the conference.