Okay. All right, everybody, we're going to get started with the next session. Thanks for joining us at the Global Healthcare Conference for Leerink 2025, which is pretty unbelievable. We're lucky to have Stoke Therapeutics and Ed Kaye, who's the CEO, Marc Goodman, one of the biopharma analysts. This has been one of our favorite ideas, and it still remains one of our favorite ideas. It's just, it's such an interesting story, and there's a lot to talk about. I want to start, Ed, maybe just give us the quick introduction to the drug, you know, kind of just go back, you know, a little bit and give us the beginning of it, right? How it's differentiated, you know, as an RNA-based approach, you know, just the technology, maybe even start there. That's probably a good place to start.
Yeah. Stoke is a company that started out as really an RNA medicines company. We started about 10 years ago. The concept was really, can you change RNA splicing to upregulate protein? The focus has been, you know, going after autosomal dominant diseases that have been difficult to target. It is kind of an elegant approach. What we've discovered, and this is really a homegrown technology that was completely developed at Stoke. Even though Isabel Aznarez, one of our scientific founders and who's head of research, some of the original ideas in RNA splicing did not work, the idea of skipping out what we call a poison exon. What we're doing there is, we're skipping out a nonproductive species and producing more functional RNA that results in functional protein. It is kind of an elegant approach.
What we're doing is, for Dravet syndrome, we're bathing the brain with our antisense oligonucleotides, and we're upregulating the protein. The nice feature about this approach is that it is very, even though it's a genetically targeted approach, it's very drug-like. What we can only upregulate in are those cells that normally have the gene of interest, the SCN1A and the NaV1.1 protein. We can dose it to get to the right amount. What we found is that we need a loading dose followed by a maintenance dose to really kind of saturate the brain and get the NaV1.1 protein to where it goes.
It is a very kind of elegant science that, and for us, what we were focused on, we liked Dravet because all of the medicines to date for all of the developmental epileptic encephalopathies and all anti-seizure medicines have only been focused on controlling seizures. If you look at a lot of the diseases like Dravet, it really is a much more complicated disease. It is a disorder where you have a lot of different symptoms and especially, you know, changes in cognition and behavior, gait, many, many, many symptoms. Everyone has been focused on reducing the seizures, which is of course the most obvious symptom. Nobody's addressed the rest of the disease symptoms. By addressing the underlying genetic cause, what we had hoped to do is to really treat the entire patient and all of the symptoms.
It was interesting that when we started talking about Dravet syndrome is when the American Epilepsy Society started realizing that, you know, 50% of all epilepsies are caused by genetic mutations. It's time to develop a genetic approach to treat epilepsy. We happen to be the first company that really decided to do that. It's been for us an exciting time. I think what we've, you know, appreciated is that we had a pretty good idea that we were going to have a pretty dramatic effect on seizures. We've seen an 80% reduction in seizures on top of all of the available medicine. Yeah. I think what's been interesting for us is that beginning somewhere between nine and 12 months, we see these improvements in cognition and behavior.
We're not only seeing it in the young children, we're seeing it in children who are 17, 18 years of age. Yeah. You know, now we're looking at the adult population because we think that's a population that could also be addressable. It's been, it's really been an exciting time for us. What I can say, it's not easy being the first. We had to learn a lot of things over the years, not the least of which is doing a natural history and finding out, well, what is the natural history for the cognition and behavior of this disease?
Yeah, I definitely want to get into all that. I think, look, I think your timing is right because I've been going to the epilepsy meetings for years. This past year, it was very noticeable that, you know, it's not about seizures, it's about what else are these drugs doing for the non-seizure help, you know? It's like, what else can we do? Functional, cognition, all these other things. It just feels like there's a lot of momentum in that area. I do think it makes sense. Tell us about your drug specifically and what's the hook to the product first. Then let's go back and talk about how you developed the different cohorts and where you got to with the data.
Yeah. I think when, you know, obviously when you have a new therapy and a new modality, there's a lot to learn. I think one of the things that we were able to pioneer is that we found that the Vineland III seemed to be a very good instrument to measure cognition and behavior. We did that by looking at the natural history study. Then we did it in our multiple ascending dose study. We realized that, you know, it does take some time, but you can see improvements. This was a good cognitive measure. It was interesting that when we had discussions with regulatory authorities in Japan, the U.S., and Europe, they all agreed that the Vineland III was a really good instrument. They did not give us any pushback that that was an interesting instrument.
I think one of the focus that we've had is that it's so important for us to have to demonstrate these improvements and to put it in the label because we really need to differentiate that we're not just simply an anti-seizure drug. We are a disease-modifying therapy.
Right. Clearly that's important. That's why we should be excited. When you first started down the path of the different cohorts, talk about, you know, what you were thinking at the time and kind of how we got there and get us to March of last year where you finally kind of got that Eureka moment where you figured out the dosing.
Right. I think, you know, one of the challenges in drug development, of course, when you have a novel therapy is you've got to figure out what the dose is. We knew that 30 mg would just get us into probably a pharmacologically active range. The question is, is that, well, how good does it have to be? What's the dose? I think we went through a number of dosing regimens. It turned out that what we needed was actually a loading dose. The loading dose of 70 mg turned out to be a very good dose. We had looked at two or three doses. We didn't see any difference between two or three, but we realized that we needed that 70 mg loading dose. That was important.
Not dissimilar to what Biogen recently had reported that they, you know, remember when they first had Spinraza, they were using a 12 mg dose and they had loading doses. Now what they're using is 250 mg loading doses followed by a 28 mg. What we figured out is that you had to give, you had to get a certain level in the brain to be effective. 270 mg doses get you there. 45 mg every four months is enough to maintain. What we had is about 150 different non-human primate studies that we had looked at. We had a very good idea of what the pharmacokinetics was like and how much drug correlates with an increase of doubling that protein. That correlated really nicely to what we saw with the humans.
There was a lot of work that we had to do to really understand how to use this drug. I think what we figured out was that this was the dose regimen that was effective. That's when we saw those dramatic changes in the seizures.
Talk about what the data was a year ago that you saw. I want to fast forward to the epilepsy meeting and, you know, the follow-up data that you had.
Yeah. You know, what we saw a year ago last March is we presented data and that was the 70 mg and 45 mg. What we were seeing was dramatic reductions in seizures. We were seeing 70% to 80% reduction in seizures.
How many patients?
We had, this was on 19 patients.
Nineteen patients. Seventy to 80% seizure reduction on nineteen.
Yeah. It was, you know, and then we continued to follow those patients. What we were seeing in the open label, as they moved over from an open label extension, by nine months we were seeing improvements in cognition and behavior. I think following up and what we had reported in the AES is we were seeing as patients rolled over from the multiple ascending dose, during that first year, they can, not only did they maintain, they maintained their reduction in seizures, but they continued to improve in cognition and behavior.
If you follow them out for an additional year, for two years, they continue to get better. What we were seeing is this continual improvement in cognition and behavior. We were seeing the maintenance of that 80% reduction in the seizure control. That was what, you know, what we were announcing back in the AES.
Let's go back to a year ago. We had 19 patients. We had this 70% to 80% lowering of seizures. Let's fast forward that and we'll come back to the other stuff. Fast forward to the end of the year and where were those seizure reductions?
Again, at the same level.
Same level.
We were same level. What we were seeing is, you know, continuing improvements in addition to what we had saw in the gains for cognition and behavior, what we were seeing is that it continued to improve.
Talk about what we saw a year ago in the cognition. Like what did we see back then?
Again, changes in the Vineland. At first, what we were seeing is that we were seeing changes in the patients who had received the 70 mg loading with the 45 mg. We saw that at nine months we were seeing improvements in cognition and behavior. We also saw patients after a year at a lower dose were showing improvements in cognition and behavior. What we showed just recently in December is we followed these patients for an additional year. We continued two years out. Now we continue to see even better improvements in cognition and behavior.
At the one-year point though, what were we seeing? Explain to people what the Vineland is so they understand what are the aspects of it that were critical.
The Vineland is really looking at a number of what we call domains. There are 11 different domains. We study eight because most of these children function at around a two-year-old level. Some of the domains, basically, they're not at a cognitive level that you can actually test. What we were seeing is things like, you know, expressive and receptive language and, you know, basically play and leisure. Basically a lot of behaviors, activities of daily living that show that these patients were continuing to grow.
It's functional.
It's a functional measure.
It's cognitive.
It's cognitive and functional and behavioral.
It's kind of all aspects.
Right. One of the things that I think what was really exciting about what we showed in December is we actually had Andreas Brunklaus had a patient that he had followed, a single patient, but he was showing these dramatic improvements in her ability to play soccer. You know, basically when she started before she at the baseline, she could barely, you know, kick the ball or dribble. She was actually able to play with her sister nine months later and was kicking the ball into, you know, the goal.
Is that the same one with the writing ability?
In the same one with the writing.
Yes. The same, you know.
It is not just one patient. What we are seeing and we have heard from a number of different investigators is that they have been basically following these patients, getting video recordings, and they are always talking about what are some of the improvements that we are seeing. Interesting, we had one of our, at J.P. Morgan, we had one of our investors and he said, you know, the reason why I came in your stock was I had a friend of mine whose son is in your trial. She said, you have to invest in this company. It is a miracle. He saw us.
That's great stories to hear.
That's right.
That's funny. Just to give us a sense, what were the improvements seen at one year versus two years? Just so we understand.
What we were seeing is.
Quantify a few of them.
Yeah. We were seeing a two to three improvement in many of these domains, which are considered, we've done the studies on this. They're considered clinically significant. In other words, meaningful both to the caregivers and also to the clinicians. We've done those studies to show, you know, not, yeah, statistically significant, but then the question, what does it mean? You know, okay, statistically significant, but is the patient better? What we've determined is in fact the improvements that we are seeing are considered significant for the patients and for the clinicians. In other words, they're, you know, an example of patients who hadn't been able to speak at all are now speaking. Patients who, for instance, you couldn't go on vacation.
We've heard families, you know, went to Disneyland for the first time because now the patient, either from a seizure control or from a behavior, they can go and they can do more. They can go to a restaurant. I mean, these are things that are, you know, look like small changes perhaps to you and I and our families, but are huge changes for these families. They're changing. Also things like, you know, not having to have someone accompanying them in school, you know, those kind of changes. We heard one, an example of, you know, a patient who was now helping cook at dinnertime. I mean, this was a patient who was not very functional, but now was helping the mother prepare dinner.
These are the kind of changes that we're, you know, we're hearing from the patient population. It's not just from, you know, a single patient. It's from all over the world that we're hearing this.
Let's talk about the phase 3 trial that you're literally about to start very soon. What is it going to look like? What are the expectations? What are the powering? You know, just give us a sense of the details behind it.
Sure. What I can say, it's going to be almost identical to what we did in phase 2. All right. If you think about failed trials, it's when you change endpoints, change your population, do all kinds of changes that you don't know and what to expect. I think we learned so much from the phase 2 that we decided, you know, the most positive likelihood of success was to recapitulate what we learned in the phase 2. We will be having, it'll be the same population, two to less than 18 years of age.
Say that again.
Two to less than 18 years of age.
Two to 18, right? Okay.
Yeah. It will be 150 patients. We will be using seizure reduction as a primary endpoint, both at 28 weeks and at 52 weeks. We will be having the Vineland III as a key secondary endpoint, both composite and looking at some of the individual domains.
The composite is all 11 domains.
It would be all eight of the ones that we're testing.
Oh, you're taking, okay. The FDA agreed that eight of the 11 were.
Were appropriate for the age.
Appropriate, relevant, right? Okay. We're going to do a composite of the eight and then we're going to.
We'll have key secondaries. Obviously it depends on the geography. For instance, the FDA often likes to look at the composite. Many of these things are going to also be a review issue when they look at it. They also look at the individual domains, whereas in other regions of the world, they're more interested in some of the hierarchy of the domains. What we've done is, what's interesting is that the things that we saw the greatest change on are like expressive and receptive language, which are the areas that were considered most important to the families and the clinicians.
Right. How does the FDA look at, for instance, that if the composite were not to be statistically significant, however you hit on several really important domains, like how does the FDA look at that?
Yeah. I mean, one of the things is that, you know, obviously the famous saying that the FDA always says, it's a review issue.
Yeah.
Which means they'll look at the data at the time and make a decision. I would say we've powered the study for the seizures at a 0.01 level and it's greater than 90% power. We've overpowered it. The reason is we wanted to make sure that we would reach statistical significance with the key secondary. That was very, very important. You know, I think we feel very confident that the seizure endpoint will hit. The key secondaries are typically at a 0.05 level, not quite the same level of rigor because there's a lot more flexibility, but again, you know, we can't necessarily predict, you know, what the FDA or the regulatory authorities, but there is more, let's just say there's more flexibility.
Your interactions with the FDA lead you to believe that if a few of these domains were to hit and the composite were not to hit, that's still positive. They would look upon that positively.
Yeah. Again, it's going to be a review issue. You know, they'll never promise you anything.
I'm not saying you to promise. I'm just saying like.
I would say.
What interactions are there?
The interactions, what I would say, what was very helpful, I think one of the things that came across very forcefully, I think from the FDA is they saw the importance of the, including the key secondary endpoints in the label. They basically said, we want you to make sure, we want to help you to make sure that these are in your label because this will differentiate and this means it's a disease modifying therapy. When we received breakthrough therapy, all, you know, what it said is that for the treatment of Dravet syndrome, right? All other drugs that are on the market, anti-seizure medicines are for the treatment of seizures in Dravet. The FDA recognized that this was really a differentiator.
This was important and we're treating obviously the entire patient and making sure that we're, you know, or all of the symptoms are actually getting better. So they're very concerned. We've had a lot of help. We have breakthrough therapy. We'll be having many meetings with the FDA. You know, they've reviewed the protocol. We've submitted it. I would say it's, you know, and even globally, I think there's been a lot of uniformity and agreement that this is a reasonable trial. Very little pushback from the authorities globally.
What are these patients on as far as standard of care drugs in the phase 2 and what will they be on in the phase 3?
It'll be identical. One of the things that we're seeing is that these patients are coming from epilepsy centers of excellence. They're well treated. 50% of the population was already on fenfluramine, which is really considered the best anti-seizure medicine for Dravet syndrome. Typically, you know, over 80% were on three or more, you know, and some of the patients were on as many as five or six different anticonvulsants.
They will be on treatment. Again, remember it'll be a one-year study. Obviously, we, you know, we need to make sure that the patients who are on the sham control, they're going to continue to receive therapy. We'll see that on top. The expectation is that what we saw is that the treatment, and we're not seeing huge differences in different geographies. Europe is using very similar medicines as the US and the same thing in Japan. It is pretty even.
The phase 2 was run where though? It was run in the U.S.
That was run in the U.S. and in the U.K.
Right. Okay. I got it. I guess just thinking about maximizing success, minimizing placebo, making sure the phase 3 works, obviously making it as identical to the phase 2 as possible. What are some of the things that we should be thinking about that you're doing to minimize the placebo effect?
Yeah. One of the things that we have an advantage on is if you think about a placebo, a placebo effect is typically early in the course of the clinical trial. People can't maintain a placebo effect for months upon months. If we look at the previous studies that have been done in Dravet syndrome, there was anywhere from a 5% to 25% placebo effect. These studies were three to four months at maximum. We're doing a one-year study. I think the likelihood that we will have a placebo effect that lasts for a year would be very, very unusual. Despite that though, we've chosen a 25% placebo effect and we've powered the study at 90% to make sure that even if we would see a 25% placebo effect, we would see a significant difference.
Wow. 25%.
Yeah.
That's actually pretty.
Yeah. Our expectation is it's going to be, it's going to be certainly overpowered.
Right, right, right. Interesting. The anticipation here is that, okay, we get seizure reductions of 70%, whatever it is on top of standard of care. We check the box for the primary endpoint. We start to show the Vineland, if it's not the full composite, we get many of the domains that work, the key domains that everybody cares about, and we can get that on label. You think that would be enough in every jurisdiction basically to get a Dravet syndrome?
Yes. I think that would be, and that what we've heard from the regulatory authorities that that would be. I think the other aspect of what we're trying to make sure that we achieve is not only do we have to have registration, we have to have reimbursement. As probably most people know, reimbursement is actually harder than even registration. Having it in the label is one thing.
What we, and Jason Hoitt, who's in the room with us as our Chief Commercial Officer, we've had discussions with payers globally and asked, what do we need to show to get this reimbursed as a disease- modifying therapy as opposed to an anti-seizure medicine? They've been very clear that we need to demonstrate the cognition and behavior. They said, you know, in essence, you know, if you show that, you know, we'll be forced to pay it. I mean, because it is life- altering for these patients and disease modifying.
Give people a sense of how we should be kind of thinking about pricing.
Obviously we haven't set the price because we don't have the results of the phase 3 and we don't have the label. I think, you know, if you think about this, this is again, not an anti-seizure medicine. This is disease modifying. You need to kind of anchor that price into disease modifying therapies. You know, people have used the example of Spinraza.
Wouldn't that be a good one?
That certainly would be one, but there's certainly others. It is an intrathecal therapy that is really changing the natural history of the disease. Obviously that brings much more value than just simply another anti-seizure medicine.
Yeah. Yeah. That drug, just for everybody's sake, is $700?
Yeah. It's around 750 in the first year.
What's it like, 500 in year two? I'm just trying to.
Yes. Around that.
Yeah. Okay. Good. Just to make sure everybody understands. Pretty good pricing. That is with Dravet syndrome. I guess, is there a situation where you lower seizures by 70%, whatever it is, and we are just not seeing the Vineland kind of move? What happens there? Can we get approved as a seizure reduction drug and, you know, it would be a, you would launch it as a seizure reduction? I am just trying to think about that scenario.
Yeah. That's an interesting scenario. I think though, if we, when we think about this as just simply an anti-seizure medication.
Seizure medicine is pretty good.
It's very good.
We have anything that does that well. That is why I'm asking the question.
Yeah. I think that's good. I think our baseline assumption has always been that we would show an improvement in the other aspects of the disease. Again, if you think about it, we're not just simply like treating the electrical activity in the brain to control the seizures. What we're doing is changing the underlying genetic cause.
What we know is that there's a lot of neurons, not just inhibitory interneurons that are involved in seizure control, but many other neurons that are involved in cognition and behavior and gait that are so critical that I think since we are correcting that and we've demonstrated in a number of different animal models, not only in the murine models of the disease, but also in non-human primates, we can show that we can upregulate that protein in all the critical cells. Our baseline assumption is this should work to treat the entire disease. That's how we've always planned it. So far all the data is confirming that.
Okay. Okay. Let's talk about the Biogen deal, which just a couple of weeks ago. What was your mindset kind of going into that? How competitive was it and why you chose Biogen? Also after that, give people a sense of what the deal was.
Yeah. The first step we had to make is do we want to have a rest of world partner? I think based on my experience, because I had spent 10 years at Genzyme, and thinking back, it took us about 15 years to have a really significant global footprint for the rare disease. You know, if you think about a lot of companies that have built out their own for the first drug, Bluebird is a good example of a medicines company. They did not do very well in the rest of world. It is challenging. We know also that after registration in a lot of regions, especially in Europe, it takes two to three years before you get reimbursement.
Having a partner like Biogen, who has enormous experience in rare disease, intrathecal therapy, they were very successful with Spinraza. There were 71 different countries. Our feeling was that they could do it faster than we could. The main objective was, can we make sure we get medicine to everybody as quickly as possible? We had to admit that having a partner like Biogen would do it faster. It was a very competitive process. We had a number of companies that were very interested in. It came down to, we thought that Biogen was probably the best partner for us. It made sense given their experience. You know, the other thing that was really important with this deal was it gave us, we had focused really on the upfront. We had $165 million upfront with the deal.
We had a developmental milestone that was pretty significant. We had the cost sharing. That allowed us to have a runway to mid 2028. That gets us through the readout, gets us well into preparation for commercialization. That was a real value for us too. It was not only the commercial partnering, but it was also the capital that infused in us. Again, non-dilutive, obviously from that perspective. At the time, it was a very good deal, I thought for us. The other thing is that we really did not give up a lot of the economics because, you know, we have certainly milestones for sales, but also we have significant royalties, you know, double digit going up to the high teens. We think that milestones that are very reasonable that we could reach with Biogen.
The cash position with that payment that they're doing is what now?
Mid 2028.
No, but how much is the cash position total?
Oh, the cash position?
Yeah.
Yeah. $400 million.
Over $400 million.
Yeah.
So, and.
The check cleared, by the way.
I'm glad to know their check cleared. I wasn't that worried about them, but you know.
I was.
That's funny. Excellent. Excellent. Just in the last, you know, 30 seconds, what have we not hit? What do you want to kind of, you know, just anything that we didn't?
Yeah. I mean, I think one of the things, you know, everyone's been obviously focused on Dravet as our first indication. I think, you know, what it suggests with the data that we have is that this platform is really clinically credentialed. We are very excited about some of our other programs. We have a very interesting program in autosomal dominant optic atrophy to upregulate the OPA1 gene and protein. That is a key structural and functional element in mitochondria. We are looking at this for one of the leading genetic causes of optic atrophy, but there is the potential to use in other diseases of the eye and even of the central nervous system to upregulate ATP, which is kind of exciting.
We have a lot of programs with our other partner, Acadia, in Rett and SYNGAP1 and another program that we're making some significant progress in. SYNGAP1 is very, very, very similar to what we saw with Dravet, almost an identical disease. All the lessons learned from Dravet, we hope to bring that to it. I think stay tuned for a lot of other indications that I think we're going to be doing.
Excellent. Thank you.
Thank you, Marc.
Thanks for joining us.
Appreciate it.
Appreciate it.
Yeah.
All right.
All right.