Hey, good afternoon, everyone. My name is Jess Fye. I'm a senior biotech analyst at JP Morgan, and we're continuing the 40th Annual Healthcare Conference today with Stoke. I'm joined by the company's CEO, Ed Kaye, who's gonna give a presentation, and then we're gonna have a Q&A session after that. If you wanna ask a question during the Q&A session, just hit the blue button on your screen. That'll send me the questions, and I can ask management those questions for you. With that, let me turn it over to Ed.
Good morning, everyone. Jess, thank you for the introduction and allowing us to speak today. I'm Edward Kaye, CEO of Stoke Therapeutics. I will say that I will be making so me forward-looking statements, so please refer to our SEC documents for full disclosure. On page three, I tried to really describe what Stoke Therapeutics is. Simply put, it's an RNA company that is focused on making RNA medicines that upregulate protein expression. What we're focusing on right now is on our lead clinical program for Dravet syndrome, and this is for STK-001. What we're trying to do is make the first potential disease-modifying approach for this genetic epilepsy. Our next program is for autosomal dominant optic atrophy.
This program also is a severe genetic cause of blindness, and what we're trying to do is upregulate the missing protein for that disease. We're continuing to expand our pipeline, both by internal discoveries, and as you'll hear later in what many of you saw this morning, our collaboration with our new partner, Acadia Pharmaceuticals. Going on to slide four, our RNA approach is really called TANGO, and that really is targeting pre-messenger RNA splicing with the purpose to restore the target protein in the gene to back to normal levels. It is a disease-modifying approach, and what we aim to address is really the underlying genetic cause of a disease.
It has a broad therapeutic potential, and we have identified approximately 1,200 monogenic disease genes and have an additional 6,500 targets that have a TANGO signature. We are a clinical stage company, and we have an emerging pipeline. We have two phase I/II-A studies with our lead drug, STK-001, for Dravet syndrome, and we are in preclinical development for our second drug, STK-002, for autosomal dominant optic atrophy. Going to slide five, TANGO represents Targeted Augmentation of Nuclear Gene Output. What we are attempting to do is to really restore protein levels, but we're doing it in a slightly different way. We're targeting the functional and normal copy of a gene. Now, this has several advantages, especially over some of the therapies, such as gene therapy.
We can selectively boost expression only in those tissues and cells that normally express the protein. The concern for off-target toxicity is lessened. Also, unlike many other exon-skipping therapies, we use one drug for the disease that can be caused by many different mutations that result in the loss of function. We are not limited to the size of the gene because we're just simply bringing in an 18-mer ASO, and we can address any size gene, small or large targets. Going on to slide six, to try to explain what TANGO does, we have two cartoon figures. On the left is an example of just a normal copy of the gene. I think it's important to remember that these TANGO signatures are on all of us, so these are naturally occurring signatures.
What occurs is a, in this case, an NMD exon gets stuck on the pre-messenger RNA. Because it stays on that NMD exon, that mRNA is degraded and never becomes a protein. So we don't reach the full potential of the amount of protein that could be expressed from this gene. On the right, what you can see, when we add an ASO to this wild copy of the gene, we are forcing out and splicing out that NMD exon. That enables us to increase the amount of full-length messenger RNA and thereby increase the protein. What we're trying to do in all of our diseases, especially for the haploinsufficient diseases, is to take a 50% level protein and try to get it as close to 100% as we can. Going to slide seven.
Last year, 2021, was a year of execution for us. We were able to initiate our open label extension study for Dravet syndrome. We also initiated our multiple ascending dose study in the U.S., and that's the MONARCH study, and that was for, again, Dravet. In the third quarter, we reported our preliminary safety PK and CSF data for the single ascending dose portion of MONARCH. We opened up our U.K. study, which was the ADMIRAL study, that was a multiple ascending dose study, that complements what's being done in the U.S. We've also initiated our autosomal dominant optic atrophy natural history data collection. Finally, we identified our lead clinical candidate for the treatment of ADOA.
Going on to slide eight. For those of you not familiar with Dravet syndrome, it is a very severe progressive genetic epilepsy. It occurs at a frequency of about one out of 16,000. It is caused primarily by a haploinsufficiency of the SCN1A gene, which expresses the NaV1.1 protein. This disease is caused by a 50% reduction in the NaV1.1 protein, which is an essential protein for the sodium channel. This is a severe disease, not only because 90% of these patients have uncontrolled seizures despite being on numerous antiepileptics, but also 20% of children and adolescents with Dravet syndrome never survive till adulthood, mostly because of sudden unexpected death related to epilepsy. Going on to the next slide, on slide nine.
One of the challenges of this disease, which makes it so severe, is that it's not simply epilepsy. There are many other comorbidities that are not associated with epilepsy that are very significant. There is a progressive intellectual decline and developmental delay that occurs. There's problems with speech and language. There's significant problems with sleep and also a mood disorder. These non-seizure comorbidities are not being addressed by the current therapies. Our hope with our genetic therapy that we are approaching is to really try to take care of the seizures and also address some of these other comorbidities associated with Dravet syndrome.
Going to slide 10, what we can see is one of the ways that we try to understand how to measure these comorbidities is we began an observational study called the BUTTERFLY study. The purpose of this study was really, can we use the normal neurocognitive scales that are used for pediatrics in the Dravet population? What we found is that it was possible to use these scales and that they were reliable and reproducible. This is an example on the right of a Vineland Adaptive Behavior Scales. What we showed in this natural history study, looking at this composite of the adaptive behavior composite, is that beginning around two years of age, these children have a progressive decline in their intellectual abilities that continues through adolescence.
We could monitor and actually measure what that decline was going to be. We will use these particular tests for our phase III studies to not only measure the seizure activity, but to measure some of these other comorbidities. Going on to slide 11. What got us excited about Dravet syndrome and using this approach was really some of the early animal data, which you have seen before. This is an example of a Dravet mouse model, which recapitulates the human disease quite well. It's a very severe heterozygous mouse model. That red line, which you see in the Kaplan-Meier curve, is that about 80% of these mice will die, typically starting within weeks of life.
What you can see with the orange line, which is the mouse model that was treated with STK-001, we saw a near normal survival that approached the wild type and the control levels. Again, a dramatic improvement in survival with a single injection of STK-001. What we learned, and we'll see this on slide 12, is there was a number of things that really supported our advancing this into the clinic. We saw that a single dose of our drug restored NaV1.1 to near normal levels for greater than 3 three onths in the Dravet mouse model. We also, in addition to reducing mortality, we saw a very significant drop in the seizure frequency in these mice.
When we looked at non-human primate studies, we saw a broad distribution, biodistribution of our ASO throughout the brain, and it could increase NaV1.1 levels from two to three times above normal. Most importantly, it was well tolerated. We did this in single and multiple dose toxicology studies in the non-human primates. Taking this into the clinic, what we are currently on slide 13, we are in two phase I/II-A trials. Two trials are MONARCH, which is in the U.S., and ADMIRAL, that is in the U.K. These differ slightly. One, we are evaluating up to 45 mg in the U.S., but have the ability to go up to 70 mg in ADMIRAL study in the U.K.
The MONARCH is a SAD followed by a MAD study, whereas the ADMIRAL study is a MAD study. The primary endpoints are similar, as safety and tolerability for both. We are characterizing the pharmacokinetics and the cerebrospinal fluid drug exposure. An important secondary endpoint is really the change in seizure frequency in the overall clinical status and quality of life. Now going to some of the studies that we reported recently last month in the American Epilepsy Society on slide 14. Again, our primary endpoint was really to look at the safety and PK in these patients. We didn't expect much from low single dose injections in the patient population.
What we were able to record in this study is in fact, we did see, and we saw a 100% of the patients in the ages from two to 12 showed a reduction in seizures. Overall, 70% of the patients had a reduction in seizures. We did see that the greatest reduction was in the cohort from two to 12 years of age. This was somewhat expected on talking to our clinical advisors in that the longer the disease progression, very likely the longer it would take to reverse. I think an important aspect of this approach is this is not simply an anticonvulsant that's trying to treat the symptoms.
What we're trying to do is upregulate the NaV1.1 protein, and what is required is we really need to rewire the brain, the synaptic connections. Presumably, patients who have the disease for a longer period of time, it will take a longer period to reconnect some of those synaptic connections. What we also saw, moving to slide 15, is that the greatest response was between day 29 and day 84, where we saw overall with all the cohorts between a 17%-37% reduction. And again, the first month of treatment to day 29, we didn't see as dramatic reduction, and we believe that this is very likely related to the mechanism of action.
We know that it takes several weeks to get the NaV1.1 protein back up to near normal levels, and so you would expect that any response would have to be somewhat delayed, and this was confirmed in the clinical study. Going to slide 16. Another important lesson from this study was to understand the pharmacokinetics. What we found was that this was a very well-behaved molecule that correlated quite well with the PK model from animals. We had looked at certainly at rodents and at non-human primates. I think the take home message for this is that what we found is that we could predict what the brain levels would be in humans based on the CSF and the serum levels.
Our prediction for humans is that three doses of 30 mg given monthly should get greater than 95% of the patients into a pharmacologically active range. This was based on the animal models that we had seen. Our expectation is that we should begin to see some change in the clinical activity when patients are at this pharmacologically active dose. Now going to slide 17, just to summarize this phase I/II MONARCH data, the interim data. Single doses up to 30 mg and 20 mg doses up to three times were well tolerated, and we did not see any safety concerns related to the drug. The plasma CSF data from this study correlated well with our PK model, and appears likely to predict what the STK-001 brain levels will be in patients.
We did see a trend towards seizure reduction in Dravet patients who were treated. We expect that three monthly doses of 30 mg should predict that greater than 95% of the patients will have an active dose. We will plan on having the 30 mg data reported in the second half of this year. Now going to slide 18. Our next program is autosomal dominant optic atrophy, and this is a severe progressive optic nerve disorder. It has a frequency of about 1 out of 30,000 patients, which is very likely underdiagnosed, and we know that the majority of cases are caused by a mutation and a haploinsufficiency in the OPA1 gene, and this results in a deficiency of the OPA1 protein.
Right now this is an important disease because up to 50% of the patients are declared as legally blind, and we know that it begins typically 80% of the patients will begin to have symptoms in the first decade of life, and it continues to be progressive. Going to describe on slide 19 what the clinical syndrome of ADOA is. It really is again the most common inherited optic nerve disorder. It affects both central vision and also reduced color vision. In this example on the left is a healthy eye, but on the right it's a simulation of what happens to patients with an optic neuropathy. They have a very severe central scotoma. The most sensitive part of your vision is obscured in addition to the peripheral vision.
This is diagnosed when the pediatrician or the ophthalmologist looks at the back of the eye. What they see, instead of the normal yellow color, you see on the right in the ADOA patient, really this pallor of the optic nerve. Then this defect can be confirmed by genetic testing, and it shows the defect in the OPA1 gene. Going to the next slide, on slide 20. What happens when the OPA1 gene is deficient is that their retinal ganglion cells, which are the origin of the optic nerve, will gradually die. What's interesting in this disease is that all of the cells in the body, with these patients, are 50% deficient in the OPA1 gene, but only the retinal ganglion cells, for the most part, are affected.
The reason for this is these cells have the highest energy metabolism requirement in the body. When they do not have the OPA1 gene, this interferes with the structure of the mitochondria. It is necessary for cristae formation. It also interferes with the mitochondrial bioenergetics, the structure and the function of mitochondria. Eventually what happens is the cells run out of energy and will die. What we're hoping to do is to restore this balance by getting back that OPA1 protein back to near normal levels. Going and describing what we've been able to do on slide 21, we were able to demonstrate that in patient cells that were deficient in OPA1, these were from patients, we showed on the left an increase in the OPA1 protein.
More importantly, we show not only an increase in the protein, but we saw really an increase in the ATP-linked respiration, and which suggested that we could restore the function of not only the protein, but really what the protein does within these cells. Looking at the summary of our key preclinical data, we could see an increase in the OPA1 protein and ATP-linked respiration in the ADOA patient cells. We showed that there was a dose-dependent increase in the OPA1 protein expression in the rabbit retina, and very importantly, in this very sensitive animal model, following the single intravitreal injection, we did not see, you know, any significant safety concerns in these animals. Again, this program is progressing into the clinic.
We have identified our lead candidate. We're in the process of IND and CTA-enabling toxicology studies, which we hope to be completed by the end of this year. We're very pleased to announce this morning a very significant collaboration for us with Acadia Pharmaceuticals, and it really is to pursue RNA-based treatments for severe and rare genetic neurodevelopmental disorders. We've identified three targets, and we're working with Acadia. Acadia has received a worldwide license for Rett syndrome, MECP2, which they have a great deal of experience in, and also an undisclosed neurodevelopmental target. We have a 50/50 co-development and co-commercialization for SYNGAP1. In return, Stoke receives a $60 million upfront payment and also potential milestones up to over $900 million in addition to future royalties.
Just to describe Rett syndrome. Again, this is a severe neurodevelopmental disorder that has an incidence of about one in 10-15,000 girls. There are also males that may have this disease that could be amenable to our approach. It is caused by a deficiency of the MECP2 gene. What we're focused on is approximately one-third or 33% of the patients that have a hypomorphic mutation that we can upregulate in the MECP2 gene. What our purpose is is to use our ASO approach to increase protein production in these patients and restore some of the function of the mitochondria. Again, it's a severe disease, typically has this rapidly progressive period of decline, starts somewhere between 16-18 months.
In addition to epilepsy, which is significant, there are many other features and autistic features, and there is loss of purposeful hand movements, and there are many involuntary movements. Again, a very severe disorder. We are working with Acadia because of their vast experience in this disease and learning from them. The next indication is for SYNGAP1 syndrome, which is again a severe intellectual disability and a developmental and epileptic encephalopathy. The epileptic encephalopathy occurs at an incidence of about 1 in 100,000-200,000. However, what's been reported in all cases intellectual disability, SYNGAP1 has been found in 1%-2% of that population. Again, it is caused by a haploinsufficiency of the SYNGAP1 gene that results in a 50% reduction in the SynGAP protein.
In addition to preponderance of generalized epilepsy that occurs, 100% of these patients have intellectual and developmental delays, and about half of them will have behavioral or autistic-like features with this disease. This is just to represent our pipeline. We continue with our internal programs with Dravet and ADOA, and now we have three additional programs working with our partner from our Acadia Pharmaceuticals. Our strategy for 2022 is we really are focusing on advancing our Dravet syndrome program, the STK-001. We are looking for additional data on the 30 mg MAD patients, anticipated in the second half of this year. We will be also dosing at higher doses above 30 mg, both in MONARCH and ADMIRAL.
We continue to advance our ADOA program with our candidate STK-002. We will be conducting our preclinical toxicology studies. This will begin this year. We are also enrolling in prospective ADOA natural history study. We will be presenting further preclinical data this year at scientific venues. We continue to expand in our pipeline, and this is both internally and obviously we plan to execute on the collaboration with Acadia. We are fortunate to have a little over $220 million in cash and cash equivalents. With the $60 million upfront from Acadia, this allows us to really fund operations until the second half of 2024. With this, I will end my presentation and we will turn over to Q&A.
Thank you very much.
Great. Thanks Ed for that presentation. Just as a reminder for those of you watching, you can use the blue ask question button to send me questions for the management team as well. Maybe to start out on STK-001, what's your latest thinking on the potential therapeutic window? Is it your expectation that the 30 mg NaV dose could drive optimal exposure? Assuming you wanna ultimately achieve infrequent dosing, what higher dose might that exposure map to?
Well, maybe I can start, and Barry, our Chief Medical Officer, Barry Ticho, has been focused on this. You know, I think the 30 mg is what we expect to be able to get into a therapeutic dose. The purpose of the study really is to try to find the maximum tolerated dose. I think you bring up a very important point. We're not only interested in simply getting to a therapeutic level, but we'd like to also have as infrequent a dosing schedule as possible. That may require using higher doses. As you saw from the presentation, we have the ability, you know, to dose up to 70 mg in the U.K. One reason for that is to see can we get long-term exposure and also for ease of administration for patients. That's kind of what we're thinking. I'll refer to Barry.
I'll just add to that. We have done quite a bit of modeling based on our preclinical results that included results with a mouse model for Dravet syndrome. Using that, we were able to determine what clinical dose would be needed to ensure that all patients had levels of STK-001 in the brain that were pharmacologically optimal. That's how we got to the 30 mg multiple dose arm. Three doses of 30 mg, we project will allow for all patients to have the level of STK-001 in the brain that will allow for the twofold increase of NaV1.1, which is the sodium channel subunit that is deficient in these patients.
Oh, I think you're on mute, Jess.
Thank you. First time today. Thinking about the BUTTERFLY study, can you talk about how that could inform patterns of cognition and other non-seizure comorbidities in Dravet? Have you or do you plan to incorporate some of those learnings as you continue to advance STK-001? If so, how?
Yeah, I'll take that. Thanks for the question, Jess. The BUTTERFLY study, just to refresh everyone's memory, is a study of patients two to 18 years of age who have a mutation in the SCN1A gene and have ongoing seizures. This is the largest and longest prospective study of non-seizure comorbidities in patients with Dravet syndrome. As you mentioned, we are looking at some measures of cognition. What we have seen so far is that we've identified several assessments, including something called the Bayley Scales, as well as the Vineland scale, which seem to be appropriate for assessing some of these cognitive functions in patients with Dravet syndrome.
What we have shown is that with these two scales, we can demonstrate that patients with Dravet syndrome are severely affected in terms of their cognitive functioning, and they function far below the level of their age-matched peers. What we have been able to do now is using these assessments and showing that they are appropriate, we've been able to include these in our open-label extension study, which we're calling, in this case, the one in the U.S. is called SWALLOWTAIL. We also have one in the U.K. In that study, we are going to use these rigorous measures of cognition in these patients who are receiving STK-001 every four months. We've also included the Vineland measure in the ADMIRAL study, which is an ongoing study in the U.K., where patients are getting multiple doses.
In that case, those patients are receiving up to 70 mg of three doses of the drug.
You've talked about how we can look for this multiple ascending dose data, I think from both MONARCH and ADMIRAL in the back half of 2022. Is that correct?
Right. Correct.
Can we expect to see any of that open-label extension data in 2022? Is that approved?
Yes. Well, we're actively trying to get those data. Though we're not guiding exactly what will be able to be in that package, we're intending to include some of the data from the open-label extension study in that package for data release in the second half of the year.
Got it. There's a number of questions on the portal about the Acadia collaboration. This first one, how should we think about the timelines for the two Acadia programs?
Huw Nash is our Chief Business Officer and Chief Operating Officer, and he worked extensively on this collaboration agreement.
I think all three targets are preclinical, and I think we haven't provided any granularity really on timing other than to say that probably this year we won't be updating on those programs, and obviously maybe as early as next year we'd start to provide updates with our partner. At this point, we're not guiding towards any time to the clinic other than to say that we're in significant preclinical work on those programs.
Okay. You touched on this a little bit in the press release, but another question here is what's the split between you and Acadia on R&D spend?
Simply put, the two programs that are worldwide licenses, the MECP2 for Rett syndrome and the undisclosed third target for another neurodevelopmental disorder, those are going to be fully funded by Acadia. We will be doing the majority of the preclinical work for those targets and then handing it off to Acadia for clinical development, commercialization, but they will be funding all of that work. For the SYNGAP1 program, that's a 50/50 co-development, co-commercialization. It's a full cost share, profit share relationship, so they'll be paying 50%.
Okay. Another question coming in here. Can you tell us a bit about SYNGAP1 syndrome? Does the product candidate modulate splicing of the diseased gene to restore gene expression?
Barry, do you wanna take that?
Sure, I'll take that. SYNGAP1 is a, as the name implies, it's a critical protein that is present at the synapse between nerve cells. In patients who have SYNGAP1-related disease, they have a haploinsufficiency of this protein. Only half the normal amount is present on the surface of the nerve cells, and that impairs the function of nerve cells in the brain and in multiple different regions of the brain. The approach that we are using is very similar to what we're using for Dravet syndrome, where we are targeting a region of the mRNA to allow for increasing mRNA levels. This is done in a mechanism that's independent of the actual mutation that's present in the patient. There are several hundred mutations that have been identified that cause SYNGAP1-related disease, but we can use one oligonucleotide to increase the protein levels regardless of what the mutation type is.
Another question from the portal here. Does the Rett syndrome product candidate use the same playbook as STK-001 and STK-002?
I'm not sure what a playbook means. The Rett syndrome is somewhat more complex disease, both in terms of the biology as well as the symptoms, and that's a large part of why we are so pleased to have a partner like Acadia Pharmaceuticals to help us because they have a tremendous amount of experience in this disease. One part of the playbook is to titrate the amount of MECP2 protein that's increased. This is a protein that can affect transcriptional levels and is a splicing modulator, and it's well known that too much of MECP2 can cause disease as well.
It's going to be very important to be able to titrate the amount of increase, and that's what our technology is quite good at doing in terms of being able to have a dose response to the amount of medicine we give. That's an important part of the playbook. The other part is that MECP2 or Rett syndrome itself has a seizure component. That does overlap with some of the approach that we've had with Dravet syndrome. But there are other behavioral components that are different, and there is a composite measurement which our partners at Acadia Pharmaceuticals are quite expert in that is, it has been used to assess the effect of interventions there. That would be more likely a way to assess the effect of an oligo that we designed in that disease.
There are definitely similarities, similar pages in the playbook, but there are also differences which make us very happy to be able to have this partnership.
Maybe switching to STK-002. When could that enter the clinic, and what could a phase I trial design look like? I guess what are the main goals you would try to achieve in phase I?
You know, I can start out, Jess. You know, I think we've been very pleased. We've made some very good progress on this program. We've identified our lead candidate at the end of last year. We're in the process of starting IND-enabling studies now. We have had confirmation of what those studies will be. We expect to be able to complete those by the end of this year. Unless there's problems, we hope to be in the clinic for next year. You know, Barry has given a lot of thought about What the trial design could look like. Obviously, this is a slowly progressive vision abnormality. But there are some biomarkers and maybe, Barry, maybe you can talk about that.
Yeah. Again, the phase I study is still under consideration, but the idea would be to enroll patients who have ADOA, who have an identified OPA1 gene variant that's contributing to the disease and across a variety of ages, adults as well as pediatric patients. Of course, the main focus of the study would be to look at safety of these intravitreal injections, so an injection into the vitreous of the eye, and also assess the pharmacokinetics as we can measure the medicine in the blood. There are also quite a few different assessments that can be made for the progress of the disease.
We are embarking right now on a natural history study to assess some of these and know what the natural course of these assessments would be in patients so that we can apply that to phase I as well as to phase III study. These would include measures of visual acuity, which is a standard way of looking at the letters on a wall and looking at them at different contrast levels. There are also structural measures that can be done, especially using a measurement called OCT, that measures the thickness of the retinal layers, and we know that the retina thins out with this disease, so we can try to assess what the course of that is over time.
There are functional measures that can look at both the function of the retina, especially in terms of the electrical signals that are coming in the retina, but even to look at mitochondrial function. There are ways using a visualized but non-invasive technique to actually look at mitochondrial function in the retinal cell. A variety of assessments that we're going to be looking at, first in the natural history study and then hopefully to apply in phase I and phase III.
Okay. We've got one minute left, but can you tell us what the route of administration is for 002 and what the potential administration interval is?
The route of administration is intravitreal, so it's a needle that gets put into the vitreous of the eye. This has become a very standard now means of administration now because there are quite a few anti-VEGF therapies that are administered this way, and some patients get them administered even every month. Even newborn babies and babies who are premature are getting this sort of a treatment, so it is a relatively well-established treatment. We don't know the exact interval of administration, but given what we have seen in our preclinical models and what has been seen for antisense oligonucleotides with other programs, we anticipate perhaps every six months or potentially even every 12-month administration.
Okay, great. Well, we'll leave it there.