Ovid Therapeutics Inc. (OVID) Earnings Call Transcript & Summary

Good afternoon, ladies and gentlemen. Thank you for standing by and welcome to the Ovid Therapeutics webinar. [Operator Instructions] It is now my pleasure to turn the call over to Dr. Jeremy Levin, Chairman and CEO of Ovid Therapeutics. Please go ahead.

Thank you, Jonathan. Hello, everyone. Thank you for joining us today. As we promised, we would provide an information day on 935. And before I start into that, this is in fact -- I'd like you please to take note of the forward-looking statements. And obviously, as a public company, these are important. Today's talk will be given by a number of different people. I would like to just say we made a promise to the investment committee that we would educate you as much as possible about 935. And to do that today, we've lined up the best possible array of people that we could in this short period of time so that for a short period of time, you'll have the chance to ask questions of them and get a much deeper appreciation of what we're accomplishing. So let me briefly introduce them to you so that each one will, in turn, introduce themselves and give you a better appreciation for their expertise and understanding, some you know, a couple you may not know. On the hand -- on one hand, we will have Amit Rakhit, who's the President and Chief Medical Officer, who many of you have met in the past. Then we'll have Jason Tardio. Jason is our Chief Commercial Officer, and has been brought on to prepare us for what we hope will be the launch of OV101 and then 935, subsequently. So we're delighted to have him here today. In addition to which, we've got Scott Demarest. Scott is a world-renowned geneticist and neurologist, who focuses on association of -- between epilepsies and genetic background to them, in particular, the phenotypes of those genetics -- of those disorders. Certainly, he'll introduce a greater depth of what his research interests are shortly as well. And finally, Julia Tsai. Julia joins us from Marinus, having a very long and extensive career understanding rare epilepsy. So let me walk through the agenda with you for a minute now. What we'll do essentially is give you -- I'll going to -- I will give you a quick picture of Ovid and describe to you how we're going to focus today and the areas that we are going to focus. Then we're going to walk through with Amit on the -- we'll give you an overview of 935. Jason will then provide an important discussion around why this area matters and what the opportunity is within it. At that stage, it's terribly important for us to convey to you our understanding, and hopefully, we'll provide for you an understanding of how patients with these disorders are treated and what the -- what is required from a medical perspective. Following that, Julia will dive into soticlestat in the rare epilepsy. And finally, we'll have a wrap-up and fireside chat, giving you the chance to listen to some of the thinking that's gone into this particular program. Next slide, please. I want to remind you that Ovid Therapeutics is focused now since 2014 on working in the area of rare neurological disorders. We've got a very clear mission. We know exactly what we're doing. And this year is a very special year for us. This is the year with much of what we've been attempting to do is now coming to fruition. So this particular teach-in is a great pleasure for us to do. And we do this against the backdrop of a pipeline, which has expanded significantly over the years and has been successful to date. On that 1 hand, as you know, we've got late-stage compounds, which are in OV101 in the -- in Angelman's and Fragile X, and then 935, which is focused on the rare epilepsies. But I want to point out that these late-stage programs, which is -- we will talk today only on 935. These late-stage programs have progressed and have given us the confidence for us now to begin to think about our future. In order to do that, we are bolstering our preclinical pipeline that in several years' time, once, hopefully, we've launched the drugs that we have in OV101 and 935, if they are successful, we will then have the opportunity to build out new products, hopefully, with the intent to be the leader in rare neurological disorders. That having been said, let me walk you through some of the things that we've accomplished this year and intend to accomplish in the years to come. Next slide, please. First of all, there are multiple clinical data readouts across the late-stage pipeline. We've already reported positive results in ROCKET, and that's OV101 in Fragile X. And later this year, we will deliver on NEPTUNE, where we have our pivotal trial Phase III in Angelman's. We're very excited by that and looking forward to that data. However, today, let me focus on the 3 areas that's pertinent to this discussion, which is the rare epilepsies. We have 3 important readouts this year. One, ELEKTRA, as you know, we'll discuss that. This finished enrollment at the end of last year, and we're delighted that we have accomplished that. We are right on time. We'll see the data, which will be expected in Q3, just as we said we would. And then to -- we have now -- we had initial data on rare epilepsies. And that data was delivered in March. This is very encouraging. These are the rare and ultra-rare conditions where a small number of patients and participants in a trial can inform you on what needs and what can happen and what could be done. As a consequence of that, we've now accrued additional patients in ARCADE, and we're pleased to say that we're going to bring forward the readout on that, which data expected now on Q3, and not in the first quarter of 2021. So we're excited to see those data, and we're looking forward to it. Julia will talk more about both the ELEKTRA and ARCADE trials. And then finally, we also had the ENDYMION trial. Now the ENDYMION trial is open-label extension. This is the opportunity for those who've been on our treatment of 935 to participate and to continue to participate taking the medicine if they so choose. And we'll talk a little bit about that. And indeed, there have been patients which are close to 2 years on these drugs, and we will be delivering the results on that in the Q3 of this year. So a very data-rich period for us in 935, making this tutorial, this teaching, very important for you. If you're interested in this area, we hope when you leave this discussion today, you'll have a terrific appreciation of why we are excited, why Takeda is excited in -- with 935. And let me just tell you a little bit about the relationship between Ovid and Takeda. This is an intimate relationship. It is formed in a very unusual alliance. Takeda discovered the molecule 935. They then partnered with us in a 50-50 agreement where we share all the cost of development. And indeed, we -- Ovid directs development at this stage, and we are responsible for all of the commercialization in North America and Europe and Israel. What's important about this is that this is an intimate partnership. Takeda is a superb partner. They've worked hand-in-hand with us. They've participated in many decisions with us, and as we advance this program, their confidence and ours have jointly helped us think carefully about how we drive this particular molecule to the highest degree of success. So what's interesting about it further is that this molecule is just beginning its journey. We know that it's got many different areas that it could eventually go into given its mechanism. However, the most promising near term are clearly the developmental epilepsy can catalog with these. These are very important. However, we've structured the agreement such that either party can indeed participate and think through another area, if they so wish. And then if one party has not participated in it, you can buy in at a cost-plus transaction to take -- to regain your position in that particular program. Takeda is actually looking at this right now, this particular molecule, in complex regional pain syndrome. We're looking forward to that program progressing. And if the -- overall, I think you can take away from what I'm saying to you, that the Takeda relationship is one which is profound, strong and by sharing our costs, leverages our ability to develop a very promising molecule. So with that in hand, I'd now like to ask my colleague, Amit Rakhit, to take over and to give you an in-depth look at the program, followed by Julia and then Scott.

Thanks, Jeremy. And welcome, everybody. Thanks for joining us today. Just briefly, as I know many of you, as President and Chief Medical Officer of Ovid Therapeutics, I've been in the rare disease space for more than 20 years. First in congenital heart disease when I was in practice at Boston Children's Hospital. And then kind of the highlight was leading the Spinraza development program at Biogen before joining Ovid to lead the -- oversee the rare disease portfolio in neurology that we have today. So I'm very excited to share with you more about soticlestat. So soticlestat is -- has a very unique mechanism of action. And what we've developed is a very broad program in developmental and epileptic encephalopathy. And as you may be aware, the dEEs or developmental epileptic encephalopathies are several conditions that are characterized by severe refractory seizure activity in epilepsy, very refractory to treatment, which has a huge impact on overall neurodevelopment of an individual affected by one of these conditions. And there is a combination of both neurodevelopmental delays as well as severe refractory epilepsy. Many of these conditions are rare or ultra-rare and have few or no treatment options available to them. So the unmet need here is very high. Soticlestat, as Jeremy mentioned, we have in development in partnership with Takeda. And this is actually part of Takeda research activities and discovery that brought this compound to where it is today initially. Initially, this is a novel cholesterol 24-hydroxylase inhibitor. So this enzyme, cholesterol 24-hydroxylase, is uniquely found in the central nervous system, specifically in the brain and it's the mechanism by which cholesterol is metabolized to a more water soluble form, 24-hydroxycholesterol, so that it can pass out of the blood-brain barrier. Cholesterol, as you know, is very integral part of cell membrane. And so the turnover in brain tissue of cholesterol is very low, anywhere from -- at 0.3% to 0.5%, you'll see in the literature, because it's an integral part of cell membrane and specifically myelin sheaths that cover the axon for conduction. So the level of cholesterol that turns over in the brain is fairly low. But the by-product of this enzyme, 24-hydroxycholesterol, appears to have multiple effects, one of which I'll show you in a subsequent slide looking at modulating the NMDA receptor, where we believe this is where the action of soticlestat is indirectly, but to decrease epileptic activity. Soticlestat has a long history of preclinical development, initially studied in the APP/PS1 mouse model, which is the mouse model many people use to study Alzheimer's initially. And it was found here that in this mouse model that -- typical mouse model with APP/PS1 tends to die from SUDEP or sudden death due to epilepsy. And given soticlestat, these mice actually live longer. And by a further evaluation of this model, it appeared that seizure activity was decreasing. So seizure activity has been shown to decrease in the APP/PS1 model and subsequent animal models, including the Fring's audiogenic seizure model, including the SGN1A, which is the Dravet mouse model also showed activity with soticlestat in decreasing seizure activity, which then led us to the clinical program that we have today. So previously, we have disclosed the data from the adult study. This is the first clinical program with soticlestat, which was in adults with several types of dEE. And in that study, we showed a progressive decrease in seizure activity over time, both at an acute level as well as with chronic administration. We also have initiated the long-term extension study, ENDYMION, where we are looking at open-label study to look at overall seizure reduction over time as well as generating additional information on safety and tolerability. The initial data from ARCADE, which was presented in March, was in a different type of dEE. And these were the CDKL5 deficiency disorder and Dup15q Syndrome. Again, we saw a progressive decrease in activity and interesting findings, which we'll go through a little bit more detail in subsequent slides when Julia presents the data from that readout. I'll just mention that with dEE, about 50% of dEE is covered by the Dravet syndrome and Lennox-Gastaut syndrome. Another 50% of dEE is there are several conditions, about 20 or so, which are rare or ultra-rare. And CDD and Dup15q represent 2 of those conditions that make up that other 50% of the broad spectrum of dEE illness. So looking ahead, what do we have to see with this program? Overall, we have a fairly robust and comprehensive clinical development program in dEE. As I mentioned, we're looking at the overall broad Dravet syndrome, Lennox-Gastaut, which is about 50% of that population. And then we're also looking at more rare conditions, CDKL5 deficiency disorder being an ultra-rare condition and Dup15q as part of the other 50% of dEE in this clinical development program. The ELEKTRA study is the first randomized, double-blind study for soticlestat for Dravet syndrome and Lennox-Gastaut. And this data is expected in Q3 of this year. We announced earlier that this program had been accelerated because we didn't expect this data to come forward until next year. And so due to a very high interest as well as operations for this program, this study accelerated and is completely enrolled and is on track to deliver data in Q3 of this year. The ARCADE study, we had an initial data look in March. As you may recall, this is an open-label study. It's exploratory, looking for signals in the CDD and Dup15q. CDD being ultra-rare and Dup15q being rare. This is ongoing. We -- based on the data that we had in March, and then with the ongoing recruitment since March, which we'll show you in a little bit, we are now in a position to have confidence in what the next steps will be with the development program, so have completed enrollment in ARCADE, which is new guidance and we'll provide the final data expected in third quarter of this year. The ENDYMION study, which is our open-label extension study, we had an initial cut of data. The initial cut only included patients who had enrolled in the adult study or the ARCADE study. We had left anybody who was in ELEKTRA and rolled over into ENDYMION out of that initial data readout because we were -- we didn't want to unblind the study prematurely. But with the next ENDYMION cut, we will have all of that data being presented, including those patients who have rolled over from ELEKTRA. And to date, all patients completing ARCADE and ELEKTRA have opted to roll into the ENDYMION program, and we're very happy to see that. This is a long-term extension study and we'll show you more details about that study design in Julia's presentation. And again, I think one interesting piece about this overall soticlestat program is that we have a potential biomarker. It's not often that you have a biomarker in any type of therapy, particularly in neurology. But because, as I mentioned before, the inhibitor -- this inhibitor, soticlestat, acts on the cholesterol 24-hydroxylase enzyme, which is uniquely found in the brain tissue. However, because the metabolite 24-hydroxycholesterol passes through the blood-brain barrier, we can measure 24-hydroxycholesterol in the plasma, so with a blood test. And so this is a very unique way of understanding what the activity is of the enzyme, how much in addition you're receiving and could pave the way for potentially individualized dosing regimen, if needed, as we develop this biomarker further. Looking at the next slide, I'll just take you through overall the development program and how it's actually studied. But before I do that, I'll just give you a little bit more detail about what the enzyme actually does. This is a graphical depiction of soticlestat in the brain. So cholesterol gets -- is converted to 24-hydroxycholesterol, as shown on the right side of this graph, by the enzyme cholesterol 24-hydroxylase. Soticlestat inhibits this enzyme. So there is belief that 24HC modulates NMDA activity. And this has been shown in preclinical models where reduction in 24HC levels caused the reduction in glutamatergic signaling and thereby decreasing epileptic activity. In a poster that we actually presented in 2018 at the European epilepsy meeting, we showed also that decreasing this activity in epilepsy also has other functions with soticlestat looking to modulate glial cell function as well as astrocyte functions. And so given those aspects, there is potential role here for neuroprotection as well as antiepileptogenic activity. So not only could this be anti-ictal from a seizure perspective, but longer term there is a potential for changing the overall dynamics of the seizure circuit so that this program is looking at how soticlestat can potentially, in individuals with dEE, also be potentially antiepileptogenic, and that's more to come on that. So overall, we see that the effect with soticlestat has the potential to reduce seizure activity, but also beyond that, has potential to have more disease effects as well. So with that, we'll -- I'll just move on to the next slide, which is the overall strategy for the program. When you look at the development path for dEE, there are 2 buckets of studies that you see here, ARCADE, which is our Phase II open-label study. As I mentioned, this is -- has completed enrollment. Just 20 patients have been enrolled in this study, looking at Dup15q syndrome or CDKL5 deficiency disorder. Again, this data will be coming out in the third quarter. In the ELEKTRA study, which is our double-blind, placebo-controlled trial in Dravet syndrome and Lennox-Gastaut, this also is completely enrolled with 141 subjects enrolled and also on track for data readout in Q3 of this year. The ENDYMION study, all patients from ARCADE and ELEKTRA had enrolled into ENDYMION. And we will then have additional information and the data cut from ENDYMION, also in Q3 of this year. So a fairly busy third quarter for us with the soticlestat program and then informing next steps in development. So with that, I'm going to turn over to the next slide and introduce Jason Tardio. Jason is our Chief Commercial Officer; and has come to us from experiences at Biogen, where we interacted while at Biogen, and then he went on to Novartis to lead a broad team with multiple sclerosis franchise. And he's going to give us a bit more insight about his background as well as why we're in this space and the market opportunity that's in front of us. Jason?

Great. Thank you, Amit, and thanks to everyone for joining us today. Just a little bit about my background since I have not had the opportunity to engage with most of you during my short tenure here at Ovid so far. I joined Ovid Therapeutics 7 months ago with the responsibility of helping the organization pivot from a clinical -- development clinical R&D organization into a fully-integrated biopharmaceutical organization with commercialized assets. As Amit mentioned, most recently, prior to Ovid, I was at Novartis, where I was in charge of leading the multiple sclerosis business in the United States. And prior to that, I spent over 10 years at Biogen in a variety of different general management and leadership roles. And so I'm truly excited to be at Ovid. I'm truly excited to bring these important therapies to individuals living with these rare neurological conditions. So the goal of my presentation today is just provide you a high-level overview of how we think about the market and the market opportunity for soticlestat. And on this first slide, Amit referenced some of the points, but I think it's important to reiterate the differences of dEEs or developmental and epileptic encephalopathy versus general epilepsies, and of course, why we believe there's unmet need. So epilepsy, we know, is one of the most common neurological illnesses, affecting over 50 million people worldwide. But developmental and epileptic encephalopathies are rare. This is, as Amit mentioned, a group of rare clinically heterogeneous severe epileptic conditions that account for only approximately 3% to 6% of total epilepsies. dEEs are characterized by frequent, often debilitating seizures, significant developmental deficits, including cognitive, visual, verbal and ambulation impairments, and can be associated with elevated mortality risk. Now the goals of treatment for dEEs are to suppress and control the seizures, but also to prevent and/or reverse neurological loss of function, improve the patient's clinical prognosis, improve the patient's quality of life, and if possible, modify the underlying disease. And while there's over 20 antiepileptic therapies currently approved in major markets, very few of these therapies are indicated specifically for developmental and epileptic encephalopathies. Furthermore, and I think most important, the data supports that individuals living with dEEs do not achieve durable response to existing therapies with upwards of 80% of patients requiring 2 or more therapies to manage their disease. So given this, there remains a huge unmet need for new therapeutic interventions that have unique mechanism of action, that have strong and durable efficacy profiles and that have safety and tolerability profiles that help to balance what patients, caregivers and physicians are looking for. Next slide, please. So the disease burden of dEEs on all stakeholders is significant. And the impact of these severe epileptic conditions goes beyond just the patient. For example, data supports that caregivers of individuals with dEEs experienced significant burdens. Due to the need for 24-hour, 7-day a week around-the-clock care of their loved ones living with these conditions, this leads to abnormal and inefficient sleep, higher degrees of depression and anxiety, often times due to the fear of potential sudden and unexpected death of their loved one living with these dEEs and also just the concerns about their inability to communicate directly with their loved one and their children. Caring for dEE child also affects the entire family, including relationships between the parents and siblings, and the siblings often experience sadness. They have worry and stress about their siblings with dEEs. And they find that it negatively impacts the relationships with friends, leisure time and even school attendance. The impact of dEEs also affects physicians and health care providers who struggle with the inability to control these patient seizures and to positively impact the patient's quality of life. And from a payer perspective, dEEs had a significant impact on the overall health care system. We know that the treatment of dEE patients are associated with substantial health care resource utilization related to the need of utilization of things like wheelchairs and walkers. Certainly, epilepsy-related inpatient admissions and outpatient visits, home health care services and a high burden related to the polypharmacy I mentioned earlier as these patients often require 2, 3 or even more antiepileptic therapies to manage through the disease. Next slide, please. So we've talked a little bit about the impact of dEE. We've talked about the impact and the high unmet need for new therapies. But the market opportunity, we believe, is fairly large. What you see here highlighted on this slide is third-party market research which supports that there could be upwards of 180,000 individuals in the U.S. and EU5 markets living with Lennox-Gastaut and Dravet syndrome and CDKL5 deficiency disorder along with Dup15q syndrome. And of those 180,000 potential individuals, we believe that there's approximately 100,000 that are currently diagnosed. But as you see highlighted on this slide, and as mentioned earlier, recent market research conducted by ourselves and Takeda support that 80% of these patients living with Lennox-Gastaut, Dravet, CDKL5 and Dup15q are not managed on their current therapies, and they require moving to later line therapies. It's within these second and third-line therapies that we believe soticlestat is going to compete with the likes of EPIDIOLEX and Fintepla, if approved in the future. And as highlighted on this slide here, you'll notice that, that opportunity today in the markets that we have commercialization rights, again, the U.S. and Europe, we believe that there's probably 80,000 patients today that could benefit from a therapy like soticlestat. Next slide, please. And the market itself is transforming. As you can see highlighted on the left-hand side of this slide, the epilepsy market globally is shifting. And it's shifting from a market that was primarily 50% generic as recent as 2013 to a market that we believe is going to be approximately 85% branded product in 2024. Furthermore, as diagnosis rates increase, and we have the ability to better identify these patients suffering from these rare developmental and epileptic encephalopathies, we believe the market is going to grow in our respective indications to a total of 115,000 potentially diagnosed patients in the U.S. and EU5 in calendar year 2030, and if these 115,000 potential patients, that lead to a market opportunity of $3 billion-plus within this very difficult-to-treat category. So in summary, there remains high unmet needs specifically within very difficult-to-treat refractory dEE patient populations. The current therapies, though there's a vast number of them, are not optimal in their ability to control seizure activity, and 80% of these patients require step up to additional second and third-line therapy. We believe soticlestat could potentially have a unique MOA, as Amit mentioned. And based on the data, we believe soticlestat could have a solid efficacy profile, balanced with good safety and tolerability. And therefore, we're excited about the opportunity to have a positive impact on the lives of these patients living with dEE. Thank you for your time. I will now pass the baton to Dr. Scott Demarest. Dr. Demarest is the Assistant Professor of Pediatric Neurology at the University of Colorado, and is an expert in treating dEE patients. So his insights will certainly prove very beneficial today. So Dr. Demarest, the floor is yours. Thank you.

Thanks so much, Jason. As I was kindly introduced, this is really my wheelhouse, the developmental and epileptic encephalopathies. I'm a pediatrician, neurologist, and epileptologist. I specifically focus my clinical practice as well as my research endeavors really within the developmental and epileptic encephalopathies and specifically genetic causes of these conditions. With past and ongoing research in several of these specific conditions, as well as I happen to be the principal investigator for the international CDKL5 clinical research network, which includes 9 different institutions at this point across the world. Next slide, please. So this is really an opportunity for me to give background about these conditions rather than just speak specifically to soticlestat. These are, as mentioned previously, heterogeneous group of disorders, but they have several common features. Specifically, the epilepsy is really challenging to treat. While we have numerous medications that are currently available, these patients really fall into the refractory category, which means that despite antiseizure medication, they continue to have ongoing seizures. As part of this, this increases their risk for SUDEP, sudden unexplained death in epilepsy, and other causes of premature death for these patients. In addition to the epilepsy, these conditions have a range of other comorbid problems. This includes their developmental issues, and that really covers the range of different developmental features, including language, mobility, learning as well as a variety of other neurologic domains, sleep, their ability to regulate other organ systems, which may cause other comorbid features such as GI issues or pulmonary issues. Typically, these conditions all begin in early childhood. That could either be really from the first days or weeks of life through to the toddlerhood age range and persist throughout life, making these lifelong disorders. Next slide, please. This slide gives a nice overview of the prevalence of these different conditions that we're discussing today. And you can see that while they are rare, as you combine these deficient -- these different disorders together, they become less rare. And important to address from a public health standpoint, from the standpoint of being able to improve treatment options. You can also see that there are a whole slew of clinical manifestations that are mentioned here for each of these disorders. The ones in the green, Dravet and Lennox-Gastaut syndrome, are somewhat more common than those in blue, but really have still a slew of different clinical manifestations that have to be addressed when treating these patients. In the blue, these are even more rare disorders, but they also have just as much complexity in terms of their care, requiring not only neurologic expertise, but also multiple other conditions or specialists, rather. You can also see that in terms of FDA approval, there's really limited options for these disorders, specifically. Over the last 30 years within the epilepsy community, we've gone from about 3 drugs that existed to now closer to 30. And despite that, the proportion of overall epilepsy patients that remain refractory to treatment, and that would be defined as having tried and not been able to achieve seizure freedom with 2 medications, hasn't changed. So about 1/3 of patients remain refractory to treatment. And all of these syndromes and conditions listed on this slide fall into that category. The vast majority of these patients do not obtain seizure freedom for any extended period of time more than, say, weeks or potentially months. And so you're stuck in the cycle of trying numerous medications to see if you can get some benefit. We do this through a couple of mechanisms. Next slide. So traditionally speaking, we are looking at treating epilepsy with some basic concepts, and we target these essential mechanisms as outlined here. More or less these fall into 2 categories. You have the brake and you have the gas in the brain. So what I mean by that is that everything in the brain falls into a balance between excitation and inhibition, and that's the gas or the break. And those 2 things have to be in balance. If you get too much excitation or not enough break, then you get uncontrolled excessive activity in the brain, which essentially results in seizures. GABA system, as noted on the bottom left, is the break; the glutamate system is the gas. And so the medications that have been designed or brought to market so far are really designed to interact on these systems and either increase the amount of break and sort of tamp down brain activity or to reduce the amount of gas, the glutamate system, so that you can bring that balance back in patients with epilepsy. But as I mentioned, despite these several different mechanisms by which we attempt to treat epilepsy, many patients go uncontrolled, and we fail to be able to achieve seizure freedom. Seizure freedom is really important in terms of being able to impact quality of life and being able to move the bar for these patients from living with epilepsy to not. Next slide, please. Wanted to share a little bit about what this looks like from a patient journey perspective and really be a bit of their voice here today. And I'm going to ask you to sort of imagine this, you being in their shoes here. So I'll be interacting with parents who have young children. Again, these are either infants or toddlers when all of this starts. And they start having these abnormal movements. Sometimes they're not immediately recognized as being seizures. And then once they are, there's a challenge of trying to control them and what needs to happen from there. These children will begin to demonstrate that their developmental trajectory is not keeping up with other children of their age, which is obviously highly concerning for parents. All of this combines to being truly terrifying experience for parents. They are looking at a beautiful baby that has very serious problems with impacts on the future of their life. And they are really struggling to try to deal with those myriad issues. As physicians, we end up making numerous recommendations for various tests, MRIs, EEGs, genetic testing, and at the same time, we're recommending treatment options. This primarily focuses on seizure treatment, both in the early stages of these diseases, but also throughout life. Because it's one of the few things that we actually have drugs that we can attempt to influence that aspect of their disease. The parents are dealing with all of this in a time that is full of uncertainty about their future and they're trying to educate themselves about what their child has and what they're dealing with. And I'm going to read a quote from a parent directly here on the next slide that I think sums up what this experience is like for families. "We didn't get around seizure meds until she was about 2 months old, at which point, we were told by numerous doctors that soon, as we would get the seizures under control, she'll progress normally." And they mean there progress in terms of development. "That was another level of grief. It was a new level of grief because, yes, we wanted the seizures to stop. We needed the seizures to stop. We did everything in our physical power to stop those seizures. Some of that medications that were so potent for this little tiny body that it broke my heart." And I think this quote is really powerful because it talks about how central of a role epilepsy plays for these patients and how much pressure there is to try to control these seizures, when the reality is that we know that for these 4 conditions we're discussing today, controlling seizures is one of the hardest things that we try to face as physicians and parents for these kiddos. On the next slide, I explore a little bit about what this ends up looking like in reality. What we face with seizure medications for these patients is ultimately trial and error. There are several medications that are listed that may be approved for a specific disorder such as Dravet syndrome or Lennox-Gastaut with no treatments being specifically outlined as of yet for Dup15q or CDD. But despite that, the processes ends up being one of trial and error. We often are picking the medication based on the side effect profile and the chance of success. There's discussions with family about what is more terrifying to them, the seizures or the effects of the medications. And there are no perfect answers in existence right now. So this continues to be an ongoing struggle as we navigate this space alongside parents. In addition, there's all the other impacts in lives that have been mentioned today as well. That includes physical and occupational therapy to try to maximize development for these kids, as well as adaptive devices, individualized education plans for these kiddos, as well as specialists that are needed to provide these children the best chance they can in terms of development. All of those things come together in a cyclic process of trying to make an adjustment, see what the impact is, make an additional adjustment. And I often tell my patients that as part of this, they end up in a clinical trial of one where we are constantly trying to make adjustments for that specific patient's need in an ongoing and editor fashion. Part of the reason that we still deal with this type of challenge is because the treatment options remain limited for these patients, and we are often having to make a difficult decision between controlling seizures and side effects of medications because we don't have the arsenal that we really need in order to be able to address these issues. And with that, I'm going to turn it back over to Julia Tsai now to discuss soticlestat more specifically for the rare dEEs.

Great. Thank you, Scott. Before I go through my section, a little bit more about my background. I've been in the epilepsy field for about the last 15 years. Most recently, I was at Marinus Pharmaceuticals as their Vice President of Clinical Development for Epilepsy, where I led programs in both orphan and nonorphan indications, the most relevant being the first pivotal study in CDKL5 deficiency disorder. I'm very happy to be joining Ovid and more excited about soticlestat's potential in treating seizures and rare dEEs. With that, I'll kick off my section, which will walk you through the different clinic studies with soticlestat and orient you to what data will be available at the third quarter data readout, and what this means with respect to next steps for soticlestat development for rare epilepsy. Okay? Next slide, please. As previously mentioned, I think Amit mentioned that soticlestat has been through a battery of preclinical seizure models demonstrating anticonvulsant activity. It's been tested in a mouse model of Dravet syndrome. And this model mimics several features of DS, including spontaneous generalized tonic-clonic seizure or also known as convulsive seizures, which is a major seizure type in Dravet. These mice also experience sudden death. And with Dravet syndrome, it's associated with a 15% to 20% mortality rate in children younger than 18 years of age due to SUDEP or sudden unexpected death in epilepsy. So then these mice were treated with soticlestat. They showed a statistically significant increase in seizure freedom. And so what this means is that soticlestat increased the threshold for the hyperthermia-induced seizures, reducing overall seizure susceptibility. And in addition to anticonvulsant activity, soticlestat treatment also increased the survival rate of these transgenic mice. Overall, soticlestat has the potential to treat 2 core features of DS, the convulsive seizures as well as the higher probability of sudden death. Encouraged by these results, next slide, a Phase Ia/IIb clinical study in adult dEE mutations was conducted. This was a 12-week adjunctive study in which oral soticlestat was added on top of standard of care of at least 1 anti-seizure medication. There are 2 parts to this study, Part A, with a double-blind randomized placebo-controlled study evaluating safety and tolerability; followed by Part B, which was a 60-day open-label treatment phase to evaluate soticlestat's effect on seizures. Overall, the study enrolled 18 adult patients with various dEE study -- dEE indications, next slide, including 6 with LGS. And again, these are very highly refractory patients. So this means that the seizures remain uncontrolled despite trying at least 2 anticonvulsant drugs and they were also an at least 1 concomitant anti-seizure medication. Despite that, patients had to have at least 1 bilateral motor seizure in the 4-week prospective baseline to qualify. With respect to safety and tolerability, the study met its primary endpoint showing that soticlestat was safe and generally well-tolerated in this patient population. The majority of the AEs were adverse events, were mild in severity, and there were no trends in clinical laboratories, ECGs or vitals. With respect to seizure control, soticlestat treatment resulted in a 61% median seizure reduction compared to baseline at the end of treatment in 11 patients who completed the study and were not on concomitant perampanel. 2 of these 11 patients actually became seizure free during the last 28 days of the treatment. Overall, this study showed that soticlestat was well tolerated and generally based in the patient population with various dEEs. This also was the first clinical study to show soticlestat's potential as an anticonvulsive therapy in a highly refractory dEE population. Patients completing the adult dEE study had the opportunity to continue to pick up that treatment in the open-label ENDYMION study, which looked at long-term safety as well as efficacy. These patients enrolled in this study for at least -- they're now open up to 4 years or they'll be receiving study drug until it is available for purchase. So the only condition for enrollment into ENDYMION was that the patient had to complete a previous soticlestat study and then continue to show benefit from treatment. Next slide. There was about a 6 weeks to a 1-year gap between the completion of the adult dEE study and when the ENDYMION study was available. So out of the initial 11 completers, only 6 adult dEE patients roll over to ENDYMION. In addition, these 6 patients were already off of soticlestat for some period of time during this gap, and so they actually had to be retitrated up on soticlestat once they entered ENDYMION. So as you can see to the bar on the left, these 6 patients had overall a 59% reduction in seizure frequency during the last 28 days of the adult dEE study. And then when they entered ENDYMION, they actually had to be retitrated up further from week 1 to 12. These patients actually regained seizure control and showed a median seizure reduction of at least 48% in seizure frequency and continued to show a time-dependent seizure control over time with 4 patients reaching 90% seizure reduction in the last portion of the treatment period. There is, as you can see, a drop between 6 to 4 in the end -- in the numbers towards the end, but that wasn't because these patients dropped out. It is actually because our 2 patients have enough time to complete the interval share. With respect to safety, soticlestat continue to remain fairly safe and well tolerated. The majority of the adverse events considered mild in severity with nausea being the only drug-related adverse event during this long term treatment, thus far. So overall, the long-term ENDYMION study continue to show favorable safety profile with long-term durability of effect. Okay. Next slide. Highly encouraged by the adult dEE study and the long-term durability of effect, a small open-label Phase II study in 2 ultra-rare highly refractory patients was conducted in CDD in Dup15q. This was a multicenter study, will be recruited only here in the U.S. in which a soticlestat BID is being evaluated in both pediatric and adult patients. So we are allowing patients with a minimum age of 2 years with confirmed diagnosis of CDD or Dup15q syndrome into the study. Again, these are highly refractory patients with uncontrolled seizures, so they've had to have failed at least 2 anti-seizure medications and currently taking a stable dose of at least 1 concomitant anti-seizure medication and still exhibit 3 motor seizures in the 4 to 6 weeks prospective baseline period. Similar to other seizure studies, the primary efficacy endpoint is the percent change in 28-day motor seizure frequency during the maintenance period compared to baseline. Why motor seizure frequency? Well, these are actually the easiest seizure types to be identified, reliably counted and the most impactful as abated. Other secondary efficacy endpoints include the traditional responder rate, which is the proportion of patients with at least 50% reduction in seizure frequency compared to baseline. We will also have insight into the Clinical Global Impression of Change as deemed by the investigator, who will take into account both therapeutic efficacy as well as treatment-related adverse event. We will also solicit feedback from the caregiver themselves, where the caregiver will also give an overall impression of change during soticlestat treatment compared to no treatment at all. In addition to some safety endpoints, we will also look at exploratory endpoints, specifically nonseizure endpoints. We'll be looking at insight into changes in behavior and adaptive functioning in domains such as communication, daily living, socialization, irritability. So in addition to anticonvulsant activity, we will also look for signals outside of seizures. Next slide. As mentioned earlier, there was a release of preliminary results in ARCADE. There was data for 11 patients, 6 on Dup15q and 5 from CDD. The majority of these patients were white female patients with a median age of 12 years of age. Again, these were highly refractory seizure patients with the majority of them on 3 or more concomitant antiseizure medication. With respect to safety, soticlestat was generally safe and well tolerated and consistent with the previous adult dEE study. The majority of the adverse events were mild in severity and consistent with this patient population. There were no negative trends in safety in labs and ECGs and vitals. And so it is very well tolerated and fairly safe. With respect to efficacy in the CDD cohort, you saw a meaningful reduction in a variety of motor seizures. The most common in the CDD population were generalized tonic-chronic seizures and the very hard-to-treat epileptic spasm. And the Dup15q cohort, this is for variable seizure control in both motor and non-motor seizures, and we did see individual improvement. Overall, we were very encouraged by the trends in efficacy and safety and tolerability profile in the CDD and Dup15q cohort from the preliminary data. So much so that, next slide, that we have now declared the end of enrollment or completion of enrollment in ARCADE. So what does this mean? We currently have 20 patients enrolled in ARCADE, we'll have 12 patients in the CDD cohort and 8 patients in the Dup15q. This is nearly doubling the sample size that we had from the preliminary readout. So we're going from 5 in the preliminary readout for CDD to a total of 12, and we're adding additional 2 patients from the Dup15q cohort. And if all remaining patients continue to see the same trends that we saw in March, there is sufficient data to make a development decision for CDD and Dup15q. In addition to the primary efficacy endpoint of a change in median seizure frequency compared to baseline, we will also have a responder rate data available in third quarter as well as insights on the clinical meaningfulness of the soticlestat treatment as assessed by both the investigator as well as the caregiver. We will also have insights into other benefits outside of seizure control including improvements in behavior, communication, attention. Again, these are collected from caregiver exit surveys on the impact of soticlestat treatment on daily life and functioning. Because of the small number of patients in these ultra-rare and highly refractory dEE, there is regulatory precedence in advancing a single pivotal study with an open-label safety and efficacy data from small Phase II studies. So we feel that the final third quarter readout from ARCADE will be sufficient to move soticlestat to a pivotal Phase III discussions with regulatory authorities. Next slide. Another major milestone for soticlestat is a much anticipated data readout for the double-blind randomized placebo-controlled trial in pediatric patients with DS or LGS. There is much excitement around this study and the study as Amit mentioned, enrolled ahead of schedule and the reporting or the data will be ahead of schedule as well. The study was a global study and, ultimately, randomized 141 pediatric patients aged 2 to 17 months of age with a clinical diagnosis with DS or LGS. Again, these are very highly refractory patients who had failed at least 2 anti-seizure medications currently taking at least 1 anti-seizure medication but still exhibiting 3 convulsive seizures for Dravet syndrome or 4 drop seizures for the LGS during the 4 to 6 week prospective baseline period. Patients were randomized at a 1:1 ratio and titrated up to 300 milligrams BID with soticlestat or placebo over an 8-week titration and dose-optimization period, followed by 12 weeks of maintenance. For kids weighing less than 60 kilograms, they were dosed on a mg per kg dosing schedule. Patients completing this study had the option to then enter into the long-term open-label ENDYMION study. For those who didn't complete the study or choose not to roll over ENDYMION will be down-titrated from the study drug and then have a safety follow-up after deescalation. Next slide. In terms of efficacy endpoints, the primary efficacy endpoint is consistent with other DS and LGS study. This is the percent change from baseline in 28-day seizure frequency in convulsive seizures for DS and drop seizures for LGS during the 12-week maintenance period for soticlestat versus placebo. In terms of secondary efficacy endpoint, we will also have the responder rate or the proportion of patients with each of the defined responder rate intervals in each respective DS or LGS stratum. In addition, we will also have investigator reported Clinical Global Impression of Change again take into consideration efficacy and tolerability. We will also solicit feedback from the caregiver themselves, again also can take into consideration efficacy and tolerability. In addition to the safety and tolerability of adjunctive soticlestat treatment. We will also have insights into some non-seizure benefits, such as sleep, changes in behavior, mood and quality of life. There's also a potential of using 24HC as a biomarker versus soticlestat treatment. As promised, this data is on track for the third quarter 2020 readout. This data will provide sufficient information to advance soticlestat into Phase III pivotal studies in DS and LGS. Next study. Again, there's multiple readouts in the third quarter that will determine soticlestat development and regulatory pathway. To summarize, there's a much anticipated data readout from the double-blind placebo-controlled ELEKTRA study, which involve DS and LGS patient data from the proof-of-concept Phase II open-label study in ultra-rare CDD and Dup15q in which there's already regulatory precedent to use open-label safety and efficacy data to launch into a single pivotal study in ultra-rare dEE. We will also have long-term safety and efficacy data from ENDYMION that will support the durability effect. As mentioned, we will have data from the 6 adult patients from dEE who have treatment for almost 2 years. We will also have long-term safety and efficacy data from adult and pediatric patients rolling over from the ELEKTRA and ARCADE study. Again, we're highly encouraged that all these patients who completed their respective parent studies have elected to roll over into the long-term ENDYMION study. The data readouts in all 3 study will set soticlestat's regulatory and development pathway in dEE in the second half of this year. So with that, I hand it back to Amit.

Great. Thanks, Julia. So just to recap, this is a slide that was presented earlier. We have a real robust program with soticlestat. Given this unique mechanism of action, given the strong preclinical information as well as the data that we have to-date with the clinical programs and looking forward to multiple data readouts in Q3 of this year from a double-blind study, ELEKTRA in Dravet and Lennox-Gastaut, the ARCADE study in CDD and Dup15q as well as the open-label long-term ENDYMION study. All this together really puts us in a position that we can make development decisions moving forward into Phase III programs given once we have the data in hand for this program. So we're really looking forward to the next steps for soticlestat in this very difficult-to-treat high unmet need area of dEE. And with that, I do want to just move now into the fireside chat as well as the Q&A. And I'll actually invite Scott and Julia back online with us. And before we go to the lines, I'll just kick off with Scott.

Scott, I think you gave a great overview of the patient journey and the difficulties in treating people with the various developmental and epileptic encephalopathy conditions. Dravet and Lennox-Gastaut are areas that some people are more aware of than CDD and Dup15q. But overall, they all -- all the individuals who have these conditions seem to follow a similar treatment journey. Could you speak a little bit more about the refractory nature of the patient population? How they cycle through the existing drugs that are out there? And what happens that they need to change treatments so frequently or often, so start with just giving us a perspective about that?

Sure, Amit. I can actually provide sort of specific data that we have related to CDKL5 for this CDD. We know that the vast majority of patients try more than 10 medications over the course of their life. We know that the majority of patients are on 2 to 4 seizure medications at any one point in time. And out of 100 patients, we may only have 1 or 2 that actually achieve seizure freedom for any prolonged period of time. So what we're really doing is constantly trying to improve on seizure control bit by bit, knowing that seizure freedom may not be possible. But if we can make seizures less frequent, less severe or less disruptive to overall quality of life, then that's a big success for this patient population. So as a result, we are making a change, looking for an effect of that change. Do the side effects cause problems? Do the seizures get any better? After we try that, for what may be months or maybe years, depending on how well that works, we then are making another change to try to improve, again, even a little bit better and this result in the statistics that I mentioned, where there's a huge number of medications that are tried over the course of these kids' lifetime and there's a high number of seizures that are being used -- seizure medications that are being used at any one point in time.

Yes, that's great. And maybe could you dive into a little bit, what drives some of that treatment decision that you mentioned? And there's a period of time that people will be on a therapy. And then there is a decision point whether you change the therapy, you add a therapy, you end the therapy, what drives some of those decisions as you're looking -- working with individuals who have these conditions?

Sure. So the overall decision-making is really about those 2 sides of the coin. What are the side effects of the medication? And what is the efficacy or how well does the medicine work? And unfortunately, there's not a way of knowing that often for these conditions before we try the actual medication. So the most immediate change may be if a medicine is not tolerated. So if there are side effects, that's usually the fastest cause to make a change, which would happen as soon as there are unreasonable side effects from a medication. The longer-term [indiscernible] harder piece is often, how well is it working? One of the things that's important about epilepsy is that it's unpredictable. Seizure frequency fluctuates over time and it's often somewhat challenging to figure out, well we made this change, is that what's caused this change in the child? Or has something else happened? They got stick at that time. They went into summer break and their family dynamics changed or their sleep pattern or any number of other things that might. And so we often end up trying to sort of ride out some of the small fluctuation and look at overall trend on a particular medication for a particular patient. Ultimately, if a patient is still having seizures and they are causing a significant disruption to that child's life, and what I mean by that is that some very short, smaller seizures that aren't particularly frequent may have a minimal impact on overall quality of life. And sometimes families choose to accept those rather than to continue to cycle or try to find new medications. But the vast majority of the patients are still having debilitating seizures on a frequent basis. And we have to try to make a change in order to find a better overall treatment strategy for that patient.

Yes. And it seems that, that continues to be a very high unmet need in terms of being able to treat the seizure activities, but still having refractory kind of seizures occurring. As you mentioned, people just decide to live with it. What do you see as the kind of highest unmet need now in the rare epilepsy treatment field given some of the older compounds that are out there as well as some of the newer ones, what's kind of the unmet need still that needs to be looked at?

Yes. I would say that the biggest unmet need is still finding compounds that are going to meet that balance more appropriately. The -- some of the medications that are most effective also had the least tolerability in terms of side effect profile. We sometimes sort of tongue in cheek discuss with families that we can stop any 1 seizure. But if we had to put you in an ICU with a coma, then that's not really a great trade-off. And I think that's part of the trade-off that we're having to deal with in epilepsy, is really [indiscernible] side effects to some medications that can actually control seizures versus other medications that may be better tolerated, but do not do a very good job controlling seizures. And so anything that increases our armamentarium of compounds that are able to find few side effects and improve seizure control, that's going to be a win for these communities.

That's great. Maybe 1 last question before we go to the line. Based on what you've seen thus far with soticlestat and the program that we have in terms of the data as well as what's coming, what are you most excited for about soticlestat? And what -- how do you see soticlestat in the treatment options for rare epilepsy?

Yes. So I think there's some that's still to be seen as we move towards the pivotal trials in some of these conditions, and I'm excited to see what those results look like. The early data presented is encouraging in terms of side effects, which is great. And I think that's going to increase the likelihood that a provider will try a medication. Side effects actually often influence parent decisions and thoughts about a medicine more than how much it works unless it works really, really well. So it's encouraging to see that overall, it might be better tolerated, which will encourage its use. And I'm anxiously awaiting the data in terms of how well it works, that will help us to be able to figure out where in that order, this medicine is going to fall. I think of particular interest to me, because I've spent a great deal of my time dealing with CDKL5, CDD that is, is that there aren't any specific medications for this condition at this point in time as is also true for Dup15q. And I think it would be very exciting to have something specifically indicated for the disorders that we know has data that supports it, if that's the way that these trials work out as we go forward.

That's great. Yes. I'm looking forward to the data in Q3. Well, thanks, Scott, for sharing those insights. I think we'll go to the lines now. I think there are some questions out there for us. So I'll turn to the operator to go with the first question.

[Operator Instructions] Our first question comes from the line of Charles Duncan from Cantor Fitzgerald.

Really nice update on ENDYMION and some of the other progress, could be a transformational year. I had a question, though, for the KOL, Dr. Demarest. I'm wondering if you could provide us a little bit more color on some of your answers to Amit what he just asked you with regard to interest in 935 or soticlestat. Are you most interested in the differentiated mechanism of action and impact on seizure control that could be or perhaps, neuroprotection? Or is it just an additional drug in your treatment armamentarium? What really compels you on this candidate?

Yes. I think it's interesting, and it may not end up being the same for all of these conditions. That's what the data will really show us. But I think, first, it would be a win if it was another drug in the armamentarium. Second, if it actually does demonstrate that there's some of these broader impacts, as you mentioned, that's really quite exciting. For CDKL5 deficiency disorder specifically, there is some mechanistic information that might suggest that this actually plays into the way that this disease manifest in terms of the glutamatergic system as was outlined a little bit. And so that's potentially exciting. And I think that if that works out that way, then that would be great for CDKL5. What that also might mean is that if there's that sort of mechanistic effect, then we might see some of these impacts such as seizure control, as Julia mentioned, and that would be really exciting. So controlling seizures is great, and I will absolutely take it because it's hard to control seizures in these kids. If we actually see that there's some impact on other aspects of their quality of life or their development, for example, that would just be a bonus as far as I'm concerned. That would be really exciting.

And then if you can -- thank you for the...

I'm sorry, Charles, I was going to add to that. I was going to add to that, Charles, that, that's part of the reason that we're also looking at OV935. For example, Takeda is looking at this in chronic regional pain syndrome. We looked at it in kind of this broader potential impact beyond seizures itself. And I think we're excited about at least from a preclinical and know more about what the effects are. That's why we're looking at some of these other measures in the trials as well, going beyond seizure.

That's helpful, Amit. I appreciate the added color. I was going to ask Dr. Demarest if considering these mechanistic differences from recent and potentially emerging branded drugs such as Epidiolex and Fintepla, where would you see -- I mean, assuming something about, call it, efficacy, which I know is probably a little premature to do. But where would you see this drug fitting within the treatment paradigm, for example, for especially LGS or Dravet patients?

Sure. I think as you could tell, for LGS and Dravet patients, there's a little bit more other medications in the field. And so that does become somewhat of a decision that you're adjusting with each family individually. We discussed the side effects and the efficacy together, to try to determine which medication is going to be appropriate for them. Some families are highly risk-adverse in terms of the side effect profile. So I think a medication with a good side effect profile tends to find its way to earlier treatment in patients. Because something like felbamate, for example, that can be highly effective in Lennox-Gastaut syndrome, but can cause death from liver failure, it's something that families like to avoid. So I think it will be interesting to see what that data shows in terms of that balance in efficacy and side effects. But again, if side effects are well minimal or well tolerated, then that's going to tend to move a medicine up earlier in the list of options?

Helpful. Last quick question regarding the potential use of a biomarker to gauge, I guess, response criteria. Would you be excited about 24-Hydroxycholesterol being available as a clinically useful biomarker? Or do you just see it as a nice to have that helps you kind of understand what's going on within the clinical trial setting?

Yes. Scott, if you want to talk about maybe the biomarkers and then -- and potential biomarker for 24HC using that other trial biomarker [Technical Difficulty]

Yes. I think anytime you have a biomarker that suggests whether something is going to be tolerated or more effective that's going to be very helpful, right? Because right now, as I mentioned earlier, we're really dealing with a trial and error process for treating epilepsy. So anything that gives greater precision to that to allow us to [ supply ] our patients that are going to be optimal is going to improve the way we use that treatment option and make sure that we're able to get it to the patients that are going to benefit the most.

Very well. Thanks, Scott. I think, in the interest of time, we got to move on, but happy to address anything offline as well. So we'll move on to the next question.

Certainly, our next question comes from the line of Tim Lugo from William Blair.

Maybe going back a bit to 24HC, how close of a correlation is there in the kind of seizure decline seen at week 1 to 12 in ENDYMION and maybe later time periods? And also, just a follow-up as well. Could you capture any neurocognitive data at baseline and, therefore, maybe we can see some potential for improvements as patients are on therapy longer, at least maybe in the younger patients?

Yes. I think, I'll answer that. So in terms of the 24HC levels what we have right now is basically a much data from the adult data, right? So if you look at the adult data in the part A with the titration effect going from placebo versus treatment arms, [ for 7 arms ], the you saw over time and I decreased the level of the 24HC from baseline to almost 80% to 90% decreased levels. While in the placebo arm, transition over to the open-label section, Part B, you saw that same decrease in 24HC levels in the plasma over the similar treatment period. So that's the best data we have right now. For ENDYMION, we also see decrease in levels. I think cognitive studies were collecting that information. But in -- at least in the historical adult study and what we have, anywhere above a 60% reduction in that level looks to be about 60% to 80% inhibition. And that's where you're seeing seizure frequency reduction. You see further see seizure frequency reduction with even more decrease like up to -- even if you go up to 99% inhibition that is like getting kind of [indiscernible] like adverse events. So that sweet spot is probably somewhere around about 50% to 85%, but can be calculated individually. We'll have more of that information as some of these new data come out?

All right. And so neurocognitive benefit, is that something that we should expect?

So we are collecting kind of a secondary endpoint difference of behavioral and assessment skills and development, the BABS. For example, the Vineland Scale, which is indirect measurement of some of these cognitive functions. Some of these cognitive studies take much longer, as you know, but we'll have some of that information from the current studies that are coming out in Q3, but that's something that's in the area that we'll further explore for the effect beyond seizure alone.

Okay. And maybe broader, when you go and discuss with the agency about a dEE type of label indication, how -- can you just maybe talk how the agency has been viewing dEEs historically versus maybe how that's moved over time? Obviously, some of the other therapies have kind of been shaving off certainties and moving forward for those niche indications. But especially when we see Dup15q with really no standard of care versus Dravet, which is, obviously, more active, how should we think of that?

Yes. So I think it's one of a longer-term strategy perspective. I'll just mention this also from a regulatory perspective. Typically, to have a class labeling of some sort of like a broad bucket like dEE, you need to show effect, similar effect across multiple disease areas that are part of that bucket. That's it. So if you look at Dravet, Lennox-Gastaut as part of dEE, CDKL5, Dup15q. Once you have information in multiple disease areas, that's when you can start having a further discussion about dEE as a label indication, but it's a much longer-term strategy. So you start with individual and then you kind of move towards a broader label ultimately. And yes, thanks for the question. So I think we're going to move to the next question just as there's several people on waiting. And we can always follow-up afterwards as well.

Certainly. Our next question comes from the line of Ritu Baral from Cowen.

I'm going to limit myself to 2 here. One, I guess, Dr. Demarest, you mentioned something interesting about the mechanism of soticlestat being particularly effective in CDKL5. And it looks like some of the CD -- CDD data looks pretty compelling. Can you elaborate on sort of that mechanism of benefit? And then as we think about the Phase III trial, how should we think about background meds, potential drug-drug interactions. I mean, Dr. Demarest, as you said, these patients are constantly cycling through meds. They've got an assortment to the background. Given the clobazam experience with Epidiolex, what do you need to do before going into Phase III? Or what do you need to do in Phase III to, I guess, derisk that?

Sure. So I think that on the mechanism front, there's some basic science evidence that suggests that the way that epilepsy and developmental challenges in CDKL5 are created is by acting through several proteins in the synapse that stabilize the NMDA receptor at the synapse. And so by manipulating that system and potentially augmenting this, this might be something that is somewhat specific to this disease. I say that, honestly, with a bit of caution. The things are early and sometimes basic science doesn't translate into a fact in clinic. And so I don't want to necessarily overstate that, but I do think that it's interesting and that there may be some mechanistic impact or sort of rationale for that effect in CDD if that holds true. I think on the other side of things in terms of Phase III trials, multiple medications, there's been numerous epilepsy trials over the last 20 years that have dealt with refractory epilepsy patients that were typically on multiple medications. So I think there is a clear path for that. If we start to see that there are medication interactions that either influence dosing, side effects or efficacy, may actually improve the efficacy of the medications or in combination, then I think that's something that we learn over time. But ultimately, that's the data that drives our knowledge of that. And I don't know if Amit or Julia have anything to add to that.

Yes, Julia, anything else to add to that? I think your experience with CDD also is relevant.

Right. Now, again, you try to maintain sort of the balance there, and you don't want to change the medications during the trial, the co-founder, obviously, but you would have to be able to allow them some changes if medically warranted.

Got it. And last housekeeping question, Julia. You mentioned that we would get a responder rate analysis from ARCADE in Q3. Can you give us the definition of responder in this study?

Yes. So actually, we're looking at different variables. So the traditional responder rate is typically 50% or greater decrease in baseline seizure frequency. But because of the rare -- ultra-rare population and very, very refractory, we'll be looking at responder rate defined across the whole entire spectrum. So we will have rates between 0 to 25, 25 to 50, so we will have data that goes across the spectrum.

Our next question comes from the line of Brian Abrahams from RBC Capital Markets.

A couple of questions for Dr. Demarest. You talked about some of the AE challenges and the side effect challenges with the current antiepileptics. We've seen signals of deepening effects over time with soticlestat, so I'm wondering whether you might foresee using this agent as almost like an antiepileptic sparing drug, where over time, you might be able to explore withdrawing or reducing doses of existing medications? And then I have a follow-up.

Sure. I think that if -- again, if it works out that way and the data supports that improvement over time, then I would absolutely expect that, that would be one of the ways that we would utilize that clinically. Families are always seeking to get on to less medications. We see better overall balance between side effects and efficacy on fewer medications, in many cases. So if this was a medication that allowed us to reduce the number of other medications that patients are on, then that would be a good improvement for patients.

Got it. And then just building on some of the earlier discussion about the differential pathophysiology and the glutamatergic pathophysiology for CDKL5. Would there be any rationale as to why the drug may have greater or lesser effects across any of the other seizure disorders being explored?

So I think, in my analogy, with the gas and the brake, that's still applicable to epilepsy across the board. And so in this case, we're still talking about our ability to influence that excitatory-inhibitory balance, which would be something that might improve any epilepsy. For CDD, there happened to be the specific thing. But I think any of the other mechanism -- any of the other diseases, which, particularly as we move towards LGS is more heterogeneous with multiple causes, multiple sources of their epilepsy and developmental challenges, you could see a variety of impacts still in that system by influencing that excitatory-inhibitory balance.

Got it. That's really helpful. Maybe then just one last one for the company. And I apologize if I missed this. Can you talk about the cadence of readouts in third quarter? Will ELEKTRA be -- will it be ELEKTRA, ARCADE then ENDYMION as it's represented on the slide? Or might those all come at the same time? And I'll hop back in the queue.

Yes. Thanks, Brian. So the teams are working really hard to get all the data kind of analyzed as quickly as possible, so right now I can only say Q3, which is definitely on track on Q3 in terms of the cadence. And which one is first, it really -- it depends on which one gets analyzed and interpreted the fastest. So right now it's Q3 and I don't have really an additional guidance on exactly which one is coming first yet.

Our next question comes from the line of Michael Higgins from Ladenburg.

I'm especially interested to see additional data on ARCADE. Question there. How many sites enrolled? And with the patients that have enrolled in the, call it, the first half, the data we've seen so far, are they also enrolled in that same set of sites in the, call it, the second half of those enrolled in ARCADE?

Yes. Thanks, Michael. Maybe, Julia, you could take that question about the number of sites and what's happened with -- since the March readout?

Yes. So I think -- believe that there's about 7 sites that involve patients. And so again, some of these sites did enroll more than 1 patient, where others only enrolled 1. But currently, sites have an uneven distribution, some sites have enrolled 3 versus others with 1.

Okay. So it's the same sites then that will continue to be enrolling into that second half, and that's what we're going to see is that same group? Is that right?

Well, no. I mean, I think we just announced that ARCADE has completed enrollment. So we will not be enrolling additional patients into ARCADE. So we've got 20 total right now, and we feel that, that is a good sample size to make our determination on next steps.

Okay. Let me just switch gears. Last one here will be, when did you begin to collect 24HC levels as a biomarker? Which studies did that begin to impact?

So that's -- Well, go ahead, Julia.

Yes. I was going to say, we've collected 24HC on all of the studies.

Yes, all studies, Michael. And I think, I'll just mention also that I think in the CDD population, for example, which ARCADE is looking at, there is -- as Julia mentioned before, the sample size really is an estimate. It was not powered for efficacy, so anywhere between 10 to 15. And there's been development decisions made in other kind of programs in much less than 10 to 20 patients that we have coming through in our study, so I think we're very confident about the Q3 data, making a decision about that.

Our next question comes from the line of Jason Butler from JMP Securities.

I have 2. The first, maybe for Dr. Demarest. When you think about all of these rare epilepsies, can you just talk about in terms of the responder threshold for those that is assessing 25%, 50%, 75%, 100%, what you view as a really meaningful, what would be -- gets you in the door versus what becomes a really impressive or game-changing level of effect? And then for the company, we've seen a couple of different datasets in both Lennox-Gastaut and Dravet over the last few years, can you just talk about how you're thinking about both baseline and placebo, expected placebo responses for the ELEKTRA study?

Scott, do you want to go first? And then, Julia, do you want to answer the placebo piece?

Yes. So I think that, obviously, bigger seizure reduction is good, but it's not just about number of seizures, it's also about the types of seizures and the impact those seizures have on the quality of life. So in some cases, for example, we might see that a medication has a significant impact on the worst types of seizures or on the seizure severity, overall, which improves quality of life even at a lower rate of seizure frequency reduction. So I think that there's a combination of effects there that really determine how excited we would be. Again, in these populations, where epilepsy tends to be highly refractory, a signal, at all, is a good thing because many medications have a very limited impact on any type of seizure control. So I think, clinically, we are excited about something that moves the bar.

And with respect to the placebo rate, I think in the Phase III studies for Epidiolex and Fintepla, these range somewhere in the single digits up to about 20% placebo responses. And so we anticipate that will be somewhere between 10% to 20% for placebo rate.

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Dr. Jeremy Levin for any further remarks.

Well, thank you very much. Much appreciate everybody coming and listening to us today. We hope this is helpful, constructive and valuable to you as you think through the next few months for Ovid. And I hope you'll join us in feeling as excited as we are by having had the encouraging results that we've had over the past year. And now we're going to some really great events where we're looking forward to seeing the data. So much appreciated. The third quarter is a very big quarter for us, as will be the fourth quarter. So thank you very much for the support you've given us, and I'd like to thank the presenters. Scott, much appreciate the time that you spent with us today. And my colleagues at Ovid, a great job, and much appreciate what you've done today. So thank you. And Jonathan, I think we're ready to sign off.

Thank you, and thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.