Hello, everybody. Thank you for joining us today. This is our, hopefully, very enjoyable R&D day. Looking forward to lots of questions from you. We are, as you can see, my colleagues and myself, embarked on an incredibly important area. It's the area of neuroscience. It's an area which will change fundamentally. It's an area that I hope many of you analysts will be paying attention to and drive your focus, too. Before I launch into our program, I want to just take note of the fact we are a public company, and being a public company, we will be making forward-looking statements, so please take note of this. Our focus is epilepsy and seizure-related disorders, and I'm going to show you in this talk today that we are participating in unlocking part of that revolution. It's in front of you. We're a part of it.
What's crucial is that it's about what we're focused on, is the portion that's focused on small molecules. That's important. The reason why it's important is because you have a number of very critical events that have occurred in science, which have unlocked opportunity. Those areas of science include, for example, click chemistry, and also the areas that you now have, which is remarkable, the ability to do the three-dimensional structure of proteins floating in a membrane. What today we'll discuss is, in fact, our programs, which show you our pipeline. What's very important, because of that science, we have a much broader set of opportunities ahead of us. That science leads to broader opportunities, and those broader opportunities, as you look at our company, offer you not just exciting new clinical opportunities, but much lower risk that comes from those opportunities.
We have a very substantial news flow, and indeed, what you'll see, we have multiple news coming out of that related to both the clinic and science. Our capital base is strong for a company of our size. This is unusual, and it's something because that we've developed because we interlock our financial strategy with our our strategy related to our pipeline. So and at the end of the day, as you know, many of you do know, we have a substantial amount of potential non-dilutive capital coming into the company, should Takeda be successful in its efforts with soticlestat. So for us, we're in the right, in the midst of something very special. We have developed an incredibly focused pipeline. That focus is epilepsy and seizure-related disorders.
We are harnessing this revolution that I discussed with you and said to you, but we want to do it in a fashion which takes cognizance of what small molecules can do, oral or IV, inhaled, getting to the brain or oral or IV, and getting to the parts of the body that we want it to get to. But how do we know about that? Where do we want them to go? We want them to go to those novel targets, those targets which have been unlocked in the scientific revolution. Remember what I said, floating in a membrane is very tough to find the crystalline structure. Later on today, you'll hear that we actually do know where our drugs are going. We know what they're targeted to. Now, that's very different from before in neurology.
That means that we, today, are on the cusp of something that changes the whole world of treatment of disorders in the brain. And our goal is efficacy, tremendous safety, and tolerability. We focus on that from the day we start our program. We want best-in-class or unique first-in-class. And we've got it. We have it in our pipeline. You'll hear about all elements of this pipeline today, but our pipeline stretches from Phase 3 soticlestat, all the way through multiple set of targets, down to what you'll, some of you will know us, indeed, know us well, will say a platform, KCC2. But I want those of you who know our company to take note of something. Our pipeline is expanding. It's expanding within each area as we science unlocks areas, so we've taken advantage of that. For example, take a look at OV329.
We are now looking not just at oral, we're looking at IV. We know the science is leading us to areas that we've not been in before, but we now know a lot about, and we believe there's a tremendous amount of opportunity for us to unlock value. And while it's a little difficult at this stage on this slide to see it, you will hear about it. There is a flow of news coming out over the next 15 months, very substantial flow. And this all reminds me of something very unusual. I'm willing to bet that every single analyst and those, many of the investors here have focused on oncology. I've had the great privilege of watching the inflection in that area, even participating and helping drive it. But let me point you to one fundamental thing, and then I'll draw the analogy.
Back, way back when, we had the Gleevec. Suddenly, a small molecule changed the entire trajectory of cancer. The possibilities opened up. You had, for the first time, people saying, "We can get targeted cancer therapies." Thereafter, that started to create the opportunity that led to the development of immuno-oncology and the revolution that we see ahead of us. Today, we are on that cusp. Today, we are driving the possibilities of neurology into a whole new era. Small, targeted disease-modifying medicines are here, and that draws the analogy with what I saw in oncology a decade and a bit ago. I will add one thing, that revolution unlocked the era of new ways of looking at three-dimensional structure, new animal models, new ways of thinking about, for example, click chemistry, all of which are now driving neurology.
So science is driving neurology, giving us a very focused portfolio, and then, in addition, opening up broader opportunities for us. So we're super excited today to introduce you to some of the things that we're doing. Hopefully, it's a completely refreshed look for you, and I think you'll agree that as you walk out of this room, you will have had many, hopefully, many of your questions answered. Today, what we've asked to join us, we've asked several key people outside of the company to join us, amongst whom the first will be Dr. Imad Najm over there. Imad will join us very shortly. Imad is one of the world's experts in epilepsy. He leads an extraordinary, perhaps the best, center for epilepsy in the world out of the Cleveland Clinic. He's published 275 papers.
He has hundreds of graduate medical students who've gone under him, fellows, and are now attending. So his influence goes way beyond his own publications, but the whole field as well. In addition to which, we're very pleased to say. I'm delighted, Dr. Connie Lee, thank you very, very much for joining us, Connie. Connie is not just an expert on cavernous angiomas, she is the mother of somebody, a child, with this disorder, and so can really give you the feel for what this is about. And so we appreciate greatly your coming here. And then an additional invitee, and we thank you very much, is Professor Steve Moss. Steve, I was about to say professor. He is professor, but he's a good friend and somebody that I regard as a mentor.
Steve has forgotten more about KCC2 than I'll ever know. Steve is a world-renowned expert on this and the core of what happened with AZ when they wanted to develop this field. So let me just and then, of course, you'll meet my team, many of whom will. Each and every one of them will introduce themselves. So before we go to our next speaker, who I admire, and I'm very excited to have him, I just want to lay out the day for you. We will be done at 2:00 P.M. During that period of time, I will host, and I will take questions. There'll be two blocks of questions. There'll be plenty of time for that. But if you'll direct your question to me, I'll pick the person who's there, who is the right person to answer it.
I'll be fairly strict on it, but those who can stay afterwards, please feel free to talk to the others. The reason we have to be fairly abrupt on timing is we have people in Great Britain, France, Denmark, and in Israel who are also on this call and are listening in, and of course, others who went to a place in Boston. We call Boston, I think that's right. It's some other organization's running a therapeutic conference, and they're listening in on us as well. So we want to make sure that everybody gets a chance to ask their questions. So with that, let me hand over to Imad, and let me say what a great privilege it is to listen to you today.
Thank you very much, Dr. Levin, for the nice introduction, and good afternoon, everyone. Good evening, for those of us who are listening in from Europe or the Middle East. So my job is very simple. Why is it simple? Because it's close to my heart. So I'm here to share with you the state of epilepsy as we deal with patients with epilepsy every day, discuss with you some of the challenges, and in particular, the unmet needs in epilepsy, and probably introduce ways for a path forward to change the trajectory of epilepsy as a disease, not epilepsy as a disease producing seizures only. So I'm sure many of you know more about this data than I am, but it's always important when we talk about a disease such as epilepsy, to highlight the demographics and the incidence of the disease.
In the world, it's estimated that we have around 50 million people suffering from epilepsy as a disease. In this country alone, we have around 3.5 million people suffering from epilepsy, and amongst them, around half a million children who suffer from epilepsy and seizures almost on daily basis. With an aging population, it's estimated that at least one out of ten of us will develop one seizure, at least one seizure in our lifetime. So the problem here is clear and present danger here to society and to all of us to deal with patients with epilepsy. And then, if we look at those patients with epilepsy, and we try to find out what are they taking, how many medications they are taking? The data is staggering.
We know now that around 47%, almost half of the patients with epilepsy, they are taking almost five anti-seizure medications at the same time. This is huge and considering the side effects and the problems that come from these seizures, but it does indirectly highlight the fact that we are not being able to treat the disease. We are running after the disease. And we know because of the problems with seizures, that seizures may lead to fractures, injuries, death, depression, anxiety, all of these things. Our insurers, public and private insurers, they've been covering so far these multiple medications that the patient is on. Now, what about the unmet needs?
If we're gonna go from left to right on this slide, we know that around 47% of patients with epilepsy, they respond to the first anti-seizure medication, and this is data from 2000 published in New England Journal of Medicine out of the United Kingdom, and then since then has been confirmed and validated in multiple additional studies. Now, if we go here and try to find out what happened with these patients with seizures, they do not respond to the first seizure medication, 53%. We know that around maybe one-third, if not more, there is data showing probably more. One-third of these patients, they do not respond to any anti-seizure medication after failing two or more anti-seizure medications. And this is according to the International League Against Epilepsy, what was described as pharmacoresistance or drug-resistant epilepsy.
Now, if we look at specific diagnosis, for example, look at patients with some of the developmental epileptic encephalopathies, such as, for example, Dravet syndrome or Lennox-Gastaut syndrome. Around 90% of these patients, they are not adequately controlled from a seizure standpoint. More than half of the patients with tuberous sclerosis, they continue to have seizures, and more than 64% of patients with infantile spasms continue to experience refractory seizures. Why we are highlighting this? Because these type of disorders, these pathologies, they affect the children, the infants, and the young amongst us, and the persistence of seizures in these patients will completely change the trajectory of their neural development, and will basically impede the development of a generation going forward.
So epilepsy and seizures, they need to be controlled in order to stop this vicious cycle that we are experiencing with them. So the question here is, why is this happening? We have so many medications. We all know we have more than a couple dozen anti-seizure medications that are available at our disposal, at my disposal as a physician to treat my patients. But why are we still failing? We're still failing because we have three major issues with these medications. The first thing here, the medications that we have now, they fail to adequately address the cause or causes of the underlying disease. Epilepsy is not only one disease, there are multiple, one disease with multiple etiologies. And then second thing here is they fail to achieve maximal effective dose.
We cannot go with the effective dose in many of these patients because of the side effect of the medications. We are obliged to stop halfway through. Even though this medication may be able to control these seizures, we are obliged to stop halfway because of the intolerable side effects the patient may be suffering from. And the third thing here, which in particular in the early anti-seizure medication, first generations or second generation, also of anti-seizure medication, is what we may call the off-target effect of these medications. What we mean by that is the effect on our organs, such as the liver, for example, that is most of the medications are metabolized in the liver.
The interference between the anti-seizure medications and any other medication that a person may be taking, and the, what we call enzyme induction of the liver, the protein binding that we have. All of these things will make the anti-seizure medications potentially more toxic, more associated with side effects, forcing us to decrease the dose and expose the patient to more seizures. These are clear unmet needs that we have in epilepsy. We need to find ways to control for them. Now, if we think about what would be where we are or where we were and what we wanna do, it's just, it's very simple. If we think about the anti-seizure medications, the first generation of anti-seizure medication were basically central nervous system suppressant medication.
It means they are designed to shut down almost every receptor in the brain, in the cortex, in particular, where the generation of seizures are. But when we suppress these seizures indiscriminately, what we call the good, bad, and ugly receptors, we lead here to significant side effects. And here we have to choose either more side effects and seizure control or less side effects and more, less seizure control. And the next generation, second and third generation of anti-seizure medications, were able to remedy to some of these side effects, in particular, to remedy to some of these off-target side effects. But they did not increase the percent of patients who are seizure-free. So patients are tolerating medications better. The medications are more benign on the body and on systems. The medications are less interacting negatively with other medications.
But we still have the same % of patients who are seizure-free as we had 20, 30, 40, 50, almost 100 years ago since the advent of the first medication that is still on the market, that is called phenobarbital. To a point that I will relate to you an encounter I had when during my first year after my fellowship, I saw this patient, 45-year-old lady, who was brought to me by her daughter, who is finishing nursing school, and she heard that, "Oh, there are so many good medications." This is 2000, year 2000. And her mother was on phenobarbital. Phenomenal anti-seizure medication, but it has all of the problems that I delineated in the unmet needs. It does create side effects, it does create tolerance, it does create interaction with other anti-seizure medications.
Her mother was either sleepy and tired and less interactive with seizure control, or if they would decrease the phenobarbital, she would start to have seizures again and again. So what I did with her, I said, "Well, let us try to move her to another anti-seizure medication." And we did. But what happened here? She came back into what we call status epilepticus, uncontrolled seizures. And this highlights something that we don't talk about it, which is the tolerance to the medication. So if we stop the medication in some situation, and in particular, the older anti-seizure medication, the patient will end up developing rebound seizures that may end up in the intensive care unit.
That is the problem, the balance that we have to, we had to deal with, and we continue to have to deal with in our everyday life, taking care of patients with epilepsy. What is the path forward? We have to move from anti-seizure medication to anti-epilepsy medication. We cannot continue to treat the symptom and forget about the disease and its trajectory. We need to have, as Jeremy mentioned, we need to have disease-modifying medication or line of medications that we introduce to our patients with epilepsy, similar to what was introduced 30 years ago to those patients with multiple sclerosis, where now, instead of seeing our patient, multiple sclerosis, come in on wheelchairs, they are walking to our clinics. The transformation is clear.
We need to create the same revolution in anti-seizure treatment, modify it to anti-epilepsy treatment, and then, as a first step, to modify the trajectory of disease, which is from bad to worse. Seizures beget seizures. We have to stop this. And ultimately, this hopefully will lead us to developing medications that will stop seizures and epilepsy from developing preventative treatment for epilepsy. Thank you very much for your attention. I hope I made some sense about the pain that our patients and their families are going through, that we all need together as a community of individuals to help in development of new anti-epilepsy medications and stop developing anti-seizure medication. Now, it's my pleasure to cede the podium to Meg Alexander, who's the Chief Strategy Officer at Ovid, at Ovid Therapeutics.
Thank you, Dr. Najm. And, thank you for reminding us about how serious and significant the unmet need remains despite knowing about epilepsy for 3,000 years. And I just want to take a moment, acknowledging some of the caregivers in the room that the need is that great. We know many of these children. We know their parents, we know the adults, we know the caregivers, and we know many other physicians like you who endeavor to treat them. They are why we're here today. They're the purpose behind our business, and they're our partners in all the programs that you're going to hear about today. And without them, we couldn't be doing it. So thank you. What I have been very much looking forward to telling you about today is really the underpinnings of the scientific strategy that has led to the curation of our pipeline.
So unlike other companies of our size, where you may see, expect to see a company that has one program or compound that they look to expand to multiple indications, as you heard Jeremy say earlier, we, within our pipeline and portfolio, we have four unique first-in-class, best-in-class mechanisms of action. All are small molecule, which enables us to enjoy the efficiencies of small molecule, very cost-efficient clinical development. But what's truly unique about our pipeline, you'll hear three that we're developing today, one of which we've since out licensed our right to Takeda, is the unique biological targets and mechanisms of action that we approach. So from the biological target perspective, we look very much to find and curate targets that impact the regulation of neurons. And we look at this both extrinsically and intrinsically.
So extrinsically, we look at factors like the environment surrounding the neuron, so the environmental milieu, looking at things like neurotransmitters or, essentially structural or anatomical causes in the brain of seizures. Intrinsically, we look at some of the factors that actually impact the hyperexcitability of the neuron intracellularly. We do this with unique mechanisms of action, which you'll hear my colleagues, Zhong and Manoj, and Jason talk about throughout today's discussion. We basically act on mechanisms, unique mechanisms, that modulate, metabolic, enzymatic, underlying endothelial cell structure, as well as intrinsically within the neuron itself, helping to return a hyperexcited neuron to a normalized state. All of this is, of course, important because hyperexcitation is not just central to seizures and the epilepsies that we're wanting to treat, but we think the opportunity is potentially much greater.
We feel very encouraged that our medicines have the promise to be not just powerful anticonvulsants, but they may actually have legs and opportunities in other neurological pathologies, which we have clinical-preclinical evidence that we'll walk you through today. So when we think about the real goal of an anti-seizure medication, we think about a schematic that looks similar to what you'll see behind me. And in essence, the goal for all of us that are in drug development is we want to essentially try to return a hyperexcited neuron to a physiological homeostasis, or what we call a more balanced neuron. We want to come back to that green circle that you see, the sweet spot. And in pathological conditions, like what you'll see on the top right or the lower left, we see an imbalance.
In the top right, you're seeing essentially a pathological state where there's too much excitation, too much neuronal hyperexcitability, which can lead to conditions like seizures, like pain, like schizophrenia. And in the lower left, you see basically a brain in too much of an inhibitory state, leading to other setbacks like depression and sedation. We ideally, and many of our peers in this space, want to be able to, again, return the neuron to the homeostasis.
But historically, as Dr. Najm described in the different generations of medicines, what we've seen with anti-seizure medicines is they're blunt instruments, essentially. They over-modulate, or they may hit a target, but they may hit other targets as well. So what does that mean? If you over-modulate, we're hitting a situation where sometimes we see an imbalance leading to too much depression or sedation, essentially dampening the entire immune system, as Dr. Najm said. And in other cases, we may be able to crush a seizure with these older generations of medicines like lamotrigine or levetiracetam or carbamazepine, but there's also other off-target effects that we may see as well.
So our goal within Ovid is to really work on the extrinsic and the intrinsic causes of hyperexcitability of neurons. Going across the top, if you look at the programs that we have that operate extrinsically, so around the environment, around the neuron, we have our OV329 program, which is the next generation GABA aminotransferase inhibitor. We have soticlestat, which we've outlicensed to Takeda. That's a 24 cholesterol hydroxylase inhibitor. And our newest program with Graviton Bioscience is a ROCK2 inhibitor, acting on structural changes in the brain. And then our intrinsic programs include the KCC2 direct activator program.
You'll hear Zhong and Steve talk a little bit about this later, but actually works within the homeostasis, trying to return the homeostasis within the neuron itself. So if you look at our pipeline, you'll see these four unique mechanisms of action, and we think they're truly creating a differentiated pipeline. So we very specifically work on the metabolic side with our soticlestat program. Again, that's essentially modulating glutamatergic signaling and inflammation in the brain to be able to suppress the excitatory neurotransmitter in the brain. With our GABA aminotransferase program, we're increasing levels of GABA to try to inhibit the hyperexcited neuron. In the case of our ROCK2 program, that's really operating on the structural and cellular integrity of the underlying condition.
We know with one of the indications that Connie and Zhong will be telling us about later today, cavernous malformations, that there's underlying, essentially anatomical pressures that can occur on the brain from these lesions that lead to pressures and at times bleeds. So what we're endeavoring to do is really a disease-modifying treatment there, where we're restoring the endothelial cell function using ROCK2 inhibition. And then finally, within our KCC2 program, which is the earliest program in the pipeline, but one we're incredibly excited about, we're actually modulating the intrinsic properties within the cell and restoring neuronal homeostasis through chloride extrusion, and Steve is going to walk you through that. But why is this important? We think it's very exciting science. We think it has tremendous medical opportunity, but we also think it's good business.
So this very busy chart behind me, you don't need to call out every dot. It's a bit of an eye chart. But essentially, what this maps out is most of the programs in clinical development today for epilepsy or hyperexcitability targets. And you don't need to wear glasses to see that some of the areas are very busy. This starts all the way from Phase 3 at the top down to the preclinical at the bottom. And the takeaway is, if you look at this, even if some of these programs shake out and don't make it to late-stage clinical development, certain target areas are going to be very crowded three to six years from now. We, on the other hand, have been very deliberate about the areas we've selected to play.
Specifically, we're not only looking at the scientific opportunity and the medical opportunity of what it may mean, but across the programs that we're developing in, we're keen to look at areas where we can lead and expand, again, in areas like KCC2, GABA-AT, and cholesterol 24-hydroxylase and ROCK2. Importantly, we believe these areas will be very key to anticonvulsant and anti-seizure therapies. We also think they represent tremendous opportunity for growth. Several of our compounds, which you'll hear about today, have opportunities, not just in broader epilepsies, which we hope to expand to, but also in areas of psychiatric indications and in pain. And we know this to be the case, not just from our encouragement of the preclinical science that Zhong is going to walk you through, but also from history.
If you look back at how anti-seizure medicines are used, we know that many medicines that are anti-seizure medicines are also used in other neurological conditions, or they're essentially used off-label. But the past was serendipitous, and you have to keep in mind, these were very blunt instruments. So now, as we're entering an era of much more precise, selective compounds, and the right types of animal models who have caught up with the science, we can be very intentional and rational in what we choose to pursue. So with that strategy overview in mind, what you're going to hear today is broader opportunities across our programs, supported by very encouraging preclinical findings that we've come together with in the last year. And we think that's going to allow us to accelerate and de-risk many of our clinical programs earlier and potentially expand them.
In a moment, I'm going to turn it over to my colleagues, Zhong and Manoj. They're going to walk you through our clinical stage programs, the ROCK2 program that we're collaborating on with Graviton and OV329. We'll take a pause, and then we'll come back, and we'll hear about our KCC2 program and the status with soticlestat. Thank you. Zhong?
Thank you, Meg, for the introduction. So my name is Zhong Zhong. I'm the Chief Scientific Officer. I'm going to talk to you in this section is a newest program at Ovid. It's a ROCK2 inhibitor program with its lead compound, OV888. So we formed a partnership with Graviton Bioscience in May of 2023 to take a highly selective ROCK2 inhibitor for cerebral, to develop that for cerebral cavernous malformation. In a very just few minutes, you're going to hear from Dr. Connie Lee, the patient experience, the medical disease there. For patients who suffer a repeat hemorrhage and seizures, the disease is horrible. It's mercilessly unpredictable. And after Dr. Connie Lee, you're then also going to hear from Manoj, our chief scientific, our Chief Medical Officer, the clinical progress.
But just to give you a very quick update, the headline is we have initiated multiple ascending dose study for OV888, and also we intend to initiate a dose a signal finding trial in the second half of 2024. What I'm going to do the next few minutes is to walk through the scientific rationale, why ROCK2 inhibition makes sense to treat cavernous malformation. And also going to talk to you about this compound, formerly GV101, now renamed OV888. It has why a blood-brain penetrant compound with a well-characterized safety profile and high potency, high selectivity, why that makes sense for as a potential to be the first disease-modifying treatment for cerebral cavernous malformation. So if you focus on the left-hand side of this slide, the panel, you see the brain, the human brain, that's marked by cerebral cavernous malformation.
You see this mulberry-shaped lesion that's characterized by this leakage, blood cell leakage, and the result, that's resulting from the endothelial dysfunction, cell dysfunction. And if you zoom in, in the endothelial cells on top of that graph, you see a couple of cell biology phenomena. You see ROCK activation, ROCK2 activation. It's a kinase. You see the ROCK2-induced stress fiber. You also see the cell junction dysfunction. So we have learned a lot about disease through the genetic dissection of the root cause of the disease. There are three genes that's responsible for causing human diseases, CCM1, CCM2, CCM3. On the right-hand side of this slide is a panel of a cell biology experiment. When people introduce the mutation of these CCM1, CCM2, CCM3 genes, you actually can reproduce the stress fiber formation in these cellular models.
So even though we understand the genes, the proteins are responsible for causing the disease, we actually, these proteins, they are not well characterized in terms of our chemical functions. They are not part, particularly druggable from that sense, for that sense, but we know very well how it mediates function to regulate cytoskeletal network. And the key player is this protein called RhoA, and we know a lot about RhoA. RhoA has been studied very, very extensively in endothelial biology, in neurobiology. RhoA works through its partner. It's, there's a kinase called the ROCK kinases. There's ROCK1, there's ROCK2. They are the key players modulating the Rho's function in regulating cytoskeletal network. So this particular slide, on the right-hand side, if you look focus on the right-hand side, this is a very elegant biochemistry studies to look at the RhoA function.
So when you have CCM mutation in these cell models, you actually see an elevated Rho activity, which is demonstrated by a prominent substrate, which is called the myosin light chain 2 . So that particular protein actually is the key mediator of the Rho function, being a substrate of ROCK2 and mediating the stress fiber formation. So the ROCK2, the ROCK has been shown to be a key regulator for the cellular dynamics, the skeletal dynamics. The ultimate proof for ROCK inhibition being a validated target for CCM come from genetic studies. So this is done from Dr. Awad's lab at University of Chicago and Dr. Marchuk's lab at Duke. What they have done is to generate a transgenic model based on the CCM3 mutation.
So in that particular model, you actually have fair amount of disease features, very similar to human CCM patient. You see lesion, that's the red dots here on the left-hand side, and you also see the pathology of the lesion, which is the bleed of the brain. The hemorrhage is measured by the non-heme iron deposition. With a single mutation of ROCK2, just lose one copy, 50% reduction of ROCK2 activity. You significantly reduce the lesion, which is shown by the red dots here on the left-hand side, that's reduced on the right-hand side of that panel, and also the significant reduction of the hemorrhage, which is the blue dots here. That effect is not true with ROCK1, so inhibiting ROCK1 has no such effect.
Therefore, demonstrating that ROCK2 rather than ROCK1 is really the target for cerebral cavernous malformation. And with that, I think you understand our rationale of taking OV888 into treating CCM. Because compared to everything that's on the market, everything that's available, everything that's been studied for this kinase, the OV888 as a ROCK2 inhibitor has the highest potency. It's a nanomolar inhibitor for ROCK2. It has the highest selectivity. It's over a thousandfold selective over ROCK1, and it's brain penetrant. So this is what we try to do, to bring OV888 into patient and to treat the underlying root cause of the disease, to restore the endothelial cell integrity, and then to treat the disease, to reduce a lesion. So with that, let me hand over and welcome Dr.
Connie Lee to talk about the unmet medical needs of CCM.
Thank you. Thanks. I'm gonna move over to this side. It's a pleasure to be here today, and I never imagined 20 years ago when I started the organization, that I would ever have an opportunity to be in an event like this. I'm Connie Lee. I'm the founder and CEO of The Alliance to Cure Cavernous Malformation. And so I'm going to be talking about the disease that Dr. Zhong just talked about, and honestly, I think it's, it's a very specific disease, not so much a broad category as, as epilepsy is. As he mentioned, cavernous malformations on the basic level are abnormal capillaries. They look somewhat like mulberries or raspberries. They can grow. They can become 3 cm, 5 cm large in brains or in spinal cords, and they are leaky, inherently leaky.
They can occur anywhere in the central nervous system, and the blood that flows through them, unlike in aneurysms or in arteriovenous malformations, the blood that flows through the cavernous malformation flows slowly. So when they hemorrhage, it is a slow-motion event that frequently occurs over the course of a few days. What it leads to, though, is stroke. It leads to the neurological deficits that one would expect to see with stroke. Even in the absence of hemorrhage, though, these things become symptomatic. 50% of people who get diagnosed with the disorder first show up with a seizure and go on to develop epilepsy. 25% come with hemorrhage, and then another 25% come with functional neurological deficits, but the imaging does not necessarily show that there's been any kind of hemorrhage.
So this is probably from mass effect, or because these are leaky, they have iron deposits, blood deposits outside of the lesion that can continue to irritate the brain. Also, as mentioned before, the malformations can be classified as either sporadic, about 70%, 75% of patients have just one lesion. It is not hereditary. They develop it just, stochastically, is what they call it, but just by chance over the course of their lifetime or familial. The familial form follows an autosomal dominant, inheritance pattern, which means that each child has a 50/50 chance of inheriting the disorder.
In the case of CCM, this means that you can have some very large family lines, and I can talk with some of you afterwards about our common Hispanic mutation and about the CCM2 exon 2- 10 deletion, which are founder mutations in this population. Aggressive sporadic and familial lesions can also sometimes harbor PIK3CA or MAP3K3 mutations that are driving the aggressiveness of the growth. So how are they diagnosed? Typically, folks show up with some sort of neurological symptom, as I mentioned, seizure, stroke, something else, and they get an MRI. You'll see here that on some sequences, the lesions look like popcorn, but again, they have a dark rim. On other sequences, they look like very dark blots.
In the familial form, patients develop multiple lesions and develop more over the course of a lifetime. That second picture there, that looks a little bit Swiss cheesy, is actually my daughter's brain. It's an image of her brain just last year when she was 23. That is the best that it's gonna look for the time being. She will only develop more lesions over time. So we have a high unmet need. One in 500 people has at least one cavernous malformation. That does not mean that everybody's going to become symptomatic, but all of you know someone who has a cavernous malformation, whether they know it or not. It is the third most common central nervous system vascular abnormality, and it can hit, become symptomatic at any age.
My daughter was first diagnosed when she was four months old, with her first surgery, her first hemorrhage, and first brain surgery. But most commonly, it hits when people are in the prime of their life, between the ages of 25 and 45. It then leads to a lifelong disease burden for these individuals. Prior CCM hemorrhage is a significant risk factor for another hemorrhage. So we talk about temporal clustering of hemorrhages. Once you've had a CCM hemorrhage, you have as much as a one in three chance of hemorrhaging again within the next five years. That's really high risk and obviously very anxiety-provoking, considering there is absolutely nothing you can do at this moment except have brain surgery, and many people are not able to have brain surgery because their lesions are in places that are inaccessible.
We have 8,000 new patients diagnosed in the U.S. each year, and eventually, 50% of them will go on now to have the only treatment, which is brain or spinal cord surgery. And it has an incredibly big economic burden in the U.S. $2 billion is probably a gross underestimate, but didn't wanna boost that up a little bit more than that. And make it look like it's exaggerated. So our patients. Our patients, again, are often young. The one wearing the poncho is my daughter. The one on the top passed away when she was 21 because of gelastic seizures coming from a thalamic lesion in the thalamus that had hemorrhaged multiple times. And then, the picture on the bottom is Ryan Westmoreland, who was the top prospect for the Boston Red Sox.
No, not here. I can't do that. In 2009, and wound up having brainstem hemorrhage surgery, came all the way back to batting practice when the lesion recurred, and he wound up having a second surgery and was no longer able to come back. He's covering one half of his face there with the bat because it's completely paralyzed. He is not walking well still, but he is coaching, so he has high school and college coaching, and he's a dad now, and his life is not awful, but it's not what it would have been. So our patients experience hemorrhage, symptom exacerbation, and seizure that can happen at any time, and as I was quoted before, it's mercilessly unpredictable, which means it is always anxiety-provoking, and as I write there, traumatizing.
In our patient registry, 15%-20% of patients are seriously disabled, which means that they cannot do everything on their own anymore. They need assistance. When they become seriously disabled, they often have long-term deterioration, sometimes from multiple hemorrhages, but just sometimes from the severity of the disabilities. This can lead to premature death, and even more commonly, death comes from seizure, from sudden seizure. Brain surgery and symptom management are still our only options, and that is not where we want to be. And then, because the illness often strikes young adults, we're talking about a family, a greater family effect. Frequently, these are patients who have children already, or they are patients who need to move back in with their older parents, who then wind up becoming their caregivers. It is a full family disease.
So, I wanna thank you for listening, and our patients are hopeful for a day when they no longer live in fear, no longer live in fear of the next hemorrhage. Is this going to be the day that I wake up and have that life-changing hemorrhage, or a new onset seizure disorder, or the next life-changing neurological event? And I would like to pass it over to Manoj, the Chief Medical Officer of Ovid.
Thank you, Connie. So I'm Manoj Malhotra, the Chief Medical Officer, and it gives me great pleasure to walk you today through our OV888 clinical development program for cerebral cavernous malformation. So we were actually very excited when we inherited this program. When we were evaluating it, it had already finished a Phase 1 study in a nanosuspension. It was found to be well tolerated, as well as it had no serious adverse events. Currently, it's in the clinic in a multiple ascending dose Phase 1 trial, now looking at a gel formation, and it has been found to have no serious adverse events. We will be finishing up the multiple ascending dose, and then we'll be asking for regulatory feedback with a pre-IND meeting. So let me tell you a little bit about what comes next, and you've already heard wonderful background from Dr. Connie Lee.
So when you talk to patients, what patients will tell you is that even though they have a cerebral cavernous malformation in a specific part of their brain, all of them can have different manifestations. What I'm gonna tell you is that size, location, and former events make a huge difference. There is a lot of heterogeneity in these patient population. So what are we thinking about when we're thinking about a clinical trial program? We wanna establish a proof of concept, looking at both radiographic as well as clinical endpoints. We want to enrich the patient population by prioritizing those with brainstem cerebral cavernous malformation. So if you look at the right side of the screen, what you see is a picture of a patient with a cerebral cavernous malformation in their brainstem.
The reason we're doing this is, would give us an opportunity to have a more homogeneous patient population. It's not to say that they won't have cerebral cavernous malformation in other parts of their brain, but at least this way, we can focus on one specific areas. And of course, we will also be evaluating these other cerebral cavernous malformations since the pathophysiology is the same. But to try to keep the clinical trial as homogeneous as possible, we really will be focusing on these brainstem lesions for which surgery is not an option and for where these patients actually are having neurological deficits. Of course, we're gonna be looking for radiological endpoints, looking for either shrinkage or stabilization, and how those correlate with clinical endpoints as well as life adjustments. So I wanted to give you a little background, natural history on cerebral cavernous malformation.
This study was done by a prominent thought leader in the field, Dr. Kelly Fleming, at Mayo Clinic. She actually followed these patients over a 3.5-year period, and what you find out is patients with brainstem or without brainstem lesions tend to bleed about 50% of the time. As Connie has just told you, once you bleed, the chance of you having a second bleed is almost 30% within the next five years. There is a huge unmet medical need when you look at the natural history progression of these patients. What Connie also said is, these patients worry about waking up the next day. Are they gonna have a bleed? Are they gonna have a seizure? Are they gonna have neurological deficits? What OV888 is doing is it's giving us an opportunity to bring hope into the CCM community.
This huge unmet medical need is there for an effective pharmacological therapy. Upwards of 400,000 patients in the seven major markets could be potential candidates for these medicines. So where is a significant unmet medical need? As Connie has said, these lesions result in intracerebral hemorrhages. They result in epilepsy, they result in focal neurological deficits, and they lead to severe disability. There's currently no drug available to prevent or reduce the symptoms of cerebral cavernous malformation. And the one therapy that's available, surgery, it's not for everyone. It's only available for those selected patients, where cerebral cavernous malformations are able to be accessed without causing further damage. So no surgery is without risks in and of themselves. So we are actually very excited to look at OV888 in cerebral cavernous malformation, but that's not where the story ends.
What Zhong is gonna do is talk to you about where ROCK2 inhibitors can go well beyond cerebral cavernous malformation to other therapeutic areas, where there might be a potential option.
Thank you very much. So what you have heard earlier from Meg and Jeremy is this mechanistic centric view of doing drug discovery and development. And this is gonna exemplify that kind of approach. So as we form a partnership with Graviton, we also have access to a number of other ROCK2 inhibitors, and this gives an opportunity to look broadly about CNS disorders that these ROCK2 inhibition may make sense. So central to that approach of using mechanism to drive drug discovery are animal models, because animal models help us to refine our view about disease indication and understand what mechanisms are at play in these diseases. And animal models also give us an opportunity to select compounds that works the best to hit these mechanisms.
So Graviton actually took on an exercise to look at one such animal model, that the ROCK2 mechanism plays a big role, and that is the TBI, the traumatic brain injury. So pre-traumatic brain injury, there are clearly structural disruptions to the endothelial cells, to the neuronal network, but also there's a significant amount of neuroinflammation that's highlighted on the right half of this slide. So all these mechanisms actually is very relevant to the role of biology in the ROCK2 mechanism. So the next slide, this particular slide highlights three broad mechanisms that we believe ROCK2 inhibition may play a role. The first is the endothelial leakage. That's really the underlying root cause of CCM that we operate on, using that compound into clinical study. And we also know that ROCK2 inhibition has a profound effect in regulating Th17 cells.
Graviton has done a beautiful preclinical work to demonstrate that. But also, there's a large body of literature on ROCK2 biology and Rho biology in axon regeneration. And therefore, this is something that we are very curious about to see if that would be, we'll see an effect in that particular area, in neural regeneration. And what Graviton has done is to take the TBI model and look at whether ROCK2 is a key player in the injury process. And as you can see on the right-hand side, this is a Western blot, just looking at the upregulation of the kinases. And the ROCK2 regulation is actually quite relevant. It's actually activated, and it's persistent over a long period of time after the injury, where ROCK1 is transiently activated and quickly went away.
So with that, it sets up the model for them to test whether OV888 or other, you know, ROCK2 inhibitors could play a role in such a model. And this is a very early experimental data that Graviton has, but it was quite exciting. So in this particular model, which is a learning and memory model, they look at the recovery of these animals post-traumatic injury, and they saw actually significant improvement, especially day nine and 10 after the injury, where these animals suffer the most from learning and memory. OV888 significantly rescued that defect, both on the left-hand side, on the time it takes for these animals to look for the underwater platform, or the path it takes on the right-hand side, the distance it takes for the animal to find these platforms.
So with that data tease, I'll close this section on OV888 and ROCK2 inhibition, and I hand back to Manoj again, to talk about the next clinical asset that we have, OV329.
Thanks, Zhong. So I am super excited now to talk to you about OV329. A lot of you have heard about OV329, and now today, the opportunity is even bigger, and I'm gonna walk you through why the opportunity is bigger. You've actually heard us talk to you about OV329 as the potential next-generation GABA aminotransferase inhibitor for the treatment of rare epilepsies, developmental epileptic encephalopathies. And I'm gonna give you an update today on everything you've heard. But the exciting news is, we've actually been talking to other epileptologists, other neurologists, and now we have clinical data ourselves in the animal model to support that not only can this drug be used for a chronic seizures, but for acute seizures as well.
So first, I don't wanna I don't wanna forget about what we've been doing all along. There's a huge unmet medical need, as you hear from this father of a 10-year-old daughter, who says, that she will never recover from this disease. So the need for a next-generation GABA aminotransferase inhibitor is huge. And when I was talking to my former peers at the Cleveland Clinic, they underscored the necessary need for another medication to treat acute seizures. It says specifically, beyond the benzodiazepines, we do not have any seizure medication to for stopping seizures. And of the randomized clinical trials that have been done, they controlled status epilepticus in less than half these patients. So the new data I'm gonna present today is bigger, it's better, and it gives me great pleasure to walk you through all of that.
For those that are new here, let me first give you a little background of OV329 and update so that we're all on the same level playing field. We have now finished three cohorts in our Phase 1 study. We have had no safety signal, and we are continuing to dose escalate. We are now forming an IV formulation, and we're expanding our clinical development program not only for chronic dosing, but also for acute dosing. For those of you who don't know OV329, it is a unique molecule for a validated target, GABA aminotransferase, which we know extremely, extremely well. It promotes the inhibitory neurotransmitter, GABA, to reduce the number of seizures that patients are having. We actually have established a therapeutic window. This is something that does not exist currently in the first-generation GABA aminotransferase inhibitor by vigabatrin.
In our Phase 1 study, it's unique. Not only are we looking for safety and tolerability, we actually have a surrogate biomarker in MRS. What are the new findings? Well, we have new findings to support low repeat dosing, which shows a prolonged effect on seizure reduction, the ability to maintain optimal levels of GABA, and to sustain a shift in both tonic as well as phasic currents. We're also establishing a PD marker for humans to study. All of this gives us great confidence in OV329 and its utility in not only chronic, but in acute seizures as well. Let me give you an update. For our oral chronic dosing, as I've stated, we have finished the first three single ascending dose cohorts. No safety signals. We're continuing to escalate, and we are now starting into the multiple ascending dose. This is new.
What is new that you've never heard us talk about before is we are now simultaneously starting a TMS study, transcranial magnetic stimulation. We want more confidence before we go into Phase 2, that this drug is gonna be working. So at the same time we are doing our Phase 1 study, we are simultaneously starting a TMS study to give us more confidence that we actually have a drug that's gonna be working. Lastly, we're conducting more animal study, which Zhong will go over, to further differentiate us from a PK/PD standpoint and from the safety of vigabatrin. From an IV standpoint, acute dosing, the IV formulation is currently in process. We are initiating toxicology for acute dosing, and we will be initiating the status epilepticus signal finding study in 2025. So let's talk a little bit about the mechanism of action.
GABA is the major inhibitory neurotransmitter in the brain. OV329 substantially reduces GABA aminotransferase activity, which is a key enzyme responsible for degrading GABA, therefore elevating GABA in the neurotransmitter junction. So what you see here in the pictorial on the left, between the two blue semicircles is a whole bunch of brown dots. These brown dots represent GABA. They're there because GABA aminotransferase is being stopped, so the GABA is not being broken down. You actually get more accumulation, and therefore, more inhibition. What we're also finding out is OV329 increases both phasic and tonic neuroinhibition at the GABAergic synapses. So what you see in the two small boxes over to the right is the phasic inhibition, which is the rapid inhibition, which occurs, as well as the tonic inhibition, which is the prolonged inhibition, which occurs. Why is this important?
It's important because all of these curb the neural excitation, and by curbing the neural excitation, you actually are reducing the seizures that these patients are having. So what are the new preclinical findings that Zhong is gonna be talking to you about? We know that low, multiple dose of OV329 has a profound effect on seizure reduction. We now have animal models that demonstrate anticonvulsive properties in both chronic as well as acute seizures. We know that OV329 induces a profound inhibitory effect on tonic inhibition in the postsynaptic neurons at very low dosages. And lastly, we have electrophysiological data, which shows pharmacodynamic effects at low dosages and supports a signal detection in humans. All of this supports that repeat low dosing in, with OV329 in humans could work for acute as well as chronic seizures.
Zhong, I'm gonna hand it to you to talk more about the preclinical data.
All right. So I just spend a few minutes on the preclinical data to support this multiple ascending dose paradigm that we can use. So give some experimental data to support this observation on the tonic current inhibition, and tell you why that's important. So just to remind you, we license, in-license this compound from Dr. Rick Silverman from Northwestern University, who actually is the inventor of Lyrica, and he's a very clever chemist and biochemist, and really studied the enzymology and used the mechanism of enzymology to design a compound that's 100- to 1,000-fold more potent. And with that increase of potency, we expect the effect, pharmacological effect is gonna be somewhat different. And we exploited that to achieve a better understanding. So on the left-hand side, you see the three blue bars. This is a dose-response curve in mouse.
So a low dose of 329, you have a certain moderate effect of inhibition of the enzyme. A higher dose, you have a stronger inhibition of the enzyme. But look at that red bar. We split the high dose into three low doses, just like the one that you see in the middle. And that achieve a much better inhibition of the enzyme, in nearly 50% in the brain, despite the fact that the total dose is exactly the same as that high dose, right? So what now we know is that, you know, you have. By repeat dosing with a small dose, you can achieve this persistent and significant inhibition of enzyme activity. With that inhibition enzyme activity, just like Manoj said, what it does to, is to elevate GABA because inhibit the degradation of GABA.
That increase, persistent and chronic elevation of GABA, is likely to modulate neuronal activity in a more significant way. And that's what hinted by Manoj earlier. We have a low dose of GABA. We have low elevation of GABA that tend to be concentrated in the synapse, that tends to activate the phasic part of the current. And that current tend to be quite transient and relatively small. But when you have a high elevation of GABA, the neurotransmitter will spill over on the cell body, and now it will activate not only the receptor at the synapse, but also the extrasynaptic receptor. And those receptors, they are more, they are higher number of these receptors, first of all, and second of all, they conduct the current longer for a more extended period of time.
Therefore, what we speculate is the right-hand side, with the repeat dose of OV329, with this persistent inhibition of the activity of GABA-AT, you elevate GABA better, and you achieve this more prominent tonic current inhibition. And that's exactly what we saw. So we leveraged our collaboration with Dr. Stephen Moss at Tufts. They have the world-class ability to design electrophysiology studies, and we treated the animals for a number of days, in this case, six days, and we look at the hippocampal slices and look at the tonic current in those slices.
As you can see, if you focus the middle, the green bar, you see that the tonic current induction in these animals that's treated chronically for a number of days is much, much, higher than either the vehicle control, which is the left-hand side, or the animals that treated just one, a single dose by acute single dose. So with that, and, and this particular phenomena is verified not just for the total current, but also when that total current is normalized by the cell surface, which is the right-hand side of that panel. So with that, what we have discovered is this chronic dosing of OV329 leads to sustained GABA increase, and that enhance the tonic current. And the tonic current change is going to lead to a stronger inhibition effect on these neurons, and therefore, will have better control of the neuronal hyperexcitability.
And with that, we expect in these seizure models the chronic dosing should work better. And that's exactly what we saw, and that's consistent with our finding in this mesial temporal lobe seizure model, epilepsy model. And this is one of the most common epilepsies that's drug resistant. And when we did the animal studies looking at 329 effects in that model, what we observed was a single dose of 329 has relatively little effect on seizure control. When we repeat the dose four times, you start to see an effect on the electric discharge that's associated with the seizure activity. We dose these animal for eight days, now you see a much stronger effect. So everything I have talked to you previously has to do with the repeat dose and chronic dose.
I don't want you to leave this session thinking that this compound only works with chronic dosing. You know, this is a compound that's hundreds to a thousand fold more potent than gabapentin. Therefore, it's actually very potent, working just by acute dose by itself. So again, this is a collaboration that we had with Steve Moss' lab. We look at the animal that's dosed just once with 329. And what we looked at is this kainate model induction of seizure. And we saw that with 1 mg per kg dose, just one dose, significantly reduced the seizure power in these animals. And associated with that is also significant change of EEG at the basal level, so without a challenge.
That signifies that, you know, OV329, by modulating the GABA-A activity, raising GABA, actually significantly modulate the neuronal activity and neuronal hyperexcitability of these, of these neurons. So with that, I'll just summarize that the new preclinical data of OV329 give us more insight on enhanced efficacy, safety, and also the ability to do lower dosing of OV329. We have shown that it delivers anticonvulsant activity at very low doses. The repeat chronic dose actually delivered very sustained seizure reduction, and also associated with that is a significant tonic current regulation. The EEG measurements confirmed the anticonvulsant activity and really give us the ability to develop that as a translational biomarker into clinics. And finally, we are also doing tissue accumulation studies to study the back of eye effect, to understand, you know, the lower ocular effects of OV329.
I'll get back to Manoj to continue to talk about the expanded clinical possibilities with OV329.
Thanks, Zhong. So let's now talk about acute seizures. There's actually mounting evidence that GABAA inhibition may lead to effective control of status epilepticus. More and more epileptologists are actually using GABAA to treat status epilepticus. You can see from these two quotes on the right, one by Dr. Gene Ramsay, stating that the results suggest that vigabatrin has a beneficial role in the management of patients with super refractory status epilepticus. He had resolution in 70% of his patients. Another by Dr. McCormick, stating that vigabatrin was successful for when used for super refractory status epilepticus after exhausting the use of all the recommended treatment modalities within 24 hours of the first dose. And what Zhong has told you, OV329 in the kainic acid-induced model status epilepticus, has demonstrated that it can significantly reduce the EEG power of seizures, as well as the power of status epilepticus.
This is important because also from the electrographic data that we have in the acute brain slices, it shows enhancement of both phasic as well as tonic current within hours of giving OV329 treatment. This is a highly, highly relevant when you're talking about the mechanisms of status epilepticus. So this gives us great promise that OV329 in the IV formulation can be used not only for acute treatments for acute seizures, but for in-hospital patients. We all know patients have breakthrough seizures because they miss a dose here and there. So now you will also have an opportunity to be able to give IV to those patients who miss a dose, who end up in the hospital for breakthrough seizures. So how is OV329 different from vigabatrin? So first, from a molecular level, it's a totally brand-new molecule, as you can see.
From a potency level, as Zhong has told you, almost 1,000 times more potent than vigabatrin. From exposure characteristics, we work, we work well, we go in, we get out. T-half-life of less than an hour, but a PD effect that lasts for a much longer time versus vigabatrin, which lasts and stays in your system for much longer. From a mechanism enzyme inhibition, vigabatrin is covalently bound to GABA-A. We're the new molecule. We're electrostatically bound. We do our job, and we get out of the system. From a purity standpoint, we're more pure. We're only the active ingredient, versus vigabatrin, which is a racemic mixture of both the active as well as the inactive ingredient. And I think the key finding here is that we actually have a therapeutic window in the Sprague Dawley rat, which is the proxy that the FDA recommends for ocular safety.
Whereas with vigabatrin, there is no therapeutic window. At the therapeutic level, that's what you get. We actually have demonstrated a therapeutic window within the animal models. So the next steps in development, let's go over both OV329 oral formulation as well as OV329 in IV formulation. We have started the multiple ascending dose cohorts, as I've alluded to. We're expected to go to higher dosages in humans. We feel very confident, and we want you to feel confident, too, as we now are starting TMS to demonstrate the PD effect. We, of course, are measuring MRS in our Phase 1 study, again, to give us more confidence and use it as a biomarker compared to vigabatrin.
We're currently assessing the back of the eye accumulation versus vigabatrin in the animal model, which Zhong has told you about, and all of this is expected to read out by the end of 2024. So potential indications for the oral formulation, we're, of course, thinking about tuberous sclerosis, we're thinking about infantile spasms, and we're thinking about conditions with focal seizures. IV formulation. As I discussed, the IV formulation is in process right now. We are conducting supportive animal toxicology and disease models. Indications, status epilepticus and refractory status epilepticus. We have data to suggest that we would be beneficial in both, and so please stay tuned. I am, again, super excited because the opportunity of OV329 is bigger, it's greater, and we're all excited about it. At this stage, I'm gonna hand it back to Jeremy, and he will be handling the Q&A session.
Super. Well, those of you who spoke, please join me up here. Just a quick correction, the end time will actually be 2:30 PM, so we've about 10 minutes for questions, another 10 minutes for break, and then we'll come back in again. So, my colleagues are here, happy to take questions. Yigal, your hand is up. Please, would you introduce yourself, if that's possible? Thank you.
Hi, Yigal Nochomovitz at Citi. Jeremy, I just wanted to get a bit more understanding in terms of the OV329 Phase 1. You said there was no, no adverse findings on safety. Could you just expand a little bit more on that?
I'll ask Manoj to answer that, if that's okay.
Specifically, obviously, on the ocular question. Then regarding the dosing, you did the single ascending dose, and you're talking about doing low repeat dosing. Can you just clarify for the multiple ascending dose, are you actually dropping the dose lower? Because you also talk about dose escalating. If you could just help clarify-
Sure.
What's going on in the mechanics there, 'cause it's not, y ou haven't disclosed all those details, but it'd be helpful to get a better understanding.
Start with you, and perhaps, Zhong, you'll chime in at the end.
Yeah. Thank you, Yigal. So for the single ascending dose, we are continuing to go up higher, and for the multiple ascending dose, we will, of course, continue to go up higher, too. What builds confidence in the low dose is once we get surrogate biomarker signaling in MRS as well as in TMS, which we're gonna be starting simultaneously. It'll give us confidence what dose we need to be at, but also, at the same time, gives us confidence that we can go to a much lower dose, should we need to. We want to first demonstrate a surrogate biomarker with MRS as well as TMS to make sure the drug is actually working. That is gonna be very important to sort of risk mitigate before we go into Phase 2.
What the low dose provides us is now an opportunity that we know that the doses at higher dosages might work. We also have low dosages that we could use based on animal models, because we know that now low dosages will work as well. As far as the ocular effect in both SAD as well as MAD, of course, SAD is just for one day. Multiple ascending dose, we're dosing for seven days. We're not expecting to see anything. Of course, we're monitoring for every possible ocular effect, but because of the short duration, we're not expecting to see anything, and we have not seen anything in the SAD portion of our Phase 1.
Thank you, Manoj. Any other, d o you like to add anything to that? That's okay. I have a question.
Yeah, just to add on that, I think the safety profile of OV321 is gonna be a big value unlocking, potentially opportunity. So when do you think we will know that this is a de-risked, you know, from the safety pers?ective?
Manoj, would you?
Yeah.
And then again.
So we have not seen any safety signal. And from our perspective, safety is our number one concern. We're gonna continue monitoring our patients, not only in Phase 1, but of course, if we go on to Phase 2 and Phase 3, we'll continue monitoring over there. Again, we have confidence based on our animal data, which Zhong can go over, which would support that, you know, we have a therapeutic window in which we can see benefit without any ocular effects.
Zhong?
So the way we think about the dose, there are two things. One is the animal model. With animal model, we are marching down the dose to see what's the most sensitive readout that we can read to detect the pharmacodynamic effects. So we have that range that we have discovered. And then we also learn from the human vigabatrin experience, because vigabatrin has been human. We know the dose that works, and we also understand at that dose what exposure you reach and what kind of enzymatic inhibition you have. And based on that, we also can estimate the dose that we need for three two nine. So these information come together to help us to define the therapeutic window, and we feel very comfortable about that.
Okay.
Hi, this is John Boyle from William Blair, representing Tim Lugo. So two from us on the ROCK program. First, could you talk a little bit about how ROCK2 inhibition compares to some of the other mechanisms in development for CCM? Is there enough disease heterogeneity that where multiple approaches could win? And second, could you talk a little bit about what ROCK2 inhibition might do in systemic circulation and what non-CNS side effects we should be looking out for?
Well, I think we have a couple answers here, but let's, I think, Connie, why don't you just quickly.
I can.
Quick overview on what you know at this stage, and then we'll go to you, Zhong, if that's okay.
Okay. Let me precede this by saying I am not a scientist. I am just a groupie. So in terms of what other alternatives there are right now that are under development, we have a ROCK, atorvastatin. It is a statin drug, as you all know, and it is in its epic trial. So Phase 1, Phase 2, experimental proof of concept. It's fully enrolled. We will get a readout in the fall of 2024, and the mechanism by which we think it is, it will, if it does affect CCM, is through ROCK inhibition. It requires very high doses of atorvastatin, 80 mg, in order to get that type of effect. So that's one. Propranolol is a second drug that's being explored.
It's not quite clear what the mechanism is for that, but there had been some case study evidence that made us think that it might have some potential for CCM. Very small trial conducted in Italy. They're seeking funding. Again, these are generics. It's very difficult to get these trials funded. In a different category, there is another industry-sponsored trial by a company called Recursion, of a superoxide dismutase, and so that is a separate, completely different mechanism of approaching CCM. It has enrolled its Phase 2a as of June. Again, we don't know whether that's going to have any success or not.
Thank you. And Zhong?
Just to add a couple of points here, if I may. So, I think there's something very unique about our program approach. One is that this is potentially disease-modifying. It works in an underlying disease mechanism. It modulates cell biology. That's really key to the root cause of the disease. I think that's really important. So compared to symptomatic treatment, this addresses the underlying, you know, biology root cause of disease. But the second thing that's important is that because it's specific on a ROCK2, it avoids hitting on ROCK1. ROCK, in general, you know, ROCK inhibition has been associated with, you know, side effects such as hypotension, and that limits its use, reaching enough dose in the CNS to treat effectively the lesion. The ability to avoid that gives you the ability to dose escalate, to hit the target really hard and produce an effect.
We have a question. And after that, Boobalan, but you guys work together, so fight it out first.
Hi, this is Boobalan from H.C. Wainwright. So with respect to OV329 target engagement, I'm sure you're looking at that in your Phase 1 study. So I just wanted to draw two parallels. So one is the Phase 1 data from vigabatrin, and the other is Phase 1 data from CPP-115. And I wanted to see how OV329 stack up against these two molecules in terms of maintaining the optimal GABA level, as you said in your slide. So with respect to vigabatrin, about 50% increase in baseline GABA levels in Phase 1. And with respect to CPP-115, it's about 50%-140% increase. So I wanted to know where you're targeting in terms of your increasing the GABA levels in your Phase 1 study, and then I have a follow-up.
Yeah. So of course, we're dose escalating right now, and we want to dose escalate to the highest tolerable dose, and then we'll make a determination based on the level of GABA and make that determination at that stage. So of course, we want to go to the highest potential dose that's tolerable and safe. Obviously, if we can get the highest level of GABA higher than vigabatrin and higher than CPP-115, that's gonna be our goal. But of course, we're looking at safety and tolerability as well.
And then,[crosstalk]
You.
Then as you think about target engagement and, concurrent TMS, that's pretty exciting, and we know the space very well. So we are curious, are you using regular TMS or deep TMS, for this concurrent TMS studies for 329? Also, are you specifically focusing on a particular brain region?
Yes. So we are in the process of formulating our protocol, so all of those things have not yet been defined. So I'm more than happy to follow-up with you, probably when we finalize our protocol, but we are just in the designer stage right now. We're, e verything's on the table right now.
I think, s orry, just one quick comment, Jeremy, to Boobalan and Adam earlier, just from a timing perspective. We'll talk about the milestones in the second half of today's presentation, but ideally, what we're looking to accomplish before the end of next year, so Q4 2024, H2 2024, is coming back with the TMS data, the MRS data that we've previously talked about, that was your question. But also, Adam, a point that you had made earlier, asking Zhong, was back-of-the-eye accumulation studies that we're doing with the animals to further differentiate. So by the second half of next year, we should have what we believe will be conviction-building data about the anticonvulsant utility, as well as the back-of-the-eye safety profile being a part and very differentiated from what we've seen in the real world with vigabatrin.
So these are both, Ram Selvaraju, H.C. Wainwright. If these are, questions related to 329 as well. Manoj, you were talking before about, you know, kind of anecdotal evidence that, epilepsy prescribers are increasingly turning to vigabatrin for SRSE-[crosstalk] solutions.
So I was just wondering if you could elaborate a little bit on that, the extent to which you're seeing that evidence, you know, how prevalent is their use of vigabatrin in those types of patients? And, you know, above and beyond those two cases that you cited, you know, when we talk about resolution of SRSE, what does that mean? You know, what kind of sustained relief are patients getting? How long are they typically staying on vigabatrin? And then lastly, in the context of clinical development in this specific, you know, indication, how would you folks go about defining the SRSE population? You know, what would kind of be the treatment history of these patients, and how severe would their conditions be? Thanks.
Thanks, Ram. So in my discussions with my former peers at the Cleveland Clinic, as well as Gene Ramsey, as well as, a few other, epileptologists, this is becoming something that a lot of the epileptology community is beginning to use. The limitation is, as you know, is due to the fact there's no IV formulation, and the second is the fact they don't have a therapeutic window, and they don't know what to do. So at least what I'm hearing is, with one dose of vigabatrin, they're getting cessation of EEG, epileptiform discharges. In Dr. McCormick's study, he said within 24 hours, and the other, key opinion leaders we're speaking with, they're seeing it as early as three hours.
So it gives us great confidence as we're talking to, especially since we're going to have an IV formulation, that they feel very confident that this is something that we should be looking at for acute seizures. And not only for acute seizures and status, but of course, as I discussed, there's a better opportunity. We know that patients miss dosages of their seizure medicines, and it's always good to have an IV formulation. All successful epilepsy drugs have had both an oral as well as an IV formulation. The second part of your question, as far as what we are thinking, it's still early stages, Ram. You know, we're thinking about a proof of concept in 2025.
I think once we get more data, I have some ideas in my mind, but, you know, I want to vet it with a lot of the other key opinion leaders. We'll be discussing this with them at AES in this December. The conversations are already occurring. Again, I'd be more than happy to provide more details on which specific super refractory status epilepticus patients we'll be pursuing.
Any further questions? Tom?
Do I need a microphone? Tom, Tom Schrader from BTIG. Slightly remedial question for 329. Is this, d o you not see fatigue? You or is this a patient population where that would be tolerated?
Well, in actual fact, we've not seen any fatigue on this at all, but would you like to-
Yeah, we have, I mean, at least in the human studies that we've tried it in, in the Phase 1 so far, we have not seen any kind of safety signal. We have seen no fatigue.
No GABAergic, conventional?
Not yet, but we're, we're dose escalating. Again, we want to go to the highest dose that we can potentially go till we see potential adverse events. We have not seen anything yet.
And for CCM, is there a biomarker or something for vascular health where that might put accelerated approval on the table?
Well, that's an exciting question. We debate it all the time. Let us come back to you on that, because I think we're right at the moment where we're defining exactly how we're going to do this, but we're looking to get this through the clinic as fast as possible. I think we've run out of time at this time. If there are other questions, my colleagues will be available. Steve looks like he's bursting to say something, but we have 10 minutes here.
Okay, I was going to say, I was gonna say two things. The basal EEG power is, has a very, very unique signature of it.
We're talking about 329, so we've gone back.
So I'm talking about OV329.
Yes.
Something that's not power, that's just total power. There's a very, very clean effect on one particular power in the EEG spectrum of this drug, which is gonna make, I think, a very interesting biomarker, and that will be published soon.
So that's a biomarker for 329-
329, yeah.
On ROCK2. Watch this space. Okay, 10 minutes for us to break. If you like, we're gonna come back. We're gonna talk about soticlestat, and we're gonna talk about KCC2, and we're gonna talk about the financial strategy and some of the business development strategy that we have laid out. So give yourselves 10 minutes to refresh, and looking forward to seeing you here. Rolling again, I think. Thank you. We got in very early. Everybody from outside in there, that would be great. Matthew. Thank you very much. Yeah, I'll come in. Yeah, I've got some more.
So we're gonna kick off. Meg, can we, y eah, the food must be absolutely excellent out there. I mean, really. We'll just give them. Okay. So we'll kick off. This is a program, KCC2, and to walk you through it, there are really gonna be two portions to this. One will be first with Zhong, and then subsequently, we'll have Steve talk you through some of the science behind it. And then we'll get to soticlestat, and after that, we'll talk about the financial and business development strategy. So with that, let me hand over to Zhong, and I'll go and drag some of those folks in, 'cause really, that food does look good. Thank you.
Thank you, Jeremy. So, I'm going to open up this session on KCC2 and the lead program on OV350, and then I'll hand over to Steve to talk about a little bit of history, why we come to where we are now, and why we are so excited about this molecule and this program in epilepsy. And then I'm going to expand also into other indications, potentially we can go into, and there's a lot of new data in this session, so I hope you'll be excited about this program as well. So, KCC2 direct activator. We are in this because of two decades of work that Steve does, pioneering the KCC2 biology, but also his collaboration with AstraZeneca to find direct activators of KCC2, which is a transporter, a co-transporter of potassium and chloride. And it has some unique properties.
KCC2 regulate neuronal activity, and this is the program we regulate intrinsically, the neuronal proper response to excitatory, inhibitory stimuli. And it represents a very novel mechanism. It's a first-in-class molecule. We are the industry leader in doing this. And every single molecule that we work on, the direct activator of the KCC2, therefore avoids the side effects, potential, you know, off-target effects, of, you know, compounds that are hitting these class of molecules. And then we're gonna share a lot of new animal data on both epilepsy models, but also, schizophrenic models. And the update is, we achieve, we aim to achieve first IND for OV350 in resistant epilepsy, second half of 2024.
We're going to share a lot of new findings, review findings, and we're going to talk about the broad therapeutic potential in CNS indications. Steve is going to focus on the benzodiazepine combination of KCC2 and how that presents a potential to treat as anticonvulsant therapies. I'm going to later on follow-up to talk about the other models. I'm gonna introduce Dr. Stephen Moss, who's the professor of neuroscience at Tufts, and also the professor of molecular pharmacology at the University College London. He has been collaborating with us for a few years now on this particular program.
Thanks, it's, it's really nice to be here, apart from that. I must avoid that light, I just noticed it. So, what I'm gonna talk about today is, I'm a bit of a nerd, you've probably noticed that, but I've literally worked on GABA receptors, benzodiazepines, neurosteroids for over 30 years. So what I'm gonna talk to you today is something that I've never seen before, and that's a lot of, y ou know, I've done a lot of work. You know, people say, you know, I like to be punished. So I'm gonna talk about KCC2, and a little bit of history about KCC2. So I've worked on this transporter for probably 20 years, and we developed biological data, mutagenic data in mice, suggesting that KCC2 activation may be a novel way of intrinsically regulating, activity of neurons.
I managed to persuade AstraZeneca to do a high-throughput screen. We did this in parallel. It was done in Cambridge, and we were screening the molecules in Boston, and we developed 106 distinct activators of KCC2. Thankfully, they've now made their way to Ovid, and I'm privileged to be still working on these molecules. So what is KCC2? It's a potassium chloride co-transporter. And what it does is, if you look at panel A, this is a picture of the crystal structure of KCC2. It seems to a little lost a little bit of resolution through the slides, but doesn't really matter. And the most important thing that's gone is an arrow showing that chloride goes out of the cell with KCC2. So neurons are very unique cells. They can maintain low intracellular chloride concentrations.
KCC2 is neuron-specific, and it's reported responsible for exporting chloride. This is very useful because synaptic inhibition in the brain is mediated by GABA-A receptors, and they allow chloride to flow down its concentration gradient to hyperpolarize the cell. Also, this hyperpolarizing activity is critical for the potency and properties of GABA-A receptor positive allosteric modulators, benzodiazepines, barbiturates, neurosteroids. To get these compounds to work, you have to have an intact chloride gradient. So KCC2 is critical for the potency of these compounds. So, to give you an emphasis of how important this is, this is a synapse, and it's in blue. And what you can see in the lower part of the cell is KCC2, and what KCC2 does is extrude chlorides. This means when you activate an inhibitory receptor, GABA receptor, chloride flows into the cell, you get hyperpolarization.
Now, when neurons are highly active, or there's a seizure, or there's damage, KCC2 is inhibited rapidly. And what this does is it means that chloride increases inside the neuron, rendering the ion channel, GABA-A receptors can no longer work because you can no longer get chloride in the neuron to hyperpolarize it. So KCC2 plays a critical role in regulating the balance inside a cell. So this is why we thought it was a great target for a drug. Now, KCC2 is a solute transporter. There's 500 solute transporters in the genome. No one's ever made an activator because it's too difficult. That's the dogma. But thankfully, with the help of AstraZeneca, we have got some very, very unique compounds. Now, the why we want to target KCC2, as I said, it's brain specific.
So if you want to regulate chloride levels in the brain, you want to target a channel that's brain specific. The other proteins that are important in the kidney, et cetera, for these processes, regulating chloride and potassium flow, NKCC1, KCC3, KCC4, and KCC1, are everywhere. So if you target these, you can have many off-target effects. Just focusing on KCC2 is going to give you brain-specific effects. So OV350 is the lead compound. As I said, it's one of 106, and it rapidly accumulates in the brain. And you can see this in B and plasma, and it's almost one-to-one brain and plasma. That's fairly remarkable for a drug. And it accumulates in the brain about 100-fold higher concentration than you need to activate it.
The other thing activation of KCC2 does. It has a very profound measurable effect on EEG power. So you can measure EEG power in mice, you can measure it in humans, and we don't quite know what EEG power represents in terms of learning and memory, but we know it's a biomarker. So our compound, OV350, when introduced into mice, by itself, has a measurable effect on EEG power. I don't want to bore you with this diagram, but what it does is it increases a particular frequency in the brain that you can measure called high gamma. So OV350 gets in the brain and has an effect on basal brain activity. Why do we like OV350?
Well, the most important thing about OV350 is, first of all, it's highly potent for the transporter, and A shows the, an increasing amount of drug versus the increase in KCC2 activity you see. Importantly, again, we want selectivity. So OV350 is roughly 100-1,000-fold more, more potent for KCC2 than any other potassium chloride co-transporter or NKCC1. NKCC1 has come into fashion as a drug target, and people can ask me questions about that if you like. So again, this molecule, as Jeremy mentioned, click chemistry. So this is a cryo, and B is a cryo- EM structure of KCC2, and the blue line is the plasma membrane, inside and outside.
Using this process called click chemistry, where you can photo label your compound and incorporate it into the protein, we were able to demonstrate that OV350 binds to a specific binding site within the portion of KCC2 in the cell. So this is great because it shows specificity, that the drug directly binds the KCC2, and it binds in a defined site. This allows us to engineer, if possible, improved versions of OV350 or other KCC2 activators, because we know the mechanism of action. So we've published this recently, and the hypothesis is: if we get seizures, we get decreased KCC2 activity, and we have cured epilepsy in mice. Hurrah! So we have used kainate, which is a convulsant widely used in mice, and seizures in mice, like those in humans, become refractory to existing standards of care.
So in the squiggly lines, those EEG traces, you can see in the top line, the mice undergo seizures. There's an arrow where we inject the drug, and the seizures aren't terminated. If we do a combination of OV350 and the current standard of care of benzodiazepine, we terminate seizures. This is 50 mg per kg. It's potent at 12.5 mg per kg. So that's showing how superior or can terminate refractory seizures. So as you heard in the morning, seizures beget seizures, and they lead to a process where you get recurrent spontaneous seizures. So how do we prevent this drive from an initial seizure to recurrent seizures? So in mice and humans, a single seizure leads to the death of neurons.
In panel A, this has been published, we can show that giving a mouse this drug after a seizure reduces the dead cells. The dead, the dead cells are shown in red. So in addition to terminating seizures, this drug prevents initial neuronal death after the seizure. We can then also look at ongoing neuronal death over a time course of weeks, and in panel B, this experiment shows that activating KCC2, you can see dying dead cells are in green with this green stain. You notice with OV350, we abolish ongoing neuronal death after the initial injury. A single dose of OV350 will stop neuronal death two to three weeks after. Secondly, we know after a seizure, you get neuroinflammation, and we can measure this.
And again, in the green panel, labeled IBA-1, you see in samples treated with the KCC2 activator, there's a decrease in neuronal death. So this is, for me, fairly amazing. I've never seen a compound. A benzo won't do this, a neurosteroid won't do this, pentobarbital won't do this, a glutamate receptor antagonist won't do this. I've never seen a compound that can terminate a seizure, a refractory seizure, and prevent this neuronal death. So I think this is a fairly remarkable molecule, although I would say that. Okay, but thank you. It's, this is, I'd go out and buy it.
Thank you, Steve.
Thank you
For doing an outstanding job presenting the outstanding data that generated at your lab and collaborating with us. But as you can clearly see, you know, that anti-neuroinflammation effect, the neuroprotective effect, that really lends OV350, in general KCC2, the whole class molecule, the opportunity to be disease-modifying, right? Not just controlling the neuronal hyperexcitability, but also through doing that, being able to modify disease. And here actually is a long list of diseases and indications where KCC2 dysfunction or, you know, lack of expression or change of expression or change of activity was clearly implicated in the disease. Therefore, you have, we believe, with the collection of compounds we have that target this, particular, KCC2 cotransporter, we have a tremendous opportunity and to build a franchise of neurotherapeutics.
Where do we focus on when we have that many that you can work on? We rely on this particular phenotypic screening platform called SmartCube by PsychoGenics. What this is, is essentially it's artificial intelligence-driven drug discovery. What they have built is a platform that you can place animal in this platform, you present these animals with series of challenges, you observe their response, you capture these data points, the visual data points, and then you capture that database. You compare to over 5,000 compounds that has been tested in that platform already. A lot of them is validated drugs that has been approved. A lot of that, compound that with known, functions, known mechanism of action, and then you can compare where does your compound land? What is the closest compound that you can compare your novel compound to?
It's a very clever strategy. And this is where, well, we had this amazing discovery of OV350. So OV350, just the headline, it acutely elicits an antipsychotic effect. It's a very dramatic effect. It's a very clean effect. So in the way they present these results, they have a panel about 10 different, about a dozen legend. Each color represents a different phenotype that you observe in this phenotypic platform. And what we observe is a single color, this purple color. This purple color represents the antipsychotic activity, and it's quick. 15 minutes after treatment with OV350, it starts to have that effect, and that effect disappears, dissipates after 16 hours. So it's very, very regulatable.
And the other thing that's important to notice, even the lowest dose that we tested, 10 mg per kg, had a very, very strong effect. That effect increased as we increased the dose. This particular platform also pick up side effects. For example, sedation, behavioral side effects. We didn't see any of that. It's very clean, up to 75 mg per kg. So all that is extremely encouraging. And, in order to confirm that particular antipsychotic effect, we, did another experiment using a different model. This is a classic schizophrenia model now. This is a PCP model. So this is using the compound of phencyclidine. You can induce the hyperlocomotion because it induce anxiety, it induce aggression.
The top curve, the black curve, actually is untreated animal or vehicle-treated animal, and you challenge them with PCP, you see this huge increase of locomotion activity, and that activity represents the, you know, the sort of schizophrenia model, the anxiety model. That, you know, dissipates over time. Then the green line, if you focus on, that's the control, that's clozapine. That's an approved schizophrenia drug. And you can see it reduced that hyperlocomotion. It kicks off, you know, after 10, 15 minutes. Then the rest of the curves represent a dose response of OV350, and it has a very dramatic dose-dependent effect. So at low dose, at 1 mg per kg, you see very little effect. At 3 mg per kg and 10 mg per kg, it's already behaving very much like clozapine, this approved drug.
At 30 mg per kg, it's essentially a flat line. It completely takes away the effect of PCP, as if the compound, you know, the animals were never treated, challenged with PCP. So it's a really very significant and dramatic effect. So just to wrap up this section on OV350, what I hope you have seen is, you know, very, really a very nice data to demonstrate the potential of OV350, application of OV350 into epilepsy applications. And we have an IV formulation already. Our intention is to bring that into clinic as soon as possible. It's a first-in-class molecule. It's a novel mechanism. We want to demonstrate in the clinic that it works. So, you know, status epilepticus actually is a really good indication for that with that formulation. We're also developing oral formulations.
OV350 is orally available. There are multiple formulation capability possibilities, so we're doing that. And then, we also are investigating the antipsychotic activity of OV350 and the potential of developing that molecule for psychosis, schizophrenia, and depression. That also represents an opportunity that we can partner with other companies on that. And for that reason, we're conducting further animal disease model studies. We're developing multiple formulation possibilities, including formulation, and we're characterizing additional KCC2 activators in the library that we have. So with that, I'll wrap up OV350, and I'll hand over to Jason to speak another, a different program, soticlestat, which is the tip of the spear in our pipeline, you know, hopefully to reach the status of medicine soon.
Great. Thank you, Zhong, and good afternoon. My name is Jason Tardio. I'm the Chief Operating Officer here at Ovid Therapeutics, and as we get towards the latter part of our day, I have the pleasure of talking to you about soticlestat, the flagship program within Ovid's portfolio for epilepsy. And soticlestat, if approved, will be a very important advancement for a number of key stakeholders. Clearly, first and foremost, as we heard earlier today, there remains a huge unmet need within refractory epilepsies, and specifically Lennox-Gastaut syndrome, Dravet syndrome, for novel, unique, effective, safe and tolerable approaches. Over 90% of these patients still have uncontrolled seizures, and so these communities, these patients, these families, need a new, unique approach, and we hope that soticlestat will offer that to them. But it also is a very, very important advancement for Ovid, right?
soticlestat validates our strategic approach, as my colleague, Meg, talked about today. This is a first-in-class, small molecule therapy that targets hyperexcitability, and we believe could offer huge upside to a community that needs new therapies. But it also solidifies and validates Ovid's approach to partnerships. This was the first major partnership that Ovid embarked upon, and for four years, Ovid drove the development of this medicine. And it's the success of that development in which we had companies approach us about helping them advance their epilepsy and their seizure medicines forward. Hence, Graviton with the ROCK2 inhibitor and the in-licensing of KCC2 from AstraZeneca. But it also is an important potential advancement for our shareholders, as the Phase 3 readout, which we expect in 2024, could represent a huge financial windfall for Ovid and our shareholders.
Milestones upwards of $660 million, that's commercial and regulatory milestones, and royalties upwards of 20% on global sales. But not only are we excited about this molecule and this program, the treating clinicians and epileptologists and neurologists are excited. We've conducted a lot of market research, and what we hear time and time again, when clinicians are exposed to the target product profile for soticlestat, they tell us the following, that this has a unique mechanism of action. It's a product with really strong efficacy. It's a product that has great safety and tolerability, and it's a product that doesn't interact with other medicines. And as if you think about it, Dr. Zhong mentioned this earlier, these people living with refractory epilepsies are on three, four, five medicines to control their seizures.
So a medicine that not only has great efficacy but is very safe and very tolerable is extremely attractive to the community. And not surprisingly, what we see is that the likelihood to prescribe is very high. So where are we at today with soticlestat? soticlestat is in two global Phase 3 programs, the SKYLINE trial, a trial in pediatric and young adults with Dravet syndrome, and the SKYWAY trial, a global trial in pediatric and adult patients with Lennox-Gastaut syndrome. Takeda has confirmed their guidance of anticipated global regulatory filings beginning in their fiscal year 2024, which begins on 1 April 2024. So if approved, what would the epilepsy community be getting with soticlestat?
Well, it's a first-in-class selective inhibitor of an enzyme called cholesterol 24-hydroxylase, and we'll talk a little bit more about that today, which, if you decrease levels in the body, it's believed to decrease glutamatergic signaling and thus have the potential to have a significant impact on seizures. It's studied in one of the most robust development programs in a developmental and epileptic encephalopathies, and to date, has demonstrated remarkable consistency in seizure reduction efficacy, safety, and tolerability, again, with no anticipated monitoring. So before we jump into the mechanism of action with soticlestat, it's important to understand what this enzyme, cholesterol 24-hydroxylase, is and how it plays a role in excitability. Well, the brain is rich in cholesterol, and this cholesterol plays a vital role in maintaining a number of normal physiological functions within the brain.
It's important to keep a homeostasis balance of cholesterol in the brain, and in order to do this, the body takes excess brain cholesterol and converts it into a metabolite called 24S-hydroxycholesterol or 24HC. This is conducted by this enzyme, cholesterol 24-hydroxylase. Now, 24HC is a positive allosteric modulator of the NMDA receptor. As you can see here, it binds to this yellow receptor, which is the NMDA receptor, and it modulates this signaling, this glutamatergic signaling. But we also know recent data supports that cholesterol 24-hydroxylase is involved in overactivation of glutamatergic pathway. And it does this by disrupting the reuptake of glutamate by astrocytes, and this ultimately results in hyperexcitability. So the hypothesis is that if you can inhibit cholesterol 24-hydroxylase, you then lower the levels of 24HC, and thus reduce hyperexcitability.
So Takeda set out and embarked upon a very important mission of finding a highly selective brain-penetrant inhibitor of cholesterol 24-hydroxylase. This is the only inhibitor of this enzyme in development. And what we found alongside our partners at Takeda is that in preclinical animal models, soticlestat selectively binded to the enzyme cholesterol 24-hydroxylase, and in a dose-dependent fashion, reduced brain 24HC levels. So then, okay, great in animals. Well, what about in humans? Well, what's great is that this was replicated in human studies, in both healthy volunteers and in individuals with developmental and epileptic encephalopathies. Again, soticlestat showed a dose-dependent reduction in the circulating levels of 24HC. And again, the reduction in 24HC, we believe, has a dual benefit. It has a positive effect on that overactivated glutamatergic signaling and potentially has an effect on inflammation.
So what have we seen in the development program? And again, we've seen consistent results time and time again, which gives us confidence heading into this Phase 3 result. In preclinical studies, soticlestat demonstrated efficacy, as highlighted by reducing seizure burden, improving survival, neuroprotection in animals, as well as reducing 24HC levels, again, in multiple animal models. Moving into humans, in four Phase 1 studies in over 100 healthy adults, soticlestat again appeared to be safe and well tolerated. It doses up to 1,350 mg, and again, in a dose-dependent fashion, reduced that plasma 24HC level. Moving into patients, we did a basket study, a Phase 1b, two-way basket study of individuals with developmental and epileptic encephalopathies, largely Dravet and LGS, but this also included patients, for example, with tuberous sclerosis complex.
In this population, soticlestat was well tolerated, but also was associated with a median reduction in median seizure frequencies over the study duration and reduced plasma 24HC levels. Moving into the Phase 2 ELECTRA study in Dravet and LGS patients, soticlestat treatment resulted in statistically significant reductions from baseline in median seizure frequency in the combined patient population, and again, showed a remarkable consistency in its safety profile. In a second Phase 2 study of the highly refractory epilepsy population, these are patients with CDKL5 deficiency disorder and Dup15q syndrome. soticlestat once again showed a decrease in motor seizure frequency from baseline in the CDD patients, a decrease in all seizure frequency in both of these refractory groups, and again, safety findings that was consistent with what we've seen.
Most recently, at the American Academy of Neurology, there were two-year open-label data, interim analysis of the ENDEAVOR study was presented. And in this two-year, open-label extension, soticlestat demonstrated sustained reduction in frequency of convulsive seizures in the Dravet patient and drop seizures in the Lennox-Gastaut patient population. Also, sustained reduction in all seizure frequency from baseline up to 2 years, and again, generally was well tolerated and safe. So where are we at today? Again, two ongoing Phase 3 studies. The SKYLINE study hopes to enroll 142 pediatric and young adults with Dravet syndrome. The SKYWAY hopes to enroll up to 234 pediatric and adult patients with Lennox-Gastaut syndrome. These patients will be randomized in each of these respective studies to either soticlestat BID, up to 300 mg and/or placebo.
For the Dravet patients, the primary endpoint is the frequency change in convulsive seizures during the full treatment period. And for the LGS patients, the primary endpoint is major motor drop seizures, again, during that full treatment period. And, Takeda has signaled, once again, as a reminder, that they anticipate global regulatory filings for soticlestat beginning in their fiscal year 2024, which runs from 1 April 2024, through 31 March 2025. So in summary, we believe the soticlestat opportunity is huge. There is a large patient population in the seven major markets of LGS, we believe upwards of 135,000 patients, and for Dravet, upwards of 50,000 patients. And again, I have to remind you, the majority of these patients remain uncontrolled on their current standard of care.
Market research supports that soticlestat, given its high efficacy and balancing that with great safety and tolerability, will be used as an early line option for those patients not well controlled on their current regimen. The profile, we believe, will be efficacy on top of standard of care, fewer side effects, no clinically relevant drug-to-drug interactions, no expected monitoring, which will make it easy to start patients on this therapy, and a promising safety profile. I'll conclude on, if successful, soticlestat could represent substantial milestones and non-dilutive capital into the company. Payments of upwards of $660 million, and royalties upwards of 20% based on global sales.
With that, I thank you, and I'm going to hand the presentation over to my colleague, Jeff Rona, the Chief Financial and Chief Business Officer, who will provide updates on key milestones and our financial strategy. Thank you.
Great. Thank you, Jason. Appreciate it. So as we're coming to the end of the day and towards the wrap-up, what I wanted to do was provide some additional information on two things, basically, our milestones and how we're going to pay for them. So as we've discussed with soticlestat, Takeda has maintained their guidance that they are going to file for global regulatory approval in fiscal year 2024. What that means for pivotal trial data is we would expect to see it, obviously, prior to that, with sufficient time for them to be able to prepare their filings. We're also going to complete, in the first half of 2024, our MAD study, our multiple ascending dose study for OV888. In the second half of 2024, we're going to achieve four key milestones.
This is going to be a really big period of time for the company. Very busy time for the company. First, we're going to initiate our single trial, our single finding trial in CCM. We're also going to complete our multiple ascending dose trial for 329. This trial, as we've, Manoj has talked about, is going to include biomarker data, data from MRS and from TMS. We're also working on additional animal studies that are going to be looking at the ocular effect. We're also going to complete two. We're going to file two INDs. One is an IV formulation for 329, which will allow us to move into acute indications. The second is an IND for our KCC2 program, which will allow us to initiate our initial clinical trials.
The good news is we've got the capital to propel all of these milestones. We've got $96.5 million at the end of the first half of 2023. We've got the runway to complete and to move quickly. As we've mentioned a couple of times, we also have the potential for a large amount of non-dilutive capital, up to $660 million in milestones if Takeda is able to commercialize and approve soticlestat. We've also got royalties in double digit, up to 20%. I think the key here is that it really provides us the opportunity to be able to accelerate and propel this pipeline even further, and also to look at additional activities if soticlestat is positive.
Then on the business development side, our focus is really collaborating with partners to accelerate and expand the development of our existing pipeline by expanding geographies, by expanding into non-core indications, and by expanding modalities. Something that we've done previously, we're also focused on bringing value by monetizing the IP that we're no longer developing, as we've done with OV101 and some of our ganaxolone patents. With that, I'm going to turn it over to Jeremy to make some concluding remarks.
Thank you, Jeff. Thank you, everybody. This has been a long day for several of you, and I appreciate your staying through to the end, but we're going to have questions in a second. I'd like you, first of all, to remember what I said at the beginning. We're led by science, we've seen larger opportunity, and at this stage, we are extremely confident of our pipeline as we look at those opportunities in what is a significantly risk-reduced and rich pipeline. Multiple mechanisms, multiple, news flow coming over the next 15 months, and indeed, we have the capital to execute on what we said we would do. We lock fiscal discipline with strategy, with scientific discipline and strategy, and that's the hallmark of what we feel will open up our opportunities in epilepsy and seizure-related disorders.
So as you look at us, think about Ovid as it might be today, tomorrow, three years from now, and make your choice. We're a great company. I'm proud to be working with my colleagues here. I want to say thank you to my colleagues upstairs who are watching us, and I think we owe them a great debt of gratitude. I'm proud to be presenting their work. Ovid has delivered and will continue to deliver. Thank you for coming, and now let me open up your questions. My colleagues will all join me. I want you to think about us. We're going to play a big role in this revolution, and I can assure you, we're going to execute on what we say we've told you about today. So we have questions.
I'm sure there'll be questions related to the first part that we talked about earlier today, but let's start, if you don't mind, on KCC2, an area that you will be hearing a lot about, not just from us. We have multiple inbounds right now to work with us. Secondly, let's talk about soticlestat, because obviously, for many of you, that's a primary endpoint that we need to see in the near term. And then lastly, talk about the financial strategy. So any questions from the audience? I have one there, and then a second here. Would you again, just for the record? There are over 100 people listening in at this stage, nine different countries, so they won't be able to see you, but they'd love to know who you are.
Okay, so with respect to the-[crosstalk]
No, no, no. What is your name?
Yes, Boobalan from HC Wainwright. All right, so with, with respect to soticlestat, a couple of questions. So as you're running your Phase 3 study, I wanted to kinda hear from you what are your expectations in terms of seizure frequency reduction? So I wanted to know whether there is any efficacy benchmark that you have in mind. In that regard, I wanted to touch an important concept, which is the statistical significance. So clearly, statistical significance was not achieved in your Phase 2 study, especially in the LGS population, but in the combined population, you did.
No, that's incorrect. Let me just stop you there.
Okay.
Statistical significance of a combined trial, which was not powered for efficacy, was achieved.
Okay.
Let's be clear, it was achieved. May I sharpen your question a little bit?
Yeah. So I wanted to know, are you doing, w hat are your powering assumptions for the Phase 3 study? And are you specifically looking to get something so that you can achieve statistical significance and clinical meaningfulness? Thank you.
Let me hand over that to Manoj. And again, just let me repeat, as I ran this, the Phase 2 with my team here, for everybody concerned, never was powered for efficacy. We did achieve statistical significance, and we now have moved on to Phase 3, and we believe it's highly optimized to do exactly as you said.
Thank you, Jeremy. So yes, that is correct. So although I can't talk to you about the power that Takeda has powered the study, most epilepsy trials doing Phase 3 are usually powered at 90% or greater. And I think they've mitigated against the learnings that we had in our Phase 2 and have modified the protocol so that we'll get better efficacy in our Phase 3 trial. As far as where we're thinking we're gonna land, we're hoping that, you know, for Dravet, we're gonna land at least comparable or even higher than what we did in Phase 2. And of course, for Lennox-Gastaut, with the changes that have been made in our Phase 3 trial to be more consistent with other Phase 3 trial, we're of course hoping that it's gonna be much better than it was in Phase 2.
Maybe one follow-up.
Actually, no. If you don't mind, please, go right ahead.
Hi, this is John Boyle from William Blair. So I was wondering if you could talk a little bit more for KCC2, about how you're thinking about the indication selection. There's obviously a lot of opportunity here, so just wondering how you're thinking about what you'll keep internally versus what you'll partner out. Does it have anything to do with indication size or just keeping within your expertise in anti-seizure?
John, great question. I'll start, and then if you don't mind, I'd like Zhong to end. We have, this is a, as with ROCK2, we now have two platforms, one on ROCK2, one on KCC2. I think we've learned something very substantial in our history, stick to your knitting. At the same time, where there's opportunity to expand into other areas, where there are people who are in a better ex, have better expertise than we do, we most definitely will do so. That's almost the inverse of what Takeda did. They didn't understand rare epilepsies, they came to us. Now they're benefiting from that. AstraZeneca did KCC2. They didn't understand exactly what they had in their hands. They came to us, and we had the opportunity to take advantage of that.
The second half of your question is pertinent, how do we go through selection of what we might do with KCC2, and how do we actually ascertain when are we ready to partner with them? I'd like you, Zong, to answer that, if that's okay.
Yeah, absolutely. So KCC2 is particularly exciting because of the fundamental biology it modulates and open up the possibility of going into a lot of diseases where the hyper, neuronal hyperexcitability is the underlying root cause of the disease. When you think about epilepsy, it is essentially a disease of neuronal hyperexcitability, and we have very strong rationale, we have great data from Steve's lab, and we have IV formulation that we can go into status, you know, very rapidly to share proof of concept. And I think it's important for novel, new molecule, a new target class. But then when you think about other disease indications, there are, you know, resistant seizures, for example, that's not, you know, represented by status.
You know, there could be combination of benzo, and I think there's the opportunity in this case, because now you fix the neuron, they may respond more properly. You may be able to reduce significantly the concentration, the dose you need for benzo. And that's going to represent a major improvement in treatment paradigms for these patients. So you need an oral formulation, and we're working on that, right? And then you think about, broadly, about other indications, you know, that neuronal hyperexcitability is the underlying root cause. And schizophrenia is where we had the earliest data. It's not necessarily the only area we're interested in. We're interested in other areas as well. We're doing those experiments, and as we, you know, start to get data, we'll be able to share that more broadly. And this is where we attract a lot of inbounds, like Jeremy said.
This presents an opportunity that we may be able to combine with our resource, our expertise, with other people's expertise and develop these indications quickly.
Thank you. Yigal?
Thanks, Jeremy. Yigal Nochomovitz of Citi. Just a few basic operational questions on the soticlestat program. Can you just clarify, has enrollment in the trials completed, number one? Number two, regarding the milestone structure, if you can comment, are the milestones tied to data filing or approval, the initial ones? And then finally, do we expect both Phase 3s to report out the data at the same time, or will they be different timing?
Jason, why don't you pick that up, and then, Meg, if you have anything you wish to supplement.
Yeah. So I think, in terms of, y ou know, data readouts, you know, Takeda has signaled that they expect to read out both of those trials concurrently, right? And so they're still guiding towards that. In terms of timing of when that may happen, you know, they, they keep guiding towards regulatory submissions in, in their fiscal year 2024, beginning April first.
Meg, anything you'd like to add to that?
Their guidance is consistent. We're looking forward to the data.
And the second half of your question?
The enrollment, the trials-[crosstalk]
The trials are ongoing and actively enrolling.
And with regard to that m ilestones.
They do not offer. They never, unlike small biotech companies, they don't tell you when they're fully enrolled or not. They simply tell you when you're going to get a regulatory submission, and they've kept constant on that. So we're not in possession of information that we're risk or that would inform you further at this stage.
Yeah. So Yigal, I didn't have a mic before, so you probably couldn't hear me very well. Mic issue. But when you think about regulatory and commercial milestones, I would define that pretty literally as regulatory and commercial milestones in terms of what to expect.
Okay. Thank you.
Tom?
Probably for Dr. Moss, but should we-
Ah, wait a second. I have to tell people [crosstalk]
Oh, Tom Shrader from BTIG. Sorry, even I forget that. Should we think of 350 as a repolarization drug? And should it work like KV7 activators, where those work, this drug works? Is that the best way to think of this drug in terms of where it might go?
I think it's going to be much more universal than anything to do with the KCC2. This is the fundamental force that drives inhibition. So synaptic inhibition, fast synaptic inhibition by GABA or glycine receptors is critically dependent on KCC2. So it's going to have much more broad, universal aspect. Anywhere you've got a deficit in chloride, you can have a deficit in GABA or in KCC2 function. The other thing that's very important about this compound, the mechanism I didn't explain, it's self-limiting. So you can only lower chloride so much because of biophysics. So it's gonna. I think it's going to have unique, clean side effects. It's only going to target diseased neurons, so to speak.
Thank you, Steve. Any other questions? I have one at the back. Two at the back, actually.
Hi, Sumant Kulkarni from Canaccord Genuity. Thanks for this event and for taking my question. So given the company is so focused on epilepsy, I'm going to ask a conceptual question. Several of your programs eventually could target progression of disease. So as your programs ripen, do you think that classical endpoints in epilepsy serve your programs well? Or do you think there could be some other examples of endpoints that might perhaps have a more holistic approach towards disease management versus simply reduction in seizure frequency, for example?
What an excellently interesting question, because you reflect the debate that we have. When we look to the future, I think there's little doubt that working with the regulatory authorities, and they're excellent to work with, they will eventually start to modify their thinking, much as it used to be in any other area where you're seeing an evolution of therapeutic outcome. So I'm fully anticipating that over time, perhaps not in the short term, that you will see that. Do any of my colleagues want to make comment on that?
Yeah, I mean, I think, I think that's an excellent comment because you can measure seizure engagement relatively easily, but the progression of a single seizure to, you know, a seizure disorder, there are many steps and changes in, you know, neuronal viability and neural inflammation. But I think the FDA, currently, it's a bit of a difficult landscape to get those things registered. So if there's a quantum change in the FDA realizing that we're only scratching the surface and we're not, if we can register better biomarkers or better imaging techniques, I think that's exactly what the future holds.
And one last comment on that. We have some experience in that, in that with the CDKL5 Dup15q trials, we actually had secondary endpoints in the open label study to measure the changes in the progression of the disorder with regard to its impact on behavior, communication, and other areas. And they were extremely, extremely positive in their, in their findings.
Hi, thank you for taking my question. I'm Ami Fadia from Needham. Can you talk about sort of the ROCK2 compounds behind OV888, and what got you excited about that, the depth of that pipeline, and how you could think about applying it in a variety of different indications?
Perhaps I'll start, but Meg, do you want to answer that first?
Sure, I can start, and I'm sure Zong has a perspective, too, as our Chief Scientific Officer. But from leading the joint development program with our colleagues at Graviton, we were really excited about several characteristics of the ROCK2 library, Ami. So I think one of the things that was very unusual about all of the compounds in the library is, one, highly selective for ROCK2. Zong hit on it earlier, but all the programs that we've seen in the competitive landscape hit both ROCK1 and ROCK2. ROCK1 leads to untoward side effects, namely hypotension. So we really like the fact that all the compounds that Graviton had developed in the library were highly selective for ROCK2, the most highly selective for ROCK2 we've seen in the world. The second factor that we really liked about the compounds beyond OV888, was the fact that their blood-brain barrier penetrant.
That's also been a challenge of the class, to be able to be a neurological medicine before. So we like that, and in addition to that, our colleagues at Graviton have also conducted, animal work, other characterization aspects of these programs that we haven't disclosed at this point in time, but give us a lot of encouragement because, OV888 has a very strong profile, and we're thrilled to take it into CCM. But for some of the other indications that Zhong started to allude to, some of the other programs in the library might be even more attractive for future indications. So collectively, this was very convincing to us to engage in the collaboration that we have with Graviton. Zhong, anything that you would add to that?
Yeah. Absolutely. So when you think about the Rho biology, it's very broad. There's a lot of indications, potentially, we can apply this to. This will require the inhibitors reach different parts of body, including brain. And so the PK distribution, the PK profile, is going to be something very important, brain distribution, PK profile. The second thing that's really important is that what's the ideal balance of hitting these distinct mechanisms? So you, I mentioned, for example, in a TBI model, you have the endothelial mechanism you can hit, right? Endothelial integrity. You can hit the neuronal mechanism on the axon, you know, regeneration, and you can hit neuroinflammation. What's the ideal combination, and what's the duration of this effect that makes sense to go to these different diseases?
What we hope to do is use this model to dissect that, to screen these compounds and understand its profile, and then match these compounds with the mechanism and then with the disease.
Hi, this is Sean Kim from Jones Trading. Just to piggyback on the ROCK2 question. So you mentioned about 400,000 addressable population. Can you clarify whether that's diagnosed or just potential addressable? And more generally, what proportion of patients are diagnosed at current times?
Yes, so I'm happy to tackle that. So as we've heard today from Connie and other speakers, this is a fairly prevalent condition. We believe that 0.5% of the general population have these lesions. Now, where there's some debate is how many of them actually present with symptoms. It could be anywhere from 25%-50% will actually present at some point of their life with symptoms. So that's the bulk of the potential addressable populations. You also have a sliver of patients that present incidentally, right? They have a bump on their head, they got in a car accident or something, they get an MRI, and incidentally, you find these lesions as well. And so even if they're not symptomatic, you may potentially want to address that specific lesion with a therapeutic intervention.
And so numerically, what we believe conservatively is that across the seven major markets, as highlighted today, is that there's upwards of 400,000 patients today. And if a medicine were approved, we think that that would unlock a much greater upside in terms of numbers of patients.
I think we are at the end of time at this stage. It's 2:30 PM, but if there's anybody who would like to ask a last question, we'll take that. Otherwise, we'll call it a day.
Can I ask a quick one here?
Yeah. Only if you give the name.
I'll give you my name, I promise. It's François, Frank Brisebois from Oppenheimer. Thanks for the event. It was great. And just a quick question about SmartCube, in terms of AI discovery. Is this something... Can you just talk about maybe the history, where it comes from, and has it been used, you know, any history of validation of the platform? Thank you.
So, there are actually, a number of publications on that. There are a lot of studies being done by this company called PsychoGenics. So if you, I direct you to their website, they actually have a few examples where they use that platform to generate leads, drug leads, that they, you know, suggest that that's in development. So it is a upcoming platform. It is a platform a number of company uses. They actually cited a number of companies use that platform to develop molecules, so there's a lot of information on that platform already.
Well, I think we've come to the end. Thank you so much for taking the chance to visit with us. And your, your applause is for the people upstairs who are all there watching. I'd like to thank them again. This is their work, and we're proud to present it. So any questions, there's more food outside. You can have the chance to meet with my colleagues. We'd be delighted to see you. Thank you for coming, everybody, and those online, thanks for attending.