Ovid Therapeutics Inc. Aktie

Good morning, everyone, and welcome to Ovid Therapeutics where we are on a journey to pioneer better and gentler medicines for the brain. And one of the ways we're doing that is with what we think is a portfolio of mechanisms for a very exciting target in the brain, KCC2, which stands for potassium chloride co-transporter 2. And while we've had a lot of progress in our epilepsy pipeline, there has also been tremendous progress in our KCC2 portfolio. So we're excited to take you through a deep dive today.

I'm Meg Alexander. It's my privilege to be the President and CEO here at Ovid. And I want to remind you, we are a public company, and we will be making forward-looking statements today. But why we have been so excited to have you here and host you is to tell you more about our vision for KCC2 direct activation. We're pioneering an entirely new class of medicines for the brain and a target that we believe is a master switch for excitation and excitatory inhibitory balance in the brain. We believe our first molecule oral molecule, OV4071, is a potential pipeline in a product, and it will be a better gentler medicine. And we have a very efficient path to proof of concept with what we think are very creative but thoughtful translational biomarker strategies, and we're going to walk you through all of that today. And we believe specifically the opportunity for OV4071, our first oral direct activator is significant and may serve areas of incredibly unmet need and very large opportunities, which you'll hear about.

But I'd like to start by introducing some of the other speakers who will be here with me today. So in addition to myself, we'll be joined by Dr. Oliver Howes. Dr. Howes is the world leader in psychosis. And his lab at King's College of London has looked broadly at the science and translation of psychosis medicines across areas of schizophrenia, neurodegenerative psychosis, et cetera. And Oliver will talk to us more about restoring excitatory inhibitory balance in the brain and specifically how it relates to the indications and the conditions that we're seeking to serve.

He'll be followed by Dr. Michael Halassa. Mike is an experimental neuroscientist who has done incredible work in the prefrontal cortex. And what Mike will take you through is not just the relevance of KCC2 for the indications that we're walking into. But Mike has actually used our 2 clinical stage molecules and tested them in a range of schizophrenia and behavioral models, and he'll share with you that data and start to give you the view of what's giving us conviction here at Ovid.

And then finally, I'll be joined by my colleague, Dr. Eliseo Salinas. Eliseo joined us recently. He is a 40-year veteran drug developer. He's got at least 7 medicines to his name, 5 of which are in the CNS, including some of the only medicines in the areas that we'll talk to you about today and therapeutic areas we'll talk to you about today.

But before we get into that, I just want to remind everyone what our focus is here at Ovid. As part of our journey to deliver better and gentler medicines, we are very focused on specifically developing medicines to quell neural excitability. And we're doing that by going after what we think are fundamental targets to that hyperexcitability in the brain and specifically going after mechanisms of action that are differentiated, but potentially universal that can have broad therapeutic utility. And we're doing this specifically with small molecules because we want medicines that are easy for patients to use.

And the result of this focus over the last 5 years has resulted in a very big pipeline that's progressing rapidly in the clinic. So much so that actually for our epilepsy program, half of our team is on the other side of the world, launching our Phase II program and the multiple proof-of-concept studies that we have for that.

But today, we're going to focus on the bottom part of our pipeline, or KCC2, and we're going to take you through a deep dive specifically on the oral molecule, OV4071 that was just cleared and that's going into the clinic, but it's moving very fast. And that's important because we believe the KCC2 direct activation can serve therapeutic areas that have tremendous unmet need. While we talk to you a lot about epilepsy because of our epilepsy program, I'd like to direct you to the bottom part of this slide. And specifically, some of the indication areas that we think are highly relevant for KCC2 direct activation are not well served today.

So schizophrenia, obviously, we've known about this for centuries. But in the last 20 years, there's only been 2 novel mechanisms of action, and we know there's trade-offs with the drugs that are available in terms of tolerability. Parkinson's disease psychosis, there's one approved medicine, and that carved an important path. Yet again, it's a medicine that only works for a small subset of the people who have psychosis and PD. And finally, in Lewy body dementia, there's nothing indicated for this form of psychosis. So huge unmet need that we believe we can serve.

And why we think we can serve this with KCC2 is we think this target in the brain is almost like a PD-1 moment in neurology. And what I mean by that is while it's one mechanism, we believe it can potentially be many medicines for the molecule we're talking about today and the subsequent development candidates that we'll have coming out of this portfolio. And why that is, is really unique to this particular target of KCC2.

So KCC2 is a common master switch that helps regulate neuro excitatory-inhibitory balance, something that Oliver is going to talk to you much more about in a couple of minutes. But why KCC2 is so unique is it's expressed exclusively in the CNS, unlike other ion transporters. It very precisely helps regulate and rebalance neural network hyperexcitability and its geography matters. And what I mean by that is it sits upstream of many of the approved medicines for things like schizophrenia, like the dopamine D2 antagonist. But its downstream from many of the genetic or acquired causes of hyper excitability. So it's in a perfect location to be able to serve a number of different conditions and relative to existing therapeutics.

Importantly, it only works when this transporter is suboptimally extruding certain ions, specifically chloride. And because of where it sits, it converges in a broad spectrum of both disorders and symptoms that are driven by neural hyperexcitability. And finally, what's so exciting about KCC2, you can't overmodulate this target, and that's different than a lot of the medicines we've historically seen in the brain, where when you operate on neurotransmitters, you can overdo it or underdo it. But KCC2 does not allow energetically for you to extrude too much chloride, which is one of the main ways it functions so it's hard to overmodulate, making it very attractive.

And put simply, when you look at the mechanism of action of KCC2, essentially, when this transporter is disregulated, it's not balancing potassium and chloride. Why that matters is when the neuron doesn't extrude the appropriate methochloride, GABA, the main braking system in our brain cannot operate in an inhibitory fashion, putting it really simply, it means the braking system in our brains can't work.

But when you directly activate KCC2, and keep in mind, I'm going to keep talking about direct activation, that matters, you're able to -- and we are able to extrude the appropriate amount of chloride that allows GABA to be hyper polarizing the brakes in our brain are restored. And therapeutically, this is a big deal. If you look at literature alone, you can see that the opportunity of potentially directly activating KCC2 could be enormous from addressing neurodegenerative forms of psychosis and cognition, to anxiety and behavioral dysregulation, to pain, trauma, neurodevelopmental conditions, even seizures and epilepsies. The opportunity, again, is very large here, one mechanism, many potential medicines. But frankly, I wouldn't be convinced by the literature alone, what convinces us as evidence in data. So what you're going to see from us today is a broad armamentarium of data that we have been amassing for our clinical KCC2 direct activators. Now I recognize the table on the right is a bit of an eye chart, and we're happy to go through this with you in detail today. But essentially, what you are looking at is a snippet of some of the pharmacodynamic disease biology models that we have run with our clinical direct activators of KCC2. And you can see, we've run these across psychoses and anxiety and seizures an d pain. And I will be the first to say upfront, I don't trust an individual psych model in an animal. It's not the same thing as what we experienced with someone who may be living with schizophrenia, for example, and the full panoply of symptoms that they experience. What we do trust though, and as part of our translational strategy, what we have done is we have looked at the best models, both genetic as well as [ preturbant ] models, stimulant models, to be able to look at what is the underlying biology happening in these models, and being able to trial our KCC2 direct activators to see are we restoring that [ EI ] balance. And indeed, we are. Now across more than 25 different pharmacodynamic models, we have been able to show consistently that our clinical stage direct activators are restoring E-I balance. They're doing so in a way that's consistent with the mechanism of action of KCC2, and also what gives us incredible conviction, what you're going to hear about from both Mike and Eliseo in a couple of minutes, is we're also running our medicines against reference products, so known effective drugs, including older ones and some of the more recent ones. And we're seeing activity that's not only consistent, but in some case, surpasses the medicines that we have available today.

So in totality, this armamentarium is giving us great conviction and a lot of excitement to advance this rapidly in the clinic. So I'm going to hand it over to Oliver Howes in a moment, who's going to talk about the role of E-I balance in the brain and for these indications, and then we'll continue to tell you more about our translational strategy and the data that gives us confidence. Oliver?

Thank you. So I've been working in neuropsychiatry for over 25 years, both as a clinician and a researcher. And I want to tell you why I think this KCC2 target is one of the most exciting that we've seen for a long time. And to do that, I've got to talk you through a bit of the biology, the neurobiology of psychotic disorders like schizophrenia.

So the brain is a bit like a computer in that it uses electrical impulses to transmit and process information. And this relies critically on the balance between excitation and inhibition in the brain. And on this slide in the middle circle, you can see the main inhibitory nerve cells in the brain, the ones labeled GABA, and then the main excitatory ones, the ones labeled glutamate. Now these make up the vast majority of the inhibitory and excitory nerve cells in the brain. And they're critical for this excitation inhibition balance. Multiple lines of evidence now show us that psychotic disorders like schizophrenia, there is an imbalance in these nerve cells. And we think that this leads to a glutamate driven excitation in the prefrontal and other cortical regions, which then through that projections down to the mid-brain shown in red on the brain figure lead to over excitation of dopamine in the midbrain that projects up to the [indiscernible]. So it leads to surges in stride of dopamine. And this collectively explains both the positive or psychotic symptoms, but also the other cognitive and other symptoms that we see in disorders like schizophrenia.

Now as I said, there's multiple lines of evidence supporting this that have accrued over the last decade or so. I've summarized some of them on the left, starting with the genetics and epigenetics where we've now had these really massive studies with tens of thousands of patients in them that have shown genome-wide significance for excitatory pathways being implicated in the disorder. So that gives me great confidence that there's something to do with excitation, inhibition imbalance in the disorder. But on top of that, we've also got postmortem data, which has shown repeatedly that there are lower levels and loss of inhibitory GABAergic markers in cortex in people with schizophrenia, particularly in the prefrontal cortex. And then we've also got consistent evidence from imaging on a variety of techniques, EEG, FMRI, PET, that all indicates that there is E-I imbalance in the disorder. So this is converging evidence from multiple different streams of evidence for this.

for this cortical E-I imbalance that could lead to all aspects of the syndrome.

Now I want to drill down on to the EEG in particular, because I think this is really interesting as a marker because, as I said, the brain is working through electrical impulses and electrophysiology, like EEG techniques, these techniques are measuring electricity. You can see that on the left. You see the skull cap with the electrodes. This is what we use to measure the electrical activity of the nerve cells. And below that, you can see actual recordings in people when they're doing one of the tasks that you'll hear more about later on, the ASSR task. So you're actually measuring in real time this function of the brain.

On the right, what you can see is measurement of this electrical activity in people with first episode psychosis compared to healthy controls. And the first episode people are -- the data are in blue. And what you're seeing is the level of high-frequency activity, this gamma band activity. So this is from 30 hertz up.

Now this is particularly dependent on these GABAergic cells that sculpted the interaction between the E-I and the E-I balance. And you can see that you've got overactivity in this resting gamma in first episode patients. We don't just see it in the first episodes, though, studies have also been done in chronic schizophrenia and even in the prodrome. And you get this repeated pattern across these studies, indicating this E-I imbalance.

Now I also want to show you some work that we have done that have tested whether this leads to the striatal dopamine changes. So here, this was a study in mice where we used ketamine. This is an NMDA antagonist. You'll hear more about this model later, but it disrupts E-I balance. And you can see on the left that when you give this repeatedly to mice, then wash them out, you get this lasting reduction in inhibitory GABAergic cell markers in the cortex of these mice. So this is reproducing what we see postmortem in schizophrenia. But on the right, you see that this also leads to the same striatal dopamine changes that we see in psychotic disorders like schizophrenia. So the ketamine treated mice in red showed higher striatal dopamine activity measured with PET, which is the same technique that we use in patients and have shown that, that patients have higher dopamine in the striatum, and that is associated with the severity of their psychotic symptoms. So this is consistent with this model that E-I imbalance in the cortex is leading to this upregulation of striatal dopamine and the psychotic symptoms.

So how does this lead to something that might target the unmet need in schizophrenia? Well, on the left, you can see the circuit diagram and the prefrontal cortical E-I imbalance. The prefrontal cortex is really important for motivated behavior. So this is having motivation to go out and do your tasks, interact with people, get a job, work, et cetera, et cetera. If this is impaired, you can see how this might lead to the negative symptoms of schizophrenia. So these are symptoms like loss of motivation and social withdrawal, which are amongst the most disabling symptoms of the disorder.

Prefrontal cortex is also important for planning and working memory, and you can see how this would impair cognitive functions that lead to cognitive impairments. And on the right, you can see that these are major unmet therapeutic needs in schizophrenia and other psychotic disorders. We have no treatments that are licensed for them. They're seen in about 2/3 of patients with schizophrenia, and they are amongst the main predictors of long-term outcome. You can imagine if you've got no motivation to get on with life, you don't -- you're not able to get a job, you don't have a family, et cetera.

And underneath, you can see the psychosis angle. Now of course, we have D2 blockers for psychosis, but these are ineffective in a large proportion, about 1 in 3 patients and have lots of safety liabilities and side effects, which are listed there. And then we've got drugs like xanomeline and trospium combination, which you'll hear a bit more about later. This is effective for psychosis, but again, probably not in everyone, and it is also limited by poor GI tolerability. So there's an unmet need here for a treatment that will also address psychosis as well as these other aspects of the syndrome.

And you can see where the KCC2 activation might work for this because by targeting this GABA dysfunction, it could help restore E-I balance, reduce the negative symptoms, restore cognitive function and potentially also reduce the psychotic symptoms as well. So this is the potential to target the whole syndrome. That excites me. But it also is relevant to other psychotic disorders where we also see this E-I imbalance.

So one that I also want to highlight is Parkinson's disease psychosis. So you get psychosis in about 40% of people with Parkinson's disease. You also see it in people with Lewy body dementia. And here, you get E-I imbalance across the cortex, and you can see some of the regions highlighted in that pink color on the brain on the right. And one area where you've got particular reductions in GABA is the visual cortex. And this may explain why you get a lot of visual hallucinations in Parkinson's psychosis. These occur in about 28% of people with Parkinson's disease. And you can also see how this might disrupt cognitive function and cause delusions as well through disruptions in E-I imbalance in other regions.

Now in terms of treatments for Parkinson's disease psychosis, we have treatments like clozapine, which are not licensed and have major metabolic issues. And believe me, I've used this to try and treat Parkinson's psychosis. It is really hard to use. It's hard to use in schizophrenia, but even harder in people with Parkinson's disease because they're even more sensitive to the side effects.

And then we've got pimavanserin, which is licensed but has limited efficacy and also has side effects as well. So there's major unmet needs here. And again, you can see where KCC2 activation might help because, again, by targeting the upstream pathophysiology, this E-I imbalance, it could help address both the delusions and hallucinations that we see in the disorder.

So I hope I've set the scene for you. I'm now going to hand over to Mike, who's going to give you more direct evidence about KCC2.

Thank you, Oliver. Good morning. So I wear 2 hats. I'm a psychiatrist. I see patients almost exclusively with psychotic disorders, schizophrenia. And I also run a lab that goes after the mechanisms, the fundamental mechanisms of cognition, how neural circuits give rise to all the mental faculties that we have. And that allows us to reverse engineer many of the functions that we're interested in and that are perturbed in schizophrenia.

Now schizophrenia clinically is a devastating illness. Parents see their kids growing up through teenage years with all the promise in the world. They hit 18. They have their first break, and it's a downward slope for many of them. They never recover function, don't have jobs and never do the normal things that every adult aspires to do. So what do we do about that? And the fundamental problem is what Oliver was talking about is the loss of frontal function. We have medications to quiet the voices, but we have very little in the way of restoring their functional capacity.

Well, one of the clues to what may be perturbed in addition to the loss of GABAergic neuro activity is the loss of KCC2 itself, the molecule that we're talking about today. Multiple postmortem studies in schizophrenia suggest that there is an actual reduction in KCC2 expression in the prefrontal cortex. What -- how can we start asking questions about what that does to frontal function and cognition? Well, that's why we use animal models. So my lab specializes in the ability to reverse engineer these deficits using animal models.

So on the top part of this slide, what you're seeing is our ability to go into the frontal cortex and ask, does KCC2 levels also change in models that are relevant to schizophrenia? And here, I'm showing you 2 different models, a genetic model called the 22q11 deletion syndrome. In humans, that genetic change increases schizophrenia risk by 25-fold. The other one is chronic methamphetamine use. It is well known that chronic methamphetamine use in humans gives you a syndrome that is -- that you cannot distinguish from schizophrenia proper. So that's the top part of the slide.

The bottom panel is electrophysiological readout of KCC2 activity, it's indirect in prefrontal neurons. So this is the application of GABA. And as Meg was talking about, GABA looks hyperpolarizing in normal -- in the black trace. But in these 2 different schizophrenia model, it becomes more depolarizing, meaning that it doesn't work the same way in these 2 models.

So now we have expression is reduced, function is reduced at the single neuron level in 2 models relevant to schizophrenia. Does that impact information processing in ways that we can measure? And the answer is yes. One of the things that we do in the lab is direct readout of electrical activity, population electrical activity in the prefrontal cortex. The setup is all the way on the left. We do multi-electrode recordings, measure activity for multiple neurons at the same time and use a technique called optogenetics where we activate populations of neurons using light.

And in the middle panel, I'm showing you the actual readout of this technique. The top part of that panel is what normal prefrontal activity and response to exogenous stimulation looks like. Each of these blue ticks is optical stimulation of a subpopulation of cortical neurons and the black trace is the population response of their neighbors. So what you see is excitation followed by very sharp inhibition. That's the E-I balance that we've been talking about. That's exactly what the readout looks like. If you look at the bottom panel, that is the 22q11 deletion model. What you basically see is that you get excitation, but the inhibition looks pretty wimpy. So there is -- and what accumulates in between these pulses is what we call neural noise. So the traces are a lot more noisy, reflecting the type of noise that may accumulate in actual cognitive tasks.

On the right-hand side is a direct quantification of that summary statistic. And again, you see wild-type or control maintains a high signal-to-noise ratio, which you can see, and the 22q11 has a lower signal-to-noise ratio. We see the exact same thing in the chronic methamphetamine model. I'm just not showing it for the sake of time.

Okay. How does that impact behavior? Are we able to read this out in prefrontal relevant behaviors? And the answer is yes. So in the lab, we've developed a variety of tasks to be able to directly evaluate prefrontal function. Those tasks are we give animals instructions, and we then ask them to categorize -- allocate their attention to categorize different objects. And what we basically are able to do is tax the prefrontal function using 2 different manipulations that I'm showing you on this slide. We change the delay between the instruction that we give the animal and the categories that they present. We do that parametrically. So it's akin to giving somebody a phone number to remember and then waiting for different periods of time to ask them what that was. So that's the longer you wait, the harder it is.

And then the second is task switching. We can switch the instructions that we give them. And you can see, this is on the right-hand side, their performance drops after the switch, and it takes a few trials to recover. It's similar to if you play video games, you can play game 1, and then you switch to game 2. And if you're not very careful, you might be playing game 1 still, so you make a lot of mistakes until you realize, okay, this is a different game. So that's what happens to mice in this assay.

Now this is a substrate upon which we can evaluate directly schizophrenia relevant changes in prefrontal function. And across these 2 different models, we see deficits, both in working memory, 22q11 on the left-hand side, red traces and in the chronic methamphetamine model, orange trace on the right. And that becomes the substrate by which we can evaluate schizophrenia relevant medication, including Ovid novel compounds. Okay. So now if we look in the 22q11 model and ask, what do commercially available antipsychotics do for our prefrontal readouts? And the answer is nothing. So if you look all the way to the left, we use risperidone, a traditional D2 antipsychotic. It does nothing for working memory or task switching. Xanomeline and trospium, Cobenfy, which is a first-in-class muscarinic agent in this particular model doesn't seem to have any efficacy on any of these readouts.

But if you look at the Ovid KCC2 direct activation, it improves both working memory and task switching in this 22q11 model. What happens to the chronic methamphetamine? Again, risperidone does nothing. Cobenfy improves task switching. So in 1 of 4 conditions, Cobenfy seems to be doing something that's consistent with what has been published in clinical trials on its pro-cognitive effect. So we can read that out. But if now you look at the KCC2 direct activation, it restores both working memory and does improve task switching.

So -- and this is -- okay, sorry. So what I just showed you is basically across 2 different schizophrenia relevant models where we've measured physiology, where we've measured behavioral readouts. KCC2 direct activation improves working memory and task switching and outperforms existing and commercially available antipsychotics in these particular readouts.

So to summarize, and as my colleagues mentioned, excitatory inhibitory balance is disrupted in the schizophrenia prefrontal cortex. And I want to emphasize that, that the -- what we're treating in clinical psychiatry are many of the downstream consequences of that kind of initial blast. Reduced KCC2 function may be an underlying mechanism. That's why we do animal work at all because we can't really do these direct measurements of KCC2 function in the human brain. So we use appropriate animal models. KCC2 activators have utility across genetic and pharmacological models related to schizophrenia. And KCC2 activation has broad symptom targeting beyond positive symptoms, including cognitive function, which is correlated with negative symptoms.

And now I hand it off to Dr. Salinas.

Thank you, Michael. Good morning. Happy to be here to talk about how we plan to study OV4071 in the clinic. As Meg mentioned, I've been for a long time doing drug development. In fact, I was telling Oliver that the first study I wrote a protocol 38 years ago with the first amisulpride placebo-controlled trial. And as you know, [ LB Pharma ] now has been successful with a new version, of amisulpride. But the fourth one, not much has changed since then. Not much has changed then, as Meg said.

This is what brought me to help of it. OV4071 is a direct KCC2 activator. It's important the word direct. It has a broad potential in the psychotic syndrome, that means that it applies to psychotic aspects in different disorders of schizophrenia, Parkinson's disease psychosis and so on and so forth, including to Alzheimer's psychosis, which is a very big indication.

We have a lot of data, conversion data rescuing signs of positive symptoms and negative symptoms in animal models of psychosis with commensurate or superior activity when compared to established antipsychotics like xanomeline or pimavanserin. Importantly, no sedation. You don't want to have the psychotic patients sedated, in particular the elderly. We have seen no sedation or catalepsy.

And finally, as you have heard from Michael and Oliver, something very important in drug development, which is a biomarker, a translatable electrophysiological marker connecting pharmacology and behavior.

The fundamentals are here, potent and selective KCC2 direct activator with an [ ED or EC50 ] of 0.6 micromolar, suitable for chronic dosing, clear bind and activation demonstrated preclinically, very nice therapeutic index. We can go very high on doses without problems, no sedation, no anticipated significant drug-drug interactions and a good brain penetration, which is essential for a CNS active drug.

This is a busy slide I will let you read after the presentation. But essentially, what it talks about is the convergence of data. As Meg mentioned, we are not dependent on a single model to determine the value of this GABA convergent. And you have here summarized 4 different models, MK-801 and amphetamine hyperlocomation. This is important, and I'm going to describe them later that measure what is called positive symptoms, hyperleucomotion in the case of animals. The middle one is social interaction, a different construct that only achieved with chronic dosing of PCP. And finally, a genetic model of Rett syndrome, which is not schizophrenia, but share some of the aspects that we are talking about.

So getting into the data now. This first slide describes the results in the MK801-induced hyperlocomotion. This is a single-dose model. You give MK801 to animals and the animals behave like crazy 30 minutes later. You see in the graph on the left before -- so you pretreat the animals with the testing compounds, in this case, OV4071 at different doses starting at 0.3 milligram up to 60 milligram. And you see their baseline activity before you give the MK801 injection. Then with the MK801, you see an explosion and ambulation in those animals, which is reduced by OV4071 started at the 3 mg per kg dose. Please remember that dose because we're going to see it consistently.

On the right-hand side, you see the dose effect curve, which allow us to estimate the expected ED50, which is 1.6 per kg. So we have an idea of what are the doses that might be effective in humans. Same -- different aspects in the same model is represented in this graph. As I mentioned, you give MK801 30 minutes before mentioning activity, but you pretreat the animals with the target compound. And the question is how long should you pretreat those animals for 1 day, 2 days, 3 days. And this graph represents -- so in some animals were pretreated with OV4071 for 7 days. Some animals were pretreated for 5 days, others for 3 days, and 1 group of animals receive 1 single dose of OV4071 30 minutes before the injection of MK801. And what we see in the graph and you have the activity how much they are moving around, the strongest effect is produced by the single dose.

The testament to the efficacy and the potency of the drug to alter the behavior with 1 single dose. Importantly, you don't lose efficacy upon repeated administration. So you don't see [ tachyphylaxis. ] So this is -- it was very important, a very important behavioral readout for us. On the right-hand side, what I said before, it is brain penetrant. You see the concentrations, which is equivalent between the single dose and the 7 dose, no significant accumulation.

Now same construct, hyperlocomotion, but a different challenge with amphetamine. Why is that important? MK801 is an NMDA antagonist, like ketamine, like PCP, okay? Produce a glutamate burst in the cortex and increase in dopamine in the striatum. Amphetamine directly increases dopamine in the striatum directly. Why is this that relevant? Well, typical antipsychotics are effective on both, MK801 and amphetamine induced hyperlocomotion. Pimavanserin is effective on the MK801, is not effective in the amphetamine model. And this is in the public domain, you can search the publication, and you'll find it. So same construct, different mechanism of action, same effects quickly.

On the left-hand side, you have, like in the previous slide, the animals before they were treated with the comparator with the active drug, before they receive the challenge with amphetamine. And you see in the gray bar on the left that, that's the normal ambulation of mice in the open box. So about 4,000 inches moving around over a period of time.

When you're given haloperidol, Haldol, a typical, very effective dopamine 2 blocker, you see what happened with the spontaneous ambulation of these animals. That's why patients, families and treating psychiatries, as I was before getting into industry, we call those straight jacket drugs because if you take Haldol, everybody is going to see that you are on Haldol. They stop moving. With over OV4071, you don't see that much of an effect on spontaneous ambulation.

But then when you give the challenge with amphetamine, you see a significant increase in the ambulation. And you see on the gray bar, animals going for 4,000 inches to 8,000 inches that the hyperlocomotion, Haldol again suppressing everything. And OV4071 being statistically significantly effective. But if you compare the bars on the right with the bars on the left, you see that roughly the OV4071 treated under amphetamine challenge have similar levels of ambulation as they had before receiving the amphetamine. And again, previous model, minimal effective dose, 3 mg per kg, different model, 3 mg per kg, this is effective.

Finally, as Michael mentioned, psychosis. It's not -- or [indiscernible]. It's not only about how designations, dilutions and agitation. It's about these negative symptoms that are the most challenging to control. One as Michael showed about cognition and how this direct activate those affect cognition, this is another aspect. Social interaction, this model measures how much rats interact with each other. And in order to produce a deficit on social interaction in rats, a single dose of PCP, of MK, 1 is not enough. You need to pretreat the animals at least for 5 days. And that testament of the different mechanism of the challenge. So probably producing a cortical deficit that Michael was talking about, that is the origin of this decreased social interaction.

What we see in the graph is that comparing the black bar with the gray bar, you see a significant decrease in social interaction. Next, on the red bar, corrected by clozapine, not the perfect antipsychotic, but one of those that we consider that still a dopamine [indiscernible] blocker, but having pretty good efficacy. And you see similar efficacy of OV4071, again, starting at 3 mg per kg. And all this is oral. I mean, the 3 molecules I mentioned is oral dose. So of course, we don't hang our hat in our models, but the convergence of data is what gives us confidence that we are targeting here something that is relevant for the disorder.

Now both Oliver and Michael were talking a lot about electrophysiology. Electrophysiology is the connection between the pharmacology and behavior. And we spent a lot of energy assessing the pharmaco, the electrophysiological profile of these drugs. What we have here is quantitative EEG. That's different from the EEG we look at to see if a patient has seizures. Quantitative EEG measures the fraction of delta, theta, alpha, beta or gamma frequencies in the EEG. And what we have here is the model of Rett syndrome I mentioned earlier. You have in white the frequencies, the power of the animals before treatment with OV4071, and in purple, after treatment on OV4071 at 1 to 3 hours. And what we see is a decrease in gamma frequencies and the animals treated with OV4071. The same gamma frequencies that Oliver was mentioning are increased in first episode schizophrenic, the same gamma frequencies that get increased when you give ketamine to help the people.

We see also an increase in delta frequencies, which might be suggestive of an effect on synaptic strengthening, and we can discuss that later.

Another way to look at electrophysiology is the following. Now we heard a lot about the cases to channel and GABA, and then some sort of reasonable person would say, well, give them more GABA. Why don't you give them more GABA? And this is what happen when [indiscernible] GABA, which is benzodiazepines, for example, excellent GABA activators. They work very well in a lot of things, not in schizophrenia.

What we have here is the results with OV350 and OV4071 to KCC2 direct activators. And you see the darker curve represent post-treatment and the lighter curve before given the drug. And what we see that the 2 drugs do essentially the same. They suppress gamma frequencies. From 30-hertz onwards, you see a shift downwards. Then we have on the extreme right, [indiscernible] compound. So we try to compare head-to-head same type of animals, same lab, what a GABA activator does. And that's exactly what benzodiazepines do. What do they do, they increase beta frequencies, that's the typical effect of benzodiazepine in the qEEG.

So it's not only about GABA. So it's a way of making existing GABA more effective. If you have a defective cases in 2 channels, probably on the GABA of this world is not going to help that much.

Finally, these are a result of the ketamine challenge in mice. Why ketamine, because it's an NMDA blocker, it produces the same effect in animals as we saw with MK801. And we're going to be doing, as Meg is going to tell you, a ketamine challenge in humans. What we have here, these are different doses of OV350, one of our direct activators. And what you have here is all the frequencies, first, the total power. Does it go up? Does it go down? With benzodiazepine, its total power goes down. There's a decrease in total power. You don't have that with OV4071. And then you have the different frequency bands from delta to gamma, and the horizontal line represents the effect of ketamine.

So above, it's more than ketamine. Below, it's less than ketamine. And what we see here is exactly what we expected, mostly a decrease in gamma frequencies, statistically significant at the 3 dose levels. You also see this increase that doesn't reach statistical significance on the slow frequency balance, and I'm really looking forward to seeing the data from our human studies looking at those.

To summarize. We have seen data with robust results indicating activities in different aspects of the psychotic syndrome in different animal models. We have seen that OV4071 is potent and effective at single and repeated doses. We have data showing that the decrease in striatal dopamine consistent with what we have seen in behavior. Importantly, with this biomarker that enable us -- will enable us to track how the drug is performing in the clinic. And finally, with strong brand penetration and no sedation.

And with that, I'm going to hand it over to Meg.

Thank you, Eliseo. And I will talk a little bit more about our translational clinical strategy. But just to recap, Oliver has told us about the role of E-I imbalance in a number of different forms of psychosis. Mike has told us about specifically the role of KCC2 expression and E-I imbalance related to the indications we're interested in for OV4071, and he's shown with our direct activators that he's actually able to restore this regulation of KCC2 and in doing so, rescue cognition and more normalized behaviors and working task memory.

And now what we've shown you, we get it, it's a lot of animal data. But what it's doing systematically is confirming the underlying disease biology that our KCC2 direct activators are moving the neurotransmitters as they should that is highly relevant for the underlying disease process that's driving some of the worst symptoms across a range of psychosis. And all of this together is giving us incredible excitement and conviction to get our direct activators now into patients.

And with OV4071, we believe that the opportunity is very large. Specifically, we see it as a broad syndromic psychosis medicine and also relevant for other psychiatric disorders. And the picture behind me gives you a sense of where we think OV4071 has therapeutic utility. Now don't worry, we're not going to try to prosecute all of these at the same time in the clinic. But what you will hear us say today is in addition to our original interest in PD psychosis and psychosis associated with Lewy body dementia, we will also be initiating a Phase II proof-of-concept study in schizophrenia next year if our clinical translation plans go as we expect that they will based on our totality of data behind the program.

And let's talk a minute about the translational strategy because we've talked a lot about neurotransmission in animals relative to genetic and stimulant-induced versions of psychosis. But essentially, our strategy has been this because we are sensitive to the challenge of developing in psychiatric indications. Many smart companies and researchers have come before us. So as you can see, what we've been looking to do is really assess the underlying biology and pharmacodynamic activity of our direct activators, including OV4071, both in phenotypic screens, but also in disease models. And we're looking at this in a variety of ways, right, both genetic models of these diseases, induced models, and we're doing it against reference drug comparators, and we're using electrophysiology. So we're not looking at behavior alone.

What that is now enabling us to do is to take biomarkers like quantitative EEG, but frankly, many more into our healthy volunteer study. Of course, we need to step through the right drug development steps of safety and tolerability assessments. But while we do this, much like we handled with our epilepsy program, we will cast a broad deck characterizing the electrophysiology based on all of these robust insights that we've now gotten from the disease biology models.

Similarly, we will be running a ketamine challenge study, as Eliseo alluded to. Why does that matter strategically? As Eliseo has said, ketamine is an NMDA antagonist. So what it does is it directly reproduces the same biological and neurotransmitter surges of glutamate and dopamine in a healthy volunteer. And we can assess against quantitative EEG some of these same biomarkers and others if we're able to shift the neurotransmission function back in the right direction. What does that enable us to do? It enables us to make smart and hopefully confirmatory decisions about how we're able to modulate the biology that's underpinning some of the worst symptoms of psychosis. And it allows us to make smart decisions about indication sequencing.

And then finally, of course, we're trying to move rapidly into patient proof-of-concept studies because we believe the opportunity with OV4071 is broad. We think this is, as I said before, essentially a pipeline and a product under itself. But it's not just animal data that we're resting on. I recognize we've given you a lot of animal data here today that's giving us conviction, but we also have human data. So many of you recall, we had a tool program that we read out at the end of last year. It was an intravenous direct activator of KCC2. That program name was OV350. Eliseo alluded to it a couple of times in some of our earlier animal models. We spoke to you at the time, mostly about safety and tolerability. We were excited to show that we can safely drug this class. But what we didn't spend as much time talking about is that we also saw suggestion exactly of the same kind of biomarker signals that now we've shown you over and over and over again in animal models. And what I mean by that is on quantitative EEG, so same types of biomarkers that Eliseo was just mentioning a moment ago, we were able to see central activity that was consistent with the [ spectral ] power shift, so consistent with the KCC2 mechanism of action, and we saw gamma band changes specifically in that Phase I study in healthy humans. And that was aligned with when we knew we had drug exposure in the brain.

So encouraging that all the disease biology that we've seen in animals, we've also seen start to play out in a very focused human study with our tool program. So that's giving us the conviction to walk into our Phase I program. In many ways, this is a traditional Phase I. There's a couple of things I'll call out about it. One, you can see we've got a number of cohorts. The reason why that is, is we think we have a drug that's going to be highly effective based on low doses, as Eliseo had mentioned, and we have very good safety margins. So we may have superb tolerability. We will fully characterize the opportunity here because we think it could be very broad.

In addition to that, you'll see we have an elderly cohort because we have conviction that this could potentially be a very good future drug for various forms of neurodegenerative psychosis. And then finally, you see that we will also have the ketamine challenge, and we'll initiate that once we have our PK well characterized and our [indiscernible] characterized. It's important from a design perspective. So what that means is the next 12 to 18 months is going to be very busy for our team here at Ovid. We're initiating that Phase I this quarter. We've been cleared, as many of you know.

The ketamine challenge, we intend to start in the second half of this year based on what I said a moment ago. And then in the middle of next year, we intend to initiate or basically near the end of H1, we intend to initiate a true schizophrenia Phase II proof-of-concept study. Concurrent to that, we will initiate a safety and signal finding study in Parkinson's disease psychosis and psychosis associated with Lewy body dementia. And you can see on the far right-hand column here, some of the primary endpoints that we'll be exploring in those studies.

But a big piece of our strategy to derisk our asset is very similar to the type of strategy that we took with OV329. We try to ask the important questions early to learn as much as possible and elucidate as much as possible the pharmacodynamic attributes of our molecules to be able to best develop them. And a big piece of that is using a biomarker strategy.

Now I will say, we are conducting a very broad array of biomarkers, both in our Phase I, where we'll use electrophysiology in healthy humans as well as in the ketamine challenge study. We don't have time, it would be a whole day lecture with our guests to be able to talk about all the biomarkers and their applications for each of the conditions that we may want to eventually explore for KCC2. But I'll direct you to a few of them here.

First, you've heard us talk a lot about quantitative EEG. That allows us broadly to assess arousal and activation. Things like mismatch negativity allow us to look at essentially the change in detection and a sensory scene, the auditory study state response gives us a sense about neurosynchrony and where you may not have synchrony. Prepulse inhibition is another biomarker that we use using -- that helps us assess essentially auditory sensory gating. And we're using both EEG, so electroencephalography as well as event-related potentials to help us explore these broadly.

But what does that mean in terms of the indications we're talking to you about? Each of these biomarkers has different signatures, as you heard Eliseo start to describe in different conditions. And we'll give you an example here, but there are many because obviously, we're looking very broadly much as we did with our epilepsy program. So for example, in a population of people living with schizophrenia, there has been good data showing quantitative EEG has a signature of how certain neurotransmitters drive frequencies. So for example, in someone who is living with schizophrenia at resting state, they tend to have essentially lower that slow wave motion, so delta, for example, and theta, and higher frequency of gamma. You heard Eliseo expand on that earlier.

So by giving our direct activator in something like a ketamine challenge, if we're able to reverse that, right, just as Eliseo showed that we have in animals where we increase delta power and we decrease gamma, that gives us a good sign that we're operating on the neurotransmitters in a way that we can see through quantitative electrophysiology that may be beneficial to the symptoms of the disease based on what we know.

And the same is true if we look at Parkinson's disease psychosis. And this one, I'll point you to a different biomarker mismatch negativity. So we're casting a broad net but these have read through from many different forms of psychosis. And this helps us learn a lot, again, early to make the best decisions for the clinical trials that we walk into. So in mismatch negativity for people who have hallucinations associated with Parkinson's disease, this particular biomarker or their visual specifically, mismatch negativity is particularly reduced.

So if we're able to show in a ketamine challenge that, again, we're able to modulate this in the opposite direction, what does that give us? It gives us more conviction that the drug is acting as it should and potentially helping with what could be pharmacodynamically beneficial attributes for the indications we're walking into. And I think it's important, sometimes we get a lot of questions when we talk about a ketamine study. I think rationally what we're all hearing, it's a very similar perturbance to what we used in animal models. It's an NMDA antagonist. So we can reproduce some of the underlying disease biology and neurotransmission that we see happening in disease.

But in the past, other drug developers have sometimes tried to use ketamine challenges to change behavior, right? And what we see is the true advantage of the ketamine challenge is to look at electrophysiology, to look at the activity of neurotransmission in the brain and allow us to confirm that we're seeing the changes that we want to see that should be supportive of symptom relief in these indications. And this gives you a sense of what the protocol for the ketamine challenge will look like.

So it will be a true crossover study. The subjects will be healthy volunteers, but they act as their own natural controls. And on the right gives you a sense of some of the electrophysiological biomarkers that we'll be assessing. So we'll be looking at quantitative EEG, as we mentioned before, event-related potentials, some of those biomarkers I mentioned just a moment ago are the exact same ones that we'll be looking at in addition to cognitive testing, which we will also do a battery of series that are well characterized as well as plasma-based biomarkers. So we expect to reap a lot out of this, and we'll be reading it out by -- around the end of this year.

What does that mean to where we go next? Well, we want to get to patients as rapidly as possible. I mentioned we'll be conducting a true Phase II proof-of-concept study in schizophrenia. We expect that to be a multisite study here in the U.S., and we'll be looking specifically at acute schizophrenia. While we believe the opportunity is broad, we're going to be focused in this initial Phase II in terms of the various symptoms of schizophrenia that we can operate on. Simultaneously, we'll be launching a Phase Ib exploratory signal finding and safety study, as I mentioned, in PD psychosis as well as Lewy body dementia psychosis, and we'll be looking at safety tolerability. But again, we'll use electrophysiology to help us establish a signal.

And if we do this the right way, we think this will not only create an entirely new class of medicines that could be deeply meaningful in indications that have very few or unfortunately, very limited therapeutic options. And if we do this right, from a commercial perspective, we think the commercial opportunity could be quite vast. If you look at the 3 indications alone that we've talked about today and not some of the other ones that could also be relevant, like Alzheimer's psychosis, this is more than a $6 billion opportunity unto itself. But most importantly, we think this is a potential drug that could really help so many patients who don't have good options.

So in sum, what that means is the next 2 years at Ovid are going to be very busy. Between our epilepsy program, where our colleagues, half of our team, our CMO and CSO are on the other side of the world, launching all of our Phase II proof-of-concept studies, and this KCC2 portfolio, we have somewhere between 5 to 6 proof-of-concept studies reading out over the next 6, 12, 18 and 24 months. So it's a big year of execution, but we're very excited about the patient populations that we may be able to help.

And just in summation, hopefully, you've learned a little bit more about KCC2 today and all of the disease biology, pharmacodynamic data, tolerability data that's giving us conviction about the type of medicine that OV4071 may be. And we truly believe that directly activating KCC2 is one mechanism with infinite possibilities. We believe we have a very good molecule to take into the clinic. We think the translational biomarker strategy and the electrophysiology we are undertaking will help us ask and answer many important questions about potential indications we walk into, and we are the company that will pioneer KCC2. And if our bet is right on this, we have an entire portfolio of additional next-generation development candidates underneath of this so that we can truly unlock the full potential of KCC2 direct activation.

So with that, I want to thank you for your attention. And we'll now open the floor for Q&A along with our experts.

I saw Laura's hand up first. And we'll start with individuals in the room, and then we'll take any of our participants who are online. Sorry, we'll get you next, Laura. It looks like the mic is upfront. Ritu?

Okay. Great. Ritu Baral from TD Cowen. I guess the first question. Sorry, Ritu Baral, TD Cowen. The first question, Meg, is as you look at the different types of conditions you're going after and the Phase II studies, one, do you anticipate the primary endpoint will be sort of the more classic psychosis endpoints like the SAPs and the scales used for PDP?

And then second, as you think of the aspects of not just the hallucinations, but also the cognitive impairment of the different indications, they seem to be very different. With schizophrenia, you have the visual hallucinations. I'm sorry, the auditory hallucinations. And you mentioned that the cognitive impairment was more sort of task switching and working memory versus PDP. Eliseo, you and I talked about this way back in [ Acadia, ] where it was more visual hallucinations and like executive function. So how does like the mechanism fit into those sort of different profiles?

So endpoints was the first question. And then the second one was the broad symptoms and where we act, right?

Yes. Great to see you, Ritu. So yes, great question. The -- on the -- at the symptom level, as you said, the most prominent hallucinations in schizophrenia are auditory, the most prominent designations in PDP are visual. The field believes that this is due to the areas of the cortex that are most affected in schizophrenia and in PDP. With respect to the cognition, it's the same thing. So for Parkinson's disease, we used to call it a subcortical dementia. It's a subcortical dementia because it's very different from Alzheimer's or any other type of dementia, which are considered cortical, but memory and behavior are at the first symptom. In PDP, there is more slowness.

So the paradigms that Michael shared are very, very relevant for schizophrenia, probably less so for Parkinson's disease. In a nutshell, the proof of concept in schizophrenia, the main -- the primary variable would be efficacy with the [ bench ] total, which is a construct that has positive, negative and other symptoms, general symptoms. Then if that study is positive, then you should launch a typical Phase III program, where you can include in that Phase III program specific studies on negative symptoms and cognition.

I think we had a question from Laura Chico.

Laura Chico, Wedbush. I have two questions. On the proof-of-concept schizophrenia study, if you could talk a little bit more about the patient characteristics that are coming in. I guess I'm thinking about background medications. I think you might have mentioned inpatient study. I'm trying to understand what you would want to see on a [ PAN ] score basis?

And then actually a question for Dr. Halassa. Your preclinical work, have you investigated any combinations of the KCC2 activators with like risperidone or xanomeline in animal models. I guess I'm curious if you're restoring the E-I imbalance, how would you think about the impacts of potential combination effects?

So Eliseo, why don't you address the trial? And Mike you can talk about combination.

Okay. As I mentioned earlier, there hasn't been many, many changes in an acute schizophrenia trial from the ones we were doing in the '90s and 2000s at what have been done with the typical anti-psychotics and what Karuna just did in Phase II. The only -- we will look for a typical population for those trials, not on antipsychotics. If there were antipsychotics before, they need to be withdrawn for a period of time, commensurate with the half-life, in particular, [indiscernible] anti-psychotics. And the entry criteria for the past is going to be similar that you have been in LBPharma and Karuna.

The only difference that we might -- we were considering and we think we're going to adjust is to look at the duration of the disease. We might not want to take the oldest of the oldest schizophrenic patients with 25 relapses and 40 years of disease evolution. But other than that, it's going to be the typical acute schizophrenia trial.

Mike?

Yes. So great question. We haven't done any combination medications in animals. But maybe I could say a few things about -- that may go to the core of your question is what is being -- what is the kind of theoretical framework for KCC2 in schizophrenia or what's the circuitry that we're thinking about?

So like Oliver mentioned, the dopaminergic kind of idea in schizophrenia is probably downstream of a frontal change in kind of the regime by which the frontal cortex works.

Now traditionally, we've just done D2 blockers. They take care of the positive -- voices for the most part, delusions actually aren't particularly affected because they have a cognitive component to them. This anomaly in trospium went one step above, right, with this [indiscernible] mechanism, and it has efficacy to work -- I mean, I've used it clinically, it works much better for negative and cognitive symptoms than traditional antipsychotics.

Now the promise here or the idea here is that you're going even one step above that and going to the source of the -- what I call the blast, the prefrontal deficit. And what I didn't -- there's a couple of preclinical data that I didn't show, which would be good to mention here. One is the deficit in KCC2 in the animal models that we have is specific to the prefrontal cortex, right? So K -- we've looked across cortex hippocampus, sensory cortex KCC2 is fine, even in these models. Hippocampus, KCC2 is fine.

Another thing that we did, I think that's really relevant is we've done genetic knockdown of KCC2 in prefrontal cortex and in somatosensory cortex, as a comparison. You knock down KCC2 by 50%, you reproduce the schizophrenia relevant phenotypes. You knock it down in S1, nothing happens. You knock it down in hippocampus, you get seizures. So it's an interesting kind of -- maybe that's too much information. But you get what I'm saying. There is a story there about frontal function and schizophrenia that people have thought about for a very long time. And now we have the tools to kind of elucidate that and hopefully reverse it.

And Laura, just to be clear, in psychosis, we haven't trialed 2 drugs at once. We have in various forms of very acute seizures, put our drug on top of benzo and some things like that, and we have seen the restoration actually of excitatory inhibitory balance where benzo into itself couldn't do that, but those are seizure models.

Myles?

Two questions. One is on KCC2 biology, the other one on the ketamine trial design actually. So the first 1 just, do we know why the glycine transporter inhibitors actually failed in many of the indications you're going after? There's a lot of literature out there supporting glycine and control of KCC2 expression. So I'm wondering why that indirect pathway didn't necessarily work and why your direct activation would? That's the first one.

Second one on the ketamine trial design, is the 10-day washout period between the crossover enough. If you look at depression studies, I mean, we're having dendritic spine expansions, those sort of things happening months after single doses. And I'm wondering whether you're changing the baseline of your EEGs when you're doing that comparison.

So I see Eliseo smiling already. We'll let him take the second one. But in the meantime, since you have a world leader in psychosis translation, I'll let Oliver take question one.

So glycine transporters inhibitors, why did they not work? Well, there could be tons of reasons why they didn't work, of course, drug didn't get into the brain, didn't have enough concentrations, it doesn't hit the target correctly. You need to have glycine there for it to work, et cetera, et cetera. But I think actually, it's probably not necessarily targeting the mechanism specifically enough. It's just -- it's boosting NMDA receptors, which may be part of the problem. But actually, these GABA-ergic markers and the genetics, it's not just NMDA. This is GABA, it's other excitatory pathways as well. So I don't think the glycine transborder inhibitors may be broad enough to cover all of that.

Great question about wash out after ketamine, and we're still debating that. As you mentioned, ketamine could produce changes that outlast the PK of the drug. It's the famous PK/PD, the association of this type of drugs, and that's our concern. That's one of the reasons why we're doing the trial in a site, bio trial in Newark, New Jersey, where they have done that many, many times, okay?

So we -- if you put a gun to my head and you're going to say, it's going to be 10 days, I don't know. I think it's going to be something like 10 days. It's not going to be 2 months. It's going to be something like 1 or 2 weeks, something like that. Closer to 2 weeks than 1.

Frank Brisebois with LifeSci Capital. So just a couple here. There's obviously a lot that was discussed. We talked about the importance of kind of the convergence of all the data, a lot of preclinical data. Is there something, though, in the -- that was extra shocking or surprising from your perspective? Or is it really just as a whole, and we're not ready to discuss our favorite [ kid ] here, sort of?

So I'll go first and then maybe Oliver, if you want to speak to the second. So I think what I sort of summed up before, I think, matters a lot to us. Unfortunately, giving a rat methamphetamine, which I think Eliseo has said a lot about is, well, what can I get out of that? What does that tell me relative to the inherent risk of studying a form of psychosis. But I think what -- you've heard the word converge a lot, and we really beaten that because what we're seeing is essentially the underlying biological changes of neurotransmitters that we want to see across now 25, 30 different disease biology models, which together is giving us great conviction, coupled with the work that Mike showed about rescuing working memory, right, and certain behaviors and the specificity for KCC2 in these genetic models of schizophrenia.

And then finally, being able to hold ourselves up against active doses of reference products and see that in addition to that broad armamentarium of data that we're affecting the biology as we want to do and the neurotransmitters in a way that should be hopefully restorative relative to some of the worst symptoms of these forms of psychosis in areas like schizophrenia, for example, we now know that we are matching or outperforming drugs that are good drugs and the only drugs that are used.

So it's really the totality of that triad together that gives us a lot of conviction. And what we're trying to do before we invest in expensive and large pivotal studies or Phase II studies is extract as much helpful information from the electrophysiology and these translational biomarkers that we've established in animals to give us conviction about where we put the best expenditure of capital for the next set. So if we're seeing all the things that we hope to see in animals in healthy volunteers and then in this ketamine challenge, gives us incredible conviction to march into that schizophrenia proof-of-concept study.

But Oliver gives you an independent view, which I think is nice to have in addition to company management. So Oliver?

What I think is interesting here is that you've got a with qEEG that is measuring electrical activity that, as I said, this is how the brain works and E-I imbalance, it disrupts this. So here, we've got something that you can measure, as Meg said, across preclinical into clinical. So I think that's the real advantage. And I've been looking for something that is able to change this biology for quite a while. And so I think this is why this target is interesting.

And then just maybe a last one on that is we talked about the other drugs that are out there right now and issues with tolerability. Do we understand why we cannot over modulate KCC2 in terms of the safety side?

Yes. I'll start and then Mike, I think Mike would be a good person to answer this. But essentially, energetically, it's almost impossible for this neuron to extrude too much chloride. Do you want to speak to that, Mike?

Yes. So I mean this is kind of set by things called electrochemical gradient. So across all cells, there are uneven distribution of ions that you can think of as the batteries driving flow inside and out and they're balanced by a number of different factors, the concentration gradients and the electrical gradients. You cannot push more negative charge outside of the cell before the positive ions pull them back. So there's something called the [ neurons ] potential that kind of governs that, which is kind of the universal reason why action potentials or spikes cannot go above plus 40 millivolts because that's -- that's it, that's what the battery's limit is. Same thing is true with KCC2. You can't over modulate it because you can't push out too much chloride. Otherwise, the driving force will push them back in.

Good question. Is that [ Basma? ]

This is Basma on for Marc Goodman from Leerink. We have a couple of questions, please. So the first question is, could you provide some information on the level of the KCC2 activation that you would need for this antipsychotic efficacy, literally in terms of receptor occupancy. And does this level of activation translates well from the animal models to human models?

Our second question is about the indication for the first indication you're pursuing for the KCC2. You mentioned that you're pursuing the Parkinson's disease psychosis. Why did you decide to pursue that first before Alzheimer's disease psychosis, for instance? Did you do any animal works in Alzheimer's models and did you find similar efficacy and for strategic reason, you decided to start with PTP first?

And just to follow up on that, would you expect this mechanism to be general -- to generalize and be effective across the different dimension at the psychosis or this is something still in the works?

I'll say a few words, and I'll pass it over to Eliseo, who's given us a lot of thought. One thing, Basma, may make you a little bit frustrated, Eliseo can speak broadly, although some of our receptor occupants and some of the specifics, it does happen to be a competitive landscape. I'd prefer to not give everything to the rest of the world.

But in terms of our strategic decision-making around Alzheimer's psychosis and other forms of psychosis, we think this is a broad syndromic antipsychotic. We think this has broad relevance. Why not march into Alzheimer's psychosis immediately? Well, for a couple of real-world things, yes, we're continuing to build the armamentarium of evidence around it. We think there's some very translatable things that we could learn from schizophrenia and PD psychosis.

And also, when we look at the studies that are being done to assess Alzheimer's psychosis or Alzheimer's agitation, both of which we think KCC2 direct activation is a good target for, to get to a hard answer in terms of a proof of concept is a bigger study and a longer study. So we are very interested in that. And we probably will be talking to you about that if some of these plans go as we have suggested that we think they will. But it's a very big study out of the gate when we can get more confirmatory electrophysiology, we can start to get a read-through from other forms of psychosis, and then initiate that program when we have the totality of data in our hands that gives us conviction for a longer and, frankly, more capital-intensive trial because it's bigger in size and it takes longer to enroll.

But Eliseo, please expound on that.

Yes. On the first one, without sharing competitive information, yes, we have a strong evidence of binding and strong evidence of activity. So as I mentioned, the [ 50.6 ] micromolar. And these are concentrations that we're confident that we are achieving, and the electrophysiology that we have seen in animals. It's another evidence or a piece of the evidence that we are doing. The drug is doing what it's supposed to be doing at the concentrate -- expected concentrations.

The only thing I would add to the Alzheimer question is that, of course, I mean, all of us has, in addition to schizophrenia and Parkinson's that should be for society, for our families, terribly positive. I will point out in addition to what Mike said is that if we have a positive proof of concept in schizophrenia, you might decide to do Phase III on Alzheimer's disease as other sponsors are doing. It's a matter of funding.

Next question,[ Imagen. ]

From Cantor. Given that we have the world biology experts here, I do have a biology question. So you talked about the postmortem findings of down regulation of KCC2. Does direct activation of KCC2 impact expression? And did you find that in preclinical studies? And then as you think about the situation in schizophrenia patients may have down regulation, how do you expect activation to work?

Great question. Many things I can respond with. First is these postmortem studies were done with immunohistochemistry. We repeated those using publicly available data sets with single-cell RNA seq, and we find the same thing that this is this replicate. So the mRNA is reduced and it's very robust.

In the experiment that I meant -- so it's reduced, the expression is reduced. Under the conditions that we measure, I don't think that we're increasing the expression of KCC2. We're just activating whatever is remaining. And then the experiment that I mentioned, this came up actually yesterday is when we knock down KCC2 by 50%, we can still rescue that with direct OV compounds. So whatever is remaining, we can kind of restore the chloride homeostasis with the direct activation.

Matt Hershenhorn from Oppenheimer. Really appreciate this today. The question we had is just have there been other attempts by academics or other sponsors to develop KCC2, specifically direct activators and any lessons from those? Meg, I don't know if you could talk a bit about BiP and advantages you see there? And if you don't mind to just reemphasize why the direct activation specifically is the right approach here?

And just sort of big picture, as you look to other indications, you referenced your portfolio of other next-gen approaches presumably with different PK profiles. Just kind of curious how you look across the spectrum of these indications and what could be more appropriate for either side of that spectrum as you look at the additional indications?

Yes, very, very thoughtful questions. So I mentioned the direct activation matters because we believe at, one, we can see and we've proven it when we have a very rigorous set of criteria that any potential development candidate at Ovid goes through for the direct activation portfolio, where we need to see essentially certain clearing criteria that not only have we identified where they bind, but also that we're seeing the output that we want to see that we're able to actually test for the chloride extrusion and being able to directly activate that transporter matters, not just in order to achieve the extrusion of chloride that we want to enable GABA to be hyper polarizing, but it also matters relative to the safety and tolerability profile.

Now for example, if you go out and look in the literature, Matt, you asked the right question, which is have other people tried to do this? Yes. And it's hard. It's very hard to get to the medicinal chemistry to get into the pockets that we need to, to directly activate this transporter. It's been very hard for the field. Our team and others have worked tremendously on this.

But one of the things we know from the work of others is others have tried to drug the target, but they haven't been able to directly activate the transporter. So they don't get that efficient balance and flow of the ions out of the transporter, they may operate on it in a different way, but they might not have the same essentially mechanism of action. And if you go back and you look at, for example, literature on a tool program of another company that's tried to be in this place, you'll see that -- they -- that's referred to as a potentiator. And I believe that's probably a neuroactive drug. We've screened those backbones and run them head-to-head against our own direct activators, but they operate a little bit differently. They're neuroactive in a different way, some academics have suggested they operate a little bit more like a GABA PAM.

So essentially, what I'm saying by that is by not directly activating KCC2, but by modulating the target or hitting the target in an indirect fashion, you may have neuroactivity, but you're not necessarily going to have the same activity that we can through our direct activations, again, through the appropriate flow of those ions and balance those ions.

In terms of our discovery library of KCC2, so this has not been an easy target to crack. It's almost like a KRAS-like target in terms of the challenge from a medicinal chemistry perspective. But we have learned so much about this target in the time that we have been developing OV350, the tool program, then OV4071, and we have terrific IP on those. For OV4071, we have composition of matter IP into 2046. And we have, I think you can check me on this with Jeff, but at least 13 other method of use, patents, and we'll continue to build upon that portfolio. So very strong, long IP runway. So that's great.

But you heard us say, we are the KCC2 company. And if our thesis is right about this, we would have multiple molecules because we believe the therapeutic opportunity is PD-1 like in terms of scope. We think it's incredibly broad. So we have now identified a much more efficient screening criteria for our candidates. We have built new structures or new backbones on 2 series of next-generation chemistry. And it's our ambition and our goal to be able to yield at least one new development candidate into the clinic every year for subsequent years going forward. which, of course, is also a completely new IP because they are completely unique molecules in new series.

I think Ram has a question?

No, no, I have a question. Yes. So [indiscernible], on behalf of Boobalan from ROTH Capital. Can you confirm if you're developing OV4071 as a monotherapy or as a combination with SoC for PDP and schizophrenia? And if combining with antipsychotics is a possibility, do you have any commercial antipsychotics in mind?

And another question is, can you also discuss whether the headache, nausea and GI side effects are pertaining to -- in OV350 Phase I study, it pertains to the molecule and not the KCC2 activation?

Yes, we'd be happy to answer those questions. So let's start with your question about the monotherapy. Yes, it is our intention to develop OV4071 as a monotherapy for schizophrenia and for the other psychosis indications that we've discussed with you here today. Why? Well, we're highly potent as a monotherapy in psychosis models. So we're seeing incredible activity at very low doses and in really strong safety margins. So it's our intention to take it in as a monotherapy.

However, there is no concerns that we have right now based on the potential drug-drug interaction portfolio that Eliseo described earlier that would potentially concern us about potentially exploring combination therapies in the future. And we have trialed combinations in different disease biology models with our KCC2 direct activators.

And then in terms of the extremely thoughtful question that you have. So there's nothing that we -- to be clear, that we don't think would prevent it from being used in a polypharmacy regimen based on what we know today or future combination therapies to your point. We think there's a lot of IP and drug potential here.

In terms of your question, which is a very good question about our tool program, OV350. So you heard me say earlier, OV350 was actually a great tool program for us to ask and answer some really critical questions about trying to pioneer and drug an entirely new biological target in the brain. But as a development candidate, it had some aspects that were less attractive than what we have with OV4071. So one of the things that we did note and it was in our slide about tolerability profile. So we saw in our Phase I study with the tool program, OV350, some headache, and we saw some nausea and basically GI disturbance.

And looking at that, there was an aspect that we knew about with OV350 that made it less attractive for long-term drug development, which was a secondary pharmacology. It hits a target -- a secondary target called CCK1, that if any of you guys cover the [ GLP-1s, ] you'll know you hit that. What does it do? It induces GI motility. So we saw a bit of that with some of the subjects in our Phase I program. Importantly, one of the aspects that makes OV4071 so attractive is it doesn't have any concerning secondary pharmacology like that, and it looks to be both incredibly well tolerated and again, very potent. So we don't expect to see the same thing there, but that was one of the things that we knew about going into the Phase I program, and we saw some signs of that.

Ram Selvaraju from H.C. Wainright. Firstly, with respect to schizophrenia, I was wondering if you could comment on the specific applicability of the PANSS as an efficacy endpoint in the acute schizophrenia proof-of-concept study? And also, if you have any plans with OV4071 specifically to assess the potential applicability of this compound in a long-acting injectable formulation.

Secondly, I was wondering if you could perhaps comment on the applicability of the KCC2 activation paradigm in neurodevelopmental disorders, particularly as this pertains to ADHD and autism.

And then lastly, in DLB, since you mentioned it on the slide as one future indication area that you might explore. Can you perhaps talk about which kind of route in DLB might be most applicable within the context of KCC2 activation? I mean historically, we've seen clinically, for example, with zervimesine going down more a neuropsychiatric pathway and anxiolytic pathway. Conversely, with neflamapimod, we're talking about assessing activity on the basis of an endpoint like CDR Sum of Boxes. So which of these paradigms in DLB might be potentially most applicable for KCC2 activation?

You gave us quite a few, Ram. I'm going to answer one of them going to hand it over to my colleague, Eliseo.

In terms of formulation, yes. We are looking at multiple forms of formulation, not just for OV4071, but also for the other candidates that we have in our discovery engine because we believe exactly as you're suggesting that there's multiple ways to serve both acute and chronic potential symptoms of a range of different psychosis. So we're looking to formulate broadly, not just OV4071 but also the other candidates in the library. We feel very confident with the strength of the oral program going forward that we've got a very good oral and chronic dose. But that's work that remains ongoing and it's certainly a core feature of our strategy.

Eliseo, why don't you talk about the endpoint design? Do you want to do that?

I'll start with the last one that I remember and try to go to the -- so yes. So the -- we believe -- one important thing in drug development it's not to get ahead of your skis, okay? So what Meg mentioned is that there are a number of models very relevant for psychotic disorders to active model, single dose, 1 model repeated dose and social interaction and so on and so forth is the conversion. Based on that, we believe that there is a strong case for the efficacy of OV4071 in psychotic disorders. We plan to study dementia with living body psychosis because there is psychosis like in Parkinson's disease psychosis.

Initially, we would look at the psychotic element, the number of hallucinations and there are -- the scales we use, the SAP and the scale that are used in Parkinson's and Lewy body dementia, they come from psychiatry. So there are adjustments from psychiatric scale.

The CDR Sum of Boxes, we might use that as a secondary end point. Michael mentioned very interesting data in cognition. It might be that there is an effect on cognition. And the interesting thing of thinking about Alzheimer's disease psychosis or Alzheimer's agitation that's also that we'll be measuring both. So in the 3 dementia conditions, dementia, Lewy body, Alzheimer's agitation Alzheimer's psychosis, we will have a secondary assessment with CDR sum of boxes or some cognitive scale.

Yes. So I think you're hearing Eliseo and my colleagues say that while we think the opportunity is potentially broad to handle a range of aspects of various forms of diseases, we're trying to be very focused in the end points that we go towards psychosis and measuring that to establish proof of concept, right? I think we had really smart colleagues and peers in the field who have gone after psychiatry, but they've gone very broad. They've had a hard time showing significance across so many different domains that muddies the water. So you'll hear us very much focused on the psychiatric scale and honing in on that, that we believe the benefit of KCC2 direct activation may be even broader.

We have a question in the middle.

This is [ Jenny. ] I'm on for Tom Shrader at BTIG. I had a couple questions. First, how exciting is a safe clozapine? How exciting is a drug with measurable effects on positive symptoms and no exacerbations of negative symptoms?

And secondly, you guys made several KCC2 activators or the effects of the activators, consistent across models where the less effective activators are consistent? Or do they act more like [indiscernible] across models with some successes and some not?

Okay. So I'll start, but I think Oliver, you should weigh in, in terms of how exciting is a safe and potentially more effective clozapine. I mean I think you're hearing us -- it sounds perhaps hyperbolic, but I mean, we think [ drugging ] and directly activating KCC2 could be a PD-1-like moment for the brain and both in terms of breadth, but in terms of meaningfulness of potentially being able to address with a completely new mechanism of action that appears at least in animals that should be very well tolerated, symptoms of diseases that are just completely unaddressed today.

And we know if you just look out by 2030, we have essentially a silver tsunami coming. And what I mean by that is all of the baby boomers in the United States will be over the age of 65. So what does that mean? It means we're going to have a lot more psychosis associated with PD, Alzheimer's agitation and delusions, right? So as our populous ages, effective medicines in these areas that can be used chronically and safe and well tolerated and work with other medicines is incredibly powerful, and I would argue much needed.

But Oliver, I'll let you answer that question.

Thank you. Well, I would be delighted to have a safe clozapine. I use it an awful lot, and it's really tricky to use. But actually, why I'm excited about this mechanism is I think it goes beyond clozapine because it's targeting the E-I imbalance that isn't really addressed by clozapine. It's targeting what I think is underlying negative symptoms and the cognitive impairments as well as the psychosis. And I think KCC2 makes sense as a target for that. I'd be delighted if there were any other ways of doing it as well, but I think this goes beyond clozapine if it works.

And I think there was another really good question about how did we perform relative to reference drugs. There is not a model that I can think of, and I'm looking at Eliseo to check me. But essentially, we're seeing broad activity in these disease biology models. And in several cases, our direct activators are working in models that known reference products like pimavanserin doesn't. And we're seeing activity in all the models where we're running head-to-head that's either commensurate or superior to.

So of course, animals are not the same thing as a patient, but the totality of all this across multiple different genetic and stimulant models across now a battery of somewhere between 25 to 30 different PD models is highly consistent and giving us great excitement.

But I think, unfortunately, we're at time. I want to thank you all for the really thoughtful questions and the participation today. We have our subject matter experts in the room, including the independent physicians and clinicians and researchers. So if you have additional questions, I encourage you to speak with them. And thank you again.

Good afternoon, everyone. My name is Angela, and I will be your conference operator today. At this time, I would like to welcome you to Ovid Therapeutics business and pipeline update call. This conference is being recorded. [Operator Instructions]

At this time, I would like to turn the call over to Victoria Fort. Please proceed.

Thank you. Good morning, everyone, and thank you for joining us. Earlier today, we issued a press release announcing business and pipeline updates, and financial results for the 3 months and full year ended December 31, 2025. A copy of the release can be found in the Investor Relations tab on our corporate website, ovidrx.com.

As a reminder, during today's call, we'll be making forward-looking statements. Various remarks we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements. for the purpose of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Forward-looking statements contained in this call are subject to a number of risks and uncertainties which could cause our actual results to differ materially from those expressed or implied in such statements. These factors include, but are not limited to, those discussed in our most recent annual report on Form 10-K and other filings with the Securities and Exchange Commission.

Joining me on today's call are Meg Alexander, our President and Chief Executive Officer; and Jeffrey Rona, our Chief Business and Financial Officer. Meg will go over the clinical and business updates we announced this morning, and then Jeff will detail our financial results. followed by a question-and-answer session.

Before I hand the call to Meg, I would like to note that we are hosting today's call in conjunction with the updates that we announced this morning in our earnings release. However, we do not plan to host regular quarterly earnings calls moving forward.

With that, I'd now like to turn the call over to Meg.

Good morning, everyone, and thank you for joining us. This is a great morning for Ovid. And I'm keen to take you through both pipeline progress and business updates that we'll go into greater detail with this morning. But I'd like to start with our pipeline.

Our good news is that we've now announced that we've received regulatory clearance for the first-ever oral KCC2 direct activator, which is OV4071. I want to thank our team who worked through the holidays to achieve this a quarter earlier than expected. In addition to that, this morning, we announced that we now have safety and tolerability data associated with the 7 milligram dose of OV329, our next-generation GABA-aminotransferase inhibitor.

I'm pleased to share that there were no serious adverse events or adverse events associated with the 7 milligram dose. All of our programs are advancing on track to patient proof-of-concept studies, and this is going to mean exciting progress and potential readouts throughout the end of this year throughout 2027. But we also have new news in addition to that, we're launching additive studies for 329. We'll walk you through the data that gives us conviction. But in addition to the programs that we already have in focal onset seizures, we're launching programs today in infantile spasms and seizures associated with Tuberous Sclerosis Complex.

What has helped making this possible is additive capital that we also announced this morning through a PIPE financing that was led by Point72. I want to thank that fund as well as our top shareholders who have come in again to support us, including Janus, RA, Balyasny, Affinity, Coastlands, Eventide, Adage and ADAR1. With this capital, we will launch those programs in a way that does not compromise any of the other development programs that we've already discussed.

Importantly, for our shareholders, the clearance of OV4071 also triggers a 30-day period for our Series A warrants. If those warrants are exercised, this will bring additional capital and potential proceeds to Ovid greater than $53 million. So with this PIPE that we're announcing this morning and the potential exercise of those warrants, Ovid will have a cash runway well into 2029.

We're excited to take you through all of this progress, which we'll do in detail and answer questions. But before we do, I just want to remind you what we're trying to do and how we're trying to operate to develop gentler, better medicines for the brain.

So all of our programs are focused on calling neuro hyperexcitability, as you know, we're pursuing fundamental biological targets to address that neural hyperexcitation we do that by pursuing differentiated in what we believe are universal mechanism of action through small molecule programs because at the end of the day, we want medicines that are easy for patients to be able to take.

So I'd like to acclimate you on our updated pipeline. What you'll see is some of the programs that we've already been progressing in the clinic and the new ones that I just mentioned. So starting from the top, our program OV329 for focal onset seizures is progressing on track. As we said we would do this upcoming quarter, Q2 of '26, we will be initiating a Phase II randomized placebo-controlled trial and later this year, we'll also be initiating an open-label photosensitivity study that will show us anticonvulsant response relative to the doses that we want to take into later development.

But I'd like to focus you on the green box that you see in the middle of this slide. These are the new programs that we'll be adding as a result of the PIPE financing that we discussed this morning. Specifically, we'll be taking 329 into signal finding and safety studies both for Tuberous Sclerosis Complex seizures and infantile spasms. We'll tell you more about the design of these programs in a moment.

And now with the first ever clearance of a KCC2 direct activator OV4071. This upcoming quarter, Q2, will be initiating a Phase I study, and we'll be running a ketamine challenge that will help us better characterize what we believe is broad antipsychotic activity associated with OV4071.

But for today's news, we're going to start with 329, which let me remind you, we believe as a potential best-in-category antiseizure medicine, which we think is appropriate as a treatment, not just for focal onset seizures but also these very specific developmental epileptic encephalopathies that we're discussing.

I'm going to start today by telling you about the clinical progress we have with the 7 milligram dose. This gives us even more conviction to open those proof-of-concept studies that I just mentioned in infantile spasms and Tuberous Sclerosis Complex. So what we believe of 329 at this point in time is that it has a potential best-in-category profile. What do we mean by that? At this point, we know with 329. It is delivering inhibition in the brain and GABAergic inhibition, both in the synapse and the extrasynapse.

We believe that's leading to an optimal tolerability profile. We know that we differentiate from the safety profile of the first-generation GABA-aminotransferase inhibitor, which was called vigabatrin, which had some irreversible safety, ophthalmic issues.

And importantly, this is a mechanism that is validated in focal onset seizures. So we believe that we will have competitive efficacy, and when it comes to patients, what's important is we want a medicine that's easy to take. So we anticipate in focal onset seizures once daily dosing, very low dosing and no titration.

So let's dive into some of the data that supports this program because we know in focal onset seizures, while there are many medicines there is still tremendous unmet need with 40% of the community still uncontrolled with the existing mechanisms of action. So starting with the safety data that we have in hand.

Our 7 milligram dose, in adults and healthy volunteers, has demonstrated a very strong safety and tolerability profile. As many of you may recall, we ran the 7 milligram dose to expand dose optionality for our later-stage clinical trials. What the 7 milligram dose has now demonstrated is that we have no treatment-related serious adverse events.

And additionally, across the entire SAD and MAD cohort, there were no adverse events associated with OV329. It's important to note there were adverse events in the whole cohort but those were not associated with treatment. And some of the most common adverse events were things like cannula site reactions. Of course, there is also no ophthalmic safety concerns. But let's take a deeper dive into this.

Over the course of 329 characterization in healthy volunteers, what you're seeing in front of you is the adverse events that were reported that could be associated with OV329, these included across various doses headache, drowsiness and metallic taste. All of these were very low in frequency. They were mild and they resolved.

Importantly, relative to differentiation from the first-generation GABA-aminotransferase inhibitor, we have extremely rigorous batteries of visual testing as well as structural photography of the eye to ensure and to prove that we do not have the same retinal accumulation and dysregulation that was seen with the first-generation drug.

I can confidently say we have seen nothing associated with OV329. Of course, we will continue to run this battery of very rigorous testing throughout the entirety of OV329's development because as we move towards registration, we want to be able to take to regulators a very deep armamentarium of patient ophthalmic safety data because we want to avert the monitoring and the REMS that was seen with the first-generation drug.

So all this is good news, but what makes us really excited as drug developers is what I'm about to show you next. So we have a lot of data that we leverage to inform our dose strategy with OV329. And from a pharmacology strategy perspective, to achieve the inhibition that we seek and ultimately, the anticonvulsant activity that we want to achieve for patients. Our strategy has been to inhibit the GABA-aminotransferase enzyme between about 50% to 60%.

In order for us to achieve that, there is a drug exposure level in the plasma that we have modeled, again, across multiple streams of evidence that are reinforcing to each other. And you see that range in the middle bottom of this page here, to roughly 16-nanogram per hour per ml to 120.

Now I'd like to point you to the right-hand side of the slide. what you'll see is the actual human data, and this is mean drug exposure in the plasma associated with each dose of OV329 that we've tested. Importantly, if you look where the green boxes, you'll see that both are 5 and 7 milligram doses deliver drug exposure in the plasma that should be consistent with the inhibition and potentially the anticonvulsant activity that we seek to achieve.

Also, importantly, we have linear PK as expected and consistent clearance. In addition to this, many of you may recall, last fall, we wrote out the most expansive biomarker program that's ever been done for a seizure medicine at this stage. What that showed us across multiple biomarkers is that 329 is not just getting into the brain, but it's delivering cortical inhibition in a way that was highly significant and in a way that either matched or surpassed the levels of inhibition that we're seeing with therapeutic doses of the first-generation GABA-AT inhibitor giving us incredible conviction.

So what comes next? We have great confidence now that we have 2 doses that are within the exposure range that we predict to be therapeutic and that are extremely well tolerated. They have shown cortical inhibition as measured by multiple biomarkers and at this point, we believe these are 2 strong doses to be able to take into Phase II programs that in addition to being a safe, well tolerated and delivering inhibition, we believe, will also help optimize our responder rate.

So I'd like to tell you more about our upcoming trial designs. As I mentioned, we are now launching 2 studies to demonstrate proof-of-concept in anticonvulsant activity for 329. Later this year, we will start an open-label photoparoximal study. For those of you who aren't familiar with this design, what it does is it essentially allows us to demonstrate potential anticonvulsant activity in a population of patients who have a photosensitive form of epilepsy.

We hope to have this data late this year. And why this is helpful is while we enroll a true gold standard randomized, placebo-controlled Phase II program, which will start next quarter, this gives us in the interim anticonvulsant potential demonstration, again, giving us increased conviction in a potential derisking event about the doses that we want to take into later development. And for our Phase II randomized placebo-controlled study, again, we intend to take 2 doses into that study. And this will be a traditional epilepsy study over 8 weeks to be able to demonstrate the key and traditional primary endpoints associated with seizure trials.

So this is very good news, and I want to thank our team for delivering this result. But now I'd like to turn to the new news, which is the pediatric programs that we're adding. So you've heard us talk about the adult capsule formulation of OV329, but we've long been thinking about expanding based on the data that we have in hand, and we have the opportunity to develop a pediatric and protected weight-based formulation to be able to serve the needs of these children and adults who remain very underserved.

And I'd like to take a moment to speak about that, starting with infantile spasms. Many of you may not have heard about infantile spasms because frankly, there's been extremely little drug development in this area for the span of the last 20 years than it's needed. When these babies have infantile spasms, which occurs between 4 to 7 or 8 months of life, it is an emergency. They have associated developmental disabilities, increased mortality and the risk of lifelong epilepsies as a result of this. Despite the deep severity of this condition, there has been very little innovation.

Today, the current standard of care is Acthar Gel or other high-dose steroids as a first line and Vigabatrin, that first-generation GABA-AT inhibitor as a second line. Similarly, in Tuberous Sclerosis Complex, this is a genetic condition in which essentially children are born and form benign tumors or hamartomas across multiple different organs. But in this case, the one that we're most focused on is the brain. And people who live with TSC have high, high probability of having seizures. In fact, 80% of the community experiences them.

Similar to infantile spasms, the standard of care is very limited for these patients despite that high frequency of seizures. The primary standard of care is Afinitor as well as Sabril, and those have limitations with how they can be used based on their safety. In contrast to that, we think OV329 -- has tremendous potential and may even be disease-modifying.

Why do I say that? If you look at the profile on the left, which we'll talk to more, but then you look at the column on the right, in infantile spasms, we believe that there is an opportunity for 329 to be used first line with Acthar Gel and to be used longer to mitigate some of those developmental and epilepsy outcomes that we commonly see. We believe this because if you have a safe and well-tolerated and effective GABA-aminotransferase inhibitor, clinicians will be comfortable using it earlier and for longer.

Similarly, in Tuberous Sclerosis Complex, we believe that a safe and well-tolerated GABA-AT can be used first-line for seizure reduction and over time, because some of these babies are diagnosed very early, we may be able to build a path to possible prevention of seizures associated with TSC. We think this is hugely important. What gives us conviction beyond the data that we have in 329 from our own trials, is that this is a mechanism that we know works.

So if you look on the left-hand column, the efficacy associated with GABA-aminotransferase inhibition in these indications is proven. And in fact, it's been pretty profound. We've seen freedom from spasms freedom from treatment failure and infantile spasms, and we see a high responder rate to those who respond in TSC, including a high degree of seizure freedom. But because of everything that you see on the right-hand side of the slide, Sabril is not used much today.

But we think that the opportunity that exists is much bigger. And when you look at this, what we're showing you here is how the drugs that are used as a standard of care are prescribed for these indications. And there's a lot of information on these slides, but I'm going to mostly acclimate you to the right-hand side of the slide.

So what we see when you look at Sabril is it really under reflects what we think is the not just the unmet need but the market opportunity in these conditions. So Sabril, as many of you may know, which is the brand name of vigabatrin, was introduced decades ago was initially priced for a larger population epilepsy. But if you look across the middle row of these tables, you'll see that it's very limited in its treatment duration because the clinicians and oftentimes, the caregivers and parents are concerned about using this for a prolonged use because of its safety.

Nevertheless, Sabril in the U.S. alone had peak sales of $320 million. So we think, again, the opportunity of a safe version of this mechanism could be significantly bigger. And this just gives you a sense of what's giving us belief. If you look at the opportunity and the sales that were associated with Sabril again here just in the U.S., we already have established a better therapeutic index with OV329 than what we saw with Sabril.

If you assume that we're able to also realize ex U.S. sales, earlier line use and this treatment duration, we believe that the opportunity for OV329 in addition to the opportunity that we were already pursuing in focal onset seizures is very significant. And we hope with this enhanced penetration duration will lead to very significant commercial opportunity.

I want to quickly point to, we're not going to spend a lot of time on this today, but we also have preclinical data that gives us confidence that these are the right indications to go to. In infantile spasms, and focal onset seizure models, which is the distinctive seizure commonly seen in Tuberous Sclerosis Complex, we have demonstrated that OV329 is highly efficacious.

And for those of you who have been following us, you know that we believe that we have a much safer version of the GABA-aminotransferase inhibitor than what we've seen idiosyncratically with the first-generation compound. We have shown that in animals OV329 does not accumulate in the retina and cause the retinal dysregulation that was the hallmark safety issue associated with vigabatrin.

And we've looked at this now across multiple species. So what this means in terms of the future of OV329, we think is quite bright. If you look at the path to registration for OV329, we are continuing on with what we promised to all of you we would do with focal onset seizures with those studies that I mentioned. But importantly, we're opening what we think is not just an opportunity for orphan status, but a very efficient path to registration.

The signal finding studies that we have in Tuberous Sclerosis Complex will allow us to establish signal, safety and step down and establish our pediatric dosing to inform both a signal finding study in Tuberous Sclerosis Complex but then also confirm the pediatric dosing that we will take into infantile spasms.

We believe there's an opportunity in both of these indications for a combined pivotal Phase II/III study, thereby enabling that efficiency to registration. So as we wrap up the 329 section, we feel this is a strong win for our patients, for our shareholders and our company. This is a completely additive clinical expansion program in derisked indications. It allows us to do what we were doing before and create more value. What that means for our shareholders, as you should anticipate more milestones and catalysts, both in the interim and in the long term.

We have the potential to develop these differentiated formulations to be able to protect the -- and separate the IP and to consider the various commercial needs of both of these communities. And at the end of the day, we believe this is going to enhance the value, both through the program and for the company.

So this is great news. Again, I want to thank Point72 and our shareholders for supporting us in this. But I want to take just a couple of minutes at the end to tell you about the good news with KCC2, which we've been talking about for a long time and the oral KCC2 direct activator is now here. So let us tell you what we're on track to do.

We have clearance in Australia. That's important, as I mentioned, because it does trigger those Series A warrants. After Australia, we will be immediately following in the U.S. and then the European Union. We are on track to initiate our Phase I study, that's next quarter, in Q2. That will be followed by a ketamine study later this year to show proof of mechanism, and we're on track to start proof-of-concept patient studies late this year or early next year.

And I want everyone to know this is not the only case 2 direct activator. We have an engine of discovery and further candidates coming beyond it. And we'll be telling you more about that at a KCC2 Day that we'll be holding about a month from today on April 14. So we hope you'll join us again for that. We'll tell you more about that molecule at the KCC2 day.

But just to give you the highlights of what you should expect to see, we believe that OV4071 has broad syndromic psychosis applications. And just to point to that, we have forthcoming data that gives us conviction not only for the indications that we've talked to you about before, such as psychosis associated with Parkinson's disease and Lewy body dementia but additionally in schizophrenia and Alzheimer's psychosis agitation and well beyond.

I'd like to tell you just a little bit about OV4071, knowing that there's more to come. We are very excited about the attributes of this molecule. As many of you know, we read out our tool program last year. We got a lot of great information about that program. This molecule is much better. We have a 20-fold potency. It's highly active at low doses in a range of different animal PD models.

We have very strong brain plasma penetration, and no sedation has been observed with OV4071. But what I get really excited about with our team is that the pharmacodynamic data and armamentarium that is now mounting for OV4071 is robust across seizure models, psychosis models, pain models, genetic models of things like schizophrenia and Rett, we are seeing consistently GABAergic activity across all of these models associated with OV4071.

And what makes us also have conviction as we look at this data, is that we are running OV4071 in comparison to marketed agents, both old ones and some of the new ones that have been recently approved. And we're seeing it perform very well across these battery of animal biological models. So this is giving us conviction to advance into the Phase I study, as I mentioned. And you'll hear us talk about in April more about the KCC2 portfolio.

But if our thesis for KCC2 is right in terms of the opportunity of drugging this target OV4071 will not be the only KCC2 direct activator. It's a very good program, but we have additional discovery engines going on beneath this with further next-generation chemistry.

So that we will be the company that pioneers and unlocks the opportunity associated with KCC2. Why this matters again for those of you who are the following 329 and maybe not as focused on KCC2, this is a target that is extremely important to the brain. It's fundamental, and it's a full crumb to neural excitation and inhibition in that balance.

These are highly precise small molecules that we're developing. The therapeutic potential is broad, as you heard me say. And we believe that these will be well tolerated and we know we have direct activators. So we're very excited to unlock this opportunity. And what this means to our shareholders and our stakeholders is a really busy couple of years ahead.

So just to give you a sense of what this means from a runway and a milestone perspective, my colleague, Jeff Rona, and I will take you through this. But just starting with the milestones. There's a lot going on this page. But what you should pay attention to is the green arrows. Those are data readouts or major milestones.

So as we promised you we would do today, we're reading out the 7 milligram data for OV329 and focal onset seizures. We will be initiating that gold standard Phase II study we will also be initiating the photosensitivity open-label study, and we're on track to read those out.

We will be opening the programs that we said we would do today in Tuberous Sclerosis Complex and in infantile spasms. And you'll see that's going to start with the signal finding and safety study in a dose confirmatory study with Tuberous Sclerosis Complex in an open-label format.

How we'll be doing that, we'll be starting with older TSC patients and stepping down into younger pediatrics. That allows us to establish safety and signal as we go. It will inform and derisk our infantile spasms signal finding study, and it also allows us to share our progress with you as we enroll enough patients.

And that will help, of course, inform the pivotal Phase II/III studies that I mentioned for each of these indications thereafter. And finally, we are ready to roll with KCC2. This is what we've been waiting for. So we will be starting that Phase I study. As soon as we have enough of our PK and Cmax characterized from that Phase I study, we will be initiating the ketamine challenge study. We'll be doing that here in the United States. That will help us correlate electrophysiology along with potential clinical signs and symptoms.

That will be important because it will help us not just support the initiation of a proof-of-concept study in Parkinson's disease psychosis, but it helps us inform some of those other indications that you heard me talking about, including schizophrenia, which we have increasing conviction behind.

But I just want to turn this over to my colleague and Chief Business and Financial Officer, Jeff Rona, who's going to take us through the cash runway and what that means relative to the achievement of these milestones.

Thank you Meg. I will just briefly highlight our cash position. The full details of our financial results can be found in our fourth quarter and year-end earnings release issued this morning.

As of December 31, 2025, Ovid had $90.4 million in cash, cash equivalents and marketable securities. As Meg mentioned today, we announced the PIPE financing with gross proceeds totaling $60 million before placement agent fees and offering expenses. We are grateful to our shareholders for their support as we continue to unlock the full value of our pipeline and programs.

With the net proceeds from this PIPE, we expect that our cash runway will take us into the second half of 2028. Assuming the full exercise of the Series A warrants triggered by the milestone we met with the clearance of the Phase I trial protocol for OV4071, along with the gross proceeds from the pipe financing we expect that our pro forma cash runway will take us well into 2029.

With that, I'll turn the call back to the operator so we can begin the question-and-answer portion of today's call. Operator?

[Operator Instructions] Our first question comes from Francois Brisebois.

Frank, you there? We can't hear you.

Our next question will come from Laura Chico with Wedbush.

I was wondering if you could talk a little bit more about 329 and the visual monogram. Meg, you mentioned you would kind of continue this through Phase II. But it sounds like the 7 mg data was quite clean. So I guess, just trying to better understand specifics on what you'll be implementing during the placebo-controlled study, but also the open-label study. And a quick follow-up, if I can squeeze one in.

Laura, great questions. So where we will be continuing the ophthalmic and the retinal monitoring is in the Phase II study and then in the pivotal studies thereafter. And the reason why is not because we expect to see anything because, frankly, we don't. But what we want to be able to have, as I mentioned, as we move towards registration is a robust armamentarium of human and importantly, patient safety data that shows that we have not seen any structural changes in the eye nor have we seen any visual changes.

And frankly, this is well more robust than what vigabatrin ever did in the REMS program, but we believe that we have a safe GABA-aminotransferase inhibitor, and we want to hit the nail on the head when we take this to regulators and prove it. such that we don't have to have some of the monitoring that has really limited the use of this mechanism in the prior first-generation drug.

And Laura, if you have a quick second question we'll try to cover it.

Yes. Just briefly, the PPR study with 329. I guess I just wanted to make sure, should we assume that a response rate should be similar to what we've seen with published studies on vigabatrin. I know when you did the biomarker assessment, there were some nuances there. But just wanted to make sure I understood on the PPR study expectations there.

Yes. The way that we've designed the PPR study is that we want to be able to demonstrate anticonvulsant effect. We think in focal onset seizures to do these studies the right way, it takes time to appropriately enroll them and get to an answer and of course, have an end size to be able to show anticonvulsant efficacy. But we really like PPR studies not just because it was used with older drugs. But frankly, our peer set, right?

Other companies are using this right now. And it's a good capital efficient and clinically sound way of assessing anticonvulsant activity in a patient population. So that's really our intention. It allows us to establish potential anticonvulsant activity at the doses that we want to take into later development. And that's the intention for us pursuing this program.

Our next question will come from Marc Goodman.

This is Alyssa on for Marc. Congrats on all the progress. I was wondering if you could provide additional detail on the planned Phase II design for OV329 in FOS starting next quarter, particularly around the key endpoints and what patient population we'll be targeting?

And then separately, could you elaborate on the rationale for the ketamine challenge study for OV4071? And what you're hoping to learn from the EEG and other biomarker data in the context of the indications that you'll be targeting?

Thanks, Alyssa. Happy to. So let's start with your first question, which is the Phase II design for OV329. So to address it, it is that population that we're looking at is, of course, adults with treatment-resistant focal onset seizures. That means, by definition, these are seizure patients who have already failed a couple of anti-seizure medicines and continue to experience breakthrough seizures.

What is helpful in the space of epilepsy is that we have extremely codified endpoints that have been effective and thinking because of the work of the Epilepsy Research Consortium, ourselves and our peers in the space, there's very good methods now for testing seizures, also balancing that relative to placebo rates.

So some of the endpoints that are the endpoints to think about here, Alyssa are percent reduction in seizures, monthly seizure reduction from baseline. It's also a reduction in total seizures, it's the traditional endpoints, CGI endpoints, for example, of the traditional ones that you would expect a seizure study. And we will be doing the same thing here. And that's important, obviously, to establish efficacy.

In terms of the ketamine challenge, we get a lot of questions about this. And the ketamine challenge has been used before also with other antipsychotic drugs in development. And what we're looking to do is, as I mentioned earlier, we'll conduct a broad battery of electrophysiology. One of those things will include quantitative EEG. And we will also look at clinical discomforts and symptoms.

We'll talk more about this at the KCC2 day, and we'll go in a deep dive at it. But at a high level, strategically, what we're looking to do is to be able to show that 471 is getting into the brain that it is having an effect that, that effect is consistent with GABAergic activity, which would be on mechanism.

There are certain bands and frequency bands that we look for that are also consistent with antipsychotic drugs in certain indications. And if we're fortunate, we'll be able to correlate some of that quantitative electrophysiology with actually signs of clinical symptom amelioration relative to placebo subjects who were not exposed to OV4071. So this would give us information to show we're getting into the brain. We're having an effect that's on mechanism.

And there's also some select biomarkers, which we'll tell you more about next month that even help us have a read-through for indication identification and indication sequencing. So we think there's a lot we can extract out of us. I think you can tell from our team, we really like trying to use biomarkers to learn as much as we can early versus waiting for later development to ask and answer those questions.

Our next question will come from Myles Minter. Myles is with William Blair.

Open-label photosensitive epilepsy study. What type of going to enroll in that study. I'm just aware that depending on the stimulus and then the underlying form of epilepsy like the discharge patterns are quite different amongst those patients.

And I'm just wondering how much that will actually inform on focal onset versus something like generalized versus something like TSC, infantile spasms, that would be really helpful.

Yes. So we believe this is a good sign of broad anticonvulsant effect, Myles. We will be doing the study. As you may know, there's not many sites in the world that do these studies. We'll be conducting this at a very specialized site in the Netherlands who focuses on this.

We'll be doing it in adults who have diagnosed epilepsy, and we'll be using the -- of course, the challenge is there's not many patients in the world that actually have this form of epilepsy, but we'll be basically selecting patients who have documented photosensitivity on prior EEGs. Those will have to be reproducible. And we'll be using screening using intermittent photo stimulation.

But what you can assume is we're using that population to give us a general read-through again for anti-convulsant effect associated with their 5 and their 7 milligram doses, we believe that this is a modest and capital-efficient way of being able to confirm anticonvulsant activity while -- and before we have to wait for the full readout of the Phase II program.

So it's not necessarily the same thing, obviously, as a full Phase II study. We recognize that. but this gives us some derisking data. And again, more information that we're headed down the right trajectory before we continue to spend more capital and also start to consider pivotal programs.

And a quick one, if I may. Just on going after both prevalent population with FOS potentially generalized and then moving into TSC and IS on the rare side how do you think about long-term sort of differential pricing if that's a consideration?

It's absolutely a consideration, Myles. What we have the opportunity to do here with OV329 is, I think, to serve a number of communities that have really deep unmet need with differentiated formulations where there will be true differences here. So for the adult focal onset seizure population, as we've mentioned before, we're pursuing a capsule.

For the populations with infantile spasms and Tuberous Sclerosis Complex, these are pediatric populations. We will be developing essentially a liquid or a syrup to be able to serve them. This is going to be weight-based dosing. It will be very different. And there will be other differences, I can say, between the formulations that allow us to achieve the pharmacology strategy associated with these indications.

So that will allow us to have differential pricing relative to the communities. Obviously, we're doing so in a way that we think would be appropriate and responsible. And there's some good analogs for this environment with other major developers that we've seen that we can point you to.

Our next question comes from Francois Brisebois with LifeSci Capital.

Can you guys hear me?

We can hear you now, Frank.

Great. I don't even know how to lower my hand, so I'm not sure what happens. But all right. Well, congrats on everything. I just was wondering if you can touch a little bit more on vigabatrin and the history here. You touched on peak sales.

And maybe as you answered, maybe help us understand how -- like what kind of market size TSC and then the IS part of that is? And just when that visual issue came up with vigabatrin, what was the impact on it? And just like color around like how serious is the visual concern here?

Thanks, Frank. So when Sabril or vigabatrin was first launched by Lundbeck, the field of epilepsy thought this was going to be a multi-blockbuster epilepsy medicine. The reason why is because it works so well as an anticonvulsant.

However, it was determined post market to have this preferential partitioning in the retina that in some patients led to blindness. And it took the field and frankly, it took us several years to demonstrate that this is idiosyncratic to that compound and to show that, of course, it's not on mechanism.

And there's a lot of evidence that we have that chose that now. But what that means in terms of what the opportunity was, the sales of Sabril really understate where we think there's both a lot of unmet need and also a market. Because Sabril had that post-market safety finding, its use was very limited and constrained in the United States.

Nevertheless, between the 2 indications, primarily infantile spasms, but also Tuberous Sclerosis Complex. Its sales peaked a couple of years ago at more than $320 million. So a drug that essentially can make children blind that is only used in 6- to 9-month treatment durations for very limited use peaked at that sales figure.

So what we think in our conversations, most importantly, with the clinicians who treat these children in these babies is that if we have a safe GABA-aminotransferase inhibitor, that the opportunity to use it earlier, to use it longer can not only change the trajectory of the disease for these kids but potentially maybe a very large opportunity, and they would be much more comfortable using it for longer, hoping to improve those developmental outcomes.

And you asked one other question, Frank, that I want to make sure we address, which was what was the breakout of sales? I'd love to be able to point you to that, but Lundbeck actually never broke out their sales by indication. So that $320 million peak figure that I mentioned to you was in 2018. That included both of those 2 indications in the U.S. alone. That doesn't reflect Europe or worldwide sales.

Our next question will come from Madison El-Saadi with B. Riley.

Congrats to the really comprehensive update here. Maybe starting with 329. Maybe I missed it, how many issues in the 7 mg arm reached above the 80-milligram AUC threshold which is correlated with higher biomarker efficacy? And then wondering if there's any rationale to explore a dose above 7 mg?

Yes. superb questions, Madison. Thank you. The answer to your first question about how many were within the exposure range that we wanted to achieve. That's a good and easy answer, all 100%.

So with the 5 and 7 milligram doses, we have a lot of confidence that we're in the exposure range that we targeted. And the second question, also a super question, which is, why not go higher? And there is a reason, we know through all of our work, which is extensive now, but also looking at 30 years of vigabatrin pharmacology that there is a ceiling of how much inhibition of the GABA-aminotransporase enzyme can be achieved in the central CNS. And that's around 60% to 65%.

So when you consider that and you are well within -- and in the case of our 7 milligram dose above the drug exposure level in the plasma needed to achieve that, continuing to go higher doesn't necessarily warrant the trade-off relative to what you may start to then take on relative to possible AEs that we haven't seen any of those, of course.

So we believe that we are well within the pharmacology strategy of being able to maximize the enzyme inhibition that should correlate with therapeutic activity. And our 2 doses are delivering drug exposure level that gets us there and at the 7 milligram, it gets us over it and it gets all the subjects from our 7 milligram cohort over it, giving us again a lot of conviction behind these doses.

Understood, that makes total sense. And if I may, lastly, I just noticed you seem excited to mention the KCC 2 program. looking towards the R&D Day next month, will we see any additional preclinical data maybe in AD agitation, please?

With -- I would be in deep trouble with our Chief Corporate Affairs Officer, if I tell you too much and Scoober for a month from now. But what you will see is more preclinical data supporting biomarker strategy, supporting indication selection and supporting the broad profile that we believe that OV4071 holds is again a broad syndromic psychosis agent.

Our final question will come from Jay Olson with Oppenheimer.

Congrats on all the progress. How are you thinking about longer-term clinical development for 329 in focal onset seizure after demonstrating efficacy in the treatment refractory population.

Would you expand 329 into development as a monotherapy in earlier lines of treatment? And eventually, as you look beyond focal onset seizures, do you expect 329 to be studied in status epilepticus with an IV formulation.

Thank you for the question, Jay. So I think you've heard us and everyone at the team here at Ovid espouse, our belief that OV329 and the inhibition of the GABA-aminotransferase enzyme is a universal mechanism. We believe that safely elevating your natural levels of GABA in your brain, the braking system has broad therapeutic utility in both seizures and epilepsies, but even in indications beyond that.

I don't want to comment too much further on long-term development planning. We've got plenty to do in the next 2 years, as you can see. But what you can take away from this is that as we build more data behind OV329, much as we're doing today, we will use the evidence to inform where we potentially expand and go next.

We absolutely believe that a safe and well-tolerated GABA-aminotransferase inhibitor has a place across a lot of epilepsies particularly if we continue to demonstrate what we think may be best in category tolerability, not just within the GABA-AT mechanism, but potentially relative to the entire field of seizure medicines. Obviously, we need to continue to establish this with patients. If we do, we think this could have a very significant opportunity.

As it relates to refractory status epilepticus, we have certainly preclinical data that would support taking us into those indications. There is a lot of unmet need there. With that said, from an operational and clinical perspective, those are very complex trials to run. I don't think you should anticipate that we will be doing that in any time in the near future.

And just for the operator, I believe there is one more question from our analysts at Cowen, Ritu.

Yes. Our next question will come from Ritu Baral with TD Cowen.

I wanted to ask about the first readout from the TSC study. there's a pretty broad bar on your pipeline, Meg. And you mentioned that you were hoping to find early signal finding. Will those first signals out of 329 and TSC at the 12-week time frame, which I think is the primary endpoint of the pivotal Phase II/III or will there be of additional dose finding in there as well?

Yes. Excellent questions. So I don't want anyone to walk away from this call thinking that you're not going to hear anything about TSC until the middle of '28 because you will. You'll hear things sooner than that. We've designed the Tuberous Sclerosis Complex open-label study very intentionally as an open label.

There's a lot that we hope to get from this that we will sequentially communicate around when we feel like the enrollment and the size is big enough to have an answer that will give us all the evidence and sufficient evidence that we believe that we can make decisions and base information on.

So what I mean by that or 2 and colleagues is that because this is an open-label study, we've designed this to be able to start with older tumor sclerosis patients, including adolescents then going down to younger pediatrics before we initiate that infantile spasms study. And why we're doing this is we want to, of course, establish safety in these pediatric populations. We'd like to be able to establish a signal.

But importantly, it allows us to confirm the dose modeling. We feel actually very confident based on the modeling that we already have internally with some of our animal models and our human data, but we'd like to be able to confirm this with pediatric awards as we go. And we have the opportunity to communicate about this throughout these open-label programs.

And in fact, we have a very similar approach with the infantile spasm open label as you see here as well. And again, this is a matter of as we enroll the study, we believe that this gives us the information we need. It also allows us to communicate with these communities to give them the confidence that if we're going to move into registrational trials that we have an agent that may offer a benefit to the children.

Got it. And remind me, how many patients were in the 7 milligrams healthy volunteer arm. And I guess are you surprised that it was -- I believe it was 11, I just see in mind. Are you surprised that it was so clean compared to the prior doses? And what, if anything, does that tell you about how you expect both doses to behave from a safety perspective going forward?

So you did answer the question for me, but I'll just reinforce what you said -- it was 11 in the SAD/MAD cohort that we're taking the 7 milligram dose of OV329. And at this point, we've had, I think, nearing 70 people throughout the Phase I study. So we've had a good lean number of healthy volunteers be now treated with various ascending doses of OV329.

And in terms of the tolerability, I'm not surprised. This is on mechanism for we believe some of the differentiators of OV329. And importantly, it would be one thing if we just have this tolerability and safety data and didn't have the biomarker data that we have, but we have the benefit now of not just knowing that OV329 is getting into the brain at these doses.

That it's elevating levels of GABA in the media part lobe that is driving cortical inhibition that's known of the mechanism that exceeds or is commensurate with that of what we've seen with therapeutic doses of vigabatrin but we're also seeing exposure increase by dose as we predicted and expected.

So we feel very good that these are doses that are doing what they need to do in terms of the pharmacology strategy. while also having that tolerability. And just for those who are newer to our story, 329 is designed to not only be safer, but well tolerated. Unlike the first-generation drug by vigabatrin, OV329 delivers GABA in the synapse and in the extrasynaptic region.

These are a couple forms of phasic and tonic inhibition. Why does any of that matter? It matters because Sabril only drops or vigabatrin only drove GABA in the signups, similar to other drugs like benzos, for example. What happens when that occurs is when you flood the snaps with GABA, you hit synaptic GABA receptors.

That drives a lot of tolerability issues like sedation and other but because OV329 has this broad therapeutic index that the first-generation drug did not have, we're able to deliver this phasic and tonic inhibition, essentially coating the entire neural environment and a more inhibitory milieu.

And it's less of the surge that you see with other drugs, and it's a more cooling down of the ecosystem around the neurons. And we believe that, that's leading to a better tolerability profile. What we're excited to go ask and answer next is will it lead to an even better efficacy profile. And that's why we're running the studies that we're running.

Great. And if I could squeeze one last one in, just about your FOS and your PPR study. As you look at those efficacy endpoints, which I believe are a percent change of certain EEG threshold, do you believe that those changes in the PPR model, I mean, as we compare it to -- well, first of all, is there a target that you guys are looking for in that -- in those EEG markers?

But second, is a PPR response proportional to ultimate seizure response basically, if you end up with stronger PPR data, is it indicative of potential stronger seizure reduction?

The way that we have looked at designing this PPR study is we feel it gives us conviction about the doses and conviction of anticonvulsant effect. I think truly to see what the anticonvulsant profile is of 329 is why we're running in the Phase II study that we're running, right, a true randomized placebo-controlled trial. But just from an endpoint perspective, what we'll be looking for in the photosensitivity study is 3 key points to be clear.

We'll be looking at reductions in the number of IPS frequencies that induce the PPR, the photosensitivity response, we'll be looking to increase -- we'll be looking for the threshold frequency to induce these photosensitive responses, and we'll be looking also at complete suppression of these photosensitive responses, both during and post dose.

So we think this will give us some helpful information. It's not the same thing as a pivotal or Phase II study. But while we do the full Phase II study, I think it gives us confidence building and derisking data that enables us as we continue to expand the life cycle and the broad opportunity of OV329 to continue to make those investments and to robustly pursue the value creation opportunity associated with this program.

This concludes our question-and-answer session. Meg, any closing remarks?

I just want to thank everyone for your time this morning and for your continued interest in our company. I want to thank Point72 and our shareholders who supported us in today's news. We're really pleased with this progress across the pipeline in the business. And I want to just take a moment to thank the patients, the caregivers and parents who are advisers, the doctors and clinicians who are our partners and I really want to thank our team here at Ovid. They made it possible. They work through the holidays in order for us to deliver early on some of these outcomes. So thank you all for your support. Keep watching us, and we're going to work to deliver.

Thank you for joining. This concludes today's call. You may now disconnect.

Good morning, and welcome to the Ovid Therapeutics data call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Ovid Therapeutics website following the conclusion of the event.

I'd now like to turn the call over to your host, Victoria Fort, Senior Vice President of Corporate Affairs and Corporate Strategy. Please, go ahead.

Thank you, and welcome. Good morning, everyone, and thank you for joining today's call to discuss the top line OV329 Phase I readout. Joining me on today's call are Dr. Jeremy Levin, Chairman and Chief Executive Officer of Ovid; Meg Alexander, President and Chief Operating Officer; Jeff Rona, Chief Business and Financial Officer; and Zhong Zhong, Chief Scientific Officer.

As a reminder, during today's call, we'll be making forward-looking statements. Various remarks we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the purpose of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Forward-looking statements contained in this call are subject to a number of risks and uncertainties, which could cause our actual results to differ materially from those expressed or implied in such statements. These factors include, but are not limited to, those discussed in our most recent annual report on Form 10-K and other filings with the Securities and Exchange Commission.

Dr. Levin will provide an overview of Ovid Therapeutics, and Meg Alexander will walk listeners through the OV329 top line Phase I biomarker and safety data. We will encourage Q&A after the presentation.

With that in mind, I will turn the call over to Dr. Jeremy Levin.

Thank you, Tori. I'd like to welcome everyone to the webcast. We're incredibly excited to share our Phase I OV329 data with you. Before we dive into that data, I would like to provide our listeners with an overview of Ovid's pipeline, discuss the significant unmet need in epilepsy and the challenges with current GABA-modulating medicines. I will then turn over the presentation to Meg to provide detailed Phase I results for OV329.

Ovid's focus is threefold. First, we're drugging fundamental biological targets implicated in conditions driven by neural hyperexcitability and which have broad potential therapeutic utility. Second, we are developing a pipeline of highly specific small molecules, with intention of creating a fully integrated neurotherapeutics company. And third, our candidates have been differentiated mechanisms of action from the growing field of me-too medicines. It's our belief that in 3 to 5 years, we will see mechanistic category winners and novel compounds and modes of actions will be highly valuable, especially if they're well tolerated and efficacious.

In front of you now is our focused neurology pipeline, which encompasses OV329 for treatment-resistant epilepsies and focal onset seizures and our portfolio of potassium-chloride cotransporter 2 or KCC2 direct activators. Our pipeline is highly differentiated, pursuing novel mechanisms in the CNS. If you look at the right-hand column of this slide, it highlights the numerous clinical and regulatory catalysts that we expect to achieve between now and mid-2027.

Now let's start with OV329, our next-generation GABA aminotransferase or GABA-AT inhibitor. Now that we've successfully completed the Phase I safety and biomarker strategy, we anticipate initiating a Phase IIa in Q2 2026, followed by top line data in mid-2027. We will simultaneously conduct a small open-label seizure-reduction study to demonstrate anticonvulsant properties.

Our portfolio of KCC2 direct activators has also made significant progress. This portfolio includes OV350, an IV KCC2 direct activator, which is currently being studied with the objective of demonstrating safety, tolerability and PK for a first-in-human MoA in the CNS. The OV350 Phase I was initiated earlier this year, and we expect a readout of top line safety, tolerability and PK data in Q4 2025. It will provide rich insights into our oral programs.

Excitingly, the first oral direct activator, OV4071, is currently completing the final pieces of our IND-enabling package, which we will submit early in 2026. This will support a Phase I/Ib set of studies that will initiate in Q2 2026. For OV4071, while we characterize safety, tolerability, PK and exposure in our Phase I, we plan to conduct a proof-of-mechanism study in a ketamine challenge, which may significantly derisk future studies in schizophrenia. In late 2026, we will initiate Ib studies in psychosis associated with Parkinson's disease dementia and Lewy body dementia and separately, schizophrenia with the goal of delivering early proof-of-concept data in Q1 2027.

As we do this, it's important to take account of the need in treatment-resistant epilepsies, despite 30 anti-seizure medications being approved over the last 15 years, only 2 with novel mechanisms have been authorized, leaving a significant unmet need. Even in a crowded epilepsy landscape, one in three patients live with uncontrolled seizures and 47% of the U.S. epilepsy patients report polypharmacy with an average of five medicines. A safe, well-tolerated GABA-aminotransferase inhibitor is clearly needed.

The next slide that you see before you, highlights the challenge with current GABA-modulating medicines. The first-generation GABA-AT inhibitor, vigabatrin, has a challenging safety profile with irreversible retinal changes and vision loss in some patients. Dosing isn't patient friendly, requiring 2 to 3 grams of drug. Even drugs that work well in reducing seizures have tolerability issues. Specifically, drugs that surge GABA in the synapse have been associated with high instances of sedation and dizziness, and other GABA-modulating drugs have limited durability of effect. Those are the challenges we took on and are tackling.

I'll now turn the call over to Meg Alexander to discuss the top line Phase I biomarker and safety data for OV329.

Thanks, Jeremy. Well, this is a really exciting day for us. As you can see in front of you on Slide 10, based on our Phase I and preclinical results, we believe OV329 has the potential to make an important impact on the treatment of drug-resistant epilepsies and potentially deliver a superlative safety and efficacy profile relative to the broader category of anti-seizure medicines.

The results that we're going to describe today demonstrate a positive safety profile relative to a broad and historical category of anti-seizure medicines. And of course, this includes clean ophthalmic safety results. You will see that we showed positive biomarker data across a range of metrics, which support that our medicine engages and inhibits the GABA-aminotransferase enzyme. The inhibitory effects of 329 are on par or in excess of the first generation of GABA-AT inhibitors like vigabatrin, as Jeremy described.

We observed in our results a clear responder rate, such that we know that we are having inhibition at the modeled drug exposure levels in the brain, as we had predicted. And we believe that OV329 has the potential to be a blockbuster, and we have patent protection through 2041 with the opportunity for patent term extension as well as future IP.

So we strongly believe that the data we're going to show you today rapidly support advancing OV329 into a Phase IIa patient epilepsy trial. But first, let's take a moment to stop and discuss the mechanistic and therapeutic index differences that we've characterized and that are associated with OV329.

So as we introduced at the top, OV329 is a next-generation GABA-aminotransferase inhibitor. And that means that essentially, our drug is inhibiting the enzyme that degrades the main neurotransmitter in the brain, GABA. Unlike other drugs, vigabatrin -- most particularly like vigabatrin, OV329 is unique, in that it delivers GABA both in the synapse and in the extra synapse. And in this way, OV329 is delivering what we call phasic and tonic inhibition.

By optimally tuning GABA levels in the brain, OV329 is creating an overall inhibitory environment surrounding the neurons. Therefore, OV329 has a therapeutic index that can deliver this phasic and tonic inhibition, where the prior generation medicine, vigabatrin, cannot. But why does all this matter? It matters because the phasic and tonic inhibition may deliver a preferable tolerability and efficacy profile relative to prior anti-seizure medicines that primarily surged GABA in the synapse and led to tolerability challenges.

And the robust efficacy profile that we've now observed in humans really set the stage in earlier preclinical models, where we saw a lack of accumulation in the eye, differentiating from vigabatrin. And also, we saw strong anti-seizure efficacy that supported advancing OV329 into the clinic. Specifically, OV329 was studied and shown to have anticonvulsant properties in nine chronic and acute seizure models. This is perhaps more than what we have seen for any prior anti-seizure medicine.

And on the left-hand side of the slide, you'll see that plasma and tissue exposures for OV329 differ substantially from vigabatrin in a mouse model intended to look at ophthalmic safety. Importantly, we have proven that vigabatrin, the first-generation medicine, preferentially and idiosyncratically partitions and accumulates in the retina rapidly. In fact, we've been able to see this in animals within days and even weeks. Whereas in -- for 329, in the brain, eyeball and retina, we know that our therapeutic doses are undetectable. We get into the plasma and tissue and clear it rapidly. This makes us very comfortable that OV329 has a differentiated ocular and ophthalmic safety profile, where we do not anticipate the vision issues that were experienced by the first-generation vigabatrin.

So as we think about the future of what this medicine could be, we designed OV329 with a target profile to address the challenges that Jeremy elucidated a few moments ago about prior GABA-acting medicines. At this point, we know with OV329 that we are quelling hyperexcited neurons and optimally tuning that synaptic and extra-synaptic GABAergic inhibition.

OV329 is delivering cortical inhibition that we've measured now in humans that either matches or exceeds what we've seen of therapeutic doses of vigabatrin also studied in healthy volunteers. And this gives us incredible conviction about the anticonvulsant and anti-seizure efficacy that OV329 may deliver.

We anticipate that 329 will be given once daily at significantly lower doses than vigabatrin. Our dosing estimated for patients is 5 to 7 milligrams versus 2 to 3 grams for vigabatrin, significant difference. 329 has a superlative safety profile, not just compared to vigabatrin, but really even as we look out at the entire class of anti-seizure medicines, and of course, none of the vision changes are expected that are unique to vigabatrin. This means that we do not anticipate future ocular monitoring.

We expect to see sustained focal reduction -- or sustained reduction, rather, in focal seizures with no intended titration. And with this overall target product profile, we believe OV329 is poised to serve a broad population of people living with treatment-resistant focal onset seizures as well as other disorders where neural excitation is implicated.

So let us get on to telling you about the results. What we're showing here is the trial scheme for the Phase I SAD/MAD study that we just recently completed for OV329 in healthy volunteers. We had 69 participants who were enrolled, 51 of those were receiving active treatment. The largest cohort in our study was our 5-milligram cohort that included 15 participants who were receiving actively the medicine and 5 who are receiving placebo.

Importantly, we had several objectives for this study, one of which was measuring ophthalmic safety and tolerability, which included a number of very rigorous metrics such as best corrected visual acuity, fundus photography, indirect dilated ophthalmology, automated threshold visual field perimetry and optical coherence tomography. These were very rigorous methods that measured not just clinical effects, but even the back of the eye for changes.

In addition, we leverage the following technologies to look at pharmacodynamic activity for OV329, and these are predictive biomarkers, specifically that we leverage technologies such as transcranial magnetic stimulation, or going forward, we'll refer to this as TMS; magnetic resonance spectroscopy or MRS; and electroencephalography, which is EEG. So here, we'll quickly hit on patient demographics. You'll see they were well balanced across our MAD cohorts, and there are no significant differences in gender, age, height, weight or body mass index.

But let's get right into the results, starting with safety. We're very pleased to report that OV329 demonstrated a very favorable safety and tolerability profile with no treatment-related serious adverse events. In fact, only three participants experienced treatment-related adverse events, all of which were graded as mild, all of which were transient and resolved. These included, in our 2-milligram cohort, one account of headache and one account of drowsiness. And on our 5-milligram cohort, one incidence of metallic taste. The most frequent adverse event was actually cannula site reactions at the site of lab and blood draws, which 13 participants experienced. Of course, all of those were mild and moderate and not related to OV329.

Importantly, as we expected, OV329 demonstrated a clean ocular safety profile with no ophthalmic safety findings or retinal changes in the five measures we applied in the study. As we know, this includes the best corrected visual acuity, the fundus photography, indirect dilated ophthalmoscopy, automated threshold visual field perimetry and OCT. These are very rigorous metrics, and we'll continue to conduct similar ophthalmic studies throughout the entirety of OV329's development. And the reason why is beyond the preclinical derisking work that we've already done, we want to build a robust human and patient safety database that will ultimately support our registrational package. And our goal, as you recall, is to mitigate the monitoring that people who took vigabatrins are required to adhere to.

So let's talk about how we are seeing OV329's PK and PD performance behave. In the Phase I study, OV329's irreversible binding and incredible potency, coupled with the low turnover rate of the GABA-aminotransferase enzyme in the brain, enabled low daily dosing and delivered a prolonged pharmacodynamic effect. We observed linear increases in AUC and Cmax using repeat dosing and achieving study state by day 3. We also had consistent renal clearance, which was observed after single and repeat dosing. So we know at very low potent doses, we're able to leverage the slow turnover of the enzyme and maintain our pharmacodynamic activity.

But now, let's shift to the really fun part, which is the biomarker results for this study. As mentioned, we used TMS, which is a well-accepted technology for measuring GABAergic drugs using a range of very specific biomarkers, most particularly that evaluate changes in cortical inhibition. Specifically, we looked at the long-acting intracortical inhibition, or the LICI, and the cortical silent period, or CSP for short. These two biomarkers are pure quantitative measures of cortical inhibition, and they provide an optimal way of measuring GABAergic inhibitory activity, short of an actual seizure-reduction trial.

We utilize these biomarkers in both our 3 and 5-milligram cohorts, where we anticipated to see pharmacodynamic activity. And whenever we could, we compared them to therapeutic doses of vigabatrin as had been previously studied in healthy volunteers. Based on the results, we believe OV329 has delivered more confirmatory evidence of inhibition in the brain than any prior seizure medicine that we have seen at this stage of development.

On the two measures that vigabatrin historically demonstrated an effect on TMS, which were the long-interval intracortical inhibition at 150 milliseconds, or the LICI, and the cortical silent period, OV329 delivered greater inhibition while acknowledging, of course, that these are still cross-trial comparisons, which must be taken into account. Importantly, OV329 replicated the signature fingerprint on TMS that's been associated not just with vigabatrin, but with a broader GABA-aminotransferase inhibition mechanism.

Specifically, we saw the greatest inhibition for OV329 was delivered at approximately 150 milliseconds on this LICI, which is a paired-pulse biomarker, and we see that inhibition diminish at 200 milliseconds. Why does that matter? It's measuring millisecond-level reactions of inhibition in your brain. And importantly, it replicates and exceeds therapeutic doses of vigabatrin.

So let's talk just about the methodology for how we measure this. We'll start by talking about the LICI, which again is a measure of cortical activity, and it uses two separate high-intensity stimuli or paired pulses that come in intervals. A magnetic coil is placed on the volunteer set to measure an electric field, and electrodes are placed on target muscles to measure motor response.

This paired-pulse stimuli are then delivered at varying time intervals to obtain levels of GABA-mediated inhibition. The mean responses were -- to measure were pretreatment, so we measured before any participants were dosed with our medicine on day 1. And then we measured again after 7 days of daily dosing.

We'll take a moment now to show you the results from our 5-milligram cohort. At 5 milligrams of OV329, we demonstrated a highly significant improvement in the LICI measured at 150 milliseconds as compared to placebo, and we measured that on day 7 in the APB muscle, which stands for the abductor pollicis brevis muscle. You can see that 53% inhibition compares very favorably to the approximately 35% inhibition that had previously been determined for a therapeutic dose of vigabatrin as dosed at 50 mgs per kg in a study by Pierantozzi et al.

In another muscle that we measured this biomarker in, the first dorsal interosseous, at the 5-milligram dose of OV329, we also demonstrated highly significant improvements in the LICI measured at 150 milliseconds compared to placebo on day 7. You can see here is the 44% inhibition compares favorably to the approximate 35% inhibition of vigabatrin. In both of these biomarker metrics, you can see that our key value is highly significant. And as you can see, each of these biomarkers were measured in two different muscle groups, delivering highly confirmatory results of the signal and the inhibition that we're seeing with OV329.

What you're seeing in front of you on this slide, Slide 25, illustrates how OV329 compares to vigabatrin's performance on this particular biomarker, the LICI measured at 150 milliseconds. And these results were measured in the FDI or first dorsal interosseous muscle. And you can see, as you look at this slide, the dotted green line is essentially showing where vigabatrin delivered its most profound inhibition, roughly between 140 and 160 milliseconds on the paired-pulse stimuli. We set OV329 to see if we could achieve inhibition at the similar paired-pulse time range and indeed, OV329 did. It delivered more inhibition, which is suggested here by the square at the bottom, that's the difference and inhibition relative to the pre-drug baseline at the top. And as you can see, OV329 delivered cortical inhibition of approximately 53%, surpassing that seen from vigabatrin.

Moving along, we saw the similar results on other muscles as well. The cortical silent period is another biomarker that had been used to study cortical inhibition and is described here on this slide. This particular biomarker uses muscle exertion and the stimuli on TMS to measure cortical activity. And what we want to see, when you have an inhibitory drug on board, is treatment-related prolongation of this cortical silent period, and that's indicative of GABAergic activity.

If you look at the right, that's the metric of someone who has a reading of the cortical silent period without an inhibitory drug. If you look on the bottom right, you'll see prolongation of the cortical silent period that's indicative of a drug that's having an inhibitory or GABAergic effect.

So now let's take a look at the results. On the cortical silent period, our 5-milligram dose of OV329 had highly significant prolongation of more than 10.4% at day 7 compared to the participants pretreatment baselines, whereas placebo showed a nonsignificant improvement of 2.5%. So we've been quite pleased with the biomarkers that we've now seen using TMS. We've replicated the results, not just that vigabatrin achieved, but also what OV329 has achieved across multiple muscle groups in highly statistically significant fashion.

So now let's move on to some of the other biomarkers that we also measured. On magnetic resonance spectroscopy, our results highlighted -- our results are highlighted here. Magnetic resonance spectroscopy showed that signs of drug effect and target engagement for 329 based on an observed change of GABA concentration in the brain. We measured and looked for signs of GABA in the medial parietal lobe within 24 hours of the last day of dosing OV329, so on day 7, and we measure that relative to our participants pretreated baselines.

In the results, we observed numerical increases in both doses of OV329 relative to placebo. While the results were not statistically significant due to variability and baseline variability in the participants, regardless, we saw a clear separation from the placebo subjects and an elevation of GABA in the brain. Putting this together, the results suggest that OV329 is getting into the brain, inhibiting the GABA-aminotransferase enzyme and importantly, increasing GABA levels in the medial parietal lobe, as was studied.

And finally, the last technology that we applied in this comprehensive biomarker program was EEG. It's important to understand that EEG methodology is just a more exploratory area of the field, though the results that we saw, excitingly, were also supportive of having a dampening effect relative to excitation in the brain.

Specifically for OV329, we saw statistically significant increases in beta, delta, gamma and theta power. We saw this both in the 3 and 5-milligram doses of OV329, while placebo showed statistically significant reduction in beta power. These tend to be reflective of GABAergic activity, and may indicate some signs for some of these brain wave bands, signs of drowsiness, though there were no reports of drowsiness in our high dose cohorts from our drugged participants.

Finally, and really importantly, as drug developers, we measured exposure of OV329 in the brain and found that it was highly correlated to inhibition. This is demonstrating in front of you a clear responder rate. Essentially, what it's showing you is that patients who achieved the target exposure threshold in the brain of approximately or greater than 80 nanograms per hour per mill were highly correlated with cortical inhibition as measured by the biomarker, the LICI 150 milliseconds. And you can see that reflective of the blue circles in the lower right-hand circle of this pictorial, which is showcasing that at our 5-milligram cohort, we are delivering drug exposure in the brain as predicted. And simultaneously, that is delivering highly significant inhibition.

So we're extremely pleased with these Phase I results. They showed positive, and potentially best-in-therapeutic area safety, and that profile is, of course, recognizing that our AEs were mild, transient, and of course, we didn't anticipate nor did we see any concerns of ocular safety. So we can firmly say that we've demonstrated that OV329 is crossing the blood-brain barrier and engaging and inhibiting the GABA-aminotransferase enzyme. We are exhibiting similar or better inhibitory effects of therapeutic doses of vigabatrin, which is incredibly encouraging for what the possible anticonvulsant efficacy of OV329 may deliver.

Patients and participants who achieved target drug exposures in the brain of approximately 80 nanograms per hour per ml or greater saw cortical inhibition as measured by the LICI 150, this is demonstrating a clear responder rate that will help us make decisions for dosing and powering as we move into Phase II patient studies. And the results very much support advancing OV329 into Phase IIa seizure and epilepsy trials, and where we will go first is patients who are experiencing treatment-resistant focal onset seizures.

So let's tell you about what's coming next. In front of you, you're seeing our proposed Phase IIa trial design in treatment-resistant focal onset epilepsies and seizures. It is our intention to evaluate a 7-milligram dose of OV329 as compared to placebo for 8 weeks in a 2:1 randomization. Patients with diagnosed treatment refractory focal aware and focal awareness impaired motor onset seizures with 0 to 3 concomitant anti-seizure medicines will be enrolled.

The efficacy outcome measures will include percent change from baseline and monthly seizure frequency, responder rate, time to pre-randomized monthly baseline seizure frequency, seizure-free days and, of course, Clinical Global Impressions of Improvement among caregivers. These are very traditional epilepsy metrics that will help us assess the full utility of OV329. We'll also run concurrent open-label cohort to be able to potentially get a readout of seizure effect size and reduction, sooner than this Phase IIa placebo-controlled trial that we're showing you here.

In terms of the market opportunity, we believe that OV329 can deliver a highly differentiated, efficacious and well-tolerated profile, which will be rewarded in epilepsy even in spite of it being a dense and competitive market. In fact, the refractory and polypharmacy market in epilepsy and focal onset seizures represents approximately 40% of epilepsy patients and more than $1 billion commercial opportunity. Reimbursement and coverage dynamics remain quite favorable in this space and unfortunately, for patients today, polypharmacy remains to be the norm and remains to be heavily covered and reimbursed.

So with the financing that was concurrently announced today, our company has sufficient resources to be able to fund development of our programs in our company through 2028, during which time, we'll initiate the following milestones and programs that you see in front of you.

We intend to initiate a Phase IIa program for OV329, similar to the design that I just showed you, and we expect to have top line proof-of-concept data reading out by the middle of 2027. For our KCC2 program, we expect to read out safety, tolerability and pharmacokinetic information about our intravenous KCC2 direct activator, OV350, and we'll do that later this year before the close of 2025. We think this is very important. It's the first time anyone has drugged and directly activated KCC2 in the brains of humans. And there's much we'll learn from this for our oral KCC2 development programs.

From there, we intend to initiate a Phase I and Ib study for, excitingly, the first-ever oral KCC2 direct activator, which as you heard Jeremy describe, is OV4071. That's scheduled for regulatory submission early next year and initiation of the Phase I program in the second quarter of 2026.

During the time that we're running our Phase I study, we will concurrently run what's considered to be a proof of mechanism ketamine study challenge, which will help us potentially derisk future development in indications such as schizophrenia. We anticipate running two Ib studies near the end of our Phase I, and that will be to explore OV4071 in indications that include psychosis associated with Parkinson's disease and Lewy body dementia as well as schizophrenia. So what will all of this get us? It will essentially get us proof of concept like readouts in early Q1 2027.

And then finally, we have additional KCC2 molecules that we continue to characterize and develop. So in this period of time, we'll initiate IND-enabling studies for the second and the next generation oral compound in our KCC2 portfolio. We'll do that in late 2025, and we anticipate regulatory and IND submissions for that second oral, OV4041, by the second half of 2026.

So now, thank you for sharing this exciting moment and the results with us. We'll conclude the presentation part of this discussion, and we'll open the door -- open it over to Tori and open it to Q&A.

Thanks, Meg. Operator, please open the line for Q&A.

[Operator Instructions] Our first question comes from Laura Chico at Wedbush.

Just two for me. With respect to the Phase IIa readout, has the bar for seizure reductions increased in the refractory focal population? We've seen some recent readouts there. So just curious, as you're heading into the Phase IIa, how should we think about the bar for success for OV329?

And then second, given the safety tolerability profile, I think it certainly makes sense to explore a 7-mg dose, but wondering what additional data you might have to support that?

Laura, thank you for the very thoughtful questions. So this is Meg. I'll tackle the first one, and then we'll go into the second. So your question is, is the bar getting higher for seizure reduction in focal onset seizures. And I think the answer is yes. There are very good mechanisms out there, and there's development programs in existing medicines that seemingly do a pretty good job of reducing focal onset seizures.

What is important to us as we look at this and as we project out where we think the field will be in 3 to 5 years, we think that there will be essentially mechanistic category winners. And what we mean by that is there's some good sodium channel drugs out there. There are some good potassium channel drugs out there, but there's also many in development. So we think eventually, you will get a mechanistic category winner there. And what will be really important to bring to the field is having differentiated mechanisms of action beyond that. As Jeremy said in the presentation, there's only been two new MoAs been brought to epilepsy in the last 30 years. GABA-aminotransferase inhibition and OV329 are that.

So based on the data that we now have in hand, we believe that we'll bring to bear to the marketplace a differentiated mechanism that's safe, that's well tolerated, that has competitive efficacy that should be on track with what we expect to see from vigabatrin and potentially better than what we saw with vigabatrin based on the inhibition that we're delivering. And based on that phasic and tonic inhibition that 329 has.

So when we look out at the field, we think we will have competitive efficacy from a seizure-reduction perspective. And so far, it appears that we may be having a safety profile that looks better than just about any other seizure medicine we've seen marketed or in development. So that's the answer to question one.

And just on the 7-mg dose, I guess, any additional data that gives you confidence there?

Yes. Yes. So on the 7-mg dose, Laura, the way that we look at this is a couple of different fold. Of course, first, the safety profile that we have at the 5-milligram dose has really been superb. So we feel very comfortable being able to up-dose based on the safety data that we've seen in humans. But the other important string of evidence has really been developed by my colleague, Zhong Zhong, who's sitting next to me.

And what we've done is we've used animal-based modeling. We used enzyme-based modeling, vigabatrin historic performance as well as our own human PK and exposure data from our clinical trial to be able to model what should be therapeutic drug exposure levels in the plasma. We have that, that very much guided the dosing paradigm that you've already seen in the clinic between the 3 and 5-milligram dose.

We knew with the 5-milligram dose that we had exposure levels that were well, well within our modeling for pharmacodynamic effect and inhibition. The 7-milligram dose is on the far right-hand side of that continuum. So we don't want to leave any efficacy on the table, and we think the 7-milligram may get us a little bit more, and we feel extremely comforted by the safety that we see to date.

The next question comes from Ritu Baral at TD Cowen.

So back to seizure reduction, can you give us any more detail about this open-label seizure-reduction study that you guys are thinking about? Will it similarly have no titration? And as we put all of this biomarker data together and how you guys have comped it to vigabatrin, what sort of level of seizure reduction is that pointing to in this open label? And then I have a follow-up.

Very good. So in terms, Ritu, of how to think about the Phase II design, we're trying to get the -- really the best of both worlds here and robustly explore OV329. So what we mean by that is we feel it's very important to have a placebo-controlled Phase IIa program. With 329, while our inhibition is looking exceptional and the safety is looking exceptional, at the end of the day, we always know that we have to be able to differentiate from vigabatrin and the ophthalmic safety that we believe we have and that vigabatrin does not. So having a placebo-controlled trial is important to us.

Nevertheless, we would like to be able to demonstrate the seizure-reduction efficacy for OV329 sooner. So knowing that the placebo control is important, we are going to concurrently run an open-label study of 329, while that doesn't necessarily give us placebo-controlled safety, what it does give us is seizure effect size. We think this will be important to enrollment, and it will be also helpful as we look at our modeling assumptions for the pivotal programs.

What are the assumptions for top line data from that open label?

For -- in terms of the seizure reduction, which is what I think you're getting to, Ritu, and that's similar to the question that you asked before. So we know vigabatrin had very compelling seizure reduction in focal onset seizures as well as other indications of which focal seizures are a symptom. Depending on the studies you look at, we have seen seizure reduction anywhere in the range of 40% to 60% to 35% to 50%, depending on the indications.

So keep in mind, Ritu, the one thing that we have that vigabatrin cannot do is we deliver both phasic and tonic inhibition. Why does that matter? It matters because we can cool down the entire environment around the neurons, whereas vigabatrin actually could never achieve that. Mechanistically, it theoretically could, but from a tolerability perspective, you can't. It can't get to doses where animals and humans can actually achieve tonic inhibition. So we think that we may have differential, not just tolerability from that factor, but also potentially efficacy.

Got it. And then the when, like when do you think the -- when could you gather sort of the full seizure-reduction effect from 329, would that give us from that open label? I'm wondering if that's like an 8-week endpoint or a 12-week endpoint? And would that allow us -- allow investors to see seizure-reduction activity, say, in 2026?

Yes. So for the Phase II programs, Ritu, we're assuming 8-week studies. We think that's important. If you look at historic guides to understand when seizure medicines, like 329 can show separation from placebo, you want to have at least 5 to 6 weeks. So we're well on the outside of that with an 8-week paradigm.

Understood. And then last question, going back to what Laura said about the 7-milligram. So it sounds like you are confident that, that 7-milligram is getting you to the sort of ceiling effect of that pharmacodynamic range. I'm just wondering what other options may be in play given that very, very clean safety profile that you have. It obviously changes the risk-benefit profile if that side effect profile remains that clean, the ability to dose up.

Yes. So we feel -- first of all, Ritu, we feel very confident with the 5-milligram dose that we have. So we're delivering inhibition that is competitive with vigabatrin and has what we think is a pretty superlative, potentially best-in-category safety profile with the 5-milligram dose. So feel terrific about that.

With that said, if we can push it further and not leave any seizure-reduction efficacy on the table, that's something that we want to endeavor to do. And we feel that, as you rightly point out, the safety that we've seen to date is highly permissive to push that. So for the 7-milligram cohort, when you look at, again, drug exposure in the plasma that we are trying to achieve, that matches what we think is the really maximal area for pharmacodynamic seizure reduction, coupled with good tolerability, the 7-milligram dose delivers that.

But we will be running it in a Phase I cohort of just healthy volunteers. We're actively doing that now to qualify it for safety, tolerability, exposure and PK. So we'll have that information in our hands as we begin to enroll the Phase IIa program. And you mentioned something about titration, Ritu. We do not anticipate needing titration based on the profile that we have to date.

The next question will come from Madison El-Saadi at B. Riley.

Congrats on the data and a very nice presentation of the data set. Maybe on the 7-mg dose, would you expect this dose to ensure all the treated patients kind of reach that area under the curve threshold that is needed to achieve benefit based on your PK responder rate analysis?

And then maybe on side effects, could you comment on the metallic taste? I believe, there was one sedation. Is this something that kind of resolved after a couple of doses?

Yes. Thanks for the questions, Madison. So in terms of addressing your first question, which was what level of exposure would we expect to see at the 7-milligram dose, would our PK help deliver that, so as we model our 7-milligram dose based on the data that we already have in human healthy volunteers and that regression analysis that you alluded to in our presentation, the answer is yes. 7 milligrams would put us squarely in a level where we would be expecting to see exposure in the brain well in the range of somewhere between 120 to 140 nanograms per hour per ml.

We see that when we get to that level of drug exposure in the plasma, it is highly correlated to inhibition. And we would expect to see a very good responder rate. Even if you look at the modeling and the regression analysis from our 5-milligram cohort, you see that we're currently delivering an exposure in the plasma of somewhere between 80 to 100 nanograms per hour per ml. And we have a high degree of responders in that regression analysis that had very strong inhibition. So 7 milligrams should just even further enhance that.

And then to speak to your comments about the adverse events. So metallic taste was something that we did see in one subject. There's not a clear explanation for why that was, but it was mild and transient and completely resolved.

And then you're correct, in our 2-milligram cohort, we did have one account of drowsiness. Drowsiness and sedation can be associated with inhibition in GABAergic drugs, but what we are seeing with OV329 and what makes us very excited, is we're not seeing significant tolerability issues. For example, with vigabatrin, you see actually a high degree of sedation at their therapeutic doses. We're not seeing that yet at the same time, we have now proven that we are delivering competitive and in-excess inhibition to that mechanism.

So this is what the field has always wanted to achieve. We want to have highly effective anticonvulsants that are gentler medicines. That's what the profile and what we believe the phasic and tonic inhibition of OV329 is allowing us to deliver.

The next question comes from Myles Minter at William Blair.

Congrats on the data. I had two on the data and then just one on the 7-milligram dose. So the first one is on the cortical silent period data. You've shown a 10.4% increase in the FDI muscles, 6.7% in the ABP. Just wondering how that compares to Dr. Rotenberg's expectations for that particular data that he announced at R&D Day.

And then the second is on the LICI. I think in the placebo arm for the FDI muscle that may have been numerically larger, the improvement there than we saw with 329. So is that just low-end numbers, noise in the data there? I just wanted that explained.

And then finally, on the 7-milligram dose, is that pretty much just bringing forward the time to steady-state concentration as well? And are there any sort of drug-drug interactions that we should be aware of considering, I would imagine these FOS patients are probably going to have three or more concomitant meds, if you enroll them.

So I will try to get to all of those Myles. So -- and if I miss one, just flag it or for me. So in terms of the performance on the cortical silent period, so Dr. Rotenberg works with us and advises us closely as an independent expert and one of the world leaders on applying TMS biomarkers to the evaluation of anti-seizure medicines. And basically, Alex would tell you, yes, this performance on the cortical silent period actually looks very good for a seizure medicine.

And the reason why is if you look at our materials, what you'll notice is that therapeutic doses of vigabatrin have been studied in two different studies of healthy volunteers. In one study, a therapeutic dose of vigabatrin achieved a 19% increase. In another study, it showed actually no impact on the cortical silent period.

So, of course, we have moved the cortical silent period and prolongated it in a statistically significant fashion, but what I believe Dr. Rotenberg would likely tell you of looking at the cortical silent period versus another biomarker like the long-interval intracortical inhibition is that the CSP, the cortical silent period, is probably a less specific predictor of this mechanism. So you can pick it up on TMS, but it might not be as specific as the LICI, for example, is. But nevertheless, we moved those parameters in a statistically significant fashion.

I'll go next to your question about the 7-milligram dose, and I think you had asked the question -- hopefully, I addressed the comments about the exposure level that we believe it will deliver.

In terms of steady state and just overall performance of the 7-milligram in terms of the safety and tolerability perspective, for 329, we have now modeled across multiple doses and multiple species at this point that we hit steady state, typically within about 3 days and we also know that we're hitting our target pharmacology inhibition by also 3 days.

So what I mean by that, Myles, is that our strategy is to inhibit the GABA-aminotransferase enzyme by roughly 50% to 60%, in that corridor. And we know that we achieved that after 3 days of repeated dosing. And because the enzyme turnover is very slow with very low, but potent doses, we are able to keep the enzyme suppressed.

So we know that we hit steady state within that period of time. We believe, based on the safety and tolerability that we have in animals and importantly, much more importantly, that we now have in humans, that we expect that the 7-milligram should perform very well.

Myles, let me just take a beat there and see. I think you had an additional question about the 7 milligrams, and let's make sure we cover that for you.

It was, just any sort of drug-drug interactions that we should be aware of?

No, no. No, none.

Congrats.

The next question comes from Jay Olson at Oppenheimer.

Thank you for providing this comprehensive update and congrats on the impressive results for OV329. Looking ahead to your proof-of-concept study in focal onset seizures, could you please talk about lessons learned from previous focal onset seizure trials, especially with regards to managing placebo response?

And how do the differentiating features of OV329 translate into potential clinical benefits versus other GABAergic anticonvulsants? And we have a follow-on question, if we could, please.

Okay. Very good. So when we look at the landscape of focal onset seizures, we really benefit from being able to walk through the learnings that the field has had over time and that our peers are having, who we're also cheering for. This is a category where better medicines are needed.

Most particularly, I think one of the things that we look a lot, of course, is at data capture. So the field has improved very much when we think about electronic seizure diaries, how do we optimize our enrichment population relative to the number of ASMs they're on, the number of baseline seizures they're having to more optimally be able to count change. These are things that we work hand-in-hand with the epilepsy research consortium to do. We also have the benefit, of course, of being able to see the results that another GABA-aminotransferase inhibitor, vigabatrin, had demonstrated over many studies over many years.

But I think, Jay, when we look out at the next steps for 329, one of the things that we are most keenly focused on is, of course, enrollment. This is a busy area. We feel that we're very well positioned with the completely unique mechanism of action that seems to have really good safety and already has quantitative measures of inhibition far beyond what I think any other seizure medicine has had at this stage of development. But we're very much focused on enrollment, optimizing our sites to be able to ask the right questions and get answers.

And then you asked an important question also, Jay, about, so what is the profile of 329 look like relative to the treatment-resistant focal onset seizure landscape. And we think it looks really good. And the reason why, there are not other medicines out there that naturally help increase your local or endogenous levels of GABA and tuning those in a way that is more optimal. When you think about other seizure medicines that are good anticonvulsants, they tend to search GABA in the synapse primarily. That leads to some of the tolerability and side effect issues we see such as sedation, dizziness and headache.

So by more optimally tuning GABA and bringing this differentiated mechanism to the fore that we don't anticipate titration, it will be once-daily dosing, highly potent, and it appears to also have -- on track to have very competitive seizure reduction based on what we see from the inhibition it delivers and what appears to be best-in-therapeutic area safety so far. So this could be a really meaningful medicine to people with epilepsies.

Great, that's super helpful. And I just want to follow up on the safety comments. It seems like today's findings support a level of ocular safety that could preclude the warning for loss of vision and the requirement for ocular monitoring that vigabatrin has. So we're curious if that clean ocular safety would eventually enable earlier lines of treatment with 329.

Certainly, that would be something that we would like to pursue as part of our strategy, Jay. We felt, and thanks to our research team and my colleague, Dr. Zhong Zhong, we have spent an extensive amount of work derisking 329 in the preclinic, well before we ever got into humans.

With that said, we will continue to build an ocular and ophthalmic safety database, really starting today, for OV329. And that will enable us, we believe, in our discussions with regulators to avoid the monitoring that vigabatrin as a class was previously subject to.

So all of the safety and ophthalmic metrics that you saw in our Phase I program, we will continue in perpetuity through OV329's development and also into open-label extension programs. This will allow us to build a very robust ophthalmic safety database that supports 329 and the registrational package that we will take to regulators to avoid the monitoring that was needed with the -- previously with vigabatrin.

This concludes today's Q&A session. I'll now turn it back to Victoria for concluding remarks.

Thank you, everyone, for joining today's event. As a reminder, a replay will be posted on our website following this call. Have a nice day, and you may now disconnect your line.