Ovid Therapeutics Inc. (OVID) September 2026 Conference Transcript

Good morning, everyone. Thank you for joining us today. It is my pleasure to welcome Meg Alexander, the President and CEO of Ovid Therapeutics. She's going to be giving us an update on their lead programs in neurology and a passion on treating epilepsy in adults and children and other indications as well. Meg, it's a pleasure to have you today.

Thank you.

Thank you for joining and the floor is yours.

Thank you. Thank you to the team at H.T. Wainwright for hosting us. I'm Meg Alexander, and I'm excited to tell you about our progress at Ovid and our mission to pioneer better, gentler medicines for brain conditions. We are a forward-looking company, and we will be making forward-looking statements. So at Ovid, I open with saying, it's our mission to create better, gentler medicines for the brain. And there's very unique ways in which we do this. We decided years ago, looking out at where neurology was, that unfortunately it was a sea of sameness. What do I mean by that? We were seeing a lot of companies and developers go after targets that we already know with mechanisms that we already know work. And while that's good, we always want better pharmacology and incrementally better medicines, we didn't think this would really be a step change for patients. So we went out to go after fundamental biological targets that drive too much excitation in the brain, so neural hyper excitability. We specifically went out to find programs and mechanisms of action that were completely unique and that we thought would have more universal efficacy, so broad therapeutic utility. And finally, we have been doing that with the hope that if we deliver these novel mechanisms for fundamental targets in the brain, that we may have first-in-class and best-in-class medicines that would really bring that step change to patients. And that's where we are. We're a clinical stage company today with a desire to be fully integrated, and we have four to six proof-of-constep milestones coming out over the next 6, 12, 18, and 24 months.

So this strategy has helped us build a pipeline.

Can you see? There we go. The pipeline that you will see in front of you momentarily that looks like this. So as I mentioned, we're a clinical stage company, and we have two very unique mechanisms that we're progressing in the clinic. One is a program called OV329, and I'll tell you a little bit more about this mechanism, but this is designed for a set of very intractable epilepsies, including focal onset seizures and very devastating pediatric epilepsies, including tuberous sclerosis complex and infantile spasms, and potentially others over time. These are advancing in signal-finding and phase-two proof-of-concept studies as we speak, and we'll tell you more about that. Below that, in the purple part of our pipeline, you see what is a very, the beginnings of a very novel and exciting franchise of direct activators of a target called KCC2, which stands for potassium chloride co-transporter 2. And this has been the target that many have wanted to drug in the brain for decades because it's highly implicated in diseases and symptoms that are driven by too much excitation of neurons, but it's been really hard to do until now. We now have the first oral KCC2 direct activator in the clinic. I'm very excited by this molecule. It appears to have very broad therapeutic utility across a number of different conditions and symptoms of the brain. But first, we'll go ahead and we'll start with the epilepsy program, and that's OV329. So the field of epilepsy is having more medicines come to the fore. That's great news for patients and hopefully better medicines at that, though unfortunately the holy grail of a seizure reduction medicine has not yet been achieved. And when I say that, what I mean is we want medicines that work to deliver anticonvulsant efficacy, that don't make you feel bad, so they're safe and well-tolerated, and that they're easy to use and take, which unfortunately, despite a lot of innovation and a lot of progress by my peers, the field hasn't been able to achieve that yet. OV329 appears to be the drug that will do exactly that. It's highly potent. It's a validated mechanism, but only one drug tried to drug this target before, and that first-gen drug had a unique compound-specific toxicity that we were able to rationally design around. And if we do this and have both the efficacy, potency, and the superb tolerability that this medicine appears to have today, we believe this will be a very big opportunity, not just in focal onset seizures, where there remains tremendous unmet need, but also in developmental epileptic encephalopathies, which are very severe pediatric disorders, and also where we know this mechanism of action that OB329 has is validated and has delivered profound effects. So this really could be a game changer for many children and adults. So we'll talk about how it works. So it's a relatively simple mechanism of action. GABA is the main breaking system in our brain. It's the primary neurotransmitter and the primary inhibitory neurotransmitter. And when it can't be functional, that's when we start to see seizures and other conditions. What OV329 does, it essentially inhibits the enzyme that catabolizes or that eats GABA. So what that means is we get more GABA, both in the synapse and spilling over into the extrasynaptic region, allowing the breaking system in our brains to work as it should. And because we rationally designed OV329 to have an improved therapeutic index, we're able to do this and deliver GABA around the neurons in a more inhibitory neural environment better than many other medicines have been able to do. And all of this is seeking to solve a problem that we've known has existed now for many years, and that is there was another medicine that tried to approach this mechanism of action. It was called Sabrel, and it was marketed by a company called Lundbeck for many years. So there's a lot we could learn from that. Specifically, we could learned that it worked as an anticonvulsive mechanism. But that drug developed 40 years ago was like a lot of drugs developed 40 years ago. It came with a lot of baggage. It didn't have the same level of sophisticated pharmacology that we have today. And as a result, this drug had a very unique toxicity in the sense that it accumulated and partitioned in the retina and led to ultimately a type of irreversible tunnel vision. Not okay, right? We want to save the brain from emergency seizures, but making people blind in so doing is not copacetic. So we've completely designed around that with OV329 through very focused chemistry as well as pharmacology. And in fact, we went to the same fellow who developed Lyrica now many years ago to help us design OV329. We've since done that. We have a thousandfold potency difference, binding nuances, but the most important factor is We have run the killer experiments, many of which, and we know that our drug doesn't partition in the retina like the first-generation drug did. So we have a safety profile and what appears to be a tolerability profile that looks better than any seizure medicine in development or marketed today. So we believe OB-329 is going to be a drug. The question is, is it a good drug or is it a great drug? And we're asking and answering that in a Phase II study and also a photosensitivity study right now. And one of the reasons that gave us a lot of conviction is the nice thing about the way technologies are moving in epilepsy is you can almost run a phase two study in phase one right now. What I mean by that is the technology allows us to look into the brain and see are we restoring the breaking system in the brain when we give healthy human volunteers our drug. And we were able to do exactly that. Actually, this time last year, we read out results from a phase one study And we used a broad battery of basically electrophysiological biomarkers. But in sum, what it told us is that we were getting into the brain with OB329 at our desired clinical doses. We were increasing inhibition in the brain. And what was really neat was that we were able to compare it to therapeutic doses of that first-generation drug I mentioned a few minutes ago. And we were able to definitively show that we were not just matching, but we were actually exceeding the level of inhibition that that drug delivered in the brain. So a good sign when you have seizures and your brain is overactive, too much hyperexcitability, a good sign that we were delivering what would likely be therapeutic efficacy. And that's exactly where we are now. Importantly, safety obviously is a big thing when you're trying to replace a first-generation drug that had baggage and significant baggage. So we've been able to characterize our drug at clinical doses, OB329, and two important If you look on the left, there's a lot of numbers here, but what this is saying is this is so far the safest, best-tolerated drug that we've seen in seizure medicines, period. The second is that in terms of ophthalmic safety, we have a completely clean record. And we're not just looking at people's vision and kind of the eye test that all of us take, you know, if you go to the optometrist, we're actually looking at the back of the eye. If something was happening subclinically, we would see it. And we've de-risked this, we believe, in the pre-clinic. We didn't expect to see anything, and of course, we haven't. So now we're moving forward, as I mentioned, and we believe the opportunity is really significant. We are rapidly pursuing further development of OV329, both in a phase two study. We're running a photosensitivity study right now, which is also like a human assay to show anticonvulsant effect while we run the phase two. We'll have results from the photosensitivity study within the next few months and the phase two readout around this time next year. And if we do this right, we think this will be a very big opportunity, both for patients to deliver a meaningful medicine, but importantly, also commercially. So this gives you a sense, even in the treatment-resistant focal onset seizure landscape, which is a busy We have a lot of friends and peers that are developing drugs that I think are going to be really good medicines, and I hope they will. But even if you make very conservative assumptions about the profile of OB329, it's more than a billion-dollar opportunity for the focal onset seizure indication alone. Then, if you turn to some of the pediatric epilepsies that I was mentioning, the opportunity there is far less competitive. The need is substantial. These are children who have very bad, not just seizures, but also developmental, neurodevelopmental outcomes. And we know this mechanism works, but they're undertreated today because the first-generation drug had the safety issues that I referred to earlier. So again, we think this is a very significant opportunity here, likely greater than $700 So collectively, we think the opportunity for 329 is very significant, and there's also room to grow in other pediatric epilepsies once we achieve some proof-of-concept milestones. But now I'd like to turn to the second part of our pipeline, which is the KCC2 portfolio. And that is particularly... Sorry, we're having a little bit of trouble with clicker here, folks. Well, in any event, it's basically one mechanism, but potentially many, many medicines. So KCC2, I mentioned earlier, is the target in the brain that our field has wanted to drug for a long time. And the reason why is it may be a master switch on basically quelling too much excitation of neurons. It's a very special target because it's only in the CNS. A lot of other drugs in the past that have tried to go after other targets run into issues because they're expressed in other tissues and organs. This is neuron-specific, so only in the brain. The breaking system in our brain can't work when this target is dysregulated. And it does a really important job, both geographically, because it sits upstream of a lot of known drugs, like D2 antagonists, but downstream from many of the genetic and acquired causes of too much excitation of neurons, like seizures, among other conditions. And what's so nice about this target, it's almost impossible to over-modulate. Like so many, you know, drugs in the brain, it's sort of like Goldilocks. We're always trying to get it right. But this drug, you actually, by activating it, can't extrude too much of the ions that it balances. So it may be a very precise mechanism that broadly converges on a number of conditions that are driven by neural hyperexcitability. So at Ovid, it is our vision to be the company that pioneers and truly realizes the value of this target. We have already drugged this target safely. We read out tool program results last year. so we've been able to do that. And excitingly now, today, we are in a phase one study with the first ever oral KCC2 direct activator. And I believe we may be within six months of being able to start to really show the opportunity with drugging this medicine. So we've established biomarkers. We have a really neat translational study that we're running called a ketamine challenge, which I'll talk a little bit more about in a moment. And we believe that this is potentially a franchise. Because when you look at the literature of KCC2, it almost looks too good to be true. It almost looks like an orexin of the brain or a PD-1-like moment of the brain. And frankly, it took me and some of my colleagues a long time to get here to believe that even part of this reality of conditions that KCC2 may be linked to could be a reality. But what convinces most of us and what convinces me is data. And now we have a very large armamentarium of data supporting its therapeutic utility in a number of the domains that I mentioned here, including many forms of psychoses, like schizophrenia, neurodegenerative psychoses, chronic neuropathic pain, and other neurodevelopmental conditions, and even seizures. So this is a very exciting moment. And this gives you a sampling. This is a little bit of an eye chart. So for those of you in the audience, it may be hard to read. But essentially, this is a snippet of some of the pharmacodynamic data that we now have supporting our oral KCC2 direct activator. We've seen activity in psychoses, the positive symptoms, negative symptoms, and cognitive symptoms. If someone could do that, that would be the holy grail of a psychiatric medicine. No one's been able to effectively do that to date. The data on KCC2 here is overwhelming. It's been repeated many times over, and specifically the molecule that we have in the clinic looks to be a very good molecule. In addition to that, we've seen very good activity in behavioral and anxiety domains, as well as some interesting but earlier data in pain and epilepsies. So we think this could be a very exciting moment for KCC2. And the molecule, as I mentioned, that we had in the clinic is a really good molecule. We have many that we've been developing. It's, again, if KCC2 and our thesis on KCC2 is right, we want to be the company that truly unlocks this. We're also the only public company that has a KCC2 program. And OV4071 is the medicine that's in the clinic. It's extremely potent in psychosis models. It has very good safety margins. And we know it gets into the brain and is commensurate with chronic daily dosing. And our first plan indication for KCC2 is acute schizophrenia, though we think this is a broad antipsychotic medicine. And specifically, the way KCC2 appears to be working in people who have schizophrenia is really upstream. We know in schizophrenia a lot of the positive symptoms, so the delusions, the hallucinations that unfortunately plague people who suffer with this condition, are driven by too much excitation in your prefrontal cortex that drives too much dopamine and a dopamine surge in the striatum. What we know in people who have passed away, when we look at their postmortem tissue, KCC2 expression is reduced in the prefrontal cortex. And we also know that when we look at genetic animal models of schizophrenia, they also have reduced KCC2 expression. Yet when we rescue function in the prefrontal cortex of these animals by even 50%, we see profound therapeutic changes. So a complete amelioration of the positive symptoms, rescue of typical social, normal physiological interaction, and improvement on cognitive batteries as well. So this is very exciting, and this is just one, as I said, of several indications. It's our first planned psychiatric indication, though we anticipate more beyond that. And again, this is just a sampling of the data that we have supporting this portfolio. I'm not going to go through all of this, but essentially the most important piece is at the bottom. These are lots of different animal models that modulate the biology that's relevant to schizophrenia, but we know that we have very consistent activity at our planned doses. We've been able to basically improve the positive symptoms, restore typical social interaction, It's a very rapid effect, less than an hour, but it lasts. We've gone out over longer-term dosing. We've seen the underlying biology change to be more like a typical physiological healthy brain in the animals that we test. It's improved behavior. And most importantly, it's a more precise way of tuning GABA, so we're not seeing sedation and a lot of the baggage that happens with so many other CNS medicines, including psychiatric medicines. So this was one of the first models that showed it. We've had a dose-dependent response. importantly, again, so many drugs for psychiatric conditions essentially put the brain to sleep, right? They sedate you heavily. What we've seen with KCC2, direct activators, is it's having a therapeutic effect, but it's not putting a straitjacket on the animals or the humans. We're seeing, you know, basically a return to normal physiological behavior. Again, the holy grail of psychiatric medicine. And I'll just go through one other study. This was particularly exciting to us. Unfortunately, psychiatric models are not like some other conditions in cancer or MS or even in seizures where we operate, where you've got true translatability of one model into early clinical outcomes. So none of us at Ovid trust any one psych model with an animal. However, what I do trust is 100 different PD studies repeated many times over with the same results, and when we run our molecules head-to-head against known reference drugs, like in this case, resveridone, xenomaline and trospium is a drug called Cobenphi, which is made by a company called Caruna. You may know it. They were bought by BMS. And our KCC2 direct activators, what we're seeing is that our KCC2 direct activators are outperforming best-in-class drugs, whether that's clozapine, xenomaline and trospium, which is Cobenphi. This is a particular set of studies that was done by one of the emerging thought leaders in psychiatry, and specifically in schizophrenia translation. And on the left, if you look down the columns, it's a genetic model. The right was a sort of stimulant-induced model. And both of these are models for schizophrenia and various symptoms. And essentially, he put these reference products, including our direct activators, through a battery of cognitive tests. And what we're seeing is our KCC2 direct activators are rescuing cognition, both in working memory and task switching, in addition to some of the other things I mentioned earlier. So we're very excited about what this portfolio may mean. We're in the clinic right now. I'm not going to go into this, but we have translatable biomarkers that we've established across both of our KCC2 direct activators. And we're within a matter of months of triggering what I said before with a ketamine challenge. That is a way where essentially we give a low dose of ketamine to make this target, KCC2, less functional and try to rescue activity. And what's very exciting about this is if we see effect, what we will be able to see is getting into the brain with our clinical stage direct activator, having neuroactivity, having neuroactivity that's on mechanism, so the breaking system in the brain, GABA, is working better. And importantly, if you look down the bottom part of the screen, these are very well-codified, sophisticated biomarkers using electrophysiology that have a predictive effect into disease, and specifically predictive clinical effect. So we believe, as I said before, this is one great translational tool, and this may be one mechanism, potentially, that becomes many medicines. And this gives you a sense of the readout. So I said earlier, we've got four to six proof-of-concept milestones starting to read This is that. So we're in a phase one right now. The ketamine challenge will start before the end of the year, and we're planning an acute schizophrenia phase two program around the middle of next year. And as FICE said, we think this is going to be a very big commercial opportunity. So thank you.

Thank you so much, Mac, for that excellent overview. If there's any questions from the audience.