Good morning. Thanks for joining us for the Ovid presentation here at the 46th annual TD Cowen Healthcare Conference. I'm TD Cowen senior biotech analyst and covering analyst for Ovid, Ritu Baral. Here for the presentation with extended Q&A at the end, is Ovid CEO, Meg Alexander. Meg, thanks for joining us. Thank you, Ritu. Good morning, everyone, and thanks for joining us on the third day of the conference. Ovid is a public company, so I encourage you to take note of our forward-looking statements. I'm excited to give you an update this morning and to tell you a little bit more about the company. For those of you who don't know about Ovid's story yet and our strategy, we are a company singularly focused in the central nervous system. We focus on small molecule medicines. Our therapeutic area of focus is essentially to look at biological targets in the brain that are fundamental to the balance of neural excitation and inhibition. We've gone after extremely differentiated targets, because if you look out at the field of neurology, we've learned over the years that there are certain targets that work, and that's good for patients. The challenge is, though, as we look at that and you look at development pipelines, you see a lot of our peers in the space keep going after mechanisms and targets that work to just slightly improve pharmacology. That's good. We want gentler medicines. At Ovid, we made the very unique choice five years ago to curate a pipeline to look at mechanisms of action that we thought would be truly differentiated. It was our thesis several years ago that a couple of years from now, we're going to start to see mechanistic category winners, that we would see medicines that might be the best sodium channel or the best potassium channel. That's great. Those medicines are improving for patients. What we wanted to be able to offer was differentiated mechanisms which the field of both neurology and neuropsychiatry need. The thought would be that we would be bringing both unique mechanisms to patients in trials, but hopefully a step change in the therapeutic potential and also the commercial opportunity. This is indeed what we have built out of that pipeline and out of that strategy. I'll walk down this at a high level, but then I'm going to dive deeper into each of the programs, some of the recent data supporting them, and importantly, what to expect next, 'cause this is an incredibly exciting 6-18 months for Ovid, where we've got a number of data card turnovers and progress across all of these assets, actually. Starting with the top of our pipeline in teal here, you see our epilepsy program. The name of this program is OV329, and the way that this particular medicine works is it inhibits an enzyme called GABA aminotransferase. Why that matters is essentially GABA aminotransferase is the enzyme that catabolizes or degrades GABA. GABA is the main inhibitory neurotransmitter in our brain. If you inhibit this enzyme, you get more of GABA or the natural braking system in your brain working as it should. We just read out very exciting data for this program late last year that basically used the most expansive biomarker program that was ever done to be able to show that this particular asset in this program at the doses we tested was delivering inhibition in the brain commensurate with therapeutic doses of other seizure medicines. That was good. We could see that it was getting into the brain, working as it should, elevating levels of GABA. Importantly, it appears to be doing so in a way that's not only safe, but appears to have better tolerability than most of the seizure medicines that we see marketed in development today. The opportunity here could be quite significant. We're taking this into an open-label study this year, as well as a Phase II trial. Below that is our KCC2 portfolio. KCC2 stands for potassium-chloride cotransporter two. This is a very exciting target in the brain. The field has wanted to drug this for a long time because this particular cotransporter has potentially very broad therapeutic applications, but it's been a challenge from a medicinal chemistry perspective to drug. At the end of last year with our tool program, we've shown that we've done that. We've been able to get into the brain, safely drug this target, and we even saw signs of a signal, essentially on electrophysiology, we saw GABAergic activity, which is what you want to see. When you regulate this co-transporter the right way, it allows, again, GABA or your brain's natural braking system to work. Where are we now? After reading out that tool program, we have increased conviction that we can safely and effectively drug this target. We probably know more about binding in this target than just about any company. We now have an oral that we are submitting for regulatory clearance and initiating first in human studies with. We've guided that we would be submitting for regulatory clearance this quarter of this year and initiating human studies this next quarter, Q2. We're on track with that guidance. This is a really exciting time for Ovid. What I'm going to do is just take a quick dive through the two programs just to give you a sense of what is giving us conviction, but also to outline what's the next set of questions that we're looking to ask and answer with our clinical development. I mentioned OV329 is a GABA aminotransferase inhibitor. We are the only company that is pursuing this mechanism of action in the field of seizure medicine development. It is a validated mechanism, and we are trying to supplant a first-generation drug that we know worked as an anticonvulsant. It was a brand called Sabril, the generic name was vigabatrin, but it had an idiosyncratic safety issue that we have been able to show in the pre-clinic and have been demonstrating in humans that we don't have that same liability. We knew that also from other independent research. Essentially, the way that this works, and I mentioned this a moment ago, is that OV329 is a very potent and irreversible inhibitor of the particular enzyme that degrades GABA. What that allows us to do at the doses that we have of OV329 is elevate GABA in the synapse and actually also to spill over into this extrasynaptic region. Essentially, what we're doing is cooling down the entire environment around hyperexcited neurons. Our drug uniquely does this. The first-generation drug didn't have the therapeutic index to do it. We believe this is what's leading to a preferred tolerability profile and potentially a stronger efficacy profile than what we had seen with the first-generation drug. We now know based on the data that we had from reading out late last year that we have a medicine with a profile that is working as it should. We're delivering cortical inhibition. We should be a once-daily oral capsule. We believe that we should have seizure reduction that is competitive and potentially better than what we saw with the first-generation drug of this mechanism, which is important because in the field of seizure medicines, there's more drugs, which is good, and there's starting to be better drugs. Having competitive seizure reduction efficacy is key. We believe we should be able to do that. Importantly, we don't anticipate some of the challenges that other seizure medicines have. Tolerability challenges, titration challenges, drug-drug interactions. We don't anticipate any of that with OV329. We believe this may be a really important potential medicine, not just for focal onset seizures, where it's validated, but also in some very acute forms of pediatric epilepsies, where this mechanism of action has also shown profound impact. Indications like tuberous sclerosis complex, infantile spasms. This is some of the data that was the reason to believe. We actually, as I mentioned, ran the most expansive biomarker program that had been done for an early seizure medicine. We don't have the time to show you all of it today, but essentially, this purple bar on your far right is showcasing cortical inhibition relative to therapeutic doses of the first-generation medicine vigabatrin and relative to placebo. I think you can see that using the same methodology that the first-generation medicine was characterized on, we've been able to deliver inhibition that is actually competitive and is better using the exact same methods. What matters a lot with seizure medicines is, yes, you need to work, and you need to work well. Seizures are an emergency of your brain. The problem is too many seizure medicines work, and they also make you feel poorly. By the time you have a couple of seizure medicines on board, they have additive tolerability issues together. With three two nine, we were able to show that we have extremely good tolerability, and this gives you a sense of the AEs that we're seeing in our Phase I trial. Extremely mild headache, drowsiness, and a case of metallic taste, all of which were transient and diminished. We have very strong results. We know 329's getting into the brain. It's delivering inhibition. It elevated GABA in regions of the brain, and it's doing so in a way that appears to be commensurate with what we know of other seizure drugs. Finally, we have a responder rate. We know that when we hit our target drug exposure in the brain, we are at a therapeutic dose, and we see a high proportion of responders. We've been able to model all of this, and it gives us a lot of conviction about where we're going next. Where we're going next, what I'm showing you here is the gold standard study that we're embarking upon in this next quarter. It's a randomized Phase II placebo-controlled study. We're taking a 7-milligram dose into this study, which I can talk more about in the Q&A. We're very encouraged by this. This will read out by the middle of next year. We're not waiting to get an answer here alone. We will have safety data and tolerability data on our 7-milligram dose before the end of this quarter, so before March 31st. It's very soon. We will also have results of an open-label study near the end of this year that will be a proof of concept study in seizure patients. Over the next 3, 9, and really 15 months, you'll see a lot more data forthcoming on the epilepsy program. If we're right, this could be a very big opportunity. We're showing you here the opportunity in focal onset seizures alone, which is a pretty dense landscape. This is probably us making 2 conservative assumptions. You can see, even with conservative assumptions, this could be a pretty meaningful medicine. This does not include other expansion areas that we could walk into, like specific developmental epileptic encephalopathies, which if we see good anticonvulsant data, arguably should be the type of thing that we start to expand. I want to take just 2 or 3 minutes to quickly talk about the other side of our portfolio, which is our portfolio of direct activators of KCC2. As I mentioned, KCC2 is a target that many have wanted to drug because of the broad therapeutic potential and also the unique attributes of this particular biological target. Potassium-chloride cotransporter 2 is an ion cotransporter. It matters because when this particular cotransporter is dysregulated, GABA, the main inhibitory neurotransmitter, doesn't work. It can't do its job. This target is a master switch on neural excitation. It is only expressed in the CNS, so we don't believe that we will see some of the off-target and on-target effects that we're seeing with other ion chloride cotransporters. What's great is you can't over-modulate this. You can't actually push too much chloride out of this cotransporter. Like other CNS drugs, that's always a challenge of how do you hit the sweet spot. This drug has essentially a good self-limiting safety mechanism. From an opportunity perspective, this is what makes the field very excited. It has broad potential across a number of different indications. It's a little hard to see on this slide, but the little orange stars are areas where we all have supportive data already in this. If our thesis on KCC2 is correct, Ovid will be one of the pioneers of directly activating this particular target, KCC2. We have a portfolio of molecules. I'm just going to very quickly acclimate you. Three five O on the far left was our tool program. We read out data on that at the very end of last year in humans. We were able to show safety, as I mentioned, and we were also able to show signs on quantitative EEG that we were having GABAergic activity. It was hugely confidence building for the lavender program, which is the oral. That's the one that I mentioned that we are submitting to regulators this quarter that we anticipate initiating human trials for next quarter. Everything is on track there, and we have other next-generation direct activators behind that. What we know of this portfolio is they're behaving very much like atypical antipsychotics, but without the baggage of that. This was data from our tool program. Not going to spend too much time on it here, but basically on the right what you're seeing is a dose-dependent response of that tool program. The little green line is clozapine. The gray and the black is vehicle. Essentially what you're seeing is our tool program have a dose-dependent response and ultimately beat clozapine in a psychosis model. We've seen similar profiles for OV4071, which is the oral program that I just mentioned that we're taking into the clinic. Just to conclude, this asset is very exciting. It's very active and potent at low doses in a battery of different psychosis models. It has what we believe will be a very good therapeutic index based on all of our IND enabling work. We're very excited to characterize this as quickly as possible. We have, as I mentioned, many psychosis models. We compare it to reference drugs, both older generation ones as well as new generation ones, like some that have been recently approved, and we're seeing it essentially meet or outperform them. This is another antipsychotic model, again, a dose-dependent response to OV4071, where we're essentially mitigating the hyperlocomotion that's induced by basically an antagonist. We believe there's very big opportunities across a number of psychosis indications. We believe it'll have broad activity. Finally, just to let where we're going next, we talked about on the top row what's happening with our OV329 epilepsy program. If you acclimate yourself to the middle row, what you'll see is that we're on track. We plan to initiate the phase I study for KCC2 oral, which is OV4071. We'll have exploratory electrophysiology and biomarkers in that again. Later this year, we'll be initiating a challenge study. That's ketamine challenge. That is looking to help us see, can we quell some of the discomforts associated with an antagonist and an NMDA antagonist like ketamine, while also correlating it to quantitative electrophysiology. Can we show we're having a clinical effect while also showing that we're having the right activity in the brain? Finally, we're looking to expand and accelerate the development of this particular asset rapidly. We've said that we have interest in psychosis associated with Parkinson's disease. We will also have more forthcoming information on schizophrenia, and there's reasons to believe that this asset could be very promising in Alzheimer's, agitation, and psychosis as well. With that, I'd like to conclude and leave some time for Q&A with Ritu and Athena. Thank you. Thanks, Meg. I wanted to start off with the OV329. Actually, most of my questions are OV329. You guys, if you have questions, please just pipe up as well. I'll pass you the mic. Can you talk about how OV329 is differentiated from other drugs currently in development for focal epilepsy? Most of the ones that are discussed in investor meetings are sodium channel drugs. Mm-hmm. Can you sort of compare and contrast the mechanisms, and are there other GABAergic drugs, in development? Yes. Fantastic question. I'll start with a broader step back. This is a good time for the world of epilepsy and people who still have treatment-resistant seizures because there's more drugs in development, and they're getting better, and that's a good thing. Companies like Xenon and Praxis and others, my peers in the space, we're cheering for them, and they've got mechanisms that I believe will work and be good drugs, like sodium channel drugs, like potassium channel drugs, and other programs, even 5-HT2A. What there is not is there are no other safe GABA aminotransferase inhibitors that are used. The opportunity, I think, with this medicine could be pretty profound. It is mechanistically acting in a different way, right? It is allowing your natural GABA in your brain to accumulate in your synapse, in your extra synaptic region. It's doing so in a way that not only appears to be effective, right? We're seeing the inhibition that we want to see that we can compare alongside therapeutic doses of other seizure medicines. It's got the full complement which seizure medicines have not had. Unfortunately for too long with seizure medicines, you hit a ceiling where they may work, but they're tolerated very poorly, or you can't add them in a polypharmacy regimen. That's a problem because if you keep having breakthrough seizures, which roughly 40% of the populace with treatment-resistant epilepsies have, you need multiple drugs. You add each of them, you feel worse and worse. Three two nine is stacking up to be very different. It's a fundamental mechanism in the sense that it's elevating your endogenous levels of GABA, but it appears to be doing so in a way, and there's mechanistic reasons for this, that it's safe, that it's very well-tolerated. We don't have any drug-drug interactions, and we don't anticipate any titration. All of these are challenges with other seizure medicines, and it appears that OV329 is on track to work but also be better tolerated than any seizure medicine in development, or that's marketed today. If that thesis continues to hold, it could be a pretty profound drug for a number of epilepsies. You mentioned, Sabril. Mm-hmm The toxicity. it was an ophthalmic toxicity, like a retinal toxicity. Correct. Correct. You said you have confidence that you won't see that with OV329. Can you walk us through the data? Sure, we can. Yeah. Some of this is in the public domain, and Nope, it's not there. I can describe it nevertheless. Yeah. In terms of Sabril. First, just taking a step back. We developed OV329, and we went out looking for this asset. We actually got it out of the same fellow who invented Lyrica, who's a medicinal chemist at Northwestern, 'cause we had the conviction from the get-go that the unique ophthalmic safety issues that had been seen with Sabril were idiosyncratic. Mm-hmm To that drug. Why? First, our thesis was when we looked at data in the public domain, we could see that there were humans that had 100% of this enzyme knocked out, GABA aminotransferase, which by the way, isn't good. That's not our target pharmacology. You don't want 100% depletion. The humans who had this, including their parents, didn't have the telltale retinal issues- Mm-hmm That was occurring with vigabatrin. Other medicines do modulate GABA or inhibit GABA aminotransferase as off and on target effects. Mm-hmm. You also don't see these signature ocular issues. It was always our thesis that there was something unique to this molecule, but we had to go prove their challenge while also proving. Yeah Our safety. We've subsequently done that. We have been able to uniformly and consistently produce the vigabatrin, or Sabril was the brand name, preferentially partitions and accumulates in the back of the eye. We see it in animals in less than 48 hours, and it replicates independent research. We run our own drug in the same challenge studies now across multiple species, right? Mice, rats, dogs, humans. What we've been able to consistently show is that Sabril does uniquely partition in the retina and lead to ophthalmic dysregulation and issues. Just because of the high concentration in that one area. It's unique to this molecule. Of the tissue. Yeah Yeah Its partitioning. It has a probably longer story. It does have a unique selectivity for another enzyme that we believe. Mm-hmm May be contributing to it. Okay. The drug was like a lot of first-generation seizure medicines and kinda like first-gen oncology medicines. It worked, but it worked like a sledgehammer with a lot of liabilities. Importantly, with OV329, when we control for exposure and run it head to head with all the same challenges, we know that we get into the plasma and tissue, but we clear it rapidly, and Sabril does not. You talked about, data within the next three months. I believe that's the. Mm-hmm Phase I Yes The OV329. What are you expecting from that safety data in comparison to the five that you showed? Yeah. How are you going to make your decision on the Phase II dose? I'm assuming it's going to be one of those two. Is higher better? Is this a place where you're going to look at differential safety? Yes. right now, it's our intent and desire to take 7 milligrams into the Phase II study. What we have been actively doing is qualifying the safety and tolerability. Mm-hmm of that. We have a number of strains of evidence that we're looking at, both the tolerability, which is important. You've heard me say the. Mm-hmm Importance of that for seizure medicines. Do you mean like sedation? Is that? Sedation, dizziness, headache. Those are the ones that. Hallmark challenges associated with many CNS drugs, including. Yeah Epilepsy medicines. The goal is to have a drug that actually works, that doesn't make you feel terrible. Mm-hmm. That's the sweet spot of what we're looking to hit. We believe with seven milligrams that we will be able to maintain a good tolerability profile and safety, which is what we're looking to read out in the next couple weeks, as you heard me say. The other piece is what we know from our own modeling is that when we hit a certain drug exposure level in the plasma, that's highly correlated with our target pharmacology- Mm-hmm The amount of enzyme we want to suppress, and we also know it's highly correlated with pretty profound cortical inhibition. Mm-hmm. I know when we get to a range north of 80 nanograms per hour per ml of drug in the brain, that we see inhibition and that we see a high responder rate. With five milligrams, we had that, right? Is that a threshold effect, or is higher better? Like, what if seven shows you great tolerability, would you consider going higher than that even for the sake of better seizure reduction? If you look back at vigabatrin, there's probably, for the primary CNS, there's probably a ceiling of inhibition. Okay that you're going to get. Okay Versus the periphery. With seven milligram is our strategy that we believe will be safe and well-tolerated. Mm-hmm To not leave any efficacy on the table, and that's important. Got it. For patients primarily. Right. It's also important in a landscape where we've got other seizure medicines that'll be good seizure medicines. This drug, a winning profile in focal onset seizures has gotta be competitive seizure reduction, good safety, good tolerability, plays well with other medicines that are. Mm-hmm On board, not too hard for the clinician and the patient. That's what a good drug should look like. I feel that we've got pretty good data on a number of those already that we're looking to continue to build upon. Not leaving any efficacy on the table is what we want to avert. What's important is with that 7 milligram, when we model it, we get to almost 100% of patients should be at the target exposure level in the brain or higher to see inhibition and hopefully therefore therapeutic anti-seizure benefit. Got it. You mentioned on the slide that you are planning for an open label arm. Yes T`o the Phase II. Can you walk us through a little bit more of, the design of that? Maybe the size and duration of treatment. Is this sort of that 12-month timeframe of data that you alluded to? Yeah. If you look at the top bar of this, I'll give you some of the details now, although it's the time of year for filings, financial filings. If you're interested, I would also check out more when we have our annual report shortly. We'll read out the safety tolerability PK of the 7-milligram dose imminently, as we said. Mm-hmm. The open label study, which you asked about, Ritu, I would think about getting. This is a proof of concept in a seizure population. Mm-hmm. Right now, we had what was very compelling biomarker data, but it was in healthy volunteers. While we run the placebo-controlled randomized gold standard phase two program for ourselves, but also for the benefit of our shareholders and potential clinicians and partners at sites, showing the anticonvulsant effect of the doses that we're testing would be, we feel like, a good confidence-building and de-risking step. Yeah. This open label study will enable us to do it. It's a relatively short study. More of the design, I'm going to say stay tuned for our annual report, which is imminent. We should be able to get basically seizure reduction, proof of concept at our planned doses, not just for the Phase II, but then for the pivotal study. This is very nice because as we start to build this, again, it's a fundamental mechanism. There's other places where this drug can go to. It's starting to build an armamentarium of data that makes us have confidence, not only for focal onset seizures, but potentially in some of the developmental and epileptic encephalopathies where this has also been a validated mechanism. In the placebo-controlled portion, the one with, data sort of mid-2027, what efficacy level are you targeting? The bar seems to be around 30% placebo-adjusted, I guess, for focal on-onset epilepsy. How do you see that sort of investor bogey for activity? My view is that a winning seizure medicine, when you look out at the competitive landscape, doesn't need to have the greatest seizure reduction, but it needs to be pretty competitive. I think you could call different epileptologists and get different answers. How I define that is seizure reduction somewhere between the mid-30% to into the 50th percentile, I think. From baseline or placebo-adjusted? From baseline. From baseline. From baseline. I think a winning drug has to have that. Particularly in seizures, what's happening right now, and in epilepsies, particularly for the people who are treatment-resistant, half of them are on five drugs. What happens is the epileptologists are running out of new classes to give them additive benefit. If you think of us, like if any of you have hypertension, if you're failing a calcium channel and you've titrated up as far as you can go, adding another calcium channel to control your hypertension probably isn't a great strategy that your cardiologist is going to employ. The problem in epilepsy is there's only been two new mechanisms in the last 30 years, so they need other things. Yeah. You don't need to be the greatest seizure reduction drug, but you absolutely need to be competitive because my colleagues in this space are developing good medicines. Yeah. We've got about two minutes left. Any questions on OV329? I do have one on the KCC2. You're starting the phase I, IB proof of concept for OV4071, the KCC2. What are some of the key endpoints that you will be assessing in that study? How did you decide to pursue psychosis associated with Parkinson's disease and LBD? I'll start with the latter and end with the former. OV4071 should have broad antipsychotic applicability. We've now, more than what we've talked about so far, run it in a panoply of models, and we've run it against reference medicines, old and new, like I mentioned. It appears to be working and working without some of the baggage that atypical antipsychotics bring. That's very encouraging. When we think about initial indications, we look at where is the propensity of our data and mechanistic data showing us that the drug should have activity, and importantly, where are indications that are significant indications for them at need, but we can mitigate other risks. KCC2 is first in human biology, so any other risks that we can take off the table, enrichment strategy risk, endpoint creation risk, regulatory risk. We don't want to pursue indications that are truly novel. In, in that sense, we don't want to lay those tracks. Parkinson's psychosis, schizophrenia, and now starting to be other indications like Alzheimer's agitation. Mm-hmm. The tracks are being laid. We don't want to have to innovate there. We want to be able to study our medicine. You've got the SAPS-PD for. Exactly. Yeah. You nailed it. That's in terms. There's. Of course, mechanistic rationale is always a relative to the underlying disease biology. That's a huge portion of what we look at. In terms of what are we asking and answering? Clearly safety, tolerability, and PK are important steps of early characterization. Technology is allowing us to glean so much more earlier. With this exploratory electrophysiology, there is both biomarkers related to GABAergic activity that we can look for, but also some potential biomarkers for the phase one and for the ketamine challenge that we're running that start to give us insight into indication selection and design. Biomarkers like ASSR and the P300 and quantitative EEG and BOLD. We can understand, are we getting into the brain with OV4071? Is it having the GABAergic activity that we want to see? We can start to look at biomarkers that may have read-through in areas of neurodegenerative psychosis as well as schizophrenia. Anything that we can glean out of that early helps us make smart decisions about indication, selection, and sequencing. It's a very broad net of exploratory electrophysiology. It's exciting. I think that really just helped us tremendously with an epilepsy medicine. With each of these steps of development, it gives us more information to make sound choices about the next stage of development. Okay. Tonight. Thank you all for coming.