Ovid Therapeutics Inc.

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. All lines have been placed on mute to prevent any background noise. After the speaker's prepared remarks, there will be a question and answer session. At this time, I would like to turn the call over to Victoria Ford. 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 three months and full year ended December 31st, 2025. A copy of the release can be found in the Investor Relations tab on our corporate website, AvidRx.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 OB329, 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 growth 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, Balniazny, 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 neural hyperexcitability. As you know, we're pursuing fundamental biological targets to address that neural hyperexcitation. We do that by pursuing differentiated and what we believe are universal mechanisms 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 OB329 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, OB471, this upcoming quarter, Q2, we'll 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 is a potential best in category anti-seizure 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 had 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 O3329 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 GABA urge inhibition, both in the synapse and the extra synapse. 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 seven 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 seven milligram dose to expand dose optionality for our later stage clinical trials. What the seven 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 OB329. 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 cannulocyte reactions. Of course, there was also no ophthalmic safety concerns. But let's take a deeper dive into this. Over the course of 329's characterization in Healthy Volunteers, what you're seeing in front of you is the adverse events that were reported that could be associated with OB329. 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 immunotransferase 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 OB329. Of course, we will continue to run this battery of very rigorous testing throughout the entirety of OB329'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 OB329. 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. It's roughly 60 nanograms per hour per mil 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 OB329 that we've tested. Importantly, if you look where the green box is, you'll see that both our 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 were seen 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 two 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 two strong doses to be able to take into Phase II programs that, in addition to being 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 two studies to demonstrate proof of concept in anticonvulsant activity for 329. Later this year, we will start an open-label photoperoximal study. For those of you who are unfamiliar with this design, what it does is 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 and a potential de-risking event about the doses that we want to take into later development. And for our phase two randomized placebo-controlled study, again, we intend to take two doses into that study, and this will be a traditional epilepsy study over eight 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 OB329, 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, and it's needed. When these babies have an infantile spasm, which occurs between four to seven or eight 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 XR 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 tubers or hematomas across multiple different organs. But in this case, the one that we're most focused on is the brain. And people who live with TFC 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 Afinidor, as well as Sabral, and those have limitations with how they can be used based on their safety. In contrast to that, we think OB329 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 through more, but then you look at the column on the right, in infantile spasms, we believe that there is an opportunity for OB329 to be used first-line with Act-R-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 GABA18 inhibitor could 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 gabaminotransferase inhibition in these indications is proven. And in fact, it's been pretty profound. We've seen freedom from spasms, freedom from treatment failure in infantile spasms, and we see a high responder rate to those who respond in CSC, including a high degree of seizure freedom. But because of everything that you see on the right-hand side of the slide, Sabrel 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 Sabrol is that it really under-reflects what we think is not just the unmet need but the market opportunity in these conditions. So Sabrol, as many of you may know, which is the brand name of Vigabatrin, was introduced decades ago. It 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 prolonged use because of its safety. Nevertheless, Sabrel 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 Sabrel, again, here just in the U.S., We already have established a better therapeutic index with OB329 than what we saw with Sabral. If you assume that we're able to also realize ex-US sales, earlier-line use, and this treatment duration, we believe that the opportunity for OB329, in addition to the opportunity that we were already pursuing in focal-onset seizures, is very significant. And we hope that 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 infant spasms and focal onset seizure models, which is the distinctive seizure commonly seen in tuberous sclerosis complex, we have demonstrated that OB329 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 a GABA aminotransferase inhibitor than what was seen idiosyncratically with the first-generation compound. We have shown that in animals, OB329 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 OB329, we think is quite bright. If you look at the path to registration for OB329, 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 and 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 2-3 study, thereby enabling that efficiency to registration. So, as we wrap up the 3-2-9 session, 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 de-risk indications. It allows us to do what we were doing before and create more value. What that means for our shareholders is 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 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 for 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 one study this 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, early next year. And I want everyone to know this is not the only KCC2 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 14th. 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 that. I'd like to tell you just a little bit about OB4071, 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 RET, 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 that phase one 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, OV407 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 have been 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 fulcrum 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 years ahead. So just to give you a sense of what this means from a runway and a milestones perspective, my colleague Jeff Brona and I will take you through this. But just starting with the milestones, there's a lot going on 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 OB329 and focal onset seizures. We will be initiating that gold standard phase two 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 a signal finding and safety study and 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 de-risk 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 two, three 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 one study. As soon as we have enough of our PK and C-max characterized from that phase one 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.

Great. 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 31st, 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 1 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?

Thank you. We will now begin Q&A. To join the queue to ask a question, please press star five on your telephone. Again, that's star five on your telephone to ask a question. Please limit to one question before jumping back in the queue. Thank you. We will now pause a moment to assemble the queue. Our first question comes from Francois . Please unmute yourself and you can ask your question.

Frank, if you're there, we can hear you.

Looks like he has lowered his hand. Okay. Our next question will come from Laura Chico with Webbush.

Good morning. Thanks very much for taking the question. I was wondering if you could talk a little bit more about 329 and the visual monitoring. Meg, you mentioned you would kind of continue this through phase two, but it sounds like the 7-meg 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.

Thanks. Sure. Yeah. Good morning, 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 This 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 their 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, we'll try to cover it.

Yeah, just briefly, the PPR study was 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 done by Gabatrin? I know when you did the biomarker assessment, there were some nuances there, but just wanted to make sure you understood the PPR study expectations there. Thanks.

Yep. 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. Thanks very much. Congrats. Thanks, Laura.

Thank you. Our next question will come from Mark Goodman. Mark, please unmute, and you can ask your question.

Hi. Good morning, everyone. This is Alyssa on for Mark. Thanks for taking our questions, and congrats on all the progress. I was wondering if you could provide additional detail on the plan phase two design for OB329 in FOS starting next quarter, particularly around the key endpoints and what patient populations they'll be targeting. And then separately, could you elaborate on the rationale for the ketamine challenge study for OB4071 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 so much.

Thanks, Alyssa, happy to. So let's start with your first question, which is the Phase II design for OB329. So to address it, it is the 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 because of the work of the Epilepsy Research Consortium, our shelves and our peers in the space, you know, there's very good methods now for testing seizures, also balancing that relative to the sequence. 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 reduction in total seizures. It's the traditional endpoints, CGI endpoints, for example, the traditional ones that you would expect of 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 KCC today, 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 are not exposed to OV471. 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 this. 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.

Excellent. Thank you so much. Congrats again.

Thank you. Our next question will come from Myles Minter. Myles, please unmute yourself and ask your question. Myles is with William Blair.

Hi, thanks, everyone, and congratulations. The open label photosensitive epilepsy study, what type of people are going to enroll in that study? I'm just aware that you know, 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 that would be really helpful.

Yep. 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 photic stimulation. But what you can assume is we're using that population to give us a general read-through, again, for anticonvulsant 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 de-risking 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? Thanks.

It's absolutely a consideration, Miles. What we have the opportunity to do here with OB329 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'll 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 in the environment with other major developers that we've seen that we can point you to.

Beautiful. Congrats. Thanks again.

Thanks, Miles.

Thank you. Our next question comes from Francois Prisbois with LifeSide Capital.

Hi, can you guys hear me?

We can hear you now, Frank.

Hello? Oh, great. All right. I don't even know how to lower my hand, so I'm not sure what happened. All right. Well, congrats on everything. I just was wondering if you can touch a little bit more on Vagabitrin and the history here. You touched on peak sales, and maybe as you answer, maybe help us understand 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? Thank you.

Thanks, Frank. So when Save Roller 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 shows that now. But what that means in terms of what the opportunity was, the sales of Sabral really understate where we think there's both a lot of unmet need and also a market. Because Sabral had that post-market safety finding, its use was very limited in constraint in the United States. Nevertheless, between the two indications, primarily infantile spasms, but also tuberous sclerosis complex, its sales peaked a couple of years ago at more than 320 million. So, you know, a drug that essentially can make children blind, that is only used in six to nine month treatment durations for very limited use, peaked at that sales figure. So what we think, and in our conversations most importantly with the clinicians who treat these children and these babies, is that if we have a safe GABA immunotransferase 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 may be 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 Lundvac 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 two indications in the U.S. alone. That doesn't reflect Europe or worldwide sales.

Perfect. Thank you very much and congrats on all the progress.

Thank you. Thank you. Our next question. We'll come from Madison Alsati with B. Riley.

Hey, guys. Thanks for taking our questions and congrats on the really comprehensive update here. Maybe starting with 329, did you say, maybe I missed it, how many patients in the seven-leg arm reached above the 80-metagram AUC threshold, which is correlated with higher biomarker efficacy. And then wondering if there's any rationale to explore dose above 7 million.

Thanks. Yeah, 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 five and seven 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 Vigabatrans pharmacology, that there is a ceiling of how much inhibition of the GABA aminotransferase 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 tradeoff relative to what you may start to then take on relative to possible AEs, though 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 two 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, Magnus. That makes total sense. And if I may, lastly, I just noticed you seemed excited to mention the KCC2 program. Looking towards the R&D day next month, will we see any additional preclinical data, maybe in AD agitation?

I would be in deep trouble with our chief corporate affairs officer if I tell you too much and scooper 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 OB-4071 holds as, again, a broad syndromic psychosis agent.

Got it. Thanks again, guys.

Thank you. Our final question will come from Jay Olson with Oppenheimer.

Oh, hey, congrats on all the progress and thank you for taking our question. How are you thinking about longer-term clinical development for 329 and 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.

Thank you for the question, Shay. So I think you've heard us and everyone at the team here at Ovid espouse our belief that OB329 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 two 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's one more question from our analyst at Cowan Ritu.

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

Good morning, guys. Thanks for pulling me back into the queue. 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 in TSC be at the 12-week timeframe, which I think is the primary endpoint of the pivotal phase 2.3, or will there be some additional dose finding in there as well?

Yeah, excellent questions. So I don't want anyone to walk away from this call thinking that you're not going to hear anything about TFC 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 end 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 and base information on. So what I mean by that Ritu and colleagues is that because this is an open label study, we've designed this to be able to start with older tuberous sclerosis patients, including adolescents, then going down to younger pediatrics before we initiate that infantile spasm 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 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 cohorts as we go. And we have the opportunity to communicate about this throughout these open label programs. 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.

And remind me, how many patients were in the seven milligram healthy volunteer arm? And I guess, are you surprised that it was, oh, I believe it was 11, I just see in my, are you surprised that it was so clean compared to the prior doses? And, you know, what, if anything, does that tell you about how you expect patients

both doses to behave from a safety perspective going forward so as you did answer the question for me but i'll just reinforce what you said it was 11 in the sad mad cohort uh that we're taking the seven milligram dose of ob329 and you know at this point we've had i think nearing 70 people throughout the phase one study so we've had a goodly number of healthy volunteers be now treated with various ascending doses of OB329. And in terms of the tolerability, I'm not surprised. This is on mechanism for, we believe, some of the differentiators of OB329. And importantly, it would be one thing if we just had 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 OB329 is getting into the brain at these doses, that it's elevating levels of GABA in the medial parietal 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 the Gabatrin. 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 Vigabatrin, OB329 delivers GABA in the synapse and in the extrasynaptic region. These are called forms of phasic and tonic inhibition. Why does any of that matter? It matters because Vigabatrin only drove GABA in the synapse, similar to other drugs like benzos, for example. What happens when that occurs is when you flood the synapse with GABA, you hit synaptic GABA-A 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 in a more inhibitory milieu. And it's less of this 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 percentage change of certain EEG thresholds, 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 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 that 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 the Phase II study that we're running, right, the true randomized placebo-controlled trial. But just from an endpoint perspective, what we'll be looking for in the photosensitivity study is three 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 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, you know, this will give us some helpful information. It's not the same thing as a pivotal or a phase two study. But while we do the full phase two study, I think it gives us confidence building and de-risking 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 and the business. And I want to just take a moment to thank the patients involved. the caregivers and parents who are advisors, the doctors and clinicians who are our partners, and I really want to thank our team here at Auburn. They made it possible. They worked 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.