Pharma analyst at Leerink, we are lucky enough to have the CEO, Meg Alexander of Ovid Therapeutics, with us. Thank you very much for joining us.
My pleasure.
Fun time being CEO? Is it more fun being CEO?
Well, it was fun being the COO.
How long have you been CEO?
CEO officially now, what is today? It's about, like, 2.5 months now, I would say.
That's why I was asking you. It's still new.
It is, but at the same time, I mean, Ovid was my focus as a COO, so it's my focus as a CEO. I think what's most fun about it is I came to join the company four years ago when all of our assets were pre-clinical, and so what's fun now is the cards are turning over, right?
Yeah.
We're in the clinic, the progress is happening, and we're starting to see the medicines get to patients. More than the job title, it's the movement in the programs and what that means for the potential medicines, for the communities, but then for the company, our shareholders is what's pretty fun. So.
Yeah, that's exciting. Let's start with OV329. Talk about this mechanism. Talk about what the goal is with the product, how it works, you know, just to start.
Sure. Let's talk about what OV329 is. I’ll go, last question first, first question last. If our aspirations for OV329 turn out to be true, and now there's increasing amounts of evidence that it will be, we believe that OV329 will be a fundamental mechanism for the brain that elevates your endogenous or your own natural local levels of GABA. We think it may be a very meaningful seizure medicine and possibly more than that even, when I say it's a fundamental mechanism. The profile of what we hope and believe OV329 can be is really the following. It's a validated mechanism of action as an anticonvulsant. If we're at the right dose, it should be a seizure-reducing medicine.
It is a differentiated mechanism of action for epilepsy in a field that's only had two novel mechanisms in 20 years, and that matters because epileptologists run out of new mechanistic classes to be able to give patients, unfortunately, who still continue to experience seizures despite current medicines. It appears, though it's early in development, that it may be a better tolerated seizure medicine than any seizure medicine we've seen marketed or in development. It appears to have no drug-drug interactions, and it doesn't look like it'll need titration. It may be what the field of epilepsies and seizures have wanted for a long, long, long time.
A medicine that works as a powerful anticonvulsant, that is a differentiated mechanism in a crowded field of a lot of the same mechanisms, that reduces the seizures but doesn't make you feel badly like so many other CNS and seizure medicines do, and that can play well with other medicines for people who are treatment resistant, of which there's about 30%-40% of the community, and you can be taking easily. That's what we believe and hope it will do, and we've got tolerability data and some pretty exciting biomarker data that's suggestive of all that. The mechanism's pretty simple.
When I said it's a fundamental mechanism in hyperexcitability or a more universal mechanism, essentially what our medicine does is it goes in and it inhibits the enzyme that eats or degrades GABA. GABA is the natural braking system in our brains, right? It's the main inhibitory neurotransmitter. If we're able to inhibit the enzyme that catabolizes GABA, it allows your natural levels of GABA to accumulate in the synapse and the extrasynaptic region, and thereby have the anticonvulsant effect. What's unique about OV329, even relative to the first generation drug that we're trying to replace, is we're able to deliver GABA in that synapse and spill over into the extrasynaptic region.
That is leading to what we believe is tolerability and may even be efficacy differences from what we've seen in the class that other medicines kind of surge GABA in the synapse that can lead to a lot of sedation and things that allow it to work in terms of crushing the seizures, but again, don't make you feel great. We think with OV329, we're able to better and more optimally tune GABA, kinda cool down the entire environment around these hyperexcited neurons.
Right. Right.
That's what we're looking to prove next.
The first generation is what?
Yeah. The benefit of what you can draw upon for OV329 is there was a first-generation medicine. The brand name was Sabril. The generic name was vigabatrin. It was marketed by a company called Lundbeck, and it was kind of like almost where old school oncology medicines were except for neurology. It was an anti-seizure medicine that worked, and it worked well as an anticonvulsant. It's a validated mechanism of action that I just articulated for focal seizures as well as for other seizure types, infantile spasms, other developmental and pediatric epileptic encephalopathies. We knew this about vigabatrin, but that drug that we're trying to replace, essentially, had an Achilles heel of a known toxicity that was unique to that particular asset.
Essentially, that drug, while it worked very well, accumulated and partitioned in the retina and caused a kind of irreversible tunnel vision in patients. Big safety issue. The field didn't initially understand why. We've now done years and years of work on this, and we've been able to show that our drug doesn't have that safety liability. We were very rationally designed to avert that, whereas we've been able to replicate the work that shows time and again across species that that first generation drug had its own kind of unique toxicity.
You rationally designed it in what way? Like, what is the difference?
There's a number of differences. Just maybe taking a step back, we believe that this mechanism was a safe mechanism of action. Nobody would walk into a new category and say, "I'm going to go develop this," if I thought that the safety issue was an on-mechanism effect, right? That wouldn't be very intelligent. A couple things that gave us reason to believe that that wouldn't be the case. We had seen that other drugs elevate GABA or inhibit GABA-AT as an off-target effect, and they didn't have any of these ocular issues. There's also humans that had 100% of their GABA-AT knocked out and didn't have these ocular issues.
We had all that evidence behind us, but we still wanted to have a better GABA-AT inhibitor. Like I said, the first -gen worked, but it was worked with a lot of collateral damage, including other tolerability issues. We went out and we looked to improve on the potency, we looked to improve on the binding, and we looked to improve on the half-life in addition to the safety. With OV329, we have a thousandfold potency difference relative to the first generation drug. We irreversibly bind to this enzyme we're looking to target, and we know we get there into steady state within a couple of days.
Importantly, we knew that we didn't have the same ophthalmic liabilities, but we had to really build the armamentarium of evidence to support that across multiple species and very specific ophthalmic studies and the killer experiments, all of which we've now run.
Interesting. What data do we have so far?
We have a lot of good data, and we're building more as we speak. We felt like we had thoroughly de-risked in the preclinical the ophthalmic work, right? We've looked at mice and rats and dogs. Now more importantly, we have human data. What we've been able to do with OV329 and the data is show definitively in humans that we are delivering inhibition, specifically cortical inhibition in the brain, which is what you wanna do if you're trying to treat people with seizures. What was really terrific for us is we were able to draft off of some of the studies that had been done with therapeutic doses of that first generation drug.
People have studied that and other seizure medicines. Using the most expansive biomarker program that's ever been done this early in development for a seizure program, we were able to definitively show in healthy volunteers that we're delivering cortical inhibition on something called TMS or Transcranial Magnetic Stimulation, which some of our colleagues in the field like Xenon and others have used as a proof of concept event for their drugs as well. What was neat is we were able to show that we were delivering inhibition in the brain that were as good as, and in some cases better than, therapeutic doses of this first generation drug.
In healthy humans like me, you and me, Marc, what that lets us know is not only are we getting into the brain, but we're delivering an inhibition in the zone that should be potentially therapeutic as we move into patients. That was all good. We were able to show that we elevated levels of GABA in the brain consistent with the mechanism using a different technology. That was also very encouraging. Then finally, we were able to look at the tolerability, which is unfortunately the liability of so many other seizure medicines, even good ones that work.
Yeah
What we've been able to show so far, and granted it's a modest size N, it's 50 people treated roughly with OV329, but it appears that at this stage of development, OV329 is better tolerated than any seizure medicine we've seen while not compromising on the cortical inhibition. Now the next big step is to show. There's mechanistic reasons for that. Being able to deliver that GABA in the synapse, extra synapse, is a gentler way of helping mitigate this neural hyperexcitability. We thought we might see that from a tolerability perspective.
Now what we're going to embark on as our next step is in our phase two programs, and our proof of concept studies in seizure patients, can we deliver on incremental efficacy, even what's been known with the mechanism before? That's a pretty exciting moment for us, and that's what we're actively embarking on right now.
Are you in some type of, like, pre-phase II discussions with FDA to decide like what this?
Yeah. We are. Yeah. We've guided. As part of as you think about where we're going next, we've guided that we would be in discussions with regulators all around the world. We are looking to run a gold standard randomized placebo-controlled phase II study with OV329, and we're looking to take in a 7-mg dose, which I can talk a little bit more about in a moment.
Yeah. Yep.
We're doing that, and all that work is getting up and started. We said we would initiate those studies in this upcoming quarter, Q2. We intend to read that out by roughly the middle of next year. We're not gonna wait till that amount of time to get more information on OV329. There are very efficient ways in our field, thanks to good technology, where we can test anticonvulsant effects sooner. We just showed in healthy volunteers that we're delivering inhibition that should be at a level that is pretty encouraging to be therapeutic, right? We could essentially run it and reproduce and beat methods of effective anticonvulsants.
What I'd love to show you and our other shareholders and investors and clinicians is that we're now doing that with seizure patients while we wait for the full phase II to run and complete. You can expect more data from us on that, around the end of this year. Importantly, I'd said we wanna take 7 mg in. We have great data on our 5-mg dose. That's the one that actually matched and beat the first generation drug, as I mentioned. Our drug was so well tolerated that we really wanna see if we can max out our pharmacology.
Given focal onset seizures is a competitive dense field, we wanna be as aggressive on efficacy for patients as we can without trading off tolerability, right? We wanna find the sweet spot of a drug that works while not making you feel poorly.
You're gonna do 7 mg in the phase II, or are you gonna do some type of work before phase II?
Both. We had said we would read out the safety, tolerability and PK of the 7-mg dose before the end of this quarter. There's roughly like two or three weeks left in the quarter.
That's when you'll know. That 7-mg’s the right move.
We'll provide that. Yeah. We'll read that out. It's our goal to take 7 mg into the phase II. Could always titrate down to a 5 mg if we ran into a tolerability issue. Don't anticipate that. This is, you know, it's a good thing for patients. This is a field where we've got peers that are doing well. We had a peer do well today. It's great. It's a field where you need to be competitive from a seizure reduction perspective, while also trying to have all these other attributes that seizure medicines haven't been able to have. We think we can do that. That's why we wanna be pretty assertive in terms of the 7 mg dose.
Let's talk about that in the two questions. First is, what magnitude of seizure reduction do you think is realistic to, you know, is your goal? Like, what are we looking for?
Yeah. I'll take a step back. The mechanism is very proven as an anticonvulsant. Across different epilepsies, it's had very good seizure reduction data to profound seizure reduction data, so GABA-T inhibition, that is. I think the bigger question to ask is, in a field like this, even when you have a drug that's a known anticonvulsant, you've got to be a good drug relative to the competitive landscape around you, which is evolving literally day by day, including
Yeah
This morning, right?
Yeah.
In terms of what I think a good drug is gonna look like in the next three to five years, you have to have seizure reduction efficacy. I think that's between the mid 30 %- 50% seizure reduction in focal onset seizure.
Yeah.
I don't think you need to be the drug that is the greatest seizure-reducing drug to necessarily be a winning medicine because all these other attributes matter too, right? If you have great efficacy, but you make someone feel poorly, or you can't work onboard with other drugs.
Right
That's a problem. There's room to have a couple players. There are winners in here. What I think will not work is I don't think we're gonna see, in three to five years, lots of sodium channel drugs winning, lots of potassium channel drugs winning. We made very definitive choices at Ovid, four years ago when our pipeline was still in the preclinical, and we mapped out every asset from the preclinical to marketed drugs to generics, and we said, "Where is the field going?" What we saw was there was lots of good programs from our colleagues who we respect very much, but there was a lot of density around mechanisms for targets that are known. Okay, so are we.
The problem is there was three, four, five, six candidates from different companies in those target areas and mechanisms, and that's not gonna work forever, right? In a field where you've got to go out and enroll patients, you're not gonna have five winning 5-HT2A programs or sodium channel programs. Even if you get through registrational trials, and you're competing that much, you are not going to have a situation where maybe there's enough differentiation across five different programs. You're not all gonna commercially win.
The payers are gonna start to manage more. We think there is room as a differentiated mechanism that has competitive seizure reduction and these other attributes to potentially be a very big medicine, not just in focal onset seizures, but also in some of the pediatric epilepsies that I'd mentioned before, where this is a validated mechanism.
The other attributes, no DDI, no titration, that's what you're referring to.
Yep.
Any others that we didn't talk about or anything?
I just think the tolerability. I mean, if you look at most of these seizure medicines.
Yeah
They give you headaches. They make you dizzy. Some of them make you fall down.
Make you tired. They make you tired. Yeah, yeah.
I mean, think about that as a human. Like, if you're scared about taking a shower in your own house by yourself because you need to have a caregiver there to make sure you don't fall.
Yeah
Hit your head having a seizure, or you can't drive, I mean, those are big life liabilities. When you have a drug that truly is well-tolerated that works, and it can work with other medicines, that could be a real step change for this field.
Yeah. Let's flip gears to KCC2. Explain to us, like, what the mechanism. Like, maybe take us, you know, to kind of the very beginning of it 'cause, I don't think everybody understands this. This is kinda new.
Yeah. KCC2 sort of sounds like some kinda Soviet rocket or, like, a satellite somewhere. I don't know. It stands for Potassium Chloride Cotransporter 2. Fundamentally, this is one of several Potassium Chloride Cotransporter that we all have in our bodies. This particular one is important, and it's exciting for a few different reasons. I'll start it in a very simplistic way. Again, GABA, the main inhibitory neurotransmitter in our brain, can't do its job. It can't be the natural braking system for our brain when this particular cotransporter is dysregulated.
When KCC2 is working right, it pumps out the appropriate amount of chloride that allows GABA to be hyperpolarizing. It allows it to be inhibitory. When you get too much chloride stored up in your neurons, it can't do that. That's essentially where you start to see hyperexcitability that is implicated in not so many diseases, but also symptoms of many different diseases. From epilepsies to various forms of psychoses and pain and even more. If you Google KCC2, you're gonna find it in literally hundreds of different publications. There's other Potassium Chloride Cotransporter as well, and not just Ovid.
Smart, strategic pharmaceutical companies, others have tried drugging targets and other targets like this before. What's very unique to KCC2, unlike some of these other potassium chloride transporters, it's only, it's neuron-specific. It's only expressed in the CNS. You don't expect to see some of the same off-target issues that, unfortunately, some of our peers in the space have run into in the clinic from a safety and tolerability issues because other transporters that are like this, but not the same, are expressed in different organs and tissues in the body, so they ran into safety and tolerability issues.
This is a target that essentially is a master switch on neural hyperexcitability. It allows GABA to exert its inhibitory strength. It's only in the central nervous system, so mitigating some of the risk of off-target effects. What's cool about this when we think about the brain, you can't over-modulate this particular transporter. Energetically, if you were to take our drug, right, or I would, you can't extrude too much chloride from the neuron. It's self-limiting in that sense, which has been a hallmark problem of so many other brain drugs.
It's easy to overdo it if you're fiddling with a neurotransmitter, even like our epilepsy program. You do get too much GABA in the brain, you can overdo it, you get into safety and tolerability issues. This is very attractive, not only because of its unique attributes as a target, but because of its potential therapeutic breadth.
Yeah. It's been around. Like people have known about, right? This is a validated target for years, but no one's drugged it?
This is gonna sound hyperbolic, but it could be the KRAS or PD-1 like moment of the brain. Because it's one mechanism with potentially many therapeutic indications. Yes, others have wanted to drug it, but from a medicinal chemistry perspective, it's very hard to activate a transporter, and there were three big challenges we had to step through. There's the chemistry piece, which thankfully we could build upon the work of others that gave us some tailwinds going into that. There was formulation pieces. Now we know a tremendous amount about this target, but had to work through a lot there.
The fun strategic challenge for us is then what's the best set of indications to try to truly translate and unlock the value of this mechanism for what is one of the more exciting targets in the CNS, we believe.
Yep. Describe what you found in the EEG study with the IV version.
Yeah. You're right. We read out a tool program at the very end of last year, which was an intravenous program. It was, when we brought in this set of assets, it was the most advanced that we had, and it was exciting for us 'cause it had good pharmacodynamic activity, but it also had some things that were okay, not as good as the oral that we're about to put in. It was a good tool program for us to learn on. You're right, we looked at exploratory electrophysiology, safety, tolerability, and PK. That's what we were looking for.
Probably in opposite order in terms almost of what was important to us, because this was the first time anyone's ever drugged and directly activated KCC2. We didn't take for granted that, what a moment this could be in terms of either checking the box on safety of drugging this target or potentially undermining the value of this entire franchise that we had for us and for others, right? What we were able to show with this program is, with OV350, we actually went threefold over our EC50 and got to pretty high Cmax levels with the tool program. That was somewhat intentional based on the nature of this particular molecule that we had in the tool.
The big, you know, breathtaking moment for us was being able to show safety, right? The first time anybody's drugged something, we didn't wanna see any showstopper. We, you know, cardiometabolic, liver enzymes, all that was good. What was exciting to us is we could show was that we were getting into the brain, and what was truly exploratory, we didn't know going into this, is whether or not we could show signs of GABAergic activity happening. Because keep in mind, I said the mechanism basically allows your local GABA in the brain to work better. Problem is, hopefully for you and me, our KCC2 transporters are not dysregulated.
What we didn't know walking into this, if we were to put this on you or me, is whether or not the chloride gradient and subsequent GABA change would be enough to pick up in a healthy volunteer versus someone who actually has an underlying disease biology.
Yeah
We were able to show, consistent with the PK and the exposure curves that we saw of the drug, so basically when we knew the drug was active in the system, that we were moving a band of electrophysiology or on Quantitative EEG specifically, that is basically a band that's consistent with GABAergic activity. It's the gamma band for those who know neuro really well. That was a good sign. It was a small, and it was early pilot data, but what it allowed us to show with the tool program, that we could get into the brain, we could directly activate KCC2, we could see a signal that's consistent with the mechanism when we knew the drug was active on board.
That was very encouraging to us. We're not taking that molecule forward 'cause there's some unique secondary pharmacology to that drug, that never made it perfect. We were able to learn a lot from it, and I think, you know, for a modest amount of resources, extract a fair amount of learning out of that asset. We've pumped what we can from that insight into our oral program, which we said we would submit this quarter for regulatory clearance, and we would initiate first in human studies for this next quarter, Q2 of 2026. We're on track to do all of that.
Yep. It was an N of what? How many patients?
Oh, it was a small N.
Like 5?
No, it's larger than that. 12.
12.
Yeah.
Were there any safety issues at all or?
There was a tolerability factor. We saw a headache in some of the subjects.
Yeah.
We don't know whether or not that was an on target effect or not. Like I said, because of the half-life of this drug was really short, we wanted to be able to pick up a signal if we could and test safety. We intentionally shot our Cmax pretty high. It's unclear whether or not the headache was a factor associated with that. That's something we'll clearly look for and explore as you would for any CNS medication. We also saw, and this was a result we believe of the secondary pharmacology with that one particular molecule OV350, it hits CCK-1, which as a part of its secondary pharmacology, which can essentially activate gastric activity.
We saw that. We saw some nausea with a couple of our subjects. The difference about OV350 and OV4071, which is our oral, is OV4071 doesn't have that. It doesn't have that secondary pharmacology.
Oh, I see.
We run screens on both.
You're not expecting to see the GI?
Not expecting to see the GI.
Yeah.
The headache is a question. You know, headache can be a question with CNS acting medicines, so we will look at that. With that said, you know, we had a very potent 10-minute bolus IV infusion with 350 based on the nature of how we had to run that particular study. Pretty extreme dosing and pretty high Cmax that we hit. I think I said we went three-fold over our AC50. When you think about the oral and how, what the exposure curves look like for that, and, you know, PK, I don't anticipate that we would see the same thing again. It's something that you look for all CNS medicines, and we will.
The oral is going into phase I. That's OV4071?
Correct
That you were just talking about?
Yep.
The phase one will start soon. What are we gonna be looking for? Biomarkers? What kind of stuff are we? Help us.
We have our earnings are imminent.
Okay.
We'll provide a little bit more meat on the bone than. I can give you a way to think about what we'll look at. Knowing that we just read out the most comprehensive biomarker medicine that's been done for a seizure program, we will again look broadly for KCC2. The thing that's a little bit different about KCC2 is that no one has ever walked down this path before the same way they have with our epilepsy mechanism. Nevertheless, there's things we can know. There's certain technologies that allow us to look for GABAergic activity. We will look for that.
You can assume we will again look for things like Quantitative EEG, right? If we saw what we thought was a signal with 350, we'll be looking for that again with OV4071. There are other biomarkers that we will additionally look for that will give us also more confidence as we look into indication selection, because again, if you think of one mechanism, possibly tens of indications, the more information that we can extract about not just the drug's attributes, but being able to make smart indication selection decisions is really important for us.
Well, that's a great segue, 'cause I was gonna ask you, how are you thinking about indications? Where are we gonna go first, and what are the options?
There are many options. This has been the greatest, fun and the greatest challenge I think of my career for the last two years. We have all kinds of plans, and there's still not a day that I don't think about this.
Yeah.
Part of that is 'cause we have emerging data that keeps coming in. At this point, we now, between that tool program and OV4071 the oral, we have somewhere between 25–30 different PD studies across seizures, psychoses, pain, that's basically all showing that this is working on mechanism. Which is very encouraging, 'cause not all animal models are created equal, but when all the needles are pointing in the same direction, that is encouraging in its totality. We look at that animal PD data, and importantly we look at disease biology and mechanistic data. The way that we're thinking about the initial indications right now is OV4071 has shown very profound antipsychotic activity.
Specifically we know that certain forms of psychoses, particularly in areas like Parkinson's disease psychoses, we see essentially GABA diminished and not working as effectively in areas like the prefrontal cortex, influencing some of the hallucinations and delusions that people with, unfortunately, who have these delusions and psychoses associated with Parkinson's disease have. That's one that's very attractive to us. There's also a lot of published literature, forthcoming literature that's extremely supportive of schizophrenia as well. Taking a broader step back, OV4071, based on data that you'll see come from Ovid, I think, and our partners and other investigators over the span of the next year, is appearing to have broad utility as an antipsychotic, and it appears to be extremely well-tolerated.
All that's very encouraging. It could have applications well beyond those two that I just mentioned, including areas like Alzheimer's, psychosis, and otherwise. Given that we're navigating and laying down the tracks of first in human biology, the way that we look at indications, of course first is match mechanistic biologic rationale for the underlying disease state. After that, we're looking for indications where we can mitigate any new risk, right? Don't want to have really out of the box or challenging design, endpoint design, regulatory design. Want an enrichment strategy where we can control for some degree of homogeneity of these populations, 'cause we've had some really smart colleagues and peers in this field who have had active drugs , but probably failed because they tried to go into, for example, areas of schizophrenia that were too broad.
We think a lot from an indication perspective, fundamentally about the mechanistic rationale and the biology. We show we're looking at where do we have the strongest sets of data across those 25-30 PD data sets I mentioned, and then we look at how do we mitigate risk, and also of course with time and resources. 'Cause we wanna get to answers in a way that's time sensitive for the resources that we have.
Right. At the beginning, the idea is schizophrenia or some type of psychosis. I mean, that.
Psychosis is associated with Parkinson's disease.
Yeah
Lewy body dementia is very appealing to us. We've publicly talked about that before, as well as schizophrenia.
Yeah.
We're very interested in both. I think the opportunity for OV4071 is broader than that but you hear some of the attributes of a development program that needs to be there.
What about pain?
Like pain. Have good data in pain.
Okay.
What we think a lot about at Ovid, where we try to be realistic with ourselves, is what are we as an organization very strong at developing in from therapeutic areas versus where would we be stronger with a partner? Also, 4071 is our first chronic formulation, but we have made the determination internally that if our thesis for KCC2 is right, we wanna be the company that pioneers and unlocks KCC2. We have multiple series and development candidates that we have not talked publicly about yet after 4071. The reason why we do that is because if we start to see the results that we hope to see with that asset that we want to have multiple that we can take into different indications.
Different indications, yeah.
Relative to what we know of this mechanism.
Yeah.
For pain, I don't. I think we could develop to a point. I don't know that we're the best company to take something all the way through a pain program. I think we could take a molecule to a certain point of development and then would want to have a partnership with that.
Yeah. Excellent. Oh, I think we're over. Oop, we went over.
Oops, sorry about that. Okay.
That's okay. Thank you.
Thank you for the time.
Yeah.
Thanks, everybody.
Thanks very much for doing it. Appreciate it.
This is definitely the best place to have a fireside chat.
Very, very cool.