Hi, everyone. All right, thanks for joining. On day two, the afternoon of day two of the OpCo Healthcare Conference. Here I'm Frank Brisebois. I'm one of the biotech analysts at the firm. Our next presenting company here is Ovid Therapeutics. From the company, we have Meg Alexander, who's the Chief Operating Officer. Thanks, Meg, for taking the time. I know it's busy on everyone's schedule, so I appreciate you doing this with me today.
In terms of a format, we're going to do a fireside chat. Feel free to send in some questions in the Q&A tab or my email. I will do my best to get to them. I hope I see them. It is 4:00 p.m. , and there's a lot of emails coming in, but I will try my best to get to them. Thank you again, Meg. Maybe, you know, a little intro on yourself and the company. The company's been through a lot, but there's a lot of exciting stuff going on here. A little intro would be helpful. Thank you.
Yeah, my pleasure. Thank you for having us, Frank, and for Oppenheimer. I'm Meg Alexander. I'm the President and Chief Operating Officer of Ovid Therapeutics. At Ovid, we are a company that is focused on treating and creating medicines for conditions of neuronal hyperexcitability, specifically in neurology and in neuropsychiatric conditions. It's our focus to try to alleviate the symptoms that matter most, and hopefully one day actually be able to halt diseases of the brain. We have a small molecule pipeline that's focused on fundamental targets in the CNS that really are at the root cause of many different brain diseases. We are very much going after either novel neurotransmitter targets or ion channel targets. I look forward to telling you more about the pipeline, Frank.
Okay, excellent. There's a lot. What I struggle sometimes with your pipeline is where to start. I guess let's start with 329 . Tell me if we shouldn't. I think 329 is really interesting. It's, you know, the mechanism's been de-risked in the past. Just a little history around what that is, what the mechanism of action is, and how you're trying to make kind of a next generation of this mechanism of action.
Sure, that's right. That, you know, that's fair. Maybe, Frank, just to take a quick step back, we do have lots of good things in our pipeline. So 329 is a next generation GABA aminotransferase inhibitor. We'll go into that, but that's basically working to increase endogenous levels of the inhibitory neurotransmitter, which is GABA. Below that, we have a platform of really exciting, completely novel direct activators of a biological target called the potassium chloride cotransporter 2, which is a mouthful. We say KCC2 for short. There's actually multiple programs in that particular library that we have, and they're just coming into humans now, which really excites us. In addition to that, we have a novel program of a ROCK2 inhibitor for other neurovascular indications. We can talk a little bit about that at the end.
You know, Frank, to dig in on OV-329, this is a program that I think we and many are excited about because essentially it is a better mousetrap of a validated mechanism and target that we know works. The story of OV-329, it is, as I said, a next-generation GABA aminotransferase inhibitor. Essentially what it's looking to solve is the problem of a drug that was extremely effective that was approved multiple years ago, but post-market was determined to have a very significant safety issue. The brand name of the drug that we're trying to replace is a medicine called Sabril, and the generic name was Vigabatrin.
It was a really effective anticonvulsant at the time because essentially what it did was it elevated levels of the inhibitory neurotransmitter GABA, and it had broad use initially until it was discovered post-approval that there was a safety issue associated with it. It was seen that certain patients who were taking Vigabatrin were having essentially like tunnel vision, essentially retinal degradation that was happening. What was concerning was it was irreversible. What we set out to do with OV-329, knowing that the mechanism was a powerful anticonvulsant, we decided, could we try to build a better mousetrap? We went looking for what is the best compound that we thought could do so. We think we found it in a discoverer at Northwestern University.
A fellow named Rick Silverman, who happened to be the same scientist and medicinal chemist who discovered Lyrica, had been set out to try to solve the same problem that we did. We think he'd done it. Essentially what he had looked to do is create a medicine with a much more appealing profile than what Vigabatrin, the first generation drug, had had. He increased the one, it has two active enantiomers. The chemistry is much better. It's much more efficient, but importantly, it's much more potent. It's a hundredfold more potent than Vigabatrin. From all of our characterization work that we've done across multiple species, and now we're in humans and in healthy volunteer data, we see a safety profile that is better. We have a therapeutic index. We know Vigabatrin has no therapeutic index, a sub-therapeutic dose. You actually see the toxicity early.
What's interesting is we found that the PK/PD profile of OV-329 is much more optimal. Essentially what we have learned about our unique program is that we are able to endogenously increase levels of GABA by essentially inhibiting the enzyme that eats GABA or catabolizes GABA. Like most other seizure medicines, what happens right now is they flood the synapse with too much, right? Too much GABA. You know, you're trying to crush these seizures, which are hard to bring down, but at the same time, you can flood it with too much GABA, and then what happens? You get sleepy, you get overly sedated. A lot of these patients are on multiple medicines. The layering effect of all these side effects and tolerability just gets worse and worse.
What we've learned with 329 through characterization work of my colleague and our CSO, Zhong-Zhong , is that we're able to more optimally tune GABA, where we're bringing up levels of GABA through basically inhibition in the synapse and the extra synaptic area. What that is doing is we're creating a kind of just more optimally tuned environmental milieu. What that leads to is we're not getting the same type of sedation while we still have the anticonvulsant threshold and we have a therapeutic index where the prior medicine did not. We believe in sum that this is now starting to lead to a medicine that looks to be very encouraging and may have applications associated with conditions that are caused by neuronal hyperexcitability, both in terms of potential acute and subacute indications, but also for chronic dosing. This really excites us.
We're coming up on some big card turnovers this year based on data that we have. We can talk a little bit about what that looks like too, Frank.
Yeah, I think two things. I'd love to hear what kind of data or catalysts we're expecting there, but also from the way you just presented this as well. Obviously, people are more concerned about the safety here. The efficacy has to be great for sure. That's undeniable. The safety is super important. How do we know? Is there anything that you've done to make sure that this drug, you know, doesn't maybe get to the retina?
100%. As you imagine, this is it, right? When you have a validated target, you know, okay, many people are going to have some level of conviction about the potential for you to be efficacious and therapeutic because we've seen this with Vigabatrin and there are precedents that we can compare against. Honestly, the animal models in seizures and epilepsies are more clinically translatable than other areas of neurology. Taking that aside, when you look at the safety, there is a lot of work that we've done, both in humans, but importantly, pre-clinically before we ever got into humans and healthy volunteers. There are really three aspects of this that we look at. The first is we've looked at the chemistry and the unique binding of 329.
That was very intentional the way that Rick Silverman designed OV-329 relative to the prior first-generation medicine. The second piece is the animal models that we've run this in. The regulators require a model called the Sprague-Dawley . Basically, it's set up in an albino rat model. It is important. The FDA requires it because it's one of the most sensitized species for ocular changes. It is essentially one of the greatest challenge animal models that you can run a product like this in to make sure that you're not seeing the ocular changes. We have done so and we're able to demonstrate that we have a therapeutic index that allows us to support the dose that we want to go into with humans.
Of course, the final piece is making sure, as we will throughout the entirety of our clinical development program, that we do not see any changes in patients, right? Also in healthy volunteers. As part of our phase I program, we have five different forms of ocular monitoring that we have run. We have already said in the public domain when we reported our last earnings that we have exceptional safety data already from the SAD and MAD cohorts that we have run that give us a lot of encouragement. We have done a couple of other things in addition to that, just because this is the question, as you rightly say. Everyone wants to know that safety, we are not going to have a surprising safety event later in clinical development.
One of the challenges that we chose to run about a year and a half ago was we said, okay, can we run head-to-head studies to show that we don't have the same accumulation profile in the back of the eye that Vigabatrin has? Essentially, we ran the killer experiments where we, I won't get into too many of the technicalities, but you pump Vigabatrin and you pump OV-329 into the back of the eye. You control for basically plasma levels. What we were able to find is that with a sub-therapeutic dose of the first-generation medicine, Vigabatrin preferentially accumulates in the retina fourfold within less than two days. Like, we saw it almost immediately, right? You can see the preferential accumulation in the retina.
Meanwhile, we were able to confirm with OV-329, we get into the plasma, we get into the brain tissue, we clear it rapidly, but we do not accumulate there. There are a few reasons we think this is happening. We have essentially a much more potent dose and as such, we are much more potent, so we are much lower in dose. We have a different binding profile than what Vigabatrin has. We have a very different PK and PD profile. We get in, we knock down the GABA amino and GABA aminotransferase enzyme with very precise doses. That enzyme takes a long time to regenerate. With very little doses, we can get in, knock it down, come back a little bit later on, knock it down again with a very potent, precise dose.
We don't need to flood, you know, essentially the brain with as much drug as what Vigabatrin is. Between these different characteristics, what we've been able to show is that we have a very different profile and that we don't accumulate in the back of the eye as we have seen many other independent experts confirm that Vigabatrin does.
Can you remind us maybe the peak sales of Vigabatrin and how did it do?
Yeah, it did well. Where I can start, in the U.S., it was $330 million for two extremely small indications that it was pigeonholed into after they discovered this safety issue. That was infantile spasms and it was seizures associated with tuberous sclerosis complex. That understates the total number of sales that Lundbeck was making on Vigabatrin worldwide. They do not break out their sales globally, but it was much more significant globally because Vigabatrin was used more heavily in other regions and markets than it was in the United States. It was really circumscribed to very rare and very, very refractory indications in the United States. If you are able to have a GABA aminotransferase inhibitor that is safer, does not cause sedation, and is efficacious and works across a range of seizure types, we believe the opportunity is much more significant than what Vigabatrin would indicate.
Okay, great. This could go for a while, but should we move on to KCC2? I just want to give it enough credit because this is a very exciting one that I think is early in development, but is starting to pique a lot of curiosity for good reason. Unless there's something on Vigabatrin you think we should talk about more?
I think the only point we should just say before we leave 329 is we are coming up on card turnovers this year. We feel very encouraged by the data that we have already seen. We haven't disclosed that yet outside of the safety that I mentioned earlier. We are coming up later this year. We'll provide more guidance at our next filing on the card turnover from our phase I program. Usually, you know, many people would say phase I, okay, safety, tolerability, PK, what to expect. This is a little bit different because we have a precedent drug that we can compare against. We actually have two biomarkers that are pretty interesting. One that's a biomarker that's a sign of clinical effect, which is transcranial magnetic stimulation.
For those people who like epilepsy, you may have heard about this from Xenon and other drugs where they had essentially some early de-risking and proof of concept using TMS, although the parameters they use are a little different because it's a different mechanism and target. The second is a biomarker for essentially target engagement, and that's using magnetic resonance spectroscopy. We will have those two biomarkers as part of our top line readout when we read out later this year. Beyond just the safety de-risking piece, which is clearly a really important part of the profile of the future and conviction for OV-329, what we also have is a good sign of whether or not we're having a biological effect and whether we're having a biological effect similar to therapeutic doses of the first generation medicine.
It should give all of us, if those cards turn over well, which we hope they will, should give us a good sign that not only are we marching down the right road in terms of differentiating on safety, but that we have a mechanism and a drug that works.
is something that's been used by Xenon and others as well. This is not totally new.
Yep, that's right. The parameters are slightly different, but the use of TMS as a biomarker in epilepsy is pretty well accepted by people who know it well.
Okay, awesome. Okay, great. KCC2.
Yes.
Why should people pay attention to KCC2?
Okay, I would be doing my team a disservice if I didn't reflect their excitement about KCC2. We believe KCC2, which stands for potassium chloride cotransporter 2, is one of the most exciting targets in the CNS. There's a couple of reasons why. Essentially, KCC2 is a master switch for hyperexcitability. What it does when you have KCC2 dysregulated, which it is in a vast number of indications, everything from epilepsies to different forms of psychoses to mood disorders to certain neurodevelopmental and neurodegenerative diseases, there's a deep, deep and broad list of literature that connects KCC2 dysfunction to many, many conditions and devastating chronic conditions that have no good treatments today. KCC2 is a master switch that by regulating it appropriately allows GABA to restore its inhibitory strength.
Essentially, back to who we are as a company, it helps quell hyperexcited neurons and bring it back into balance. What is exciting about KCC2 versus other ion channels that others have gone after are potassium chloride channels is it's exclusively expressed in the CNS. The way KCC2 works is it essentially manages chloride balance and the chloride gradient in cells. By so doing, the unique thing about KCC2 is it's a target that you can't over-modulate. You can't overdo it. It's energetically very hard to overexpress chloride. Essentially, what this means is it's a prime target where you don't expect to see as many off-target effects because it's exclusively expressed in the CNS. It's widely relevant to a number of diseases and it's hard to over-modulate.
It is a target that for years and years and years, many large pharmaceutical companies have tried to drug. It is very, very hard to directly activate basically a cotransporter like this. Honestly, Frank, we got very lucky. We bought this out of AstraZeneca at the beginning of COVID when AstraZeneca was really focused on their pivot to oncology and to trying to scale a COVID vaccine. We liked it a lot because we thought this was going to be a great anti-convulsant portfolio. We still believe that. In the characterization work that we have done over the last two or three years, we have started to realize that this is actually much, much bigger in terms of the different areas that we can walk down. We have done a lot of both phenotypic and disease model screening.
We have now characterized out of the hundred compounds that we brought in from AstraZeneca, which they had done superb medicinal chemistry and screening work on. We cannot take credit for that. That was really them. We now know that we have at least four programs, all completely unique structure, unique API, different characteristics that have really exciting attributes across psychoses, anxiolytic properties, and anti-convulsant properties. What this is allowing us to do is now start to really unfurl an array of therapeutic development opportunities. It is not just one program that we are trying to squeeze multiple formulations and multiple indications out of. We actually have a lot of optionality to be able to take these unique programs down different paths. They each have unique formulation opportunities. We can really match the unique attributes of these chemotypes to different conditions and different formulations.
It is taking us in some really exciting areas like psychoses. We can walk down some of the indications that we are looking at. It has been a lot of progress. We will actually be first in human with a direct KCC2 activator before the end of this quarter. It is moving very fast. There is a program a year getting an IND behind that every year for the next three to four years. There is lots of opportunity for Ovid, but also for us to work with partners in therapeutic areas that have not been our primary focus historically. That is where we are with it. We are very excited for it.
KCC2, you know, it seems kind of undeniably interesting when you say the word master switch or the term master switch. It seems like there's been, you bring down the excitability, but without sedation. Is that fair to say this is like if you, because more and more companies, if we hear about KCC2 from different companies, what makes Ovid differentiated here?
Yeah, yeah. It's, you know, it is a master switch essentially that basically allows GABA's inhibitory strength to be restored. The reason why is by maintaining low intracellular chloride within the neuron, it basically helps, it's critical for the efficacy of hyperpolarization. It helps with the shunting of inhibition mediated by GABAergic signaling within neurons, right? That's kind of just a little bit of the science of how it works. Why our library is exciting. There's one other company that we know about that has a portfolio of KCC2 activators as they describe it. They're private, so they have to share a little bit less than what we do as a public company. It's a big opportunity and plenty of room for both of us.
When we look at what that other private company that recently had a pretty significant Series A funding that they did with really a terrific set of investors, they are going after some therapeutic areas that are very interesting, but also pretty differentiated from ours. When you look at our portfolio, what you will see is that we have a number of compounds that have unique structures, unique attributes, unique formulation abilities. We've seen what they have from what they've put in the public domain. We've synthesized that. We've run it against some of our own models. They have a unique profile of a drug product that we hope will be very successful for them as well. It is different. I think what we have is just so much depth and breadth from what we got from AstraZeneca.
They started with 1.3 million different compounds and screened it down to 100. I know for a fact we have direct activators. We've done the work. I know for a fact we don't hit other kinases. I know that we're blood-brain barrier penetrant. I know our bioavailability and we know phenotypically and from disease model screens where we're behaving and why. Like our lead program, for example, that's going into humans this quarter, we had initially really liked it because it behaved super well in a really tough seizure model, like a model where you basically give mice kainate and you put them in essentially status epilepticus. It was a model that diazepam at high doses couldn't break. You add OV-350, it broke the status. I mean, which is pretty powerful for anybody that knows the field of epilepsy.
We looked at that and we loved that, but then we ran it in some broader models and saw that it actually behaved a lot like an atypical antipsychotic. Wasn't showing sedation, hasn't in any of the animal models or the toxicology that we've run to date. Interestingly, we started to put it in models where it was beating clozapine in a dose-dependent way. We have started to see these similarities across some of the different compounds in the library. This depth and breadth and the unique opportunities with each of these programs essentially is going to, we think, be very prolific, even more prolific than what we are going to be able to do on our own. I think there's room in this field for, you know, certainly a couple of companies to go after the KCC2 target.
Some of the things I would look at is, are they directly activating the target? If you're not, you have potentially a greater risk of off-target and safety issues. That was something that was extremely important to us. Historically, this has been just a very tough area to drug and formulate. That was the true challenge that we've spent the last two years trying to crack. We got a head start from AstraZeneca and we put a lot of work into the characterization and the formulation. That has led us to now have so many unique and differentiated programs that we can take one into the clinic every year for the next three to four years.
That's interesting because from the outset, you look at Ovid and it seems kind of early, we're going into humans, but you've got in epilepsy, you've got murine models that translate very well in CNS versus most diseases. What you have here is mechanisms that make a ton of sense. If your differentiator might be safety, these phase 1's first in humans are very important for you guys. Definitely exciting times. You mentioned this quarter, so we look forward to seeing that. Anything else before we take five minutes on 888?
Yeah, maybe just one last. KCC2 going into humans this quarter. Yes, safety is important. We will have an exploratory biomarker in that program as well, quantitative EEG. What's a little bit tricky is we know when people are sick, KCC2 is dysregulated. In healthy, it might not be the same way. Our exploratory biomarker, we may not see in healthies versus a patient that has an active disease state. What we're setting up, Frank, because while the platform is really interesting and where it could go, everybody, you want to know that you're headed to someplace concrete quickly, right? Which is what we're doing with KCC2 in the first program and the second program behind it. 350 is an intravenous formulation. That's the one that's going into humans this quarter. We will be reading that out before this time next year.
What we're looking to do is to hang 1Bs off of that. Using the IV formulation, if we establish the safety and tolerability that we anticipate from our toxicology program, we should be able to go into stable populations that have psychoses associated with Parkinson's disease, as well as tinnitus. KCC2 has been linked to essentially audiogenic trauma. You can see that well. What we hope to do is get proof of concepts in 2026 with that. This time next year, we'll be putting our first oral KCC2 program into the clinic. It has attributes and behaves very similar to our OV-350, IV progra m. We would be taking a proof of concept essentially with the IV that we hope to get pretty quickly and be able to translate that into the oral program that's one year behind it.
That's really the thing that the field has wanted to see was oral direct activators of KCC2 because that can unlock so many therapeutic opportunities. It could be really meaningful for patients.
Interesting you mentioned tinnitus because tinnitus is a strange one where you hear stories of you cut off the ear and they still hear the ringing, right? It turns into a central CNS kind of issue.
It is. It's a manifestation of neuronal hyperexcitability. Many don't know that. The devil's in the details with all of these CNS trials is that you need to recruit a homogeneous population. There are ways that we've been really focused on doing that. Also, we can make sure that we're matching the mode of administration with the condition itself because OV-350 is a great psychoses medicine, but I'm not going to give it to a schizophrenic right now who is having a manic event because the first formulation is an IV. When the oral comes along, then we have the opportunity to do that and it's a year behind.
Excellent. Two minutes on 888.
Yeah.
We have, I think it's super interesting, but it's on pause right now. Is that fair?
That's correct. Yep. It's, and it's a lot of people, Frank, want to know why, right? You know, why did we pause it? Particularly, why did we pause it? Because we had the opportunity to dose patients and launch our phase two last year. We had the regulatory clearance to do it. There were two reasons why we paused it. We may resume it. We love the mechanism of ROCK2 inhibition for neurovascular indications. It's really exciting, super interesting, a lot of opportunity. Our lead indication was a condition called cerebral cavernous malformations. I won't go into what that looks like because that would take the remaining minute. Essentially, what we saw was two trials we're reading out sometime this year. One was from Recursion. Another one was conducted by the University of Chicago.
The Recursion one was not enough for us to stop our phase two program, but there were things that we wanted to see in terms of their regulatory path forward. The other trial was done by the University of Chicago. That was a very well-done two-year trial using a biomarker that we wanted to use and enrichment strategy that was not very dissimilar from ours. That did not show a clinical effect at two years. When we saw that, we said, you know, we need to pause. Let's take a look at what we can learn from these two programs. Let's see how Recursion does with their regulatory path forward. We've got great IP on this program and regulatory clearance. We could resume it in a month if we wanted to.
It doesn't make sense to do that relative to the risk of the heterogeneous nature of this population. You know, just looking at time to get to an answer, that's something, you know, we always look at for not just shareholders, but also ourselves and for patients. That was the decision.
Understood. I think, I mean, we're coming up on time. Is there something that we should, in the last minute, do you want to do closing comments or is there something we should have mentioned or maybe just wrap it all up together and let us know what the catalysts are for 2024?
Yeah. Yeah. I think, you know, for those who are interested in neurology, our OV-329 program is a very straightforward epilepsy play. We've got more animal models that I think show it works than just about any anticonvulsant I've ever seen. We've got card turnovers coming later this year with biomarkers and safety that we think should be pretty important. If you're interested in the kind of tried and traditional epilepsy space, I would look very hard at that. The upside is we have something that could be really prolific and extremely differentiated with the KCC2 portfolio. It's distinct from anything else that's out there.
There's a tremendous amount of optionality within it. It will be very important in neurology as we go forward. I think almost everyone we speak to understands the importance of the target. If you can show that you've drugged it, really the opportunity is significant. That's moving forward like a freight train. Lots of productivity there starting this quarter.
A lot of info for those that are interested on your website from the R&D Day was very informative.
Thank you. Thank you. Yeah. We spent about an hour and a half going through the science of KCC2, although it's actually already outdated. We've moved a lot of programs even forward since then. Thanks to our CSO.
Excellent.
Yeah.
I think that wraps up. We're right on time. Thank you so much, Meg, for the time today. Hopefully this was helpful to the listeners.
Thank you, Frank.