Good morning. My name is Jeremy Levin, and I'm very pleased to welcome you to what I think will be a tremendously exciting day. At least for me, it's been years in the making, and today we're going to show you what we have. As we talk through this talk, please note we're a public company, and I'd like you to take cognizance of any forward-looking statement that we may do. We have a phenomenal team today to talk to you. We're going to walk you through KCC2. This is not perhaps the first time for some of you, but it is likely the first time for many of you. Those of you on the line, thank you for attending. Those who've been kind enough to attend us today, please, we look forward to a lot of opportunity to talk with you at the end.
There will be a question-and-answer session at the end, and as we walk through the day, our brain trust will talk you through our approach, and that'll be me. Thereafter, I'll leave you to a phenomenal team who'll take you a deep dive into one of the most important targets in the CNS, KCC2, and as I say, this will not be the last time you hear about this target. Why do I say that? I say that because today we're seeing a revolution in neurotherapeutics. It's been a good 15 years in the making, built on the back of all of the discoveries, first of all from the genome, then through the oncology revolution that we've seen, and now the immunology revolution, and we are unpacking an enormous number of incredibly important targets. Companies are being formed nearly on a weekly basis at this stage.
But to be successful, you need novel targets. Can't go and do the old stuff. That always happened in cancer in the past until suddenly there was a change. So for us, we've adopted a strategy, the strategy of small molecules that penetrate the brain. We believe that that will be the foundations of medicines in this area, not just today, not just tomorrow, but way into the future. There will be other approaches, but this is the one that we feel is going to be the most successful. And we believe we're a fundamental pioneer in this area. What do we do as we think about being someone, a company that unpacks an incredibly important area? Well, we focus on foundational targets. We also look at those targets and ask the question, are they driving the critically important hyper-excitability that drives everything in the brain?
Then we ask the question, will they deliver on a substantial opportunity? And once we've done that, we start working on therapeutic molecules that are absolutely critical and are small molecules. And now we have resources in order to execute on that. And we've done a lot over the last several years to prepare ourselves for the platform that you're going to see today. We are proven developers of multiple different areas in that platform. Some of these are candidates simply to mitigate the incredibly important neuronal hyper-excitabilities. The others translate what we know about existing and important receptors like ROCK2. And inhibiting that is so crucial for so many different functions. But where we are actually breaking ground and what you'll hear about today is the pioneering work that we've done in KCC2. Direct activation of KCC2 is a door opener to multiple therapeutic areas. And our pipeline continues.
Today, we will not speak about the first two areas, 329 and OV888/ Graviton101. These are really interesting programs, and I urge you to look at them. But our goal here is to note two things about those programs. Each one is a novel approach to a really important program with great clinical data, which will come from them, and they are proceeding, as you know. What I want to focus on today, and I'd like you to focus on, is the OV350 and KCC2 library. It's not one compound. It's many compounds. And we're going to break into the clinic with this at the beginning of this forthcoming year. This will be a landmark, the first ever direct activators of KCC2 in the brain. And why is that important?
Well, you know the foundations of everything that we do and that you invest in or you work in is the patient. It is that objective, improving the patient, that matters to all of us. Because if you're able to do that, you'll build phenomenal value, not just for the patient, but for our shareholders. And that's our intent. Our intent is to discover novel medicines that restore balance to the brain, that relieve the symptoms that matter most. And we can hope and we can think about, can we really halt, can we really cure brain disease? And I believe with new targets, KCC2 opens the door for doing that. And now, to take you further down this wonderful journey, let me introduce my colleague, Meg Alexander.
Thank you, Jeremy. So good morning, everyone. Thank you for being with us. I'm Meg Alexander. I'm the President and Chief Operating Officer here at Ovid Therapeutics. And we have really been looking forward to speaking with you today about the opportunity that we see and our belief in KCC2. KCC2 is a fundamental target that until now has not been directly activated. But by doing so, we believe we're going to open a massive therapeutic opportunity, and that is going to be so important to so many people living with intractable brain conditions who just don't have good medicines today. So Jeremy alluded to the fact that we're hoping to open a revolution in biotechnology and neurology. This is so needed. All of you in this room and on the phone know that medicines for neurological and neuropsychiatric conditions are so limited still. They have so much baggage.
You can see some of the factors that are limiting them behind me. We know because many medicines of the brain have off-target effects, or they over-modulate a biological target like a neurotransmitter, that you get safety issues. So what does that mean? It means that the patient oftentimes can't get to that optimal therapeutic dose. Many brain disorders are deeply complex, so these patients are taking multiple medicines. They're on polypharmacy regimens. And the challenge of that is you start to get cumulative safety issues, things like sedation, even drug-drug interactions. It makes it very hard for these patients to be treated appropriately. And then finally, what still vexes our industry so much today is that we don't understand the underlying biological and genetic root of so many diseases of the brain. We have medicines that work, but we don't know why.
So at Ovid, we set out to try to avert some of these challenges, in fact, all of these challenges. And as Jeremy said, as we've curated our pipeline and we've been very historically focused on epilepsies and seizures, we've asked ourselves, are there fundamental biological targets that by drugging them, we can actually address multiple disease mechanisms? That by drugging them, we could do it with small molecules because patients want to take pills. That by drugging them, we can try to minimize side effects and get to gentler medicines that don't have those off-target effects because they're more precise. And finally, we've been looking for biological targets that can be potentially treated as a monotherapy. They can work well with other medicines, and maybe, just maybe, they can make other existing medicines work better and be more tolerable.
As we have endeavored to curate our pipeline over the past couple of years, one of the fundamental areas that you heard Jeremy speak about is that we've been looking to really quell neuronal hyper-excitability. The hyper-excitability of neurons is at the biological root cause of so many different disorders of the brain, many of which have just no good treatments today. One of the targets that's been very exciting to us and to the field, quite frankly, but has never yet been directly activated is KCC2. Why? Because KCC2 fundamentally restores intrinsically the excitatory-inhibitory balance within a neuron. It takes that hyper-excitability, and it brings the neuron back into homeostasis. This is really central to treating, again, so many different indications.
As we think about this and we think about the role of KCC2, Jeremy made the allusion to oncology before, and we really think that fundamental targets like KCC2 can unlock a therapeutic revolution. What you're seeing behind me, of course, many of you are going to be familiar with this, many of you invested in this, is the Programmed Cell Death Protein 1 program. This is Keytruda, but this is something we know a little bit about. Our principal, Jeremy, brought Opdivo into BMS. But when we think about drugging a fundamental target in cancer, which PD-1 was, not only was it a therapeutic revolution and has led to so many different indications, like the 20 different cancers that are now treated behind me, and bent the curve of mortality in cancer.
Importantly, when you think about neurology and the parallels, it was a paradigm change because we started to treat the underlying universal biology of disease across so many different conditions. And it changed the way we translate medicines. It changed the way we develop medicines. It changed the way regulators look at medicines. And we think this similar moment is coming in neurology with more precise neurotherapeutics. And we think KCC2 is one of these same fundamental targets that has tremendous applicability that we hope will lead to an era of many medicines. So KCC2, because it can intrinsically bring a neuron back into homeostasis when it's directly activated, has application in many, many different conditions in which hyper-excitability is a core factor.
It can address potentially neurodegenerative indications, chronic pain, seizures and epilepsies, which is why we got into it, of course, in the first place, neuropsychiatric disorders, which obviously still have so much need for medicines, and neurodevelopmental disorders that oftentimes have many of these factors at play between mood, behavior, seizure-like symptoms. So we think there's a tremendous panoply of conditions that can be treated if we can drug and directly activate KCC2 as a target. So this is a tremendous opportunity for patients, and we also think it's a tremendous opportunity for our company. So I hope you hear how excited we are about the target, but we're also excited by what we have. Inside of Ovid, we have more than 100 compounds in our KCC2 portfolio. Each of these has unique properties, unique drug-like properties, and different compounds are amenable to different types of formulations.
So that means that we hope to have orals, intramuscular injections, intravenous formats in the future. And so far in all the work that we've seen, because this is very precise and we're not over-modulating the KCC2 target, we're not seeing any sedation or safety issues that we've seen with some of the prior classes of medicines. So this could potentially be an entire stable of neurotherapeutics sitting within our company. And I have to credit both our team, but also AstraZeneca, because we brought this in from AZ about two and a half years ago. We in-licensed from them that 100-compound portfolio. But before we ever got our hands on it, what their medicinal chemists had done was very sophisticated screening. They started with more than 1.3 million compounds, and they screened it to get to the point where they knew they had 100 direct activators.
That's really important, and Dr. Moss is going to tell you why in a couple of minutes. But we had 100 compounds. Dr. Zhong Zhong, my colleague, has done a lot of characterization work to know that they get into the brain to understand their bioavailability and to understand their unique properties from phenotypic screening and disease models. So we know how to best indication map what we've got. And as Jeremy said, we're really excited because just a quarter from now, we're going to have the first ever direct activator of KCC2 in humans. And this potential portfolio is going to be prolific. We have an IND coming every year from this pipeline for years and years to come.
So while many of you haven't heard about this in depth from us before, because it's been early and we've been working furiously on it, when Jeremy showed you our pipeline a couple of moments ago, you saw our corporate pipeline with our different programs of GABA aminotransferase, ROCK2 inhibition, and KCC2. But if you double-clicked on KCC2, all of these different programs would unfurl. So today, you're going to hear an awful lot about OV350, which is the first program coming from our KCC2 portfolio, both an intravenous and an oral formulation of OV350. But you'll also start to hear about the next programs behind that, 4071, and the series behind that. So we're deeply excited about what this could mean for our company. As you can hear, it's going to produce a prolific number of programs as we go forward year- over- year.
It gives us a lot of strategic optionality because we can keep the compounds for the indications that we know how to develop really well that are in our sweet spot, but we can also collaborate with or out-license to others where maybe there's a condition where they have more therapeutic experience than we do. But at the end of the day, what's most important is that for patients, directly activating KCC2 could be a new era of neurotherapeutics, where we have highly effective and gentler medicines for diseases that have hyper-excitability at the core, which are so many different conditions that just don't have good options today. So I'm going to now turn to my colleague and friend, Dr. Jeffrey Noebels from Baylor University , and he's going to tell us more about the biology of KCC2 and how it impacts so many different diseases. Jeff.
Thank you, Megan. Good morning, everyone. I'm Jeffrey Noebels. So I have had a long pioneering laboratory career looking for genes that control brain excitability, and we've made a number of pioneering discoveries. I'd like to thank, first of all, Meg and Jeremy for inviting me to share my perspective on sort of what has come out of the post-genomic era in the last 10 years in terms of aligning genes with diseases and what we can learn from each gene. That's today's topic, which is KCC2. How does this gene affect neuronal hyper-excitability? What is the neurobiology of that? And second, the emerging realization that hyper-excitability is a very broad pathway that accelerates neurological disease and impacts a number of diagnoses that you'll hear about today. So let me take one step back first and talk about the challenge of drug discovery in this era.
In the beginning, we thought one gene equals one disease. When you crack the gene, you know exactly who to treat and when. That's turned out to be a much more complicated landscape now that we've looked and found. Prominently from epilepsy gene genotyping of patients, which is going on at an explosive rate now, we have panels of 350 genes for epilepsy that routinely are now applied to children who have their first seizure. But what we're learning is that some of these gene defects actually cause more than just seizures. They cause a variety of syndromes that you see on the left that we thought were very different, but actually share hyper-excitability somewhere in the nervous system in the pathway.
We think this term is really a common target physiologically at the cellular level of how we want to treat some of these disorders, not like the old days. Now we have thousands of genes, and it turns out that due to genetic heterogeneity, there's more than one gene that causes any one of these syndromes. The challenge, of course, is to figure out what makes them different. What we found out is that not only are there different genes for a lot of these syndromes, but there are different variants even within a single gene that can make you have either one or another complaint from neurologically speaking.
And of course, mapping these onto the brain and finding out precisely which of the circuits that we can pinpoint the neurons that we'd like to fix as opposed to affecting all of them is a very active area of investigation throughout the world right now with mouse models, et cetera. And so the challenge we think we all need to understand is that can we learn to detect and correct hyper-excitable circuits without altering the ones that we need in any way and create drug therapies without side effects? That's the Holy Grail, I think. So this task has always been pursued with sort of a basic model in mind, which is that the excitatory to inhibitory balance is out of whack, and we need to restore that. And there are several ways of doing that.
You can tinker with not enough inhibition or targets that govern hyper-excitability and play around with that. But we know that clinically this is actually fraught with difficulty and for reasons that Meg described can lead to failure. And we need to understand that there's probably a simpler and better way, a downstream way. And so here's the smarter one-step method, which is to look with a fulcrum, you can leverage a lot. And so by moving the balance over, and that's what we think KCC2 does, it's a molecular fulcrum for really a spectrum of excitability disorders. So here's why we like KCC2 as a circuit. It's a precision mechanism. So it's an actual gene mechanism of action to rebalance network excitability across broad circuits. It targets the final common pathway, which is synaptic inhibition, downstream of many genetic and acquired causes of hyper-excitability.
I'll tell you a lot about epilepsy, but there are others as well. And it converges on a broad spectrum of neurodegenerative disorders where hyper-excitability accelerates disease progression. And this is kind of a new concept which is taking hold, that neurodegeneration can be driven by hyper-excitability. So the three questions we ask, first of all, is, well, what is it, where is it, and how does it modify the disease? So KCC2, and you'll hear this over again, is the main regulator of GABA inhibition by maintaining what we call neuronal chloride homeostasis. So chloride ions are negative ions. When they enter a cell, they hyperpolarize it. And that's how GABA, the inhibitory neurotransmitter, opens its chloride channel and lets it in. And that's a normal chain of events. And it allows cells to, as they develop, have this blanket of inhibition throughout the brain to maintain brain excitability.
Now, under pathological conditions, when there's not enough KCC2, which is the exporter of that, the chloride accumulates, and instead of entering the cell, it exits the cell. That depolarizes the cell and makes it more excitable, so what you can think of basically is that KCC2 activation restores inhibition in tired interneurons, and it's a battery to recharge them again, so we like this particular target, and here's one of the main reasons it's beautiful, is that the protein expression is really unlike its other family members of chloride channel transporters. It's expressed uniquely in the brain and spinal cord, so that gives you a lot of freedom from possible terrible side effects, heart and whatnot, and it's only in neurons, and it's throughout the brain.
So the other cycle that we've learned more and more about in a lot of these disorders is that hyper-excitability can drive the cascade of toxic neuroinflammation and cell death. So this is inevitable, and you don't really want to suppress it because some of it might be good. Immunosuppression has its own risks as well. But we'd really like to learn how to break the feedback. There's a vicious cycle feeding back onto hyper-excitability, and we'd like to break that contact and sort of address it at the root of hyper-excitability. So major clinical opportunities for this kind of activation therapy you've heard, we think they're widespread. And I'd like to talk about, first of all, what we've learned from epilepsy. And it's good news. KCC2 loss of function mutations actually cause epilepsy.
So we know for sure that this molecule and disruption of this molecule is in the hyper-excitability pathway for actually a very important set of neurological disorders. So we know that altering that actually causes hyper-excitability in humans. And so that's the good news. Better news is that KCC2 is located downstream of at least 40 and probably more. There's a drumroll of new genes coming that all affect and disinhibit the brain by lowering synaptic inhibition signaling. And so all of these genes that affect various attributes and functions of interneurons are all upstream. You wouldn't want to necessarily design drugs against each one of them because there are not that many patients. But look at where KCC2 is at the bottom of this. And so it presumably can actually prevent any of the defects that are upstream of that.
So a broad spectrum, and I like to think of it as a master switch to repair network break defects. Here's an example of, in the pain area, where mapping and pinpointing where the gene is can help you securely believe that it can play a role in modulation. So in the pain control pathway, there's something called G ate Control Theory, which says that in the substantia gelatinosa, which is in the dorsal horn of the spinal cord, there's plenty of KCC2 there to help GABA inhibit incoming painful responses through the dorsal roots. And so there it is. And in fact, in models where you'd make an injury to a sciatic nerve, which ends up causing a painful phenotype, there is a decrease in KCC2 activity. So that makes sense. And actually, viral neuritis and viruses in general can trigger these pathways.
Actually, using a Theiler's virus-induced epilepsy model in the hippocampus, it's also shown that KCC2 levels were decreased by this. Good scientific evidence then, therefore, correlating these two pathways. What I'd like to turn to next is this idea that hyper-excitability could be a feature unexpectedly of neurodegenerative disorders. This idea started with work in my laboratory where we were actually the first people to record an EEG from a mouse model of Alzheimer's disease. These mice have plaques. They have poor memory, et cetera. What we found was so unexpected, and that was evidence of seizure activity, but it was an interesting kind. We call it electrographic seizures. Non-convulsive behavior is not altered. The mouse is walking around in the cage while you're looking at the seizure itself, but clearly it's having a hyper-excitable brain phenotype.
And the question was, well, why didn't anyone see this in humans all these years? And the answer is, sorry, wrong button. The answer is you can't see it from scalp EEG recordings. When you look at where the hippocampus is in the human brain, it's located 6 m deep into the temporal lobe. Scalp electrode EEG recordings can't detect that activity. But if you put electrodes that are located very close to that mesial surface of the temporal lobe, you can see very clearly that there's seizure activity going on. And this has happened in an epilepsy patient. And what you also see is that even in humans, when you see this hippocampal seizure, you don't see the classical signs of someone having a convulsion with shaking, et cetera. They stop and they stare, and there are very minimal signs of any disruption of their behavior at all.
This was still met with some skepticism at first. Maybe this happens in mice, but not in humans. Recently, thanks to a really wonderful team at the Massachusetts General Hospital that we've been working with, we showed and confirmed that this happens in patients with diagnosed Alzheimer's disease. You can see in this recording that the scalp recordings show no evidence of seizures at all, while a deep temporal lobe electrode shows the seizure activity very clearly. Why would you want to treat Alzheimer's with an anti-epileptic drug or any other drug? That is because it could delay hippocampal neurodegeneration. Seizures are bad for brain cells. That kills them. Recently, it has been found that subclinically, even without the seizures, there are subclinical signs of hyper-excitability in Alzheimer's brain that you can see on scalp recordings. These are just little spikes.
They're not seizures, but it was found and reported that half of patients with sporadic Alzheimer's disease that have these spikes have more rapid dementia progression than those without, so a clear correlation, and then an earlier study showed that in early onset genetic forms of Alzheimer's disease, which are more rare, but that patients that did have seizures had preserved neurons in their hippocampus, whereas those that did had really devastating loss of neurons in the hippocampus, so neuroprotection is an excellent reason to start to think about treating Alzheimer's patients. S o again, just to review that this is something that we think is going to apply to many other disorders, and finally, I'll leave you with the thought that the therapeutic goal is really arresting the enduring impact of hyper-excitability. I think the strategy is elegant, and I'm very enthusiastic about it.
The tactics of how to activate this target is actually what our next speaker, Steve Moss, who is the world's expert tactician, will tell you about now.
Thank you very much, Jeff, for the compliment. So I have been working on this transporter KCC2 for about 20 years, and it's an obsession of mine. And I've been very fortunate to work with AstraZeneca to try and develop the first-in-class activators of this transporter. So what I'm going to talk to you about today. Oh, sorry, that's me. You heard all that. So what I'm going to emphasize today is that we spent a conservatively 15 years trying to develop direct activators of KCC2. And direct activation really matters. So why do I say that? Well, these are the points I'm going to talk about today.
I'm going to talk about how we made the activators, the screening strategy we developed to make sure we got direct activators, not indirect activators that influence KCC2 via secondary processes such as protein kinases, then I'm going to show you some data showing how we confirm that these molecules are direct activators, then I'm going to finally finish with the significance of our product profile for human development, so just to go back to the very, very start, KCC2 is shown on the right-hand side. And as Jeff said and everyone has emphasized, it is critical in exporting chloride from a neuron, and it allows neurons to maintain low intracellular chloride concentrations. Now, why this is so important is when you activate an inhibitory receptor, the type A receptor for GABA-A receptor, it's a passive ligand-gated chloride channel.
Under normal conditions, when you have active KCC2, chloride flows into the cell and induces hyperpolarization. KCC2 is critical in maintaining that low intracellular chloride concentration. If you don't have KCC2, as Jeff mentioned, chloride accumulates in the cell. When you activate the GABA-A receptor, chloride flows out instead of in, and then you've lost inhibition. KCC2 is also important for molecules that act at GABA-A receptors. There's a plethora of GABA-A receptor positive allosteric modulators, and some of them are written up here. All these drugs, to be efficacious, to exert their therapeutic efficacy, require an active GABA-A receptor because they all allosterically potentiate inhibition. They need an intact chloride gradient. That's why KCC2 is such a critical target in regulating inhibition in the brain and also the efficacy of widely used anti-convulsant and sedative drugs.
The strategy that we have is we wanted to isolate direct activators of KCC2. And this obviously has a significant advantage as you know where your target is, and you can correlate binding of your compound or activation of KCC2 with a clinical output. Secondly, indirect activators are via their very name, they have a possibility of a lot of off-target effects. So that's why we took the time to develop an educated screening process to make sure any molecules that we isolate via a high-throughput screen do as advertised. I'm not going to dwell on the first part of this slide, but this was all done with AZ, AstraZeneca, who I had the privilege of working with for 15 years. And we can just ignore the first two boxes. People can do high-throughput screens. It's relatively straightforward. You can get millions of molecules.
How can we then confirm they directly activate and don't have indirect effects on the transporter? So if you look at the third, fourth, fifth, and sixth box, this is how we did it. So first of all, we wanted to counter-screen against other molecules homologous to KCC2 that regulate chloride in the brain. The most important one of this is KCC1, and we also screened against KCC3 and KCC4. We wanted molecules that were negative in this screen. So we screened out activators of other solute transporters. The next thing is we wanted to make sure we didn't end up with a kinase activator inhibitor. So KCC2 is phosphorylated on 11 amino acids, and this regulates its activity. So this screen has a liability in that you could indirectly isolate a kinase modulator that indirectly regulates KCC2 activity.
So we screened all our compounds and these to be negative in a panel of 426 protein kinases. We then wanted to know, do they directly bind? And the way we did this is we used this thermal screen. And basically, when a drug binds to its target, it changes its melting temperature. And we ran our hits through this to confirm they all bound to KCC2 via this cellular thermal shift assay. Compounds that were positive in that, we then screened against mutated versions of KCC2 where we mutated one or more of the regulatory phosphorylation sites. And we picked molecules that worked on all those mutants. So at the end of this, we had a series of 100 compounds that we assure are specific for KCC2 and also bind directly to KCC2 and do not alter any of the kinases that regulate its activity.
Finally, these molecules do not change the amount of KCC2 on a neuron. So it doesn't affect the ability of a neuron to put KCC2 in the membrane. So they're classical direct pharmacological activators. To gain more insights into where they bind in KCC2 and how they increase its activity, we developed a tech, well, we didn't develop it. We took advantage of a technique called click chemistry. What click chemistry does, if you look at the slides from left to right, we start off with some self-explanatory chemistry. We then have a drug that is modified. And this is one of our KCC2 activators. And it's modified with these various groups that, in the presence of UV light, allow the compound to be covalently cross-linked to KCC2. And that means it labels the amino acids in the binding site. We can then purify out KCC2 from the cells.
Using mass spec, we can identify which amino acids are covalently labeled. This gives us the most precise confirmation of direct binding. I'm going to show you 10 years' work in one slide. I want to start off my presentation by showing you the most important bit I emphasized in the start. This is OV350. It's very specific for KCC2 in the green box. You can see the potency. It has a much, much 1,000-1,000,000-fold lower affinity for these other chloride transporters. That's good because it's going to limit off-target effects. The results of our click chemistry and mass spec, we identified two amino acids labeled A and B. They're not actual amino. A and B, of course, are not amino acids. It's a code for what they are.
And where they are is they reside within the cytoplasmic domain of KCC2. So the top of the slide shows the part of KCC2 in the membrane, and the bottom bits with the round balls are inside the cell. And KCC2 is a diamond. This is actually the Cryo-EM structure. And we're very confident that these sites are critical for the action of our activators. And I can tell you for two reasons why. The first reason is they're photolabeled by the drug, only two residues out of 1,360. Secondly, when we mutate these residues, OV350 doesn't potentiate the transporter. And we know that the transporter, when we mutate this OV350 binding site, is threefold more active. So what the compound does is it binds to amino acids within KCC2 that normally keep it closed.
When the drug is there, it allows the transporter to be more active. We can do this same analysis for all 100 hits because we now have screens where we can look at where they bind. Are they all working via the same mechanism? Okay. To summarize, our work over many years has led to the identification of a family of 100 direct activators of KCC2. We know they're direct activators because of our screening cascade. Finally, with our click chemistry, we've identified how these molecules, where they bind to and how they activate KCC2. As an academic, even I am getting to be convinced that we have direct activators. Why is this important? We have published papers showing that OV350 is a potent anticonvulsant and prevents neuronal death. That was published last year.
So in animals, at least, it's a potent anticonvulsant. And the second point that has been talked about a bit today is it's non-sedative. So all the evidence we have, extensive studies in rodents, shows that you can dose mice with humongous amounts of OV350, and they're not sedated. So this is quite an unusual compound because most anticonvulsants have huge liabilities, and one of the biggest liabilities is sedation. So there's another important part of our studies is that we have mentioned before that the GABA-A receptor is a very important drug target. And the current medications to increase synaptic inhibition all target the GABA-A receptor. So they're all direct binders. Now, the problem with these compounds is they only work if you have active KCC2. And in many diseases, KCC2 becomes inactivated, and you lose the efficacy of many of these GABA receptor paths.
So what our molecules give the potential for is a synergy. They can be used as a monotherapy, but they can also be used together with other GABAergic agents to increase their potency or restore how they work. So there's a critical piece of information here is that we are actually targeting the underlying pathology in many neuronal diseases, which is this loss of inhibition. People have tried to correct this loss of inhibition by direct pharmacological activation of the GABA-A receptor. That runs into problems because while that may work for a while, the underlying problem in the cell, which is this disrupted chloride homeostasis, has gone. So you can put in as much. You can activate the receptor as much as you want, but it's not going to be effective because the chloride gradient has gone.
So our compounds can act as a monotherapy and also can improve the efficacy of existing medications. So I'd like to leave you with the following thoughts. I hope I've convinced you that our strategy has identified the first direct activators of KCC2. There are plenty of other KCC2 activators, but as far as I recall, the way we developed our counter-screens really enriched our ability to isolate direct activators with all their advantages. Now, we know from some of the work I've presented, but also published, that simple activation of KCC2 as a monotherapy has potency to reduce activity in neurons as a monotherapy and slow or terminate seizures. Secondly, a most important thing for safety is it's nearly impossible to overactivate KCC2 because you can only push chloride concentrations so far.
And there's a massive driving force on the outside of the cell that maintains the potassium gradient that's critical for chloride export. And I think the thing that's really excited me is this is a new mechanism because most things that increase inhibition by binding to the GABA- A receptor or activating the GAB- B receptor, for example, are always sedative. This mechanism has therapeutic efficacy and seems to avoid one of the biggest problems in patients, which is sedation. So I'd like to thank you for your time, and I'd like to introduce you to my colleague, Zhong Zhong, who I've had the pleasure of working with for the last year and a half and has helped us move these compounds forward. Thank you, Zhong.
Thank you, Steve, for the wonderful introduction of this group of compounds, and anybody who has been in drug discovery knows finding activators of transporters is really, really hard. It's easy to find inhibitors of ion channels. It's easy to find inhibitors of transporters, but finding activators is very hard, so thanks to your work with AstraZeneca that we get to license this group of compounds, so the direct activators, now you have seen why we are so excited about direct activators, why we like the fact that they have a high degree of specificity with lower risk of off-target effects, and also, I want to thank Jeff for the wonderful introduction of the target rationale that KCC2 is the gateway of regulating neuronal hyper-excitability, and that gives us the opportunity of targeting a wide variety of CNS diseases.
In order for us to do that, we need to have multiple compounds, multiple formulations. I will talk about the KCC2 portfolio that we have and how we intend to develop that. I'm going to show you some early data on in vivo efficacy in disease models and, most importantly, highlighting the fact that they don't have sedation effect. I'm also going to talk to you about the progress we have made moving OV350, our lead compound, into human studies and the IND-enabling study in support of us going that direction. First, the KCC2 library overview. The 100 molecules that Steve talked about, which is the result of the AstraZeneca campaign of doing the screening and compound optimization, is the starting point. These molecules have high potency. They all have at least single-digit micromolar potency on KCC2.
They have a high level of specificity, demonstrate direct binding on the target. And more importantly, which we haven't talked about earlier, which was published in the paper, is that we have demonstrated the lead molecules demonstrate a very profound modulation of chloride gradient in primary neurons, demonstrated by this electrophysiology technique that Steve's lab has mastered in his lab using primary neurons to demonstrate an EGABA potential change, which is the reversal potential of GABA, which is a significant indicator of intracellular chloride concentration change. And with that as a starting point, we want to prioritize molecules we can develop. We focus on the ability to get oral formulation and the ability to get into the brain because CNS target KCC2 is expressed exclusively in the CNS. It's important to get a molecule into the action of sites .
Once we have identified the lead molecules that have these properties, then we use a phenotypic screen to identify the biological activity that's unique with this set of compounds. I'm going to go talk about that platform and what that tells us about the therapeutic indications we can go into. Finally, everything that we have detected using the SmartCube platform, we confirm that with gold-standard pharmacology models that people use and using reference compounds to offer a comparison. This is the KCC2 development map that we have come up with. This gives us the ability to deliver INDs the next few years, multiple INDs the next few years. We're going to start by taking OV350, the lead compound that Steve Moss has talked about quite a bit.
We're going to take the IV formulation of OV350 into human to demonstrate that in human, we can modulate a target with small molecules, have biological activity and biomarkers. So this will be our first-in-class direct activator going into human studies. And follow that, we'll have an oral formulation that we intend to develop that will help us to expand the indication going to a broader group of patients that we can act on. And then that will be followed by an OV4000 series compound, OV4071, with improved potency, with improved pharmacological profile that we can develop in multiple formulations in addition to oral, also have a potential to be developed as an intramuscular formulation. And following that, we have multiple 4000 series. And not only do they have various pharmacological profiles, they also have demonstrated different pharmacological activities that we have shown.
And we're going to show you some data on that. In addition to that, we are in the process of discovering additional compounds to further improve the chemistry, the physicochemical properties of these KCC2 activators that enable us to have superior formulation possibilities. So OV350 is our first KCC2 activator to be developed and enter human clinical studies. And you have already heard that it has tremendous specificity. It's a small molecule that can enter into the brain. I'm going to show you data on what kind of biological signal it can produce, what kind of biological activity we have demonstrated, and then also the IND enabling studies to demonstrate it has the safety and PK profile enable us to go into human studies. So on the left-hand side, what you have seen here is the data on the PK profile.
Essentially, it's the brain exposure and plasma exposure with different doses of OV350, in this case, a fairly high dose. But what we intend to show here is that it gets into the brain very effectively. It actually enters the brain just as much as it has the plasma exposure. So it's a very brain-penetrant compound. As consistent with that, what you also would expect, it will provide a signal in the brain. And our right-hand side is an example of that. So using EEG, we can detect that OV350 modulates the EEG power bands, especially in the high gamma region. So Steve's lab has published this wonderful work to show that OV350 has this ability to stop status epilepticus using the KD model.
We're very pleased to show here, and we're going to have a full data package presented at the AES end of the year, that in addition to the model that Steve has demonstrated, we use a different species, different model at a different lab, independently confirmed anticonvulsant activity. This is a rats model. It's a soman model. It's a nerve gas agent model conducted at the Army Research Institute. This soman stimulation, as you can see at the bottom right half of the slide, is a very, very dramatic treatment regimen that leads to status epilepticus in rats that's highly resistant to standard treatment, including atropine and midazolam. However, adding 350 at 50 mg/kg, which is the light blue curve, and 100 mg/kg, the darker blue curve, as you can see, that reduced seizure significantly in these models.
That's a really nice validation of the anticonvulsant activity of OV350. You have heard from Jeff earlier that hyper-excitability is the root cause of many neuronal conditions. We wanted to take an open-ended approach to probe if we have a molecule that activates KCC2, what kind of indication can we go into? What kind of biology does it modulate in CNS? We took an open-ended approach to use the phenotypic screen platform developed by PsychoGenics called SmartCube to probe that. SmartCube is actually an AI-powered phenotypic screen platform that it's a proprietary system that animals and mice in particular were guided through a specific set of challenges on that platform. Their activity was monitored visually and using computer vision. Then the extensive set of images were collected, then compared with molecules with known activity, therapeutic utility, and targets.
On the right-hand side is essentially the catalog of the molecules that have assayed on this platform. And therefore, you compare a molecule with all this catalog to see which molecule, which drug class or existing medicines that you have the most close relationship with or resemblance. And what's interesting here is that when we tested OV350, we saw a very clean, very efficient signal in antipsychotic activity. So that's very, very interesting to us. And it's a novel finding, obviously, for KCC2 activators. So the effect comes up very quickly. So on the left-hand side of that graph, the bar graph, within 15 minutes, you see this very, very clear activity of antipsychotic activity, which is denoted by this purple color. And it's mostly closely resembling the atypical antipsychotics. And that effect goes away in 16 hours, consistent with the pharmacokinetic activity profile of the molecule.
And it's a very clean activity in the dose range all the way from 10 mg/kg all the way to 75 mg/kg. This particular platform also picks up a lot of the side effect profile, for example, sedation and other side effect profile. And it's very clean. So some of that is denoted on the right-hand side as well. None of the other colors showed up in OV350, which is very, very encouraging, including sedation. Sedation is not picked up up to 75 mg/kg. So that phenotypic screen gives us the direction to probe further. And the way we probe further is to use a standard antipsychotic animal model. And this model uses phencyclidine or MK-801. We use that interchangeably, which acts on the NMDA pathway to induce hyperlocomotion.
So the black curve, which is the top curve here, essentially is a vehicle-treated animal that's stimulated by PCP. And the y-axis essentially is locomotion. So you can see it induces this very strong activity in locomotion. And the green curve is the reference compound. That's the gold standard. It's approved drug, clozapine, antipsychotics that works to blunt that hyperlocomotion. And the rest of the curve essentially is the dose response of OV350. At 3 mg/kg, which is the blue curve here, it performs just as well as clozapine. So it performs comparable to our reference control. And then increasing that dose to 10 mg/kg, 30 mg/kg had a further stronger effect on reducing the hyperlocomotion elicited by PCP. So that gave us really a very strong confidence based on thev SmartCube data and this particular model that OV350 has dose-dependent effect to control hyperpsychosis.
That also relates to the indication area, one of the indication areas we can go into. We have done a significant amount of IND-enabling work, including toxicology and DMPK experiments to support us going into humans. All IND-enabling study has been completed. The NOAEL, which is essentially the safety dose that we can use to support human dose selection, has been picked, identified, and based on studies in both rats and dogs. OV350, the DMPK study exhibits very dose-dependent exposure that we can use to predict human dose. The Ames test in vitro mutagenesis tests come back clean and negative. The DDI assessment, the drug-drug interaction assessment, has been completed with no concerns of going into human studies. The drug product manufacturing is on track.
So before I hand over to Amanda in a few minutes, I'm going to just talk a little bit about OV4000 series, which is the next-generation compounds, and illustrate the potential of multiple INDs and also the multiple indications we can potentially go into. So this is a graph you're familiar now. This is a typical output from the phenotypic screen that we do on SmartCube. And the different color code indicates different activities. In this case, instead of 350, we tested multiple 4000 series compounds. Now you see a variety of different colors. And what do they mean? On the right-hand side, we picked these areas that we know that we have activity on. So what we have detected in the 4000 series, in addition to antipsychotic activity, is anxiolytic activity and some anticonvulsant activity.
And all of that is consistent with the fact that we act on KCC2. We enhance the GABA signaling. These are very typical GABA pathway modulations that you pick up in these phenotypic screens. So we are very pleased to see that. I'm going to show you some examples of individual compounds, how they behave using specific animal models along those different domains. So first of all, I'm going to introduce a compound called OV4071. That's one of the next compounds we intend to develop. It shows a very robust and dose-dependent signal in psychosis models. This is the same psychosis model I showed you earlier. And I said earlier, sometimes we use PCP, sometimes we use MK-801 to induce hyperlocomotion. And the y-axis, again, here is locomotion activity, motor activity. And as you can see, MK-801 in this case induces a hyperlocomotion.
And then the different bar on the right-hand side essentially is the OV4071 dose response. So this is a slightly different way of looking at activity. But it gives us a better way of assessing the potency of the molecule. We know this molecule is extremely potent. That gives us the ability to formulate this molecule in different ways. And you have seen a new color in our SmartCube response. And that's anxiolytic activity. And anxiolytic activity requires a different assay. And this is the assay that we used. We used what we call the elevated plus maze model. Essentially, we placed animals in this maze. And it has an open arm. It's a closed arm. If the animal is more anxious, it tends to stay in the closed arm. If the animal is more relaxed, it will spend more time in the open arm.
So just by looking at the ratio between that, it gives you the sense if your molecule enhances or inhibits the anxiety of these animals. So what you can see on the right-hand side is that this 4000 series compound, two 4000 series compounds, they have exhibited anxiolytic activity. It enhanced the animal's ability to stay in the open arm. And the ability it does, these compounds did that, is consistent in some cases. In many cases, actually, it worked better than benzodiazepine. And again, they did that. These compounds did that without the effect of sedation. So finally, I want to take you away from my part of the talk on three take-home messages. One is targeting KCC2 gives us a unique and unprecedented opportunity to correct neuronal hyper-excitability.
And does that by direct activation, by normalizing the chloride homeostasis in neurons, but also restore the excitatory-inhibitory balance. KCC2 the lead program, the IV program will enter phase I study by Q1 of next year. The IND-enabling study has been completed. And we have multiple compounds, multiple formulations in development to support application broad indications. So with that, I'm going to hand over to Dr. Amanda Banks, our Chief Development Officer, to talk about the translation and clinical strategy.
Thank you, Zhong. Hi, everybody. Thanks for being here. I'm Amanda Banks. You've heard a lot about the science that supports our excitement around KCC2 as a target. And you've heard about the library from Zhong. And I'm going to try to take you through how we're thinking about translating those things into a Clinical Development Program. So a couple of points I want to make.
First, the key point that we want to get across today and something you've already heard a lot about is that KCC2 is a foundational target that we believe has broad applicability across CNS disorders. You've heard that we started with a strong foundation and evidence base in epilepsy, and now we've taken that and are using it as a springboard to bring us into the broader world of CNS indications, and the way that we have to start thinking about that is with this vast opportunity space. The really exciting opportunity we have is to use a couple of different frameworks that I'll walk you through to be able to focus down on the most important areas that we think will have the greatest potential for patient impact to improve patients' lives.
So what we do is we take, in general terms, the understanding of the biology and the compound and the characteristics of the compound and match that, on the other hand, to the realities of the clinical indication. And where those two things come together is where we think we have the greatest opportunity for patient impact. So there's two frameworks that we apply to thinking about this. And they're related. So I'll start with the first one, which is really anchored in how and where patients obtain care. Where do they get care? Where do they need care? Different settings. This is the care continuum. So when patients have uncontrolled symptoms that are debilitating, they often will need care in an acute care setting, in a hospital, in an emergency department. If they have unstable symptoms but want to stay out of a hospital, there's a subacute setting.
And then when people are controlled and have a good regimen, there's a chronic world. There's a world where they have to take a pill every day and they're doing well at home. So we've looked at this and we've applied this lens to the library that you just heard about because each of the compounds has a different characteristic profile. And each of those compounds can have different formulations, which allow us to provide patients and providers options across this care continuum. So in the first box on the left under the acute care, if we take an example for psychosis, if somebody presents with uncontrolled symptoms of psychosis, we have the ability to treat them with a rapid-acting IV formulation, which can keep symptoms under control quickly.
When we discharge that patient home, if they're still a bit unstable at home and want to avoid another hospitalization, an intramuscular formulation of that same medicine can provide that at home, and then when the regimen is stable, they can take a pill every day and be able to control their symptoms on a long-term basis, and you'll notice, as you look underneath those boxes, that the number of diseases and indications that we think we can impact gets bigger as we move toward the right, so this is one lens we take to thinking about this way to focus down our work. The second framework is grounded in the characteristics of the compounds themselves, and you've just heard about the different profiles that we're starting to tease out with the development work that we're doing across the library.
So what you'll see on this slide is four quadrants and subquadrants. On the top left, these are all, so I'll go through them. They're all big buckets of symptom categories and disease categories that fall characteristically with different labels, so top left is anticonvulsant, bottom left anxiolytic, top right antipsychotic, and bottom right mood stabilizing, and in the middle is sort of a larger category of hyper-excitability indications, including things like pain and tinnitus, but there are specific clinical entities that fall under these large diagnostic categories that we think we can access with the different formulations, and then you'll see mapped on top of that the colored rectangles that have our drug names in there and the series names in there, and you'll see how they're starting to map across all of these different indication spaces.
Now we're starting to build this multidimensional map of how we think the KCC2 library can be applied clinically. This slide walks you through in a little bit more detail where each of these drug candidates are in development. The first thing I think that stands out from this slide is that there are a lot of things going on in parallel. We have a lot of different options that we're moving forward in parallel. The first, which I'll spend a little bit more time on in a minute, is our lead compound, OV350, first in an IV formulation, which we expect will begin human studies at the beginning of next year, followed very quickly behind that with an oral formulation that will allow us to open up the kinds of indications.
In the OV350 space, we have the potential to do a small patient study in a phase I-B toward in the 2026 time frame or beyond. After that, we have a series that Zhong talked about, which is the OV4071 series that we think will begin patient studies in the 2026 time frame, and then molecules in the 4000 series and the 5000 series that are being characterized actively now, so OV350 is, again, our lead product. We expect that we will see top-line results from the phase I study in the first half of 2026. This is designed as a traditional SAD-MAD study where the primary endpoints are safety, tolerability, and learning more about pharmacokinetic profile.
When we get to the end of that SAD-MAD, we expect to have full optionality to be able to think about what indications we might perceive as biological activity in a small human population. Again, we're looking at a variety of different things, and based on the profile of the molecule that you heard about from Zhong, we're looking first at indications that include psychosis, and we're really excited about taking the IV formulation forward first because it is our most advanced compound. It is the first time, as you've heard, this category of compounds will be tested in humans, so we have a lot to learn about it, and we will learn a lot from this study. Again, we'll learn a lot about the safety. We'll learn a lot about the tolerability of this medicine. We'll learn a lot about how it behaves in humans.
It will give us the opportunity to apply those learnings to our programs that are coming up behind it. And we'll accelerate, in particular, the OV350 oral program, but also programs that come along behind it. And very critically as well, it gives us sort of that first entry point into the continuum of care in the acute care box, which we then will expand upon to allow us to go across that whole continuum from acute to patients. So before I hand over to Karl, I just want to say that I've taken care of patients for a long time. And I'm still lucky enough to do that very occasionally. And I take care of patients who are admitted to the hospital at the VA.
And a very large proportion of those people are in the hospital because they have uncontrolled symptoms of many of the diseases that we have shown you on these slides. And these things are life-altering. They disrupt people's lives, patients' lives, families' lives. They often result in patients not being able to live at home anymore. And so we work toward putting them in nursing homes. These things matter so much. And the drugs that we have right now that we can use right now often don't work, often have debilitating and crippling side effects so that patients don't even want to take them, and are very nonspecific.
And so when I think about this, I get really excited because what we have in our hands is the potential to have a very direct set of drugs and compounds and medicines that can treat the underlying biological cause in an extremely specific way that is safe, avoids sedation, and avoids some of the things that prevent people from taking medicines to get better and live at home and live their lives. So I get very excited about this. So it's not just exciting to me. I think it is potentially a paradigm shift in the way we think about CNS diseases. So with that, I want to introduce my colleague, Karl Kieburtz, who is a [audio distortion] and a direct-activation platform that works in specific patient applications and the need there. Thank you.
Thank you. We're getting close to the end. So hang in there. I don't have really any data slides, so it won't be too painful. I'm a Neurologist, Clinical Trialist. I've been doing this for 30-odd years. I've had a direct hand through various roles in academia, government, industry, in the studies that led to the approval of most of the drugs we have for Parkinson's disease, Alzheimer's disease, and Huntington's disease. So I've been around the block. I'm very excited about this program. I'm excited about this program on three dimensions. One, this is a fundamental area of biology. Two, there's a library of compounds with different activities to address it. And three, there's a large area of unmet need in a variety of clinical syndromes. It's a little bit overwhelming to have such a panoply of optionality, actually.
It reminds me of, say, pulling into Yellowstone National Park, and you have your new kit, you have your new backpack, you have a kayak, you're there. Like, should we go climb a mountain? Should we swim in the lake? Should we take the kayak down the river? At some point, you've got to make a decision about what you're going to do. And I'm going to talk about that, about what the first plan is to do in patients shortly. I want to come back to this. You've heard time and time again people talk about fundamental biology. If I were you, I'd say, what's so fundamental, actually? Like, what are you talking about? And I just want to pause on this a little because you've heard about chloride channels and so forth and cracking the genetic code.
And I just want to remind people that a lot of very complex systems are underborn by very simple code. So all of genetic diversity is encapsulated in four nucleotides arranged in various triplets in the genome. All of computing is underborn by a binary code of a zero and a one. AI, which is probably at this moment summarizing what I'm saying, is a stream of zeros and ones. Human life is born by ions flowing across cell membranes. Just stop for a sec and feel your heartbeat. I know you can't. I can feel mine. You've had it since you were in utero, and you will have it until the day you die. It happens because sodium ions rush in, just like the bridge and tunnel crowd in the morning come rushing in. And then the potassium ions rush out. Except rush hour is twice a day.
That ion flux happens on a millisecond timeframe. No ion flux, no heartbeat, no life. Now, as a Neurologist, we think of the heart as a pretty stupid organ. Thump, thump, thump, thump, right? Its main job is to pump blood to the brain, which is, of course, a very elegant and interesting organ, but if you think about this simple transmission in the electrical system of the heart, and you think about the myriad of, it's like looking up at the stars in the galaxy, the myriad of things that happen in the brain, it's all underpinned, though, by this ion flux, and this chloride thing sounds kind of obtuse, but it's really important because that chloride balance in the cell is a switch signal as to whether GABAergic input is inhibitory or excitatory. Now, probably excitatory sounds good, right? Like, that's better than inhibitory, right? No.
Actually, the brain wants this balance. Seizures are the most obvious example of super excitatory activity that can't be good. But it underpins a lot of different things. And the GABAergic system is there like a, it's to chill things out. It's like an aloe vera balm on your sunburn. It's like the sprinkler system in a fire. You want the water to tamp things down. When chloride is in imbalance, it's like gasoline coming out of the sprinkler system. It just amps up the activity. This hyper-excitability, this hyperactivity actually underpins a lot of behavioral and neuronal dysfunction. So this little graph is really important because it is a fundamental biology. It is regulated by a function, KCC2, which is only found in the Central Nervous System and is by design plastic and modifiable.
And as you heard from Dr. Moss, we've actually developed compounds that directly activate this and enable the GABAergic input, which still exists, to become back to inhibitory. So that's fundamental, in my view. That's why I think it's fundamental. Two, there's this whole array of compounds that have different characteristics. We know from 350, you saw the picture of exactly where the amino acids, where it binds to create activation of KCC2. But 4071 and other 4000 and 5000 series compounds bind in slightly different places and will have slightly different effects. So fundamental biology, diversity of library. And then there's the complexity of where that might work in the world of brain disorders. I'm going to focus on the upper right on neurodegenerative disorders. You've already heard from Dr.
Noebels, that in Alzheimer's disease, we know that there is alteration of KCC2 function and hyper-excitability in ways that were not really previously understood or well recognized, but now are well documented in the human brain. But I'm going to talk about a slightly different neurodegenerative disease, which is a common neurodegenerative disease. It's flown under two general names that you'll probably be familiar with: Parkinson's disease, which is a syndrome that is primarily characterized by stiffness, slowness, and shaking, but also has other features, and Diffuse Lewy Body Disease, a disease with those same features but characterized primarily by cognitive deficits and hallucinations. Turns out, as Dr. Noebels said earlier, we're learning that things that we thought of as being separate and diverse can have common underlying biology.
And in this case, these two syndromes together are now Neuronal Synuclein Disease because the underlying pathobiology of the disease is the abnormal accumulation of this protein, Neuronal Synuclein Disease, and that that can have multiple features. The features include the motor disturbance, but also very prominently the cognitive disturbances. Visual hallucinations, visual illusions, and psychosis are common in these disorders. Not so common early in Parkinson's disease, but 70%-80% of people develop them over time. And in DLBD or Diffuse Lewy Body Disease, it's a core common feature. These features are hard to treat because the usual way you would treat them with antipsychotics cannot be done. Not typical, not atypical antipsychotics, because they worsen the underlying motoric features of the illness.
So here we have a very unusual disease that is characterized by psychosis and hallucinations, which are commonly thought to be addressable by common medications, which cannot be used. There is one medication that is approved specifically in psychosis and Parkinson's disease, and it can be effective. I've used it in practice. I've seen that it can actually lead to resolution of the psychosis, which is transformative, as Dr. Banks said, people being able to stay home who are on their way to the nursing home. But it doesn't work in most people. It works very occasionally, and people have a profound effect. So the standard therapies don't work or can't be used, and the only available therapy only works in a handful of patients. So it's a great unmet need. This is a good test bed for our first phase I-b. KCC2 activation is lost in disease states.
GABA inhibition thereby is no longer effective. This is probably, along with potentially other contributors, is part and parcel of the psychosis and neurodegenerative disease. The fact that we're going to do Neuronal Synuclein Disease means we can biologically define and enrich the population to a specific subset that doesn't have those features from some other reason. We have a very clean population with an intractable, untreatable phenomenon. OV350 fits very nicely into this. We have an IV formulation. phase I-B study, people can come in with persistent and stable hallucinations. The SmartCube activity showed antipsychotic effects. The PCP-induced hyperlocomotion showed that there is a dose-dependent response. Here's our chance to look at in humans the acute administration of OV350 by IV on the impact on psychotic features in people with Parkinson's disease and diffuse lewy body disease, Neuronal Synuclein Disease.
We can specifically look to see whether that has any impact on other aspects such as sedation or any change in motor performance. So it's a nice test bed to look at this specific mechanism married to the effect of OV350 by IV formulation. That sounds a little bit narrow, but it's not because behavioral manifestations in neurodegenerative diseases are super common. Agitation in Alzheimer's disease, poor judgment, and impulsivity in Huntington's disease. So many of the neurodegenerative diseases associated with KCC2 lack of activation have behavioral syndromes. Anxiety is prominent among them also. So not only for OV350, but OV4071 with the anxiolytic activity. These behavioral manifestations in CNS disorders gives us a real arc of possibility about where this could be employed. Very intractable and untreated phenomena in those diseases. It may bleed over also to other primary psychotic syndromes such as schizophrenia and manic psychosis.
But for now, the focus will be on behavioral syndromes associated with neurodegenerative disorders. Lastly, Dr. Noebels brought up a very tantalizing aspect for these compounds: is that hyper-excitability might actually be a driver of neurodegeneration. So not only creating these behavioral phenotypes, but perhaps underlying and accelerating neurodegeneration associated with these illnesses. That's a bit aspirational. These studies are not targeted at that right now, but that's also a possibility here in the CNS disorders. So just to capture, again, you saw this from Dr. Banks: there's this kind of spectrum of which compound in which most acute, subacute, and chronic setting. I think KCC2 activators, these direct activators in these particular illnesses have a tremendous amount of potential to treat these disorders, Neuronal Synuclein Disease. i'm going to stop there. I'm going to hand things back to our fearless leader, Dr. Jeremy Levin. T hanks for your attention.
Thank you, Karl, and thanks everybody for listening. It's been a long day for you so far. Before we go to questions, and we're going to take them, and we'd like as many as you throw at us, and Meg will be the traffic cop for that. I'd like to just emphasize some key points here. Number one, we're cracking open an area. Number two, we know exactly where our compounds bind. Number three, we have a number of very potent and very exciting compounds, and we see delivering out of this a very clear route to therapeutic proof of concept for these compounds, and we're going to start. We're incredibly disciplined about how we use our resources to do this, but as Meg mentioned, we have optionality here, not just to do it ourselves, but to bring in partners.
We have multiple compounds we can partner if we choose to do that. But the one thing is for sure, as Karl mentioned, the arc of possibility is with us. This is exactly the same moment that you saw with PD-1 in melanoma. You start with an area that you know you can conquer, and you move up, and you explore. And that's exactly what we're going to do. KCC2 direct activators have opened the door to an enormous number of neurotherapeutic possibilities. That arc of possibilities is, in my opinion, one of the most exciting things to have emerged from the science of the neuroscience area over the last 15 years. So thank you for listening to this. Those of us who are now going to be ready, we're ready to answer your questions, and I'll hand over to my colleague, Meg.
Th anks for your attention, everyone. We'll start with questions in the room, and then for questions that come in online, we'll take them periodically. Tom, you had your hand up first. Yeah, go ahead, Tom.
Tom Schrader from BTIG. For Dr. Noebels, we're starting to think a lot about these seizure effects in Alzheimer's. Your comments about the anti-inflammatory effects of KCC2, how strong are they relative to direct modulation of immune cells? Is this really a good way to go after inflammation, or is it a side effect?
Thank you for that beautiful question. Actually, I think we don't know what we need to know about that, and we're going to find out in the future. But I think there's little question that the hyper-excitability itself can drive that cascade. So I think it's not exactly my area, but I think there's a lot of work of triggering seizures triggering microglial expansion. In epilepsies that surround glioblastoma, there's this enormous interesting reaction. And I think in a number of experimental settings, we see this correlation between increased excitability, decreased KCC2, and increased inflammation. So it's a circle. And where does the circle start? Probably in different conditions. It could begin with the hyper-excitability and trigger that. Alternatively, some viral-induced inflammation can work the other way around. So we don't know yet. And there are probably multiple answers.
But getting at that little key piece of what is the specific path or molecular trigger and signal, I don't think we know yet.
Dr. Moss, did you want to also discuss what you've been able to show in the lab? You can come up here.
Yeah. So thanks, Jeff. To directly address your question, we have looked at this issue after kainic acid-induced seizures in mice. We've already published that it stops neuronal death. I can show this. It's not published yet. But if you look at inflammatory markers 48 hours after termination of the seizure with OV350 and the standard of care diazepam, it totally blocks activation of microglia and the induction of glial cells. So in that context, which is a very, very specific model of neuroinflammation, it looks like it decreases inflammation after a seizure. Now, we can look at that in other models, but the data looks very promising. I don't know how that works, but since it terminates the seizures and prevents neuronal death, it seems to also stop this inflammatory response after this injury. I hope that applies to other systems.
And if this happens next year and I'm still around, I hope to be able to present the data. But I can share that with you.
Moss, I think, had a question. Oh, go ahead, Tom.
You also mentioned these subacute seizures, which are seen everywhere. What do you see of those? What do you think of those as endpoints in clinical trials to get an early read? And to the company, is Ovid considering using this approach to get an early read on efficacy?
Well, so two parts to that answer of that interesting question. Of course, we would love to identify seizure and hyper-excitability early on in Alzheimer's disease. We know in the animal models, the spiking that is not quite a seizure, but clear evidence of abnormal excitability in the circuitry starts very early in the animals, even before you see the amyloid plaques and other cell death. So there's something about in these models, Aβ, that triggers some important cascade. So in a patient, we would love to get there early and actually prove our main hypothesis that the abnormal electrical signaling in the circuitry is probably the most important reason for the dementia and the lack of ability to remember things. In a traffic jam, you can't get to where you want to go, and that's what's going on during a seizure. Now, what about these interictal spikes?
It's been shown in a lot of epilepsy studies that actually just single spikes can depress synaptic activity for several seconds after that. So this continuous spiking is not good for your memory circuitry either. So two reasons to stop it, to detect it early and stop it. Now, how do we detect it? That was a problem for 10 years until Alice Lam at Mass General said, "Well, why don't we use these non-invasive?" Not too many people would like to have a hole drilled in their skull to have depth electrodes put in just to find out whether you have seizures or not. But through a small little foramen in your cheekbone, you can thread semi-non-invasively an electrode so it's very close. And as she showed, could detect the seizure activity. Interestingly, they only happen during sleep.
So that means you have to get ready for a long period of time. My feeling is that the electrical signature is not going to be simple to detect in a clinical trial just for practical reasons. There must be other biomarkers. And she's working on a machine learning from the cortical EEG, where you don't necessarily see seizure activity, but it may be changed in a complicated way during a deep subcortical seizure so that you can actually perhaps design a tool that would detect deep seizures. And they're working on that. It's not ready yet.
Karl can talk a little bit about just how we're starting to look at biomarkers for our OV350 program.
Sure. I was just going to say, in the very briefly to your question, in the proposed I-B study in NSD with psychosis, EEG, quantitative EEG, scalp EEG, not invasive electrodes that you have to they're semi-invasive electrodes, but just standard scalp EEG looking at patterns for interictal spikes on top of normal cortical activity as well as changes that might. So that may be an early indicator because people with NSD and hallucinations and cognitive impairment have a very particular EEG signature, which is distinctive versus Alzheimer's disease, for example, but may be responsive to this. So it'll be interesting to see whether that can be used as a POC sort of early read in disease population.
Thank you, Karl. Now, we have Laura Chico from Wedbush. Oh.
Sorry.
Laura, give me a moment. Jay Olson, Laura had her hand up, and I tried her before.
Give her the mic.
Thank you. Laura Chico, Wedbush. First question, kind of carrying on from the biomarker question. In the phase I-A portion of the study, are there any biomarkers or assessments that can be done to assess target engagement during the SAD-MAD portion?
Amanda, do you want to take that?
Probably can chime in. But the beauty of modulating KCC2 is that it is exceptionally effective when there's an imbalance. So when we have healthy volunteers enrolled in the SAD-MAD, we don't expect there necessarily to be a change that you can detect with EEG. So again, we're just looking for safety tolerability. However, we'll still look just to get the information. And then where we think it might have real applicability is in the patient population where there is that disturbance at baseline.
Okay, and just one quick follow-up for any of the physicians that are treating the psychosis population, certainly makes a lot of sense. Are there any patients that would not be a candidate for a KCC2 activator?
I can't think of one. If you were engaging other chloride channels outside the CNS, yes, kidney and heart and things. But for KCC2, which is exclusively CNS expressed, I'm trying to think, as Dr. Moss said, you can't overcorrect this because just physical properties of the chloride gradient, you can only put so much out. It doesn't have enough energy to put out. So you can't really overcorrect a normal state. So I don't think so. But I have to think about it. But I don't think so.
I think from a genetic standpoint, if you know your target and it's not there, you don't want to give that drug to the patient. So patients with a homozygous mutation in KCC2 definitely do not qualify. And they don't even survive, actually. But in the epilepsy studies that we found, those are mostly heterozygous. And that means they have one good copy of the allele, which means they are making KCC2 protein that you can target with the drug. So I would say 99.9% of the population, go for it.
I think the next question was Jay from Oppenheimer.
Yep. Thank you. So I was just wondering, out of all the KCCs that we saw there, the KCC2, is that decision more based on safety or efficacy? And if you can tie in, you talked a lot about sedation has been a problem in the past. Do we know mechanistically why sedation seems to not be an issue here?
Yeah. Zhong, do you want to step up?
Yeah. Very happy to talk about that. I mean, we picked KCC2 because KCC2 is prominently expressed in the brain and therefore expect to regulate chloride gradient in the neurons. So it's very simple. It's an effective target in the right target cells. In terms of why it doesn't induce sedation, this is the first thing that we look at because anything that enhanced GABA signal, we worry about that. That's a possible plausible side effect. I think it has a lot to do with this being a direct activator that once you pump out enough chloride, you can't really overchange that. And the other thing that's really important is that when you think about how you regulate neuronal activity, you have two ways of doing it. One is change the neuronal milieu by changing the transmitter balance. We're not doing that. We're not increasing negative inhibitory neurotransmitter.
We're not taking away the positive excitatory neurotransmitter. We're simply modulating how neurons respond to the negative signal. So when there's not a lot of GABA signal around, you should not expect it induces sedation. So that's sort of our view of why what we saw. Thank you.
I think we have a question from Athena, Cowen.
Hi, guys. Thank you. This is Athena Chin on for Ritu Baral. So how do you see the market opportunity of a KCC2 candidate in the schizophrenia market landscape given this week's phase II clinical update? And how will you evaluate conduct and integrity in neuropsych trials given what has happened with competitors? Thank you.
Yeah. Good question. So I'll start. We think the therapeutic and the commercial opportunities here are very, very significant. Obviously, some of these have been in our wheelhouse, as you saw us talk about with seizures. Some of them, the science is starting to expand out into broader areas of neuropsychiatry. So from a commercial perspective, we think this is tremendous, which I think you've seen by some of the very bold allusions and analogies that we've been making throughout today's discussion. Amanda, do you want to talk a little bit about just the profile of the schizophrenia phase II data and how we see that relative to future medicines for schizophrenia?
Yeah. I mean, I think there's clearly a lot of therapeutic opportunity in schizophrenia because we don't have good medicines to treat patients safely right now. That looks like it's about to change with some other ones that are further along in the pipeline. I think to me, it underscores the importance of the target that you choose to begin with. And just going back to KCC2 being having this foundational capability in terms of biological activity and the fact that we expect not to see the ability of overmodulation, especially in a disease population, I think is really critically important here. I think the other piece to all of this is there's a tremendous amount of heterogeneity in the patient population as it exists. And the press release around the news this week called that out as something that they tried very hard to control for.
It's very difficult to do. We have one of the world's experts in doing that, Karl Kieburtz, working with us, and so there are people and groups that understand how to do that very well. That's another way to really focus on that. I think the sort of net-net that we take away is this is a highly specific focus target with a biological underpinning in an area that is expressed exclusively in the brain, opening up all those commercial [audio distortion]. If we are able to be smart about how we do enrollment and understand the patient population match that well, that's the challenge that I think we all have, but we have some really good experience in doing that.
We've obviously heard schizophrenia is not the first indication that we're looking at. We're looking to get proof of concept in a psychosis population where we can try to really precisely enrich to Amanda's comment. Other questions? Kalpit? Oh, sorry. Sarah.
Hi. Sarah Schram, William Blair. First, thanks to the team for a great day. This is really exciting and really informative. So thank you. So my question is, as we're talking about circuits in the brain, are there any neuronal subtypes or subpopulations that express KCC2 at a higher level if we're modulating certain portions of a circuit to restore proper homeostasis? Trying to understand if there are not necessarily over-modulatory effects within a specific cell, but within the circuit itself. Just trying to get a sense of if there's modulating parts of the circuit may have downstream effects on other portions.
Jeff, Steve, do you want to take that? Yeah. You can together.
So just to partially answer your question, there's a common concept where you see KCC2 is active. Now, that's not the case because KCC2 is highly modulated. So depending on the environment, the protein kinases, you can have inactive or very active KCC2. So different neurons. I can give you an example. If you look at KCC2 activity in the hippocampus versus the prefrontal cortex, it's different. And we don't understand why, but it is. And that's probably a result of the cellular environment and all those protein kinases I was talking about. So that is one issue that we need to think about. And again, because of the way these compounds work, you can only increase KCC2 activity to a ceiling value. And normal KCC2 that's functioning in a cell, you're not going to overactivate.
What you're going to do with this compound is selectively impact on the hyper-excitable neurons, which have got less KCC2 or inhibited KCC2. Does that help, and then Jeff can give you a clinical answer.
Well, no, just a biological one too. And that is that we know in a healthy brain that it's expressed diffusely throughout the nervous system. But what we don't know is in different diseases, at different stages of diseases, how that patchwork looks. And so as you heard, if the drug can't overactivate the normal levels, but it can bring up ones that are hypo, which is what we'd love to have as an atlas of where in the brain in different disorders and at what stages of that disorder they go low. And that's where the drug would have its effect. It wouldn't have an effect wherever else it is. So it's more of the selective vulnerability of certain regions in different disorders that we'll find out exactly how they work.
Thank you. Question in the back.
Yeah. Hi, I'm Maanasa. And I'm representing Roth Capital . I'm Boobalan's associate. So it was a very informative session. Thank you so much for that. So my question is regarding the KCC2. So given the implications of KCC2 in multiple neurological disorders, is there any particular selective or prioritization that you have towards the indications? And how fast do you think you can gain conviction for your program?
So yeah. Amanda, do you want to talk about our two frameworks and the multidimensional way we're evaluating indication sequencing?
Yeah. I mean, I think what we're trying to do is really match as closely as we can the drug characteristics and the formulation with what the real clinical on-the-ground need is. It's not just the need. It's the workflow around treating that thing, which is where the spectrum comes in on the continuum of care. That's a high-level answer. If we take 350 as an example, we've seen really interesting effects of 350 as an antipsychotic. Karl walked us through beautifully the nuances of how psychosis associated with Parkinson's disease, Neuronal Synuclein Disease can be addressed with the kind of paradigm that we've created with 350. I think that's a really interesting place to start. We have the capability, actually, with a good SAD-MAD in the phase I to be able to look at multiple different indications in patient populations.
Starting off with matching those things together is sort of the first really important step. And then we'll be able to, once we learn more about each of the compounds as they progress, we'll be able to do that with more specificity.
Yeah. And of course, I think the other thing that you heard Jeremy say in complement to everything that Amanda just outlined is that we'll also be looking at where do we have strong expertise in terms of therapeutic development, where do we have the resources, and where are other areas that may be new to us that we would be better positioned to work with a partner or a collaborator. Because there is a lot of opportunity here. And this is big, almost too big for us alone. So we'll look at all of these things in sequence in terms of how we indication select. Other questions?
Oh, Kalpit. Yes.
Yeah. Thank you. So I know you've tested this in the schizophrenia model, the data that you've shown. But any info on non-stressed models, like any impact on memory or anxiety behavior or travel distance or anything like that in non-stressed models?
Yeah. Zhong wil l take that.
Yeah. So you probably noticed that we tested multiple compounds in the elevated maze model. That actually is a very information-rich model also. So we have a lot of data. We are processing these data now, trying to understand effect on anxiety, for example. That's one of the things that come up also. And even in the PCP model, there is a pretreatment period before PCP was applied on. There's also some behavioral changes that indicate anxiolytic function. And then, of course, there's the SmartCube model. SmartCube model is very information-rich. So that gives us multiple angles that allow us to validate and to confirm the biological activities. The details we'll review that. We'll publish that work over time. So people will understand the complete profile of our compounds. Thank you.
Any further questions? Tom? Yes.
I just have one quick. You're prioritizing all of these compounds. Is that based on specific animal models that you think are characteristic of a disease? And do you expect in the end that the best drug might be the best drug for everything, or?
We don't know that yet. We're very happy that we have a first collection of compounds. They have shown very strong biological activity and very clear biological activity, and there seems to be correlation between different compounds, so one of the things you always worry about is that your lead compound has a combination of activity that gives you certain manifestation, and that's not necessarily KCC2, for example, which is not the case. We know multiple compounds behave well in this antipsychotic model. What we are doing now is systematically go through different compounds in SmartCube first so that we uncover the bigger universe, sort of the open-ended test, and then confirm that with disease models with reference compounds so that we know how this compares with reference approved medicine, for example, in certain, but we know it's coming from a different angle, a different mechanism, right?
A novel mechanism to treat diseases where other medicine has been successful but has limitations. So that's the first thing we identify. Then, of course, each compound has the physicochemical property that perhaps could limit us in terms of what indication we can go into. So that comes into play in helping us to think about the side effect profile, the chronic dosing possibility, and all that comes into play. That's why we focus so much on developing, in addition to the first IV formulation. Now we have oral formulation. We have intramuscular formulation that matches a product profile needed to address certain diseases. So that comes into a big part into the consideration of how to pick compounds for different indications.
Yeah. And maybe one additional point. So a different aspect I heard in your question, which is around how much are we relying on animal models. I think we all know that there's a lot of limitations to animal models in general, in particular in this area of drug development. So our focus on demonstrating safety in the clinic will put us in a position to be able to test these molecules in patients as quickly as we can, as long as we know we have something safe to do that and we understand how it behaves in people. So that, I think, is really another key part of the plan and the focus.
Okay. Good. All right. Well, with that, we want to thank you for your time today. We hope you've left here hearing our excitement about KCC2, our excitement about the portfolio of direct activators that we have here within Ovid. I want to thank those who came in the room in person today. There's lunch for you afterwards. We hope you'll hang out. And for those who joined us on the line. And we know many of you have questions about our other programs too. We'd love to answer them. We'll be around. So let's get lunch. And we're happy to address those after this program. Thanks again.